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Does the royal jelly contain proteins? | Yes, main bioactive compounds of Royal Jelly, include proteins and peptides. | This study aimed to evaluate the quality of the royal jelly produced by Apis
mellifera bees in the presence of different iron concentrations (ferrous sulfate
heptahydrate-0, 25, 50, and 100 mg L-1). Two-dimensional electrophoresis was
used for the fractionation of royal jelly proteins, and iron level was
quantified using flame atomic absorption spectrometry technique. The proteins
were identified using electrospray ionisation mass spectrometry. Analysis of
variance followed by the Tukey test (P < 0.05) was utilised. Dietary
supplementation with mineral Fe affected the protein content and number of
proteins in the experimental period. Further, the diet containing the highest
iron concentration showed a greater number of spots containing iron, as well as
in the abdomen of the bees. The most protein containing Fe were classified as
major royal jelly proteins. These results showed that Fe influenced the quality
of royal jelly and can improve its nutritional value. Royal jelly (RJ) is a yellowish-white and acidic secretion of hypopharyngeal and
mandibular glands of nurse bees used to feed young worker larvae during the
first three days and the entire life of queen bees. RJ is one of the most
appreciated and valued natural product which has been mainly used in traditional
medicines, health foods, and cosmetics for a long time in different parts of the
world. It is also the most studied bee product, aimed at unravelling its
bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory,
and general tonic action against laboratory animals, microbial organisms, farm
animals, and clinical trials. It is commonly used to supplement various
diseases, including cancer, diabetes, cardiovascular, and Alzheimer's disease.
Here, we highlight the recent research advances on the main bioactive compounds
of RJ, such as proteins, peptides, fatty acids, and phenolics, for a
comprehensive understanding of the biochemistry, biological, and pharmaceutical
responses to human health promotion and life benefits. This is potentially
important to gain novel insight into the biological and pharmaceutical
properties of RJ. Understanding the effect of pesticides on the survival of honeybee colonies is
important because these pollinators are reportedly declining globally. In the
present study, we examined the changes in the head proteome of nurse honeybees
exposed to individual and combined pesticides (the fungicide pyraclostrobin and
the insecticide fipronil) at field-relevant doses (850 and 2.5 ppb,
respectively). The head proteomes of bees exposed to pesticides were compared
with those of bees that were not exposed, and proteins with differences in
expression were identified by mass spectrometry. The exposure of nurse bees to
pesticides reduced the expression of four of the major royal jelly proteins
(MRJP1, MRJP2, MRJP4, and MRJP5) and also several proteins associated with
carbohydrate metabolism and energy synthesis, the antioxidant system,
detoxification, biosynthesis, amino acid metabolism, transcription and
translation, protein folding and binding, olfaction, and learning and memory.
Overall, when pyraclostrobin and fipronil were combined, the changes in protein
expression were exacerbated. Our results demonstrate that vital proteins and
metabolic processes are impaired in nurse honeybees exposed to pesticides in
doses close to those experienced by these insects in the field, increasing their
susceptibility to stressors and affecting the nutrition and maintece of both
managed and natural colonies. Honey bees provision glandular secretions in the form of royal jelly as larval
nourishment to developing queens. Exposure to chemicals and nutritional
conditions can influence queen development and thus impact colony fitness.
Previous research reports that royal jelly remains pesticide-free during
colony-level exposure and that chemical residues are buffered by the nurse bees.
However, the impacts of pesticides can also manifest in quality and quantity of
royal jelly produced by nurse bees. Here, we tested how colony exposure to a
multi-pesticide pollen treatment influences the amount of royal jelly
provisioned per queen and the additional impacts on royal jelly nutritional
quality. We observed differences in the metabolome, proteome, and phytosterol
compositions of royal jelly synthesized by nurse bees from multi-pesticide
exposed colonies, including significant reductions of key nutrients such as
24-methylenecholesterol, major royal jelly proteins, and 10-hydroxy-2-decenoic
acid. Additionally, quantity of royal jelly provisioned per queen was lower in
colonies exposed to pesticides, but this effect was colony-dependent. Pesticide
treatment had a greater impact on royal jelly nutritional composition than the
weight of royal jelly provisioned per queen cell. These novel findings highlight
the indirect effects of pesticide exposure on queen developmental nutrition and
allude to social consequences of nurse bee glandular degeneration. |
What is the brand name for erenumab? | Aimovig (erenumab; erenumab-aooe in the United States) is the only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) therapy against the CGRP receptor (CGRPR) for the prevention of migraine. | Amgen and Novartis are developing erenumab (AIMOVIG™, erenumab-aooe)-a fully
human monoclonal antibody calcitonin gene-related peptide (CGRP) receptor
antagonist-for the prevention of migraine. CGRP is a vasodilatory neuropeptide
implicated in the pathophysiology of migraine and treatment with erenumab was
associated with significant reductions in migraine frequency in phase II and III
clinical trials. Based on these positive results erenumab was recently approved
in the US for the preventive treatment of migraine in adults and has received a
positive opinion in the EU for the prophylaxis of migraines in adults who have
at least 4 migraine days per month. This article summarizes the milestones in
the development of erenumab leading to this first approval. Calcitonin-gene-related peptide (CGRP) plays a key role in migraine
pathophysiology. Aimovig (erenumab; erenumab-aooe in the United States) is the
only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb)
therapy against the CGRP receptor (CGRPR) for the prevention of migraine.
Aimovig is also the first FDA-approved mAb against a G-protein-coupled receptor
(GPCR). Here, we report the architecture and functional attributes of erenumab
critical for its potent antagonism against CGRPR. The crystal structure of
erenumab in complex with CGRPR reveals a direct ligand-blocking mechanism,
enabled by a remarkable 21-residue-long complementary determining region
(CDR)-H3 loop, which adopts a tyrosine-rich helix-turn tip and projects into the
deep interface of the calcitonin receptor-like receptor (CLR) and RAMP1 subunits
of CGRPR. Furthermore, erenumab engages with residues specific to CLR and RAMP1,
providing the molecular basis for its exquisite selectivity. Such structural
insights reveal the drug action mechanism of erenumab and shed light on
developing antibody therapeutics targeting GPCRs. In 2018, the United States Food and Drug Administration (FDA) approved Aimovig
(erenumab) for the prevention of migraine. Erenumab is the first FDA approved
antibody therapeutic against a G-protein-coupled receptor, the canonical
receptor of calcitonin gene related peptide (CGRP-R). A novel, epitope-focused
antigen was created to reconstruct the extracellular domains of the CGRP-R in a
stable conformation. Successful inoculation of XenoMouse animals and careful
screening yielded multiple candidate molecules for high potency and exquisite
selectivity toward the CGRP-R over related receptors. These efforts led to the
discovery of erenumab which has demonstrated the desired efficacy and safety
profiles in multiple clinical studies for the prevention of migraine. The
innovation developed in the discovery of erenumab furthers the ability to target
G-coupled protein receptors using antibody approaches. |
Which protein does capmatinib bind? | Capmatinib binds MET. | Capmatinib (Tabrecta™) is an oral, small molecule mesenchymal-epithelial
transition (MET) inhibitor being developed by Novartis Oncology, under a license
from Incyte Corporation, for the treatment of lung cancer. Capmatinib targets
and selectively binds to MET, including the mutant variant produced by exon 14
skipping, and inhibits cancer cell growth driven by the mutant MET variant. In
May 2020, oral capmatinib received its first global approval in the USA for the
treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose
tumours have a mutation that leads to MET exon 14 skipping, as detected by an
FDA-approved test. Clinical development for the treatment of glioblastoma, liver
cancer, maligt melanoma, breast cancer, colorectal cancer, head and neck
cancer and solid tumours is ongoing in several countries. This article
summarizes the milestones in the development of capmatinib leading to its first
approval. |
Which neuropsychiatric disorders are associated with 16p13.11 genomic copy number variants? | schizophrenia, autism, mental retardation, ADHD, epilepsy | |
What is carcinoma en cuirasse? | Breast carcinoma en cuirasse is an extremely rare form of cutaneous metastases of breast cancer, characterized by diffuse sclerodermoid induration of the skin. | Metastatic carcinoma of the skin develops per continuitatem, being disseminated
by the lymphogenous and hematogenous pathways. From 3% to 5% of these metastases
are described as cutaneous metastases. Metastases of the skin most frequently
occur in breast cancer, and manifest as carcinoma en cuirasse characterized by
thoracic wall lesions in the form of erythematous foci with induration as in
scleroderma, or as exulcerating nodules scattered all over the skin surface. We
studied patient with skin metastases according clinical and histological
features. Carcinoma en cuirasse with sclerodermatomyositis like clinical
appearances described in our female 49-year-old patient. She died one year after
several excisions of skin metastases BACKGROUND: Carcinoma en cuirasse is a form of metastatic cutaneous breast
maligcy occurring most commonly on the chest as a recurrence of breast
cancer, but it can be the primary presentation.
OBJECTIVE: To discuss the clinical features of carcinoma en cuirasse that
distinguish it from hypertrophic scars and keloids of the chest.
METHOD: We report a 63-year-old woman with primary cutaneous breast carcinoma
presenting as keloid nodules on the chest that failed treatments for keloids.
Biopsy revealed a pattern of breast carcinoma in the skin.
RESULTS: After further workup, no tumor was found in the deep breast tissue, but
metastases were found in her axillary lymph nodes.
CONCLUSIONS: Unusual keloid-like nodules or scars on the chest that fail to
respond to therapy may be primary or metastatic maligcies, and adequate
histologic verification should be obtained to avoid delay in the proper
treatment. A metástase cutânea é conseqüente à disseminação do tumor por embolização
linfática, vascular, implantação direta durante cirurgias ou envolvimento da
pele por contiguidade. Em mulheres, o tumor maligno primário que mais comumente
metastatiza para a pele é o de mama, que tanto pode se expressar por lesões
tumorais papulonodulares, infiltração erisipelóide ou esclerodermiforme, em
couraça. Relatamos o caso de paciente do sexo feminino, 78 anos, apresentando
lesões nodulares, descamativas e confluentes em mama direita, evoluindo com
edema e infiltração cutânea, com redução do volume mamário e placa endurecida
ilimitada. Invasão da mama contralateral e abdome ocorreram 4 meses após o
início dos sinais. O diagnóstico histopatológico foi de adenocarcinoma ductal
invasivo de mama com focos pagetóides epidérmicos e embolização linfática. We report the case of a patient with carcinoma "en cuirasse" of the vulva.
CASE REPORT: A female patient presented complaining of inguinal lymphadenopathy.
Lymph node excision, immunohistochemistry analyses, and further exams showed the
presence of cervical adenocarcinoma. The cancer was surgically removed and the
patient was treated with radiotherapy and chemotherapy with a good initial
response. Some months later she presented with intense edema of the lower limbs,
hardening and thickening of the labia majora, and pelvic and genital ulceration.
A cutaneous biopsy with subsequent immunohistochemical staining showed lymphatic
dissemination of adenocarcinoma to the vulva.
DISCUSSION: Carcinoma "en cuirasse" is a rare presentation of cutaneous
metastasis in which the affected skin shows hardening and induration, acquiring
a sclerodermoid appearance. This is, to the best of our knowledge, the first
report in Brazil of carcinoma "en cuirasse" of the vulva associated with
cervical adenocarcinoma. Cancer in the dermis of the breast has a poor prognosis. The breast dermis can
become maligtly involved primarily in inflammatory breast cancer, through the
direct extension of locally advanced breast cancer, or metastatically from an
underlying breast mass or a distant primary maligcy (e.g., gastric
adenocarcinoma). Breast dermal metastases have the shortest median survival
among them. Breast dermal metastases are classified into eight
clinicohistopathologic groups, one of which is carcinoma en cuirasse. We present
a case of a 52-year-old female with a history of invasive ductal carcinoma,
Stage IIIC (pT2N3a), treated with lumpectomy, axillary node dissection, and
chemoradiation therapy that recurred as carcinoma en cuirasse breast dermal
metastases. Through 18F-fludeoxyglucose positron emission tomography-computed
tomography (18F-FDG PET-CT) and clinical images, the case illustrates the rapid
progression and devastating consequences of carcinoma en cuirasse breast dermal
metastases over a 4-month period despite optimal therapy. Furthermore, the case
emphasizes the sensitivity of 18F-FDG PET-CT to detect pathology in the breast
dermis. Finally, the case highlights the crucial role that nuclear medicine
physicians play in helping clinical colleagues differentiate between the various
breast dermal maligt manifestations and benign mastitis, a common confounder
in postradiation patients. Breast carcinoma en cuirasse is a very rare form of cutaneous metastases of
breast cancer. The clinical presentation is that of a diffuse indurated
carcinomatous infiltration of the skin and subcutaneous tissues of the mammary
region and the anterior aspect of the chest. In most cases, breast carcinoma en
cuirasse develops post-mastectomy and represents a dramatic presentation of an
aggressive tumor associated with a dismal prognosis. Because of the rarity of
this type of maligcy, the optimal approach to treatment has not been clearly
defined. The systemic treatment has been associated with limited efficacy, and
the primary goal is palliative care and preservation of the quality of life
through skin-directed therapies. Herein, a very rare case of primary breast
carcinoma en cuirasse is presented, along with a review of the literature. Early
diagnosis and prompt treatment of any potential skin metastases of breast cancer
are essential to prevent the catastrophic natural progression of the disease. Breast carcinoma en cuirasse (CeC) is an extremely rare form of cutaneous
metastases of breast cancer, characterized by diffuse sclerodermoid induration
of the skin. It may be difficult to distinguish CeC from some skin diseases,
including postirradiation morphea, inflammatory breast cancer, radiation
dermatitis, and other cutaneous metastases, but it can be easily discerned by
histology. Because of the small number of documented cases, the treatment
consensus has not been clearly defined. Here, we show a 45-year-old woman with
grade III infiltrating ductal carcinoma manifesting as CeC to the chest wall.
Early diagnosis and treatment are essential to prevent the catastrophic natural
progression of this rare maligcy. |
What is carboxyglutamate? | One of the important glutamic acid modifications is post-translationally modified 4-carboxyglutamate. | Glutamic acid is an alpha-amino acid used by all living beings in protein
biosynthesis. One of the important glutamic acid modifications is
post-translationally modified 4-carboxyglutamate. It has a significant role in
blood coagulation. 4-carboxyglumates are required for the binding of calcium
ions. On the contrary, this modification can also cause different diseases such
as bone resorption, osteoporosis, papilloma, and plaque atherosclerosis.
Considering its importance, it is necessary to predict the occurrence of
glutamic acid carboxylation in amino acid stretches. As there is no
computational based prediction model available to identify 4-carboxyglutamate
modification, this study is, therefore, designed to predict 4-carboxyglutamate
sites with a less computational cost. A machine learning model is devised with a
Multilayered Perceptron (MLP) classifier using Chou's 5-step rule. It may help
in learning statistical moments and based on this learning, the prediction is to
be made accurately either it is 4-carboxyglutamate residue site or detected
residue site having no 4-carboxyglutamate. Prediction accuracy of the proposed
model is 94% using an independent set test, while obtained prediction accuracy
is 99% by self-consistency tests. |
What is Morton's Neuroma? | Morton's neuroma (MN) is a neuralgia involving the common plantar digital nerves of the metatarsal region. | Morton's "neuroma" is a perineurofibrosis of an interdigital nerve. The authors
describe various factors that may be responsible for the development of this
lesion and relate this information to two case histories. In these cases,
treatment with manipulation, various physical therapy modalities, and/or foot
orthotics, resulted in the successful resolution of symptoms. Morton's neuroma is regarded as a type of entrapment neuropathy, therefore,
neurolysis as surgical treatment is preferable to neurectomy. We have developed
a new surgical procedure which consists of a plantar zigzag incision, incision
of the plantar aponeurosis, and microsurgical neurolysis of the interdigital
nerve. We have performed this operation on 6 nerves with Morton's neuroma in 5
patients and obtained excellent results. The remaining one nerve showed fair
results. Neurectomy of the interdigital nerve has been regarded as the surgical
treatment of choice for Morton's neuroma. However, a resection neuroma and
permanent sensory deficit are inevitable sequelae after neurectomy. Since
Morton's neuroma is considered to be a type of entrapment neuropathy, it is
reasonable to think that neurolysis is preferable to neurectomy. We have
developed a renewed procedure of microsurgical neurolysis on nerves involved
with Morton's neuroma. Using this procedure, we operated 6 nerves with Morton's
neuroma on 5 patients and obtained excellent results, which forms the basis of
this report. BACKGROUND: Morton's neuroma is a common, paroxysmal neuralgia affecting the web
spaces of the toes, typically the third. The pain is often so debilitating that
patients become anxious about walking or even putting their foot to the ground.
Insoles, corticosteroid injections, excision of the nerve, transposition of the
nerve and neurolysis of the nerve are commonly used treatments. Their
effectiveness is poorly understood.
OBJECTIVES: To examine the evidence from randomised controlled trials concerning
the effectiveness of interventions in adults with Morton's neuroma.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials
register (searched January 2003), MEDLINE (January 1966 to January Week 2 2003),
EMBASE (January 1980 to February Week 2 2003), and CINAHL (January 1982 to
February Week 1 2003).
SELECTION CRITERIA: Randomised or quasi-randomised (methods of allocating
participants to an intervention which were not strictly random e.g. date of
birth, hospital record, number alternation) controlled trials of interventions
for Morton's neuroma were selected. Studies where participants were not
randomised into intervention groups were excluded.
DATA COLLECTION AND ANALYSIS: Two reviewers selected trials for inclusion in the
review, assessed their methodological quality and extracted data independently.
MAIN RESULTS: Three trials involving 121 people were included. There is, at
most, a very limited indication that transposition of the transected plantar
digital nerve may yield better results than standard resection of the nerve in
the long term. There is no evidence to support the use of supinatory insoles.
There are, at best, very limited indications to suggest that dorsal incisions
for resection of the plantar digital nerve may result in less symptomatic
post-operative scars when compared to plantar excision of the nerve.
REVIEWERS' CONCLUSIONS: There is insufficient evidence with which to assess the
effectiveness of surgical and non-surgical interventions for Morton's neuroma.
Well designed trials are needed to begin to establish an evidence base for the
treatment of Morton's neuroma pain. Morton's neuroma, known also as intermetatarsal or interdigital neuroma, is a
common foot injury that often curtails athletic activity. Nerve compression
involving adjacent metatarsal heads and the transverse intermetatarsal ligament
appears implicated in injury onset. Diagnosis is made clinically, and the
condition typically causes initial symptoms of dull cramping or burning pain and
more persistent sharp pain with nerve deterioration. Depending on injury
severity, treatment is either conservative or surgical. Morton's neuroma is a benign foot condition that occurs more often in women than
men, and particularly in those who wear narrow, high-heeled shoes. This article
presents a case study of the condition, discusses its symptoms and diagnosis,
and provides information about the range of treatments on offer. Morton's neuroma is an entrapment neuropathy of the plantar digital nerve. We
treated five patients with wound dehiscence and tendon exposure, after Morton's
neuroma surgery excision using a dorsal approach. In this article we describe
our technique. From July 2010 to August 2011, at the Department of Plastic and
Reconstructive Surgery, University of Rome 'Tor Vergata', five patients (four
females and one male), with ages ranging between 35 and 52 years, were treated
with a combination of PRP (platelet rich plasma) and HA (hyaluronic acid).
Thirty days following surgery, all patients showed a complete healing of the
wound. The use of this technique for the treatment of postoperative wound
dehiscence and tendon exposure has proven as satisfactory. BACKGROUND: Morton's neuroma is a common cause of pain that radiates from
between the third and fourth metatarsals and which, when symptomatic, creates
sensations of burning or sharp pain and numbness on the forefoot. Many
conservative and surgical interventions are employed to reduce associated pain,
but not enough research has been conducted to recommend patients to any one
approach as the most reliable source of pain management.
PURPOSE: The objective of this case report is to describe the effect of massage
therapy on one woman with symptomatic Morton's neuroma.
PARTICIPANT: A physically active 25-year-old female with diagnosed symptomatic
Morton's neuroma who has not found relief with previous conservative
intervention.
INTERVENTION: Six session of massage therapy once weekly for 60-75 minutes
focused on postural alignment and localized foot and leg treatment. The client
also completed an at-home exercise each day. Change was monitored each week by
the massage therapist reassessing posture and by the client filling out a pain
survey based on a Visual Analog Scale.
RESULTS: The client reported progressive change in the character of the pain
from burning and stabbing before the first session to a dull, pulsing sensation
after the third session. She also recorded a reduction in pain during exercise
from a 5/10 to 0/10 (on a scale where 10 is extreme pain).
CONCLUSION: This study describes how massage therapy reduced pain from Morton's
neuroma for one client; however, larger randomized control studies need to be
done in order to determine the short- and long-term effects of massage therapy
on this painful condition. Abstract BACKGROUND:Morton's neuroma is a frequently painful condition of the
forefoot, causing sufferers to seek medical care to alleviate symptoms. A
plethora of therapeutic options are available, some of which include injection
therapies. Researchers have investigated injection therapy for Morton's neuroma,
and latterly the evidence base has been augmented with methodologies which
utilise diagnostic ultrasound (US) as a vehicle to deliver the injectate under
image guidance for additional accuracy. There appears to date to be no consensus
that US-guided injections provide better therapeutic outcomes than non US-guided
(blind) injections for treatment of Morton's neuroma. METHODS:A systematic
review was chosen, as this methodology can undertake such a process. The review
process identified 13 key papers using pre-determined inclusion and exclusion
criteria, which then underwent methodological quality assessment using a
pre-tested Quality Index. A narrative synthesis of the review findings was
presented in light of the heterogeneity of the data from the extraction process.
RESULTS:This systematic review provides an argument that ultrasound-guidance can
produce better short- and long-term pain relief for corticosteroid injections,
can reduce the need for additional procedures in a series of sclerosing alcohol
injections, can reduce the surgical referral rate, and adds efficacy to a single
injection.
CONCLUSIONS: Ultrasound guidance should be considered for injection therapy in
the management of Morton's neuroma. Morton's neuroma is the fibrous enlargement of the interdigital nerve branches,
usually in the second and third interspace between the metatarsal heads where
the lateral and medial plantar nerves often join. Specific symptoms are dull or
sharp pain, numbness and/or tingling in the third and fourth digits, burning
sensation, cramping, and a feeling of "walking on a stone" around the metatarsal
heads. Numerous clinical tests for Morton's neuroma have been described, such as
thumb index finger squeeze, and Mulder's click and foot squeeze tests.
Ultrasound and magnetic resoce imaging can be used for confirmation,
especially for differential diagnosis, exact localization, and number of
neuromas. Further, performing dynamic imaging during the aforementioned tests is
paramount and can readily be carried out with ultrasound. The treatment mainly
comprises footwear modifications, radiofrequency ablation, physical therapy,
local (corticosteroid and anesthetic) injections into the affected webspace, and
surgery. Again the use of real-time ultrasound guidance during such
interventions is noteworthy. BACKGROUND: Morton's neuroma is a common cause of forefoot pain. Various
conservative methods (injections of various pharmacologic agents) have been
published with an outcome of 6%-75% success rate (free of pain in daily life)
per injection. The aim of the present study was to assess the outcome of an
improved localization technique, a higher dosage, and a higher percentage of
ethanol.
METHODS: Using fluoroscopic and electroneurographic guidance, 2.5 mL of 70%
ethanol were injected into 33 feet with a magnetic resoce imaging
(MRI)-verified neuroma. We evaluated patients at up to 5-year follow-up.
RESULTS: A "success rate" of more than 82% per single injection (defined as free
of pain in daily life) was achieved and no recurrence was seen over 5 years. All
scores (visual analog scale; Short Form-36 subscales, American Orthopaedic Foot
& Ankle Society ankle-hindfoot score) showed significant improvement (P <
.0001). Mean 1.2 injections were necessary. No significant side effects were
seen. However, some mild pain persisted in some patients who participated in
sports.
CONCLUSION: The injection of 2.5 mL of 70% ethanol under fluoroscopic and
electroneurographic guidance was a safe method for the treatment of MRI-verified
Morton's neuromas. Combining the effect of a higher percentage of alcohol and a
higher dosage and an improved localization technique resulted in a high rate of
patients without pain.
LEVEL OF EVIDENCE: Level IV, cases series, prospective. Civinini Morton's Syndrome (CMS), better known as Morton's Neuroma, is a benign
enlargement that typically affects the third common digital branch of the
plantar nerve. It is a common cause of metatarsalgia leading to debilitating
pain. It prefers the female gender, with a female to male ratio of 5:1 and an
average age of 50 years at time of surgery. Precise aetiology remains under
debate, with four etiopathogenetic theories often cited in the literature.
Clinical symptoms, physical exam and instrumental evidence are important in
assessing and grading the disease. Biomechanics seem to play an important role,
especially regarding the usefulness of correct footwear. The first approach in
the early stages of this condition usually begins with shoe modifications and
orthotics, designed to limit the nerve compression. In order to prevent or delay
the development of CMS, shoes should be sufficiently long, comfortable, broad
toe-boxed, should bear a flat heel and a sufficiently thick external sole which
should not be excessively flexible. Most authors suggested that an insole with
medial arch support and a retrocapital bar or pad, just proximal to the
metatarsal heads, displaces the pressure sites and can be beneficial to relieve
the pain from the pinched nerve. A threshold period of 4.5 months appears to
emerge from the results of the analysed studies, indicating that, beyond this
period and in neuromas larger than 5-6 mm, orthotics and/or shoes modifications
do not seem to give convincing results, proving to be more a palliation for the
clinical condition to allow an acceptable life with pain rather than a real
treatment. BACKGROUND: Morton's neuroma is a frequent cause of metatarsalgia. Operative
treatment is indicated if nonoperative management has failed. The objective of
the present study was to describe a technique of Morton's neuroma excision by a
minimally invasive commissural approach and evaluate the long-term outcome and
complications.
METHODS: A retrospective study of 108 patients with Morton's neuroma treated
surgically with a commissural approach between September 1990 and December 2010
was performed. The surgical technique is described. Clinical outcomes and
complications were evaluated. The average follow-up was 121 months. Eleven
patients were men and 97 women. The average age was 49.4 years; 56.8% neuromas
were at the third space and 43.2% at the second space. Six patients presented 2
neuromas in the same foot, and 9 patients had bilateral neuroma.
RESULTS: The visual analog scale (VAS) average pain score was 5.4 points
preoperatively and 0.2 points at the final follow-up. The author found a
significant difference between the VAS scores preoperatively and postoperatively
(P < .01). Excellent and good satisfaction outcomes were achieved in 93.6%. The
postoperative complication incidence was 3%.
CONCLUSION: The author believes a minimally invasive commissural approach has
advantages over a dorsal or plantar incision. It is a simple and reproducible
technique, with satisfactory outcomes, low complication rates, and a quick
return to usual activities.
LEVEL OF EVIDENCE: Level IV, retrospective case series. BACKGROUND: Morton's neuromas are abnormalities of the common digital nerve
branch located between the lesser metatarsal heads. Historically, interdigital
(Morton's) neuromas have been characterized as being most common in the third
interspace and predomitly identified in females. The principal investigator
observed Morton's neuromas commonly in both the 2nd and 3rd interspaces in both
genders. To the best of our knowledge, no literature exists to evaluate Morton's
neuroma location with a focus on each gender independently. The present study
evaluates Morton's neuroma interspace location and if there is a variation
between males and females.
METHODS: In this retrospective study, 582 de-identified ProScan magnetic
resoce imaging reports, with a diagnosis code for Morton's neuroma (ICD Code
355.6), were obtained from their centralized database. These reports were
evaluated for patients scanned from January 2015-April 2016. Incomplete records
and those where the radiologist findings were not consistent with Morton's
neuroma were eliminated. For the remaining 379 patients, data was collected on
several factors such as gender, laterality, history of trauma, plantar plate
tear, age and interspace location. Special focus was given to second and third
interspace Morton's neuromas. Data was then evaluated statistically utilizing
the Pearson Chi-Square and Independent Samples Mann-Whitney U Test with
statistical significance deemed p<0.05.
RESULTS: No statistically significant distribution between gender and second and
third interspace Morton's neuromas were noted. Additionally, right vs left foot,
age and history of trauma did not vary between genders in a significant way.
Lastly, there was a statistically significant difference between the presence of
plantar plate tears between genders. Male patients with Morton's neuromas were
found to have a higher rate of plantar plate tears (34/92, p=0.01).
CONCLUSION: Our study found that there was not a statistically significant
difference between female and male and Morton's neuromas location, laterality or
age. Morton's neuroma is a commonly encountered cause of forefoot pain, which may
limit weight-bearing activities and footwear choices. Although the aetiology and
pathomechanism of this condition is controversial, the histological endpoint is
well established as benign perineural fibrosis of a common plantar digital
nerve, typically within the third intermetatarsal space. The diagnosis of
Morton's neuroma is mainly based on characteristic symptoms and clinical
findings, but may be confirmed by ultrasonography. Although ultrasound is a
highly accurate diagnostic tool for Morton's neuroma, it is subject to
interoperator variability due to differences in technique and level of
experience. In this paper, the authors review the anatomy of the common plantar
digital nerves and surrounding structures in the forefoot, which are deemed
relevant to the understanding of Morton's neuroma, especially from a sonographic
point of view. Several theories of the pathomechanism of Morton's neuroma are
briefly discussed. The main purpose of this article is to illustrate the
ultrasound techniques for evaluating Morton's neuroma and performing
ultrasound-guided corticosteroid injections. BACKGROUND: Morton's neuromas are abnormalities of the common digital nerve
branch located between the lesser metatarsal heads. Historically, interdigital
(Morton's) neuromas have been characterized as being most common in the third
interspace and in females. The principal investigator observed Morton's neuromas
commonly in the second and third interspaces in both sexes. To our knowledge, no
literature exists to evaluate Morton's neuroma location with a focus on each sex
independently. The present study evaluates Morton's neuroma interspace location
and whether there is a variation by sex.
METHODS: In this retrospective study, 582 deidentified magnetic resoce
imaging reports with a diagnosis code for Morton's neuroma were evaluated for
patients scanned from January 2, 2015, through April 19, 2016. Incomplete
records and those with radiologist findings inconsistent with Morton's neuroma
were eliminated. For the remaining 379 patients, data were collected on sex,
laterality, history of trauma, plantar plate tear, age, and interspace location.
Special focus was given to second and third interspace Morton's neuromas. Data
were evaluated using the Pearson χ2 and independent-samples Mann-Whitney U
tests, with P < .05 indicating statistical significance.
RESULTS: No statistically significant distribution between sex and second and
third interspace Morton's neuromas was noted. Right vs left foot, age, and
history of trauma did not vary statistically significantly between sexes. There
was a statistically significant difference between the presence of plantar plate
tears between sexes. Male patients with Morton's neuromas were found to have a
higher rate of plantar plate tears (P = .01).
CONCLUSIONS: This study found that there were no statistically significant
differences between sexes and Morton's neuromas location, laterality, or age. Morton's neuroma is a painful lesion of the interdigital nerve, usually at the
third intermetatarsal space, associated with fibrotic changes in the nerve,
microvascular degeneration, and deregulation of sympathetic innervation.
Patients usually present with burning or sharp metatarsalgia at the dorsal or
plantar aspect of the foot. The management of Morton's neuroma starts with
conservative measures, usually with limited efficacy, including orthotics and
anti-inflammatory medication. When conservative treatment fails, a series of
minimally invasive ultrasound-guided procedures can be employed as second-line
treatments prior to surgery. Such procedures include infiltration of the area
with a corticosteroid and local anesthetic, chemical neurolysis with alcohol or
radiofrequency thermal neurolysis. Ultrasound aids in the accurate diagnosis of
Morton's neuroma and guides the aforementioned treatment, so that significant
and potentially long-lasting pain reduction can be achieved. In cases of initial
treatment failure, the procedure can be repeated, usually leading to the
complete remission of symptoms. Current data shows that minimally invasive
treatments can significantly reduce the need for subsequent surgery in patients
with persistent Morton's neuroma unresponsive to conservative measures. The
purpose of this review is to present current data on the application of
ultrasound for the diagnosis and treatment of Morton's neuroma, with emphasis on
the outcomes of ultrasound-guided treatments. |
Which company produces the HercepTest? | DAKO is the company producing the companion diagnostic HercepTest. | |
Does UBE4B promote renal cancer? | Yes. UBE4B might act as an oncogene in regulating renal cancer development. Therefore it could be served as an effective indicator to predict OS and a potential biomarker for targeted therapy of renal cancer patients. | OBJECT: This study aimed at investigating the clinical significance and
biological function of ubiquitination factor E4B (UBE4B) in human renal cell
carcinoma (RCC).
METHODS: 19 paired clear cell renal cell carcinoma (ccRCC) tumor samples and the
matched neighboring non-tumor samples were used to detect the expression of
UBE4B in RCC tumor by Western blotting and RT-qPCR. UBE4B expression was also
detected in 151 ccRCC paraffin-embedded tumor samples by using
immunohistochemistry. Overall survival (OS) in different UBE4B expression groups
were compared with Log rank test. The prognostic value of UBE4B expression in OS
was evaluated with the univariate and multivariate Cox regression models. UBE4B
was knocked down by small interfering RNA (siRNA) technology, and the effect of
UBE4B on cell proliferation, colony formation, metastasis, apoptosis and cell
cycle of RCC cells were examined in vitro.
RESULTS: Both protein and mRNA levels of UBE4B were up-regulated in ccRCC tumor
tissues in contrast to the corresponding adjacent nontumor ones. UBE4B
expression was positively associated with tumor-node-metastasis (TNM) stage and
distant metastasis in ccRCC patients. Survival analyses indicated that low
expression of UBE4B was associated with increased OS in ccRCC patients.
Functional analyses demonstrated that siRNA silencing of UBE4B expression in
SKRC39 and ACHN cells further reduced the growth, motility and invasiveness of
RCC cells. Moreover, siRNA silencing of UBE4B in the RCC cell lines did not
induce apoptosis, and an increase in the cell population was observed during the
G0/G1 phase of the cell cycle.
CONCLUSION: UBE4B might act as an oncogene in regulating RCC development.
Therefore it could be served as an effective indicator to predict OS and a
potential biomarker for targeted therapy of RCC patients. |
Does addition of valproic acid improve survival of patients with diffuse intrinsic pontine glioma? | No. Addition of valproic acid and bevacizumab to radiation was well tolerated but did not appear to improve survival in children with diffuse intrinsic pontine glioma. | Diffuse intrinsic pontine glioma is a pediatric oncologic disease with dismal
prognosis and no effective treatment. Since 2007, our patients have been using
valproic acid as prophylactic anticonvulsant. We have undertaken a retrospective
study in order to evaluate the influence of valproate in the outcomes of
children with this disease in our center. Patients were treated with weekly
carboplatin and vincristine and received conformal radiotherapy, either
concurrent or sequential. Event-free survival and overall survival of patients
not treated with valproic acid were 6.5 and 7.8 months. Accelerated failure time
model (a parametric multivariate regression test for time-to-failure data)
showed a statistically significant superiority of the median event-free survival
of treated patients (6.5 vs. 9.5 months in treated patients; HR 0.54-95 % CI
0.33-0.87; p < 0.05) and also of overall survival (7.8 vs. 13.4 months in
treated patients; HR 0.60-95 % CI 0.37-0.98; p = 0.05). PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and
radiation, followed by VPA and bevacizumab in children with newly diagnosed
diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG).
METHODS: Children 3 to 21 years of age received radiation therapy and VPA at
15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 μg/mL.
VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg
intravenously biweekly, four weeks after completing radiation therapy.
RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients
were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher
toxicities requiring discontinuation or modification of VPA dosing included
grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis
(1). During VPA and bevacizumab, the most common grade 3 or higher toxicities
were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3),
and grade 3 hypertension (4). Two patients discontinued protocol therapy prior
to disease progression (one grade 4 thrombosis and one grade 1 intratumoral
hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG
were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS
was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1)
months, and estimated one-year EFS was 24% (7%-45%). Four patients with
glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7,
10.4, and 9 months.
CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but
did not appear to improve EFS or OS in children with DIPG or HGG. |
List the main protein families found in human tears? | Lipocalin
Cystatin S (CST4),
calcyclin (S100A6),
calgranulin A (S100A8)
matrix metalloproteinase 9 (MMP9)
LTF,
LYZ,
ZAG,
DNAJC3 | Tears are highly concentrated in proteins relative to other biofluids, and a
notable fraction of tear proteins are proteases and protease inhibitors. These
components are present in a delicate equilibrium that maintains ocular surface
homeostasis in response to physiological and temporal cues. Dysregulation of the
activity of protease and protease inhibitors in tears occurs in ocular surface
diseases including dry eye and infection, and ocular surface conditions
including wound healing after refractive surgery and contact lens (CL) wear.
Measurement of these changes can provide general information regarding ocular
surface health and, increasingly, has the potential to give specific clues
regarding disease diagnosis and guidance for treatment. Here, we review three
major categories of tear proteases (matrix metalloproteinases, cathepsins, and
plasminogen activators [PAs]) and their endogenous inhibitors (tissue inhibitors
of metalloproteinases, cystatins, and PA inhibitors), and the changes in these
factors associated with dry eye, infection and allergy, refractive surgery, and
CLs. We highlight suggestions for development of these and other
protease/protease inhibitor biomarkers in this promising field. PURPOSE: This paper examines the tear concentration of cystatin S (CST4),
calcyclin (S100A6), calgranulin A (S100A8), and matrix metalloproteinase 9
(MMP9), and the correlation between biomarker expression, clinical parameters,
and disease severity in patients suffering from dry eye (DE). A comparison of
the results is obtained via ELISA tests and customized antibody microarrays for
protein quantification.
METHODS: This single-center, observational study recruited 59 participants (45
DE and 14 controls). Clinical evaluation included an Ocular Surface Disease
Index (OSDI) questionnaire, a tear osmolarity (OSM) test, the Schirmer test
(SCH), tear breakup time (TBUT), fluorescein (FLUO) and lissamine green (LG)
corneal staining, and meibomian gland evaluation (MGE). Tear concentrations of
CST4, S100A6, S100A8, and MMP9 were measured using standard individual ELISA
assays. The levels of CST4, S100A6, and MMP9 were also measured using customized
multiplexed antibody microarrays. Correlations between variables were evaluated,
and a significance level was p value <0.05.
RESULTS: The quantification of tear protein biomarkers with ELISA showed that
the concentration of CST4 was significantly (2.14-fold) reduced in tears of DE
patients in comparison with control (CT) subjects (p < 0.001). S100A6 and S100A8
concentrations were significantly higher in the tears of DE patients (1.36- and
2.29-fold; p < 0.001 and 0.025, respectively) in comparison with CT. The MMP9
level was also higher in DE patients (5.83-fold), but not significantly (p =
0.22). The changes in CST4 and S100A6 concentrations were significantly
correlated with dry eye disease (DED) severity. Quantification of CST4, S100A6,
and MMP9, using antibody microarrays, confirmed the ELISA results. Similar
trends were observed: 1.83-fold reduction for CST4 (p value 0.01), 8.63-fold
increase for S100A6 (p value <0.001) and 9.67-fold increase for MMP9 (p value
0.94), but with higher sensitivity. The biomarker concentrations were
significantly associated with the signs and symptoms related with DED.
CONCLUSIONS: S100A6, S100A8, and CST4 diagnostic biomarkers strongly correlate
with DED clinical parameters. S100A6 and CST4 are also useful for grading DE
severity. The multiplexed antibody microarray technique, used here for tear
multi-marker quantification, appears more sensitive than standard ELISA tests. Tear lipocalin is a primate protein that was recognized as a lipocalin from the
homology of the primary sequence. The protein is most concentrated in tears and
produced by lacrimal glands. Tear lipocalin is also produced in the tongue,
pituitary, prostate, and the tracheobronchial tree. Tear lipocalin has been
assigned a multitude of functions. The functions of tear lipocalin are
inexorably linked to structural characteristics that are often shared by the
lipocalin family. These characteristics result in the binding and or transport
of a wide range of small hydrophobic molecules. The cavity of tear lipocalin is
formed by eight strands (A-H) that are arranged in a β-barrel and are joined by
loops between the β-strands. Recently, studies of the solution structure of tear
lipocalin have unveiled new structural features such as cation-π interactions,
which are extant throughout the lipocalin family. Lipocalin has many unique
features that affect ligand specificity. These include a capacious and a
flexible cavity with mobile and short overhanging loops. Specific features that
confer promiscuity for ligand binding in tear lipocalin will be analyzed. The
functions of tear lipocalin include the following: antimicrobial activities,
scavenger of toxic and tear disruptive compounds, endonuclease activity, and
inhibition of cysteine proteases. In addition, tear lipocalin binds and may
modulate lipids in the tears. Such actions support roles as an acceptor for
phospholipid transfer protein, heteropolymer formation to alter viscosity, and
tear surface interactions. The promiscuous lipid-binding properties of tear
lipocalin have created opportunities for its use as a drug carrier. Mutant
analogs have been created to bind other molecules such as vascular endothelial
growth factor for medicinal use. Tear lipocalin has been touted as a useful
biomarker for several diseases including breast cancer, chronic obstructive
pulmonary disease, diabetic retinopathy, and keratoconus. The functional
possibilities of tear lipocalin dramatically expanded when a putative receptor,
lipocalin-interacting membrane receptor was identified. However, opposing
studies claim that lipocalin-interacting membrane receptor is not specific for
lipocalin. A recent study even suggests a different function for the membrane
protein. This controversy will be reviewed in light of gene expression data,
which suggest that tear lipocalin has a different tissue distribution than the
putative receptor. But the data show lipocalin-interacting membrane receptor is
expressed on ocular surface epithelium and that a receptor function here would
be rational. |
In what year did Gregor Mendel die? | The life and personality of Johann Gregor Mendel (1822-1884) | The life and personality of Johann Gregor Mendel (1822-1884), the founder of
scientific genetics, are reviewed against the contemporary background of his
times. At the end are weighed the benefits for Mendel (as charged by Sir Ronald
Fisher) to have documented his results on hand of falsified data. Mendel was
born into a humble farm family in the "Kuhländchen", then a predomitly German
area of Northern Moravia. On the basis of great gifts Mendel was able to begin
higher studies; however, he found himself in serious ficial difficulties
because of his father's accident and incapacitation. His hardships engendered
illness which threatened continuation and completion of his studies until he was
afforded the chance of absolving successfully theological studies as an
Augustinian monk in the famous chapter of St. Thomas in Altbrünn (Staré Brno).
Psychosomatic indisposition made Mendel unfit for practical pastoral duties.
Thus, he was directed to teach but without appropriate state certification; an
attempt to pass such an examination failed. At that point he was sent to the
University of Vienna for a 2-year course of studies, with emphasis on physics
and botany, to prepare him for the exam. His scientific and methodologic
training enabled him to plan studies of the laws of inheritance, which had begun
to interest him already during his theology training, and to choose the
appropriate experimental plant. In 1865, after 12 years of systematic
investigations on peas, he presented his results in the famous paper "Versuche
über Pflanzenhybriden." Three years after his return from Vienna he failed to
attain his teaching certification a second time. Only by virtue of his
exceptional qualifications did he continue to function as a Supplementary
Professor of Physics and Natural History in the two lowest classes of a
secondary school. In 1868 he was elected Abbot of his chapter, and freed from
teaching duties, was able to pursue his many scientific interests with greater
efficiency. This included meteorology, the measurement of ground water levels,
further hybridization in plants (a.o. involving the hawk week Hieracium up to
about 1873), vegetable and fruit tree horticulture, apiculture, and agriculture
in general. This involved Mendel's active participation in many organizations
interested in advancing these fields at a time when appropriate research
institutes did not exist in Brünn. Some of the positions he took in his capacity
of Abbot had severe repercussions and further taxed Mendel's already
over-stressed system. The worst of these was a 10-year confrontation with the
government about the taxation of the monastery.(ABSTRACT TRUNCATED AT 400 WORDS) Gregor Mendel, an Augustinian monk and part-time school teacher, undertook a
series of brilliant hybridisation experiments with garden peas between 1857 and
1864 in the monastery gardens and, using statistical methods for the first time
in biology, established the laws of heredity, thereby establishing the
discipline of genetics. |
List 4 monoclonal antibodies in development for the prevention of migraine. | Four monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab) | Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from
activated trigeminal sensory afferents in headache and facial pain disorders.
There are a handful of CGRP-targeted therapies currently in phase 3 studies for
migraine acute treatment or prevention. Currently, 4 monoclonal antibodies
targeting either the CGRP ligand or receptor are being studied for migraine
prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab),
and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor
antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute
treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in
clinical trials for cluster headache prevention as well. Several other
small-molecular CGRP receptor antagonists are in earlier stages of development
for acute migraine treatment or prevention. In this review, we will discuss the
growing body of clinical trials studying CGRP-targeted therapies for migraine
and cluster headache. |
Is there a role for CADM1 in Myelodysplastic syndrome (MDS)? | Yes, CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies with deletion of the long arm of chromosome 11. | Author information:
(1)Groupe Francophone de Cytogénétique Hématologique (GFCH).
(2)Laboratoire de Cytogénétique Hématologique, Centre Hospitalier Universitaire
(CHU) de Marseille, Aix-Marseille University, Marseille, France.
(3)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 16, Institut
National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.
(4)Groupe Francophone d'Hématologie Cellulaire (GFHC) and.
(5)Laboratoire d'hématologie, CHU de Guadeloupe, Inserm Unité Mixte de Recherche
1134, Pointe à Pitre, France.
(6)Laboratoire d'Hématologie, Institut Universitaire de Cancérologie de
Toulouse, CHU Toulouse, France.
(7)Department of Hematology, University Toulouse III, Toulouse, France.
(8)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 8, Institut
National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.
(9)Gene Editing, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
(10)Stem Cell Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
(11)Wellcome Sanger Institute, Hinxton, UK.
(12)Department of Haematology, Cambridge University Hospitals National Health
Service Trust, Cambridge, UK.
(13)Wellcome-Medical Research Council Stem Cell Institute, Cambridge Biomedical
Campus, University of Cambridge, Cambridge, UK.
(14)Department of Laboratory Medicine, Laboratory of Hematology, Radboud
University Medical Center, Nijmegen, The Netherlands.
(15)Institute of Medical Informatics, University of Münster, Münster, Germany.
(16)Institut Cochin, Université de Paris, Inserm U1016, Centre National de la
Recherche Scientifique UMR8104, Paris, France.
(17)Belgium Cancer Registry, Brussels, Belgium.
(18)Department of Human Genetics, Katholieke Universiteit Leuven and
Universitair Ziekenhuis, Leuven, Belgium.
(19)Laboratoire de Cytogénétique, CHU de Tours, France.
(20)Laboratoire d'Hématologie, CHU de Bordeaux, Bordeaux, France.
(21)Laboratoire de Cytogénétique, CHU de Besançon, Besançon, France.
(22)Laboratoire de Cytogénétique, CHU de Strasbourg, Strasbourg, France.
(23)Département de Biopathologie, Institut Paoli-Calmettes, Marseille, France.
(24)Laboratoire de Cytogénétique, CHU de Grenoble, Grenoble, France.
(25)Laboratoire de Cytogénétique, CHU de Reims, Reims, France.
(26)Laboratoire de Cytogénétique, CHU de Saint-Etienne, Saint-Etienne, France.
(27)Laboratoire de Cytogénétique, CHU de Paris-Necker, Paris, France.
(28)Laboratoire d'Hématologie, CHU d'Angers, Angers, France.
(29)Laboratoire de Cytogénétique, CHU de Nantes, Nantes, France.
(30)Laboratoire de Cytogénétique, CH de Versailles, Le Chesnay, France.
(31)Laboratoire de Cytogénétique, CHU de Lyon, Lyon, France.
(32)Laboratoire de Cytogénétique, Centre Henri-Becquerel, Rouen, France.
(33)Laboratoire d'Hématologie, CHU Avicenne, Bobigny, France.
(34)Groupe Francophone des Myélodysplasies (GFM); and.
(35)Laboratoire d'hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de
Paris, Centre-Université de Paris, Paris, France. |
Which drugs are in the Segluromet combination pill? | Segluromet includes combinations of ertugliflozin and metformin. It has recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. | Combining antihyperglycemic agents in order to rapidly and safely achieve the
best possible glycemic control is the standard of care today for the management
of type 2 diabetes. Agents should ideally have mechanisms of actions that are
complementary and that improve glycemic control without unacceptable gain in
body weight or hypoglycemia. Areas covered: Ertugliflozin and metformin
hydrochloride (ertugliflozin/metformin, SEGLUROMET) is a recently approved
fixed-dose combination tablet containing the sodium-glucose co-transporter 2
(SGLT-2) inhibitor ertugliflozin and metformin. This review summarizes key
characteristics of ertugliflozin and metformin, as well as the efficacy and
safety results of co-administration of these agents in the ertugliflozin
clinical development program. This information comes from the
ertugliflozin/metformin prescribing information as well as published clinical
trials obtained through a PubMed search. Expert commentary: SGLT-2 inhibitors
are an important class of antihyperglycemic agents that are efficacious as
monotherapy and in combination with other antihyperglycemic agents. Given their
favorable effects on glycemia control as well as 'extra-glycemic' parameters
such as body weight and blood pressure, they are ideal agents for appropriate
patients with type 2 diabetes. The fixed-dose combination of ertugliflozin with
metformin is an effective combination that is conveniently administered and may
improve medication adherence and persistence. Sodium/glucose cotransporter 2 (SGLT2) is exclusively expressed in the S1 and S2
segments of proximal convoluted tubules and accounts for roughly 90% of glucose
reabsorption. Ertugliflozin, a highly selective and reversible SGLT2 inhibitor,
is the latest addition to the gliflozin class of SGLT2 inhibitors for the
treatment of type 2 diabetes mellitus (T2DM). It was granted approval by the
U.S. Food and Drug Administration (FDA) in December 2017 for treatment of T2DM
as a monotherapy, and as part of two separate fixed-dose combination therapies
with sitagliptin (Steglujan) and metformin (Segluromet). Ertugliflozin
demonstrated roughly 100% bioavailability following a single dose of 15 mg. It
also has a longer half-life (16.6 hours) than presently available gliflozins,
which translates into single daily dosing and dose reduction allowing for
patient compliance. This review will focus on the preclinical pharmacology,
pharmacokinetics, clinical efficacy and safety of ertugliflozin. |
Where is the protein "Single-stranded DNA-binding protein" found? | In the mitochondrion (mitochondrial single-stranded DNA binding protein, mtSSB) and its role is the regulation of mitochondrial DNA replication initiation in mammalian mitochondria. | The mitochondrial single-stranded DNA-binding protein (mtSSB) regulates the
function of the mitochondrial DNA (mtDNA) replisome. In vitro, mtSSB stimulates
the activity of enzymatic components of the replisome, namely mtDNA helicase and
DNA polymerase gamma (Pol γ). We have demonstrated that the stimulatory
properties of mtSSB result from its ability to organize the single-stranded DNA
template in a specific manner. Here we present methods employing electron
microscopy and enzymatic assays to characterize and classify the mtSSB-DNA
complexes and their effects on the activity of Pol γ. RNA interference (RNAi) is a posttranscriptional gene silencing method that is
triggered by double-stranded RNA (dsRNA). RNAi is used to inactivate genes of
interest and provides a genetic tool for loss-of-function studies in a variety
of organisms.I have used this method to reveal the physiological roles of a
number of endogenous proteins involved in mitochondrial DNA metabolism in
Schneider cells, including the mitochondrial single-stranded DNA-binding
protein. Here, I present experimental schemes of selective suppression of
endogenous gene expression using RNAi in Drosophila Schneider S2 cells. With
this method, the function of exogenous wild-type or mutant genes can be
evaluated. Author information:
(1)Key Laboratory of Growth Regulation and Translational Research of Zhejiang
Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang
310024, China.
(2)Department of Mitochondrial Biology, Max Planck Institute for Biology of
Ageing, 50931 Cologne, Germany.
(3)Department of Medical Biochemistry and Cell Biology, University of
Gothenburg, PO Box 440, Gothenburg 405 30, Sweden.
(4)Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Stockholm 17177, Sweden.
(5)Lineberger Comprehensive Cancer Center, Department of Microbiology and
Immunology, University of North Carolina, Chapel Hill, NC 27514, USA.
(6)Proteomics Core Facility, Max Planck Institute for Biology of Ageing, 50931
Cologne, Germany.
(7)Harry Perkins Institute of Medical Research and ARC Centre of Excellence in
Synthetic Biology, Nedlands, WA 6009, Australia.
(8)Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15
Hospital Avenue, Nedlands, WA, Australia.
(9)Department of Biomedical and Neuromotor Sciences (DIBINEM), University of
Bologna, Bologna, Italy.
(10)IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di
Neurogenetica, Bologna, Italy.
(11)Wellcome Centre for Mitochondrial Research, Biosciences Institute, The
Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
(12)Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Stockholm 17177, Sweden. [email protected] [email protected].
(13)Department of Medical Biochemistry and Cell Biology, University of
Gothenburg, PO Box 440, Gothenburg 405 30, Sweden. [email protected]
[email protected]. The maintece of the mitochondrial genome depends on a suite of
nucleus-encoded proteins, among which the catalytic subunit of the mitochondrial
replicative DNA polymerase, Pol γα, plays a pivotal role. Mutations in the Pol
γα-encoding gene, POLG, are a major cause of human mitochondrial disorders. Here
we present a study of direct and functional interactions of Pol γα with the
mitochondrial single-stranded DNA-binding protein (mtSSB). mtSSB coordinates the
activity of the enzymes at the DNA replication fork. However, the mechanism of
this functional relationship is elusive, and no direct interactions between the
replicative factors have been identified to date. This contrasts strikingly with
the extensive interactomes of SSB proteins identified in other homologous
replication systems. Here we show for the first time that mtSSB binds Pol γα
directly, in a DNA-independent manner. This interaction is strengthened in the
absence of the loop 2.3 structure in mtSSB, and is abolished upon preincubation
with Pol γβ. Together, our findings suggest that the interaction between mtSSB
and polymerase gamma holoenzyme (Pol γ) involves a balance between attractive
and repulsive affinities, which have distinct effects on DNA synthesis and
exonucleolysis. |
Is periampullary carcinoma (PAC) a relatively rare genitourinary malignancy | Periampullary carcinoma (PAC) a relatively rare gastrointestinal malignancy and includes Pancreaticobiliary as a subtype of Periampullary carcinoma | BACKGROUND: The pre-operative neutrophil-to-lymphocyte ratio (NLR), when ≥5 has
been associated with reduced survival for patients with various gastrointestinal
tract cancers, however, it's prognostic value in patients with periampullary
tumour has not been reported to date.
OBJECTIVES: To determine the prognostic value of pre-operative NLR in terms of
survival and recurrence of resected periampullary carcinomas.
METHODS: This was a retrospective cohort study of consecutive patients
undergoing pancreatoduodenectomy (PD) for periampullary carcinoma (pancreatic,
ampullary, cholangiocarcinoma) identified from a departmental database. The
effect of NLR upon survival and recurrence was explored.
RESULTS: Overall median survival amongst 228 patients was 24 months
(inter-quartile range [IQR]: 12-43). The median survival for those whose NLR was
<5 was not significantly greater than those patients whose NLR was ≥5 (24 months
[IQR: 14-42] versus 13 months [IQR: 8-48], respectively; p = 0.234). However,
for those that developed recurrence, survival was greater in those with an NLR
<5 at (20 months [IQR: 12-27] versus 11 months [IQR: 7-22], respectively;
p = 0.038). This effect was most marked in those patients with
cholangiocarcinoma (p = 0.019) whilst a trend to worse survival was seen in
those with pancreatic adenocarcinoma. No effect was seen in patients with
ampullary carcinoma (p = 0.516).
CONCLUSIONS: This study provides further evidence that pre-operative NLR offers
important prognostic information regarding disease-free survival. This effect,
however, is dependent upon the tumour type amongst patients undergoing PD. BACKGROUND: In patients suspected of pancreatic or periampullary cancer,
abdominal contrast-enhanced computed tomography (CT) is the standard diagnostic
modality. A supplementary endoscopic ultrasonography (EUS) is often performed,
although there is only limited evidence of its additional diagnostic value. The
aim of the study is to evaluate the additional diagnostic value of EUS over CT
in deciding on exploratory laparotomy in patients suspected of pancreatic or
periampullary cancer.
METHODS: We retrospectively analyzed 86 consecutive patients who routinely
underwent CT and EUS before exploratory laparotomy with or without
pancreatoduodenectomy for suspected pancreatic or periampullary carcinoma
between 2007 and 2010. Primary outcomes were visibility of a mass, resectability
on CT/EUS and resection with curative intent.
RESULTS: A mass was visible on CT in 72/86 (84%) patients. In these 72 patients,
EUS demonstrated a mass in 64/72 (89%) patients. Resectability was accurately
predicted by CT in 65/72 (90%) and by EUS in 58/72 (81%) patients. In 14/86
(16%) patients no mass was seen on CT. EUS showed a mass in 12/14 (86%) of these
patients. A maligt lesion was histological proven in 11/12 (92%) of these
patients. Overall, resectability was accurately predicted by CT and EUS in 90%
(77/86) and 84% (72/86), respectively.
CONCLUSIONS: In patients with a visible mass on CT, suspected for pancreatic or
periampullary cancer, EUS has no additional diagnostic value, does not influence
the decision to perform laparotomy and should therefore not be performed
routinely. In patients without a visible mass on CT, EUS is useful to confirm
the presence of a tumor. BACKGROUND: Some 20-40% of the periampullary carcinoma is irresectable at the
time of diagnosis. Biliary stenting and surgical bypass are commonly used
palliative procedure. There is no consensus favouring one procedure over the
other. This study compares the both procedures.
METHODS: This Randomized Controlled Trial included 47 patients who presented
with diagnosis of obstructive jaundice due to periampullary carcinoma to the
Department of Surgery, Federal General Hospital, Islamabad from July 2012 to
December 2014.
RESULTS: Out of total 47 patients 27 (57.44%) were males and 20 (42.55%) were
females. Group-A included 25 (53.19%) patients while group-B included 22
(46.81%) patients. The mean age in both groups was 62.34 years (SD=±5.01). All
patients died during the study. The mean survival time for the stent patients
was 7.5 months while the mean survival time for surgical bypass patients was 8.3
months. The jaundice was relived in all surgical (22, 100%) of the patients as
compared to (18, 72%) of the patients in stent group.
CONCLUSIONS: We concluded that surgical bypass as a primary procedure in
selected patients provided better jaundice relieve as compared to biliary
stenting.. Periampullary adenocarcinomas are rare neoplasm that originates from the
pancreatic head, the ampulla of vater, the distal bile duct or the duodenum.
Surgical resection followed by adjuvant therapy is considered as the standard of
care treatment for these carcinomas. Despite several advances in diagnostics and
therapeutics, only 5% of these patients have an overall survival of five years
or more. Currently, there is a dearth of viable therapeutic targets for this
disease. The role of HER2 in cancer biology has been studied extensively in
several tumour subtypes, and HER2 based targeted therapies have shown to have
therapeutic benefits on different cancers. In this case report, we present a
case of HER2 positive distal common bile duct carcinoma - a subtype of
periampullary carcinoma with multiple relapses where multi-analyte testing with
Encyclopedic Tumor Analysis (ETA) (Exacta®) identified amplification and over
expression of HER2 gene which was used as a potential target to treat the
patient with trastuzumab. Synchronous in vitro chemosensitivity profiling on
Circulating Tumor Asscociated Cells (C-TACs) isolated from blood aided us to
design the personalized chemotherapeutic regimen with cyclophosphamide and
methotrexate. The combination of trastuzumab with cyclophosphamide and
methotrexate yielded excellent treatment response with the patient remaining in
complete response till the last follow-up. Our study suggests HER2 directed
therapy as a potent pathway for treatment in the subset of HER-2 amplified
distal common bile duct carcinomas. INTRODUCTION: Pancreaticobiliary subtype of Periampullary carcinoma (PAC) has a
poor prognosis in comparison to the intestinal subtype. We assessed the
potential of cytokeratins and mucin markers to classify the sub-types of
periampullary tumors and compared them with the survival data to identify
markers that may predict prognosis.
METHODOLOGY: PAC tumor tissues were obtained from 94 patients undergoing
Whipples Pancreaticoduodenectomy. Paraffin-embedded tissues were immunostained
with cytokeratins CK7, CK20), mucins (MUC1, MUC2, MUC5Ac), and CDX2 antibodies.
The survival status of patients was obtained as follow-up up to 5-years of
surgery. The Receiver Operating Character Curve (ROC) analysis was used for
detecting sensitivity and specificity. The survival data were analyzed using the
Kaplan-Meier survival curve.
RESULTS: Tumors were initially categorized on the basis of histological
classification as pancreaticobiliary (n = 46), intestinal (n = 35) and
indeterminate (n = 13). Further, using immunohistochemical markers (MUC1, CK20,
and CDX2), we gave systematic classification of IHC-PB (n = 51), IHC-Int (n =
30) and IHC-Mixed (n = 13). The interobserver analysis showed good agreement
between histologic and IHC type with a kappa value of 0.554. Combined expression
of CK20, MUC1 and CDX2 accurately classify the mixed type of tumor. Overall
survival rate and duration were 74.4% and 44.95 ± 2.29 months. Survival analysis
for subtypes reveal, pancreaticobiliary tumors have low survival (27.9 ± 1.63
months) than mixed type (35.5 ± 0.45 months) and intestinal-type (52.92 ± 2.18
months). Among these, intestinal-type have better survival. Only TNM Stage III
(tumor staging as per American Joint Committee on Cancer classification) and
perineural invasion have been associated with predicting poor survival in PAC
patients.
CONCLUSION: Our results suggest that the combined expression of MUC1, CK20 and
CDX2 could serve as markers to diagnose histological inconclusive specimens as
mixed subtype tumors. |
For which indication has inotersen been approved? | Inoteresen has been approved for patients in stage 1 and stage 2 hereditary transthyretin amyloidosis polyneuropathy. | |
Do SETD1A mutations predispose to schizophrenia? | Yes. There is a mutation in the gene that codes for a protein called SetD1A. This protein is involved in the development of schizophrenia. | Author information:
(1)Department of Physiology and Cellular Biophysics, College of Physicians and
Surgeons, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman
Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA.
(2)Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University,
New York, NY 10027, USA.
(3)Department of Physiology and Cellular Biophysics, College of Physicians and
Surgeons, Columbia University, New York, NY 10032, USA.
(4)Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University,
New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics,
College of Physicians and Surgeons, Columbia University, New York, NY 10032,
USA; Department of Neuroscience, Columbia University, New York, NY 10032, USA.
(5)Department of Human Genetics, Yokohama City University Graduate School of
Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.
(6)Department of Psychiatry, Columbia University Medical Center, New York, NY
10032, USA.
(7)Department of Physiology and Cellular Biophysics, College of Physicians and
Surgeons, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman
Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA;
Department of Neuroscience, Columbia University, New York, NY 10032, USA.
Electronic address: [email protected]. |
Is Sotatercept effective for Pulmonary Arterial Hypertension? | Sotatercept was shown to be effective for Pulmonary Arterial Hypertension. | While misuse of testosterone esters is widespread in elite and recreational
sports, direct detection of intact testosterone esters in doping control samples
is hampered by the rapid hydrolysis by esterases present in the blood. With
dried blood spot (DBS) as sample matrix, continued degradation of the esters is
avoided due to inactivation of the hydrolase enzymes in dried blood. Here, we
have developed the method further for detection of testosterone esters in DBS
with focus on robustness and applicability in doping control. To demonstrate the
method's feasibility, DBS samples from men receiving two intramuscular
injections of Sustanon® 250 (n = 9) or placebo (n = 10) were collected,
transported, and stored prior to analysis, to mimic a doping control scenario.
The presented oLC-HRMS/MS method appeared reliable and suitable for direct
detection of four testosterone esters (testosterone decanoate, isocaproate,
phenylpropionate, and propionate) after extraction from DBS. Sustanon® was
detected in all subjects for at least 5 days, with detection window up to
14 days for three of the esters. Evaluation of analyte stability showed that
while storage at room temperature is tolerated well for a few days, testosterone
esters are highly stable (>18 months) in DBS when stored in frozen conditions.
Collectively, these findings demonstrate the applicability of DBS sampling in
doping control for detection of steroid esters. The fast collection and reduced
shipment costs of DBS compared with urine and standard blood samples,
respectively, will allow more frequent and/or large-scale testing to increase
detection and deterrence. |
Which disease is caused by mutations in the gene CALR? | Somatic mutations of calreticulin (CALR) have been identified as a main disease driver of myeloproliferative neoplasms, | JAK2, CALR, and MPL are myeloproliferative neoplasm (MPN)-driver mutations,
whereas SF3B1 is strongly associated with ring sideroblasts (RS) in
myelodysplastic syndrome (MDS). Concomitant mutations of SF3B1 and MPN-driver
mutations out of the context of MDS/MPN with RS and thrombocytosis
(MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS
panels interrogating at least 42 myeloid neoplasm-related genes, we identified
18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with an SF3B1 and an
MPN-driver mutation. Using a 10% VAF difference to define "SF3B1-domit,"
"MPN-mutation domit," and "no domice," the majority of MDS/MPN-RS-T
clustered in "SF3B1-domit" and "no domice" regions. Aside from parameters
as thrombocytosis and ≥15% RS required for RS-T, MDS also differed in frequent
neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of
MPN-driver mutations (60%, p = 0.0346); MPN differed in more frequent
splenomegaly, myelofibrosis, and higher VAF of "MPN-driver mutations." "Gray
zone" cases with features overlapping MDS/MPN-RS-T were observed in over
one-thirds of non-RS-T cases. This study shows that concomitant SF3B1 and
MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing
overlapping but also distinctively different clinicopathological features.
Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations
may in part contribute to different disease phenotypes, which may help in the
classification of "gray zone" cases. AIMS: JAK2V617F (JAK2), calreticulin (CALR) and MPL515L/K (MPL) mutations are
important in essential thrombocythemia (ET) and may be associated with various
clinical consequences of the disease. This study aimed to compare the clinical
and haematological parameters of ET patients regarding the mentioned mutations
and the role of plateletcrit (PCT).
METHODS: Seventy patients who were diagnosed with ET between 2005 and 2017 in a
single centre were included in this descriptive study. The initial symptoms and
clinical findings were retrieved from the electronic database. JAK2 gene V617F
mutations, MPL gene exon 10 mutations and CALR gene exon 9 DNA sequence analyses
were performed. Forty-one healthy volunteers were included to perform ROC curve
analysis for interpreting PCT value.
RESULTS: The distributions of patients according to the mutations were as
follows: Thirty-seven (52.9%) patients were JAK2-positive, 15 (21.4%) were
CALR-positive, 2 (2.8%) patients were positive for both CALR and JAK2, and 1
(1.4%) was only MPL-positive. Fifteen (21.4%) patients were triple-negative. The
ET patients with JAK2 mutation showed a higher level of haemoglobin at the time
of diagnosis. The ET patients with CALR mutation presented with higher platelet
and LDH levels (P = .002 and P = .001, respectively). The PCT level was higher
in the CALR-positive group when compared to the others (P = .026). A sensitivity
value of 97.6% and specificity value of 98.6% were determined regarding PCT% at
a cut-off value of 0.37 in ET patients. In CALR-positive patients, the
sensitivity and specificity values were 100% for the PCT at a cut-off value of
0.42%.
CONCLUSION: We determined that the platelet count and blood LDH level was high
in the ET patient group with CALR mutation. Besides, we found that the blood
haemoglobin level was higher in the ET patient group with JAK2 mutation.
Additionally, the PCT level was higher in the CALR group when compared to the
other patient groups. Somatic mutations of calreticulin (CALR) have been identified as a main disease
driver of myeloproliferative neoplasms, suggesting that development of drugs
targeting mutant CALR is of great significance. Site-directed mutagenesis in the
N-glycan binding domain (GBD) abolishes the ability of mutant CALR to
oncogenically activate the thrombopoietin receptor (MPL). We therefore
hypothesized that a small molecule targeting the GBD might inhibit the
oncogenicity of the mutant CALR. Using an in silico molecular docking study, we
identified candidate binders to the GBD of CALR. Further experimental validation
of the hits identified a group of catechols inducing a selective growth
inhibitory effect on cells that depend on oncogenic CALR for survival and
proliferation. Apoptosis-inducing effects by the compound were significantly
higher in the CALR-mutated cells than in CALR wild-type cells. Additionally,
knockout or C-terminal truncation of CALR eliminated drug hypersensitivity in
CALR-mutated cells. We experimentally confirmed the direct binding of the
selected compound to CALR, disruption of the mutant CALR-MPL interaction,
inhibition of the JAK2-STAT5 pathway, and reduction at the intracellular level
of mutant CALR upon drug treatment. Our data indicate that small molecules
targeting the GBD of CALR can selectively kill CALR-mutated cells by disrupting
the CALR-MPL interaction and inhibiting oncogenic signaling. Classification of myeloproliferative neoplasms is based on hematologic,
histopathologic, and molecular characteristics, including the BCR-ABL1 and JAK2
V617F or MPL and CALR. Although the different gene mutations ought to be
mutually exclusive, several cases with co-occurring BCR-ABL1 and JAK2 V617F or
CALR have been identified with a frequency of 0.2-2.5% in the European
population. The tyrosine kinase abnormalities appeared to affect independent
subclones because imatinib mesylate (IM) treatment induced Ph+-CML remission,
whereas the JAK2V617F clone either persisted or clinically expanded after a
major response of Ph+-clone. Allogeneic stem cell transplantation is at present
the only potentially curative therapy for these patients after therapy with
ruxolitinib and TKI inhibitor. We describe the case of 3 young people treated in
our institution for the coexistence of BCR/ABL chronic myeloid leukemia and
another Philadelphia chromosome-negative (Ph-) Chronic myeloproliferative
disease. They received ruxolitinib, imatinib/nilotinib, and allogeneic
transplantation with safe and efficient results. |
Is the 22-item sino-nasal outcome test (SNOT-22) a widely used measure for Health-Related Quality-of-Life (HRQOL) associated with chronic rhinosinusitis (CRS)? | Conclusion. The German-SNOT-22 validated here matches the original SNOT-22. It is a reliable, valid and responsive questionnaire to assess symptoms, HRQOL and treatment-response in CRS-patients. | OBJECTIVES: We set out to determine the psychometric validation of a
disease-specific health related quality of life instrument for use in chronic
rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of
a pre-existing instrument, the SNOT-20.
DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for
Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study
collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS
hospitals in England and Wales. Data were collected preoperatively and at 3
months after surgery, and analysed to determine validity of the SNOT-22.
Test-retest reliability was assessed in a separate cohort of patients in a
single centre.
MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main
outcome measure. Patients were also asked to report whether they felt better,
the same or worse following surgery. To evaluate the SNOT-22, the internal
consistency, responsiveness, known group differences and validity were analysed.
RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month
postoperative SNOT-22 scores were available for 2284 patients of all patients
who completed a preoperative form (81.5% response rate). The Cronbach's alpha
scores for the SNOT-22 were 0.91 indicating high internal consistency. The
test-retest reliability coefficient was 0.93, indicating high reliability of
repeated measures. The SNOT-22 was able to discriminate between patients known
to suffer with chronic rhinosinusitis and a group of healthy controls (P <
0.0001, t = 85.3). It was also able to identify statistically significant
differences in sub-groups of patients with chronic rhinosinusitis. There was a
statistically significant (P < 0.0001, t = 39.94) decrease in patient reported
SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients
was 0.81, which is considered large. We found the minimally important difference
that is the smallest change in SNOT-22 score that can be detected by a patient,
to be 8.9 points.
CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be
used to facilitate routine clinical practice to highlight the impact of chronic
rhinosinusitis on the patient's quality of life, and may also be used to measure
the outcome of surgical intervention. The minimally important difference allows
us to interpret scores in a clinical context, and may help to improve patient
selection for surgery. BACKGROUND: Chronic rhinosinusitis (CRS) with or without nasal polyps is a
frequent and significant health problem. The 22-item Sinonasal Outcome Test
(SNOT-22) is a valid, disease-specific health status instrument translated into
several languages. The translation into Greek has been considered essential for
the individual assessment of the patients' symptoms and a reliable tool for
quality of life evaluation.
METHODS: Our study included 40 patients with CRS without nasal polyps and 40
healthy individuals as control group recruited from the ENT Allergy and
Endoscopy Clinic of Chania General Hospital. Assessment included full ENT
examination and nasal endoscopy. In the study, we compared the patients'
examination and reexamination results with the results of the control group, and
thus estimated test-retest reliability, internal consistency (determined by
Cronbach's alpha) and validity.
RESULTS: The statistical significance level calculated by the paired t test was
p < 0.05 for all questions, which proves the questionnaire's consistency. The
kappa value was estimated for each symptom, with an average value of 0.94.
Cronbach's alpha was 0.934 in the test and 0.856 in the retest. The p value was
<0.05 between both the control group and the test group and between the control
group and the retest group.
CONCLUSION: Our study certifies the existence of a valid, reproducible Greek
version of SNOT-22, which overcomes limitations of use, allows to answer the
questionnaire in Greek, and thus makes it highly recommended for Greek
clinicians. BACKGROUND: Prior study demonstrated that baseline 22-item Sino-Nasal Outcome
Test (SNOT-22) aggregate scores accurately predict selection of surgical
intervention in patients with chronic rhinosinusitis (CRS). Factor analysis of
the SNOT-22 survey has identified five distinct domains that are differentially
impacted by endoscopic sinus surgery (ESS). This study sought to quantify
SNOT-22 domains in patient cohorts electing both surgical or medical management
and postinterventional change in these domains.
METHODS: CRS patients were prospectively enrolled into a multi-institutional,
observational cohort study. Subjects elected continued medical management or
ESS. SNOT-22 domain scores at baseline were compared between treatment cohorts.
Postintervention domain score changes were evaluated in subjects with at least
six-month follow-up.
RESULTS: A total of 363 subjects were enrolled with 72 (19.8%) electing
continued medical management, whereas 291 (80.2%) elected ESS. Baseline SNOT-22
domain scores were comparable between treatment cohorts in sinus-specific
domains (rhinologic, extranasal rhinologic, and ear/facial symptoms; p > 0.050);
however, the surgical cohort reported significantly higher psychological (mean ±
standard deviation [SD]: 16.0 ± 8.4 vs 12.0 ± 7.1; p < 0.001) and sleep
dysfunction (13.7 ± 6.8 vs 10.5 ± 6.2; p < 0.001) than the medical cohort.
Effect sizes for ESS varied across domains with rhinologic and extranasal
rhinologic symptoms experiencing the greatest gains (1.067 and 0.997,
respectively), whereas psychological and sleep dysfunction experiencing the
smallest improvements (0.805 and 0.818, respectively). Patients experienced
greater mean improvements after ESS in all domains compared to medical
management (p < 0.001).
CONCLUSION: Subjects electing ESS report higher sleep and psychological
dysfunction compared to medical management but have comparable sinus-specific
symptoms. Subjects undergoing ESS experience greater gains compared to medical
management across all domains; however, these gains are smallest in the
psychological and sleep domains. BACKGROUND: Chronic rhinosinusitis (CRS) is becoming increasingly prevalent in
adults with cystic fibrosis (CF), as the median age of survival rises for these
individuals. Delayed identification of CRS may contribute to worsening
health-related quality of life and increased treatment burden. Our objective was
to investigate the utility of the 22-item Sino-Nasal Outcome Test (SNOT-22) as a
tool to identify CRS in adults with CF.
METHODS: In this cross-sectional study, participants were sampled from an
adult-specific CF clinic in Vancouver, Canada, between September 2013 and April
2014. CRS was determined by use of standardized diagnostic guidelines.
Participants completed the SNOT-22 and medical charts were reviewed for
additional predictor variables. Logistic regression was used to compare the
SNOT-22 as a univariable predictor variable to a multivariable prediction model,
in order to best differentiate CRS and non-CRS participants.
RESULTS: Ninety-three of 101 adults provided written informed consent. The
prevalence of CRS was 56.3% (95% confidence interval [CI], 45.9% to 66.3%).
Individuals with CRS reported significantly higher SNOT-22 scores than non-CRS
participants (mean difference: 13.9; 95% CI, 6.1 to 21.7). The optimal SNOT-22
score to differentiate CRS was 21 out of 110 (sensitivity: 76%, specificity:
61%, positive predictive value: 71%, likelihood ratio: 1.9).
CONCLUSION: Compared to the current diagnostic gold standard, SNOT-22 scores
greater than 21 sufficiently identified adults with CF presenting with
concomitant CRS. The SNOT-22 is a simple instrument that can easily be
implemented in adult CF clinics to assist care providers identify individuals
requiring more detailed assessment or referral to a sinus clinic. BACKGROUND: The 22-item Sino-Nasal Outcome Test (SNOT-22) is a commonly utilized
outcome measure for chronic rhinosinusitis (CRS). However, what constitutes a
normal score remains poorly defined. The goal of this study was to evaluate
SNOT-22 scores in a control population without CRS and perform a systematic
review and meta-analysis of "normal" values.
METHODS: Ninety-nine subjects without CRS were enrolled, with 95 fully
completing the SNOT-22 questionnaire. Multivariable linear regression was used
to determine whether demographic factors or medical comorbidities influence
SNOT-22 scores in a population without CRS. A systematic literature search was
performed, identifying studies that evaluated the SNOT-22 in a non-CRS
population and estimates for SNOT-22 values were pooled.
RESULTS: Thirty-six males and 59 females were included in the primary analysis
with a mean age of 53.4 ± 17.3 years (range, 18-88 years). The mean SNOT-22
score was 16.4 ± 15.2. Asthma (p = 0.003) and depression (p = 0.002) were found
to be independent predictors of higher SNOT-22 scores. Thirteen articles were
identified in the literature search and 1 was provided via author
correspondence, with 10 reporting sufficient data to be included in the
meta-analysis. Weighted mean SNOT-22 score was 11 ± 9.4 (n = 1517). Our data
differed significantly from published data (mean difference = 5.4; 95%
confidence interval [CI], 3.4 to 7.5; p < 0.0001) likely owing to differences in
comorbidities.
CONCLUSION: SNOT-22 scores vary in non-CRS populations depending upon the group
queried. Asthma and depression are associated with higher SNOT-22 scores and
should be considered when determining what constitutes a normal value. BACKGROUND: Patient-reported control of chronic rhinosinusitis (CRS) symptoms is
associated with the quality of life impact of CRS. We sought to determine if
22-item Sino-Nasal Outcome Test (SNOT-22) score is predictive of
patient-perceived CRS symptom control.
METHODS: Prospective cross-sectional study of 202 patients with CRS.
Participants were asked to rate their CRS symptom control as "not at all," "a
little," "somewhat," "very," and "completely." The severity of patient CRS
symptomatology was measured using the SNOT-22. The relationship between SNOT-22
score and patient-reported CRS symptom control was determined using regression,
analysis of variance (ANOVA), and receiver operating characteristic (ROC) curve
analysis.
RESULTS: SNOT-22 was negatively associated with patient-reported CRS symptom
control (adjusted β = -0.03; 95% CI, -0.04 to -0.02; p < 0.001), after
controlling for demographic and clinical characteristics. There was a
significant difference in SNOT-22 scores of participants reporting each level of
symptom control (p < 0.001) with the greatest differences between participants
who rated their CRS symptom control as "not at all," "a little," and "somewhat,"
which we deem poor CRS symptom control, and the group who described their level
of CRS symptom control described as "very" and "completely," which we deem
well-controlled CRS symptoms. These results were true across all SNOT-22
subdomains scores as well. Using ROC analysis, a SNOT-22 score of 35 identified
patients reporting poor vs well-controlled CRS symptom control with 71.4%
sensitivity and 85.5% specificity.
CONCLUSION: SNOT-22 score is associated with how well patients feel their CRS
symptomatology is controlled. Moreover, SNOT-22 score can be used to accurately
distinguish patients with poor vs well-controlled CRS symptoms. Chronic rhino-sinusitis (CRS) is a significant health problem whose incidence
and prevalence is rising. An emphasis has been placed on diseasespecific quality
of life (QoL as the predomit measure for most current outcome studies.
Therefore a validated measure of health-related QoL in sinonasal disease is
needed. The present prospective and observational study was conducted on 50
patients in the Department of ENT at Govt. Medical College and Rajindra Hospital
Patiala, Punjab, India. The primary outcomes were the following: (1) the chance
of attaining minimal clinically important difference (MCID) improvements of nine
points at the 22-item Sino-Nasal Outcome Test (SNOT-22) after endoscopic sinus
surgery (ESS) for different preoperative QoL levels, and (2) the percentage of
relative improvement in SNOT-22 after ESS for different preoperative QoL levels.
METHODS: Patients with CRS who were elected for ESS were prospectively enrolled
into an observational cohort study. They were categorized into 10 preoperative
SNOT-22 groups based on 10-point increments beginning with a score of 10 and
ending at 110. Standard protocol for all patients presenting for evaluation
included completion of the SNOT-22 prior to and following surgical intervention.
The scores were calculated and the data collected were compiled and analyzed.
RESULTS: A total of 50 patients were included in this study. Patients with a
SNOT-22 score between 10 and 19 had the lowest chance of achieving an MCID.
Patients with a SNOT-22 score greater than 30 had a greater than 90% chance of
achieving an MCID, and there was a relative improvement of 43.3% on their
preoperative SNOT-22 scores. CRS patients with polyp had better outcomes (47.1%
improvement) after ESS than those without polyp (33.2% improvement).
CONCLUSION: There is an increased probability of achieving an MCID at SNOT-22
score >30 and in general the percentage of relative improvement increased with
an increase in preoperative SNOT score. OBJECTIVE: To assess whether nasal nitric oxide (nNO) levels differ between
healthy and sick sinuses in chronic rhinosinusitis (CRS). A secondary aim was to
assess whether nNO levels change after treatment of CRS and whether there is an
association with radiological findings or symptoms.
METHOD: Three groups of 12 participants each were examined: patients with CRS
without polyposis (CRS group), patients with symptoms of CRS but radiologically
normal sinuses (symptoms-only), and healthy controls. Measurements of nNO were
carried out using aspiration method and humming maneuver. All participants
completed the Sino-Nasal Outcome Test (SNOT-22). A second nNO measurement was
done after treatment in the CRS group (n = 9) and the healthy control group (n =
12).
RESULTS: Nasal NO did not differ between any of the groups with any of the
measurement techniques. There was a trend toward lower nNO values in the CRS
group compared with the symptoms-only group and healthy controls, but it did not
reach statistical significance. The SNOT-22 demonstrated inferior values for the
CRS and symptoms-only groups compared with the healthy controls. At follow-up,
no statistically significant change was found for the nNO measurements in either
group.
CONCLUSION: Irrespective of occluded or open ostiomeatal complexes, no
statistically significant differences in nNO were found in CRS compared with
healthy controls using aspiration and humming methods. Treatment of CRS improved
sinus patency without accompanying a significant change in nNO. This study can
therefore not conclude that nNO can be used as a diagnostic tool for CRS without
polyposis. BACKGROUND: Medical comorbidities are commonly encountered in chronic
rhinosinusitis (CRS) and may impact both physical function and patient reported
health-related quality-of-life (HRQOL). The functional comorbidity index (FCI)
is designed to elucidate the role of comorbidities on functional prognosis. The
objective of this study was to understand the impact of comorbidities known to
impact physical function on baseline HRQOL using the FCI.Methodology: Patients
meeting diagnostic criteria for CRS were prospectively enrolled in a
cross-sectional study. Responses from the Sinonasal Outcomes Test-22 (SNOT-22),
a measure of patient HRQOL, as well as the Lund-Kennedy and Lund-Mackay scores
were recorded at enrollment. FCI was calculated retrospectively using the
electronic medical record. Information was collected and compared for patients
without (CRSsNP) and with nasal polyps (CRSwNP) using chi-square and t-tests.
Spearman's correlations, followed by multivariate regression analysis, were used
to assess the association between FCI and SNOT-22 scores.
RESULTS: One hundred and three patients met inclusion criteria for analysis.
There were no significant differences in age, gender, and SNOT-22 scores between
patients with CRSsNP and those with CRSwNP. FCI was significantly and
independently associated with worse SNOT-22 scores (P = .012). FCI did not
correlate with endoscopy and computed tomography scores. The mean FCI for
patients with CRSsNP and CRSwNP was 2.02 and 2.24, respectively, and did not
differ significantly between the two cohorts (P = .565).
CONCLUSIONS: Major medical comorbidities known to affect physical function are
associated with worse SNOT-22 scores in patients with CRS as measured by the
FCI. |
Is pRETRO-SUPER an adenoviral vector? | No, pRETRO-SUPER is a retroviral vector. | OBJECTIVE: In this study, we investigated the effect of small interfering RNA
(siRNA) of connective tissue growth factor (CTGF) by pRetro-Super (PRS)
retrovirus vector on the expression of CTGF and related extracellular matrix
molecules in human renal proximal tubular cells (HKCs) induced by high glucose,
to provide help for renal tubulointerstitial fibrosis therapy.
METHODS: HKCs were exposed to d-glucose to observe their dose and time effect,
while the mannitol as osmotic control. Retrovirus producing CTGF siRNA were
constructed from the inverted oligonucleotides and transferred into packaging
cell line PT67 with lipofectamine, and the virus supernatant was used to infect
HKC. The expression of CTGF, fibronectin (FN) and collagen-type I (col1) were
measured by semi-quantitative RT-PCR and Western blot.
RESULTS: In response to high glucose, CTGF expression in HKCs was increased in a
dose- and time-dependent manner, whereas the increase did not occur in the
osmotic control. Introduction of PRS-CTGF-siRNA resulted in the significant
reduction of CTGF, FN, col1 mRNA (p < 0.01, respectively) and CTGF, col1 protein
(p < 0.05, respectively) expression, while PRS void vector group did not have
these effects (p > 0.05).
CONCLUSIONS: CTGF siRNA therapy can effectively reduce the levels of CTGF, FN
and col1 induced by high glucose in cultured HKCs, which suggested that it may
be a potential therapeutic strategy to prevent the renal interstitial fibrosis
in the future. |
Which tool has been developed for annotation of Gα, Gβ and Gγ subunits of G-proteins? | GprotPRED is an online tool that uses profile Hidden Markov Models (pHMMs) and application to proteomes. The sensitivity and specificity for all pHMMs were equal to 100% with the exception of the Gβ case, where sensitivity equals to 100%, while specificity is 99.993%. | |
Describe applications of the CHALICE rule? | The children's head injury algorithm for the prediction of important clinical events (CHALICE) is one of the strongest clinical prediction rules for the management of children with head injuries. It can be used to predict death, need for neurosurgical intervention or CT abnormality in children with head trauma. | BACKGROUND: A quarter of all patients presenting to emergency departments are
children. Although there are several large, well-conducted studies on adults
enabling accurate selection of patients with head injury at high risk for
computed tomography scanning, no such study has derived a rule for children.
AIM: To conduct a prospective multicentre diagnostic cohort study to provide a
rule for selection of high-risk children with head injury for computed
tomography scanning.
DESIGN: All children presenting to the emergency departments of 10 hospitals in
the northwest of England with any severity of head injury were recruited. A
tailor-made proforma was used to collect data on around 40 clinical variables
for each child. These variables were defined from a literature review, and a
pilot study was conducted before the children's head injury algorithm for the
prediction of important clinical events (CHALICE) study. All children who had a
clinically significant head injury (death, need for neurosurgical intervention
or abnormality on a computed tomography scan) were identified. Recursive
partitioning was used to create a highly sensitive rule for the prediction of
significant intracranial pathology.
RESULTS: 22,772 children were recruited over 2 1/2 years. 65% of these were boys
and 56% were <5 years old. 281 children showed an abnormality on the computed
tomography scan, 137 had a neurosurgical operation and 15 died. The CHALICE rule
was derived with a sensitivity of 98% (95% confidence interval (CI) 96% to 100%)
and a specificity of 87% (95% CI 86% to 87%) for the prediction of clinically
significant head injury, and requires a computed tomography scan rate of 14%.
CONCLUSION: A highly sensitive clinical decision rule is derived for the
identification of children who should undergo computed tomography scanning after
head injury. This rule has the potential to improve and standardise the care of
children presenting with head injuries. Validation of this rule in new cohorts
of patients should now be undertaken. INTRODUCTION: Paediatric head injury is a common presentation to emergency
departments (ED), and the 2007 National Institute for Health and Clinical
Excellence head injury guidelines included a paediatric section to deal with
this. This is based on the Children's Head Injury Algorithm for the Prediction
of Important Clinical Events (CHALICE) head injury rule. To date, no studies
have examined the impact of the guideline on ED resources.
METHOD: The 2007 guideline criteria were applied to records of patients seen
pre-2007. By comparing the number of scans done with these criteria with those
done in actual practice, the resource implications of the 2007 guideline could
be assessed.
RESULTS: If the pre-existing (2003) guideline had been strictly applied, 28 (6%)
of the 464 patients analysed would have received a computed tomography (CT)
scan. Applying the 2007 guideline to the same 464 patients resulted in an extra
21 (4.6%) scans.
DISCUSSION: The cost effect of an extra 21 CT scans per annum is estimated at
£3570. This is offset against a potential cost saving on admissions of £10 450.
The neoplasia risks of increased scanning are also discussed. Problems in this
study were the preference for admission over scanning in children who qualified
for scan under both guidelines and absent data from clinical records. Further
work could include a prospective study of the guideline. INTRODUCTION: Clinical decision rules aid clinicians with the management of head
injured patients. This study aimed to identify clinical decision rules for
children with minor head injury and compare their diagnostic accuracy for
detection of intracranial injury (ICI) and injury requiring neurosurgical
intervention (NSI).
METHODS: Relevant studies were identified by an electronic search of key
databases. Papers in English were included with a cohort of at least 20 children
suffering minor head injury (GCS 13-15). Studies of a decision rule derived to
identify patients at risk of ICI or NSI had to include a proportion of the
cohort undergoing imaging. Study quality was assessed using the QUADAS
checklist.
RESULTS: 16 publications, representing 14 cohorts, with 79 740 patients were
included. Only four rules were tested in more than one cohort. Of the validated
rules the paediatric emergency care applied research network (PECARN) rule was
most consistent (sensitivity 98%; specificity 58%). For neurosurgical injury all
had high sensitivity (98-100%) but the children's head injury algorithm for the
prediction of important clinical events (CHALICE) rule had the highest
specificity (86%) in its derivation cohort.
CONCLUSION: Of the current decision rules for minor head injury the PECARN rule
appears the best for children and infants, with the largest cohort, highest
sensitivity and acceptable specificity for clinically significant ICI.
Application of this rule in the UK would probably result in an unacceptably high
rate of CT scans per injury, and continued use of the CHALICE-based NICE
guidelines represents an appropriate alternative. BACKGROUND: Clinical decision rules (CDRs) for paediatric head injury (HI) exist
to identify children at risk of traumatic brain injury. Those of the highest
quality are the Canadian assessment of tomography for childhood head injury
(CATCH), Children's head injury algorithm for the prediction of important
clinical events (CHALICE) and Pediatric Emergency Care Applied Research Network
(PECARN) CDRs. They target different cohorts of children with HI and have not
been compared in the same setting. We set out to quantify the proportion of
children with HI to which each CDR was applicable.
METHODS: Consecutive children presenting to an Australian paediatric Emergency
Department with HIs were enrolled. Published inclusion/exclusion criteria and
predictor variables from the CDRs were collected prospectively. Using these we
determined the frequency with which each CDR was applicable.
RESULTS: 1012 patients (69.9%) were enrolled with 949 available for analysis.
Mean age was 6.8 years (21% <2 years). 95% had initial Glasgow Coma Scale 15. CT
rate was 12.8% and neurosurgery rate was 0.7%. No CDR was applicable to all
patients. CHALICE was applicable to the most (97%, 95% CI 96% to 98%) and CATCH
to the fewest (26%, 95% CI 24% to 29%). PECARN was applicable to 76% (95% CI 70%
to 82%) aged <2 years, and 74% (95% CI 71% to 77%) aged 2-<18 years.
CONCLUSIONS: Each CDR is applicable to a different proportion of children with
HI. This makes a direct comparison of the CDRs difficult. Prior to selection of
any for implementation they should undergo validation outside the derivation
setting coupled with an analysis of their performance accuracy, usability and
cost effectiveness. BACKGROUND: Head injuries in children are responsible for a large number of
emergency department visits. Failure to identify a clinically significant
intracranial injury in a timely fashion may result in long term neurodisability
and death. Whilst cranial computed tomography (CT) provides rapid and definitive
identification of intracranial injuries, it is resource intensive and associated
with radiation induced cancer. Evidence based head injury clinical decision
rules have been derived to aid physicians in identifying patients at risk of
having a clinically significant intracranial injury. Three rules have been
identified as being of high quality and accuracy: the Canadian Assessment of
Tomography for Childhood Head Injury (CATCH) from Canada, the Children's Head
Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) from
the UK, and the prediction rule for the identification of children at very low
risk of clinically important traumatic brain injury developed by the Pediatric
Emergency Care Applied Research Network (PECARN) from the USA. This study aims
to prospectively validate and compare the performance accuracy of these three
clinical decision rules when applied outside the derivation setting.
METHODS/DESIGN: This study is a prospective observational study of children aged
0 to less than 18 years presenting to 10 emergency departments within the
Paediatric Research in Emergency Departments International Collaborative
(PREDICT) research network in Australia and New Zealand after head injuries of
any severity. Predictor variables identified in CATCH, CHALICE and PECARN
clinical decision rules will be collected. Patients will be managed as per the
treating clinicians at the participating hospitals. All patients not undergoing
cranial CT will receive a follow up call 14 to 90 days after the injury. Outcome
data collected will include results of cranial CTs (if performed) and details of
admission, intubation, neurosurgery and death. The performance accuracy of each
of the rules will be assessed using rule specific outcomes and inclusion and
exclusion criteria.
DISCUSSION: This study will allow the simultaneous comparative application and
validation of three major paediatric head injury clinical decision rules outside
their derivation setting.
TRIAL REGISTRATION: The study is registered with the Australian New Zealand
Clinical Trials Registry (ANZCTR)- ACTRN12614000463673 (registered 2 May 2014). OBJECTIVE: Despite high-quality paediatric head trauma clinical prediction
rules, the management of otherwise asymptomatic young children with scalp
haematomas (SH) can be difficult. We determined the risk of intracranial injury
when SH is the only predictor variable using definitions from the Pediatric
Emergency Care Applied Research Network (PECARN) and Children's Head Injury
Algorithm for the Prediction of Important Clinical Events (CHALICE) head trauma
rules.
DESIGN: Planned secondary analysis of a multicentre prospective observational
study.
SETTING: Ten emergency departments in Australia and New Zealand.
PATIENTS: Children <2 years with head trauma (n=5237).
INTERVENTIONS: We used the PECARN (any non-frontal haematoma) and CHALICE (>5 cm
haematoma in any region of the head) rule-based definition of isolated SH in
both children <1 year and <2 years.
MAIN OUTCOME MEASURES: Clinically important traumatic brain injury (ciTBI; ie,
death, neurosurgery, intubation >24 hours or positive CT scan in association
with hospitalisation ≥2 nights for traumatic brain injury).
RESULTS: In children <1 year with isolated SH as per PECARN rule, the risk of
ciTBI was 0.0% (0/109; 95% CI 0.0% to 3.3%); in those with isolated SH as
defined by the CHALICE, it was 20.0% (7/35; 95% CI 8.4% to 36.9%) with one
patient requiring neurosurgery. Results for children <2 years and when using
rule specific outcomes were similar.
CONCLUSIONS: In young children with SH as an isolated finding after head trauma,
use of the definitions of both rules will aid clinicians in determining the
level of risk of ciTBI and therefore in deciding whether to do a CT scan.
TRIAL REGISTRATION NUMBER: ACTRN12614000463673. |
What is the KDEL retention signal? | the -KDEL retention signal sequence is characteristic of many proteins localized to the ER. | Prostaglandin endoperoxide H (PGH) synthases 1 and 2 are both
membrane-associated proteins localized to the endoplasmic reticulum (ER) and
nuclear envelope. The carboxyl terminal tetrapeptides of PGH synthases 1 and 2
are of the form -P/STEL. These sequences are similar to the -KDEL retention
signal sequence characteristic of many proteins localized to the ER. To
determine if the -PTEL sequence (residues 597-600) functions as an ER retention
signal for ovine PGH synthase-1, we prepared and analyzed five mutants (L600N,
L600R, L600V, E599Q, and delta 597), all having modifications that would be
expected to alter the subcellular location of PGH synthase-1 if the -PTEL
sequence were involved in ER targeting. Native ovine PGH synthase-1 and each of
the five mutants were subcloned into the pSVT7 expression vector and were
expressed transiently in cos-1 cells. The L600N, L600R, E599Q, and delta 597
mutants retained both cyclooxygenase and peroxidase activities. Moreover, when
subjected to immunocytofluorescent staining, cos-1 cells expressing native and
mutant enzymes showed similar patterns of fluorescence corresponding to ER and
nuclear envelope localization. Finally, culture media bathing cos-1 cells
transfected with native or mutant PGH synthases were tested for secreted PGH
synthase-1 protein by Western blotting, but no PGH synthase-1 was detected in
any of the culture media. Our results demonstrate that mutations in the
C-terminal sequence-PTEL do not change the subcellular location of ovine PGH
synthase-1. Thus, targeting of PGH synthase-1 to the ER can occur independent of
its -PTEL sequence. We investigated the suitability of transformed rice cell lines as a system for
the production of therapeutic recombit antibodies. Expression constructs
encoding a single-chain Fv fragment (scFvT84.66, specific for CEA, the
carcinoembryonic antigen present on many human tumours) were introduced into
rice tissue by particle bombardment. We compared antibody production levels when
antibodies were either secreted to the apoplast or retained in the endoplasmic
reticulum (ER) using a KDEL retention signal. Production levels were up to 14
times higher when antibodies were retained in the ER. Additionally, we compared
construct sencoding different leader peptides (plant codon optimised murine
immunoglobulin heavy and light chain leader peptides from mAb24) and carrying
alternative 5' untranslated regions (the petunia chalcone synthase gene 5' UTR
and the tobacco mosaic virus omega sequence). We observed no significant
differences in antibody production levels among cell lines transformed with
these constructs. The highest level of antibody production we measured was 3.8
micrograms g-1 callus (fresh weight). Immunological analysis of transgenic rice
callus confirmed the presence of functional scFvT84.66. We discuss the potential
merits of cell culture for the production of recombit antibodies and other
valuable macromolecules. Despite the significant advances of antibodies as therapeutic agents, there is
still much room for improvement concerning the discovery of these
macromolecules. Here, we present a new synthetic cell-based strategy that takes
advantage of eukaryotic cell biology to produce highly diverse antibody
libraries and, simultaneously, link them to a high-throughput selection
mechanism, replicating B cell diversification mechanisms. The interference of
site-specific recognition by CRISPR/Cas9 with error-prone DNA repair mechanisms
was explored for the generation of diversity, in a cell population containing a
gene for a light chain antibody fragment. We achieved up to 93% of cells
containing a mutated antibody gene after diversification mechanisms,
specifically inside one of the antigen-binding sites. This targeted variability
strategy was then integrated into an intracellular selection mechanism. By
fusing the antibody with a KDEL retention signal, the interaction of antibodies
and native membrane antigens occurs inside the endoplasmic reticulum during the
process of protein secretion, enabling the detection of high-quality leads for
expression and affinity by flow cytometry. We successfully obtained antibody
lead candidates against CD3 as proof of concept. In summary, we developed a
novel antibody discovery platform against native antigens by endoplasmic
synthetic library generation using CRISPR/Cas9, which will contribute to a
faster discovery of new biotherapeutic molecules, reducing the time-to-market. |
What are the diagnostic criteria for hemophagocytic lymphohistiocytosis? | Hemophagocytic syndrome (HS) is a severe hyper inflammatory condition whose cardinal symptoms are prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages. | In HLH-94, the first prospective international treatment study for
hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria
(fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or
hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria
are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble
interleukin-2-receptor levels. Altogether five of these eight criteria must be
fulfilled, unless family history or molecular diagnosis is consistent with HLH.
HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A
upfront and, in selected patients, intrathecal therapy with methotrexate and
corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is
recommended for patients with familial disease or molecular diagnosis, and
patients with severe and persistent, or reactivated, disease. In order to
hopefully further improve diagnosis, therapy and biological understanding,
participation in HLH studies is encouraged. Hemophagocytic syndrome (HS) is a severe hyper inflammatory condition whose
cardinal symptoms are prolonged fever, cytopenia, hepatosplenomegaly, and
hemophagocytosis by activated, morphologically benign macrophages. The clinical
course resembles sepsis, sharing similar physiopathological features. We report
four patients with the syndrome. A 61-year-old female presenting with fever and
pleuritic pain. During the course of the disease, a pancytopenia was detected
and a bone marrow aspiration was suggestive of HS. The patient was treated with
cyclosporine and steroids with a good response. A 61-year-old male with fever
and pancytopenia and a bone marrow aspirate suggestive of HS. The patient did
not respond to treatment and died. A 23-year-old male with fever, pancytopenia
and positive Hanta virus antibodies. A bone marrow aspirate was suggestive of
HS. The patient recovered without any treatment. A 72-year-old male admitted
with the diagnosis of pneumonia, that developed a progressive pancytopenia and
bone marrow aspirate was suggestive of HS. A bronchoalveolar lavage showed the
presence of Acinetobacter baumanii. Despite treatment with methylprednisolone
and gammaglobulin, the patient died. Awareness of the clinical symptoms and of
the diagnostic criteria of HS is important to start life-saving therapy in time. Hemophagocytic lymphohistiocytosis is a multisystem inflammation, generated by
the uncontrolled and excessive activation of cytotoxic T lymphocytes and natural
killer cells. Severe immunodeficiency and generalized macrophage activation can
often be detected in the background of this life threatening disorder. It is
classified as a primary immunodeficiency. Functional abnormalities of the
perforin protein or defects in granule secretory mechanisms are caused by gene
mutations in most cases. Diagnostic criteria of hemophagocytic
lymphohistiocytosis are the following: fever, splenomegaly, cytopenias affecting
at least two of the 3 lineages in peripheral blood, hypertriglyceridemia and
hyperferritinemia, elevated serum level of soluble interleukin-2 receptor
(sCD25), hypofibrinogenemia, hemophagocytosis in bone marrow and decreased
cytotoxic T cell and natural killer cell activity. In this case report the
authors summarize the utility of functional flow cytometry in the diagnosis of
hemophagocytic lymphohistiocytosis. Using flow cytometry, elevated intracellular
perforin content, decreased killing activity of cytotoxic T cells and natural
killer cells, and impaired cell surface expression of CD107a (LAMP1 protein)
from in vitro stimulated blood lymphocytes were detected. Abnormal secretion of
perforin was also demonstrated. Genetic testing revealed mutation of the MUNC
13-4 gene, which confirmed the base of the abnormal flow cytometric findings.
This case report demonstrates the value of functional flow cytometry in the
rapid diagnosis of genetically determined hemophagocytic lymphohistiocytosis, a
condition in which early diagnosis is critical for optimal management. The
authors emphasize the significance of functional flow cytometry in the
differential diagnosis of immunodeficiencies. Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever,
splenomegaly, jaundice, and pathologic findings of hemophagocytosis in bone
marrow or other tissues such as the lymph nodes and liver. Pleocytosis, or the
presence of elevated protein levels in cerebrospinal fluid, could be helpful in
diagnosing HLH. However, the pathologic diagnosis of the brain is not included
in the diagnostic criteria for this condition. In the present report, we
describe the case of a patient diagnosed with HLH, in whom the brain pathology,
but not the bone marrow pathology, showed hemophagocytosis. As the diagnosis of
HLH is difficult in many cases, a high level of suspicion is required. Moreover,
the pathologic diagnosis of organs other than the bone marrow, liver, and lymph
nodes may be a useful alternative. Publisher: Zusammenfassung. Sekundäre hämophagozytische
Lymphohistiozytose-Syndrome beschreiben eine vom Erscheinungsbild heterogene
Gruppe überschiessender entzündlicher Reaktionen des Immunsystems, die durch
Hyperinflammation mit Vermehrung zytotoxischer T-Lymphozyten und Makrophagen bei
gesteigerter Hämophagozytose-Aktivität reagieren. Das sekundäre
hämophagozytische Lymphohistiozytose-Syndrom wird häufig unterdiagnostiziert,
was zu einer hohen Morbidität und Mortalität beiträgt. Die Abfrage der
etablierten diagnostischen Kriterien in einem systematischen
Abklärungsalgorithmus soll helfen, durch frühzeitige Diagnosestellung und
Initiation einer passenden Therapie höhere Heilungsraten zu erreichen. BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive
syndrome of excessive cytokine requiring prompt recognition and aggressive
therapy.
AIMS: We aimed to systematically characterize HLH in moderate-to-severe
inflammatory bowel disease (IBD).
METHODS: We performed a systematic review of the literature (PubMED; EMBASE) and
FDA Adverse Event Reporting System in accordance with the PRISMA statement. Use
of biologics was used as a surrogate definition for disease severity (consistent
with usual and contemporary clinical management), to enable identification of
rare HLH cases with the highest fidelity.
RESULTS: 58 cases of HLH occurring in IBD patients are known (mean age:
26.0 years, 70% male, 83% with Crohn's disease, mean disease duration
7.0 years). 34.5% of patients were undergoing induction therapy at HLH
diagnosis. All cases occurred on patients exposed to anti-TNF agents, but cases
with anti-integrin or anti-IL-12/23 exposure were reported. 2/3 of cases did not
report prior AZA/6MP exposure. Underlying opportunistic infection or lymphoma
was found in > 80% of cases. Survival was 70% if promptly recognized and
treated. Five patients restarted biologics after HLH resolved, and one patient
developed recurrent HLH.
CONCLUSIONS: HLH is rare among IBD patients exposed to biologic therapy. Most
cases had an identifiable infection or maligcy at the time of diagnosis as
well as history of immunomodulator use. Risk factors may include younger age,
male gender, presence of Crohn's disease, and induction phase of treatment. Our
study is not intended to assess risk of HLH with specific IBD therapies. Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an
acute and rapidly progressive systemic inflammatory disorder characterized by
cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical
manifestations of HLH are acute unremitting fever, lymphadenopathy,
hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release,
this clinical condition is considered as a cytokine storm syndrome. HPS has
primary and acquired (secondary, reactive) forms. Its primary form is mostly
seen in childhood and caused by various mutations with genetic inheritance and,
therefore, is called familial HLH. Secondary HLH may be caused in the presence
of an underlying disorder, that is, secondary to a maligt, infectious, or
autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis
and the clinical picture of HLH, and its severe complication, the cytokine
storm, with a special emphasis on the developed classification criteria sets for
rheumatologists, since COVID-19 infection has clinical symptoms resembling those
of the common rheumatologic conditions and possibly triggers HLH.
MED-LINE/Pubmed was searched from inception to April 2020, and the following
terms were used for data searching: "hemophagocytic syndrome" OR "macrophage
activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine
storm". Finally, AND "COVID-19" was included in this algorithm. The selection is
restricted to the past 5 years and limited numbers of earlier key references
were manually selected. Only full-text manuscripts, published in an English
language peer-reviewed journal were included. Manuscript selection procedure and
numbers are given in Fig. 2. Briefly, the database search with the following
terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR
"Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results
from inception to April 2020. The selection is restricted to the past 5 years
and only limited numbers of earlier key references were selected, and this
algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19")
resulted in 115 publications of which 47 studies, together with four sections of
an online book were used in the final review. No statistical method was used.
HLH is triggered by genetic conditions, infections, maligcies,
autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients,
secondary HLH and cytokine storm may be responsible for unexplained progressive
fever, cytopenia, ARDS, neurological and renal impairment. Differentiation
between the primary and secondary forms of HLH is utterly important, since
primary form of HLH requires complicated treatments such as hematopoietic stem
cell transplantation. Further studies addressing the performance of HScore and
other recommendations in the classification of these patients is necessary. |
When was Vitravene approved in Brazil? | Vitravene was approved in Brazil in the summer of 1999. | |
Is there a dependence between chromatin organization and dorsoventral gene expression in Drosophila? | No. There is independence of chromatin conformation and gene regulation during Drosophila dorsoventral patterning | |
Is vocimagene amiretrorepvec effective for recurrent high-grade glioma? | No. Despite initially promising results in a randomized, open-label phase 2/3 trial, among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC did not improve overall survival or other efficacy end points. | Findings from a phase I study suggest that delivering high concentrations of the
chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene
amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade
glioma. This investigational treatment was well tolerated and induced robust,
durable responses lasting a median of 3 years. Glioblastoma and anaplastic astrocytoma are two of the most aggressive and
common glioma maligcies in adults. These high-grade gliomas (HGG) universally
recur despite aggressive treatment modalities and have a median overall survival
(mOS) of approximately 14 months from initial diagnosis. Upon recurrence, there
is no standard of care and these patients have a dismal prognosis of around
9 months at time of recurrence. Areas covered: In this article, we assess the
newly published phase I data of Toca 511 and Toca FC, a two-drug combination
therapy for recurrent HGG (rHGG) tumors, for effectiveness and safety. Expert
opinion: These early studies provide very encouraging results for Toca 511 and
Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of
11.9 months in 56 patients, an improvement compared to historical controls.
Furthermore, all responders were complete responses after extended follow-up.
The drug is well tolerated for most patients. Responders tended to be young and
have high-performance scores prior to beginning therapy, but more studies are
necessary to understand the patient profile that receives the most benefit.
Randomized-controlled trials are warranted for Toca 511 and Toca FC to confirm
drug efficacy. Conflict of interest statement: Conflict of Interest Disclosures: Dr Gruber is a
member of the board for Tocagen Inc. Drs Rao, Hogan, Accomando, Ostertag,
Montellano, Kheoh, and Kabbinavar were Tocagen employees. Dr Cloughesy reported
personal fees from Roche, personal fees from Trizel, personal fees from
Medscape, personal fees from Bayer, personal fees from Amgen, personal fees from
Odonate Therapeutics, personal fees from Pascal Biosciences, personal fees from
Del Mar Pharmaceuticals, personal fees from Tocagen, personal fees from
Kayopharm, personal fees from GW Pharma, personal fees from Kiyatec, personal
fees from AbbVie, personal fees from Boehringer Ingelheim, personal fees from
VBL, personal fees from VBI, personal fees from Deciphera, personal fees from
Agios, personal fees from QED, personal fees from Merck, personal fees from
Genocea, personal fees from Celgene, personal fees from Puma, personal fees from
Lilly, and personal fees from BMS outside the submitted work; in addition, Dr
Cloughesy had a patent to 62/819322 issued and licensed; and Member of the board
for the 501c3 Global Coalition for Adaptive Research and CMO for the entity;
Co-founder and board member of Katmai Pharmaceuticals. Dr Petrecca reported
other from Tocagen during the conduct of the study. Dr Walbert reported personal
fees from Tocagen outside the submitted work. Dr Damek reported grants from
Tocagen during the conduct of the study; grants from NovoCure, grants from Kazia
Therapeutics, grants from Genentech, grants from Orbus, grants from Roche, and
grants from Forma outside the submitted work. Dr Bota reported personal fees
from NovoCure and personal fees from Zai Lab outside the submitted work. Dr
Bettegowda reported he is a consultant for Depuy-Synthes and Bionaut
Pharmaceuticals. The activities associated with those entities are not related
to the work presented in this manuscript. Dr Zhu reported grants from Tocagen,
Inc and personal fees from Tocagen, Inc during the conduct of the study. Dr
Iwamoto reported personal fees from Tocagen during the conduct of the study;
personal fees from Merck, personal fees from Guidepoint, grants from BMS,
personal fees from NovoCure, personal fees from Alexion, personal fees from
AbbVie, and personal fees from Regeneron outside the submitted work. Dr
Placantonakis reported personal fees from Tocagen during the conduct of the
study; personal fees from Monteris, personal fees from Synaptive, and personal
fees from Robeaute outside the submitted work; in addition, Dr Placantonakis had
a patent to “Method to treat high grade glioma” pending. Dr Brem reported
personal fees from Tocagen during the conduct of the study. Dr Piccioni reported
personal fees from Tocagen during the conduct of the study. Dr Chen reported
other from Tocagen during the conduct of the study; personal fees from Tocagen
outside the submitted work. Dr Gruber reported grants from the US Food and Drug
Administration orphan drug grant, other from Apollo Bio, other from Abentis, and
other from Denovo Pharma during the conduct of the study; other from Apollo Bio,
other from Abentis, and other from Denovo pharma outside the submitted work; in
addition, Dr Gruber had a patent to many pending, issued, licensed, and with
royalties paid, a patent to many pending, issued, and licensed, and a patent to
many pending, issued, and licensed; and Stock and option ownership in Tocagen.
Dr Hogan reported other from Tocagen Inc during the conduct of the study. Dr
Accomando reported personal fees from Tocagen Inc. during the conduct of the
study; personal fees from Tocagen Inc. outside the submitted work. Dr Ostertag
reported a patent to US20130130986A1 issued, a patent to US20130323301A1, a
patent to US20180021365A1, and a patent to US20140178340A1 . Dr Montellano
reported grants from the US Food and Drug Administration Office of Orphan
Products Development during the conduct of the study. Dr Kheoh reported other
from Tocagen Inc during the conduct of the study. Dr Kabbinavar reported other
from Tocagen Inc during the conduct of the study; other from Tocagen outside the
submitted work; and Employee of Tocagen Inc. Dr Vogelbaum reported personal fees
and other from Tocagen during the conduct of the study; other from Infuseon
Theraepeutics and personal fees from Celgene outside the submitted work. No
other disclosures were reported. |
Which proteins are markers of myositis? | Blood tests showed significantly increased CK and aldolase values in patients with myositis (p < 0.001 and p < 0.0001). | Changes in muscle elasticity are expected in patients with untreated myositis.
The purpose of this study was to define the accuracy of shear-wave elastography
(SWE) in diagnosing myositis. This case control study included 21 patients (mean
age, 49.4 y; 12 women) with myositis who underwent SWE, magnetic resoce
imaging (MRI) and biopsy of the involved muscle group. SWE was performed
accordingly in a control group (n = 24; mean age, 51.2 y; 8 women). Blood tests
consisted of creatine kinase (CK) and aldolase. Two operators performed SWE in
longitudinal and transverse planes of muscular fibers, quantifying the mean
shear-wave velocity (SWV) and the pattern of stiffness. On MRI, short-TI
inversion recovery (STIR) signal hyperintensity and T1 contrast enhancement of
muscle was considered diagnostic for myositis. The patient group suffered from
different types of myositis (nine patients with polymyositis, eight with
dermatomyositis and four with other types of myositis). Blood tests showed
significantly increased CK and aldolase values in patients with myositis (p <
0.001 and p < 0.0001). MRI showed a sensitivity of 0.95. In the patient group,
the mean SWVs of longitudinal and transverse measurements were 2.8 ± 1.4 m/s and
3.1 ± 1.2 m/s, respectively. In the control group, SWVs were 2.3 ± 0.5 m/s and
2.4 ± 0.5 m/s, respectively. The difference between transverse measurements was
significant (p = 0.02). Increased heterogeneity as a marker for myositis in
transverse SWE showed a sensitivity of 0.8, specificity of 0.79, positive
predictive value (PPV) of 0.76 and negative predictive value (NPV) of 0.82.
Inter-observer difference was very low (κ = 0.92). Increased heterogeneity in
both planes compared with histologic results showed a sensitivity of 0.56,
specificity of 0.93, PPV of 0.91 and NPV of 0.62. Spearman correlation between
CK <1000 U/L and SWE was 0.54. In conclusion, transverse orientation SWE may
serve as an imaging biomarker for the diagnosis of myositis through the display
of a heterogeneous pattern and increased absolute SWV values of inflamed
muscles. |
What is the association between maternal and fetal alloantigens and RANTES production? | Induction of maternal tolerance to fetal alloantigens by RANTES production. | Cytokines such as monocyte chemotactic peptide-1 (MCP-1), interleukin-8 (IL-8),
RANTES (Regulated on Activation and Normally T-cells Expressed and presumably
Secreted) and interleukin-10 (IL-10) are thought to play pivotal roles in immune
recognition, acceptance of the fetal allograft, maintece of pregcy and
parturition. Their secretion and regulation within the third trimester uterus
is, however, less well defined. We therefore investigated the release of these
cytokines by third trimester amnion, chorion, placenta and decidua, and studied
the influence of prostaglandin E2 (PGE2) infusion on their release in a dynamic
placental cotyledon perfusion system. MCP-1 was released predominately by the
chorion (78.2 +/- 7.3 pg/mg wet tissue weight; mean +/- SEM), decidua (112.4 +/-
5.2 pg/mg) and placenta (101.8 +/- 5.0 pg/mg) with low amounts from the amnion
(1.3 +/- 0.4 pg/mg). High concentrations of IL-8 were released by the amnion
(39.9 +/- 5.3 pg/mg), chorion (52.8 +/- 1.9 pg/mg), decidua (42.2 +/- 1.5 pg/mg)
and placenta (45 +/- 1.3 pg/mg). Release of RANTES was not detectable from the
amnion but was detected in moderate amounts from the chorion (6.0 +/- 1.2
pg/mg), decidua (15.2 +/- 1.4 pg/mg) and placenta (26.9 +/- 1.6 pg/mg). Low
concentrations of IL-10 were secreted by the chorion (6.8 +/- 0.8 pg/mg),
decidua (9.0 +/- 0.9 pg/mg) and placenta (3.3 +/- 0.3 pg/mg) with none
detectable from the amnion. MCP-1, IL-8, RANTES and IL-10 were all released by
perfused placental cotyledons. PGE2 stimulated release of MCP-1, IL-8 and IL-10
into the maternal and of MCP-1 and IL-8 into the fetal circulation of the
placenta but had no effect on RANTES release. It is suggested that MCP-1 and
IL-8 may be involved in the inflammatory process of parturition and IL-10 in the
protection of the fetal allograft. In addition, PGE2 may have an important
immunomodulatory role within the uterus at term. PROBLEM: Previous studies have demonstrated a requirement for RANTES (regulated
on activated normal T-cell expressed, and secreted) at immune privileged sites;
we have investigated the role of RANTES in the induction of maternal-fetal
tolerance.
METHOD OF STUDY: Endometrial and peripheral T lymphocytes were obtained from
women with recurrent pregcy losses (RPLs) and fertile women. RANTES
modulation by progesterone or paternal alloantigens was measured by
enzyme-linked immunosorbent assay or flow cytometry analysis.
RESULTS: Progesterone significantly increased intracellular RANTES expression in
CD4+ and CD8+ endometrial T cells. Moreover, alloreactive lymphocytes from RPL
patients produced lower RANTES levels when compared with those from fertile
women. At the local level, treatment with recombit RANTES induced a decrease
in CCR5 and CXCR4 messenger RNA that correlated with an increase in T-bet
expression. RPL patients and normally fertile women express RANTES similarly,
but differ in their patterns of RANTES receptor expression.
CONCLUSION: RANTES may be implicated in the local induction of a Th1-type
response necessary for successful implantation. Altered response to RANTES
stimulation among some RPL patients may be responsible for poor pregcy
outcomes. PROBLEM: Several studies indicate that RANTES (regulated on activation, normal T
cell expressed and secreted) is able to downregulate T-cell responses which
suggest it might be relevant for fetal tolerance induction. However, the role of
RANTES in pregcy had not been established. Here we investigate RANTES
regulation during early pregcy and potential failures leading to losses of
pregcies.
METHOD OF STUDY: RANTES and progesterone levels were determined in sera and
feto-placental units from high resorption rate CBA/JxDBA/2 pregt females and
compared with CBA/JxBALB/c normal pregt mice. RANTES in vitro modulation was
also studied in nulliparous, primiparous and multiparous CBA/J and BALB/c cells
in response to paternal alloantigen and progesterone stimulation.
RESULTS: Nulliparous CBA/J females were quantitatively deficient in RANTES sera
levels, whereas pregcies with male BALB/c or DBA/2 increased its production.
However, feto-placental units from CBA/J females are high producers of
progesterone and RANTES.
CONCLUSION: These data suggest that the beneficial effect of RANTES on
feto-maternal interface requires an optimal concentration range and might be
modulated by progesterone, hence exacerbated placental expression could be
associated with high resorption rate. |
What is Tagsedi? | Tagsedi is a second-generation antisense oligonucleotide with 2'-O-methoxyethyl modification designed to bind to the 3' untranslated region of the transthyretin mRNA in the nucleus of the liver cells. | |
Should perampanel be used for amyotrophic lateral sclerosis? | No. Perampanel should not be used for amyotrophic lateral sclerosis. | |
Is Satb1 a transcription factor? | Yes,
transcription factor Satb1. | In the vertebrate retina, amacrine and ganglion cells represent the most diverse
cell classes. They can be classified into different cell types by several
features, such as morphology, light responses, and gene expression profile.
Although birds possess high visual acuity (similar to primates that we used here
for comparison) and tetrachromatic color vision, data on the expression of
transcription factors in retinal ganglion cells of birds are largely missing. In
this study, we tested various transcription factors, known to label
subpopulations of cells in mammalian retinae, in two avian species: the common
buzzard (Buteo buteo), a raptor with exceptional acuity, and the domestic pigeon
(Columba livia domestica), a good navigator and widely used model for visual
cognition. Staining for the transcription factors Foxp2, Satb1 and Satb2 labeled
most ganglion cells in the avian ganglion cell layer. CtBP2 was established as
marker for displaced amacrine cells, which allowed us to reliably distinguish
ganglion cells from displaced amacrine cells and assess their densities in
buzzard and pigeon. When we additionally compared the temporal and central fovea
of the buzzard with the fovea of primates, we found that the cellular
organization in the pits was different in primates and raptors. In summary, we
demonstrate that the expression of transcription factors is a defining feature
of cell types not only in the retina of mammals but also in the retina of birds.
The markers, which we have established, may provide useful tools for more
detailed studies on the retinal circuitry of these highly visual animals. The establishment of cell fates involves alterations of transcription factor
repertoires and repurposing of transcription factors by post-translational
modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2
and SATB1 balance pluripotency and differentiation by activating and repressing
pluripotency genes, respectively. Here, we show that conditional Satb2 gene
inactivation weakens ESC pluripotency, and we identify SUMO2 modification of
SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation.
Mutations of two SUMO-acceptor lysines of Satb2 (Satb2K →R ) or knockout of
Zfp451 impair the ability of ESCs to silence pluripotency genes and activate
differentiation-associated genes in response to retinoic acid (RA) treatment.
Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2K
→R or Zfp451-/- ESCs rescues, in part, their impaired differentiation potential
and enhances the down-regulation of Nanog The differentiation defect of Satb2K
→R ESCs correlates with altered higher-order chromatin interactions relative to
Satb2wt ESCs. Upon RA treatment of Satb2wt ESCs, SATB2 interacts with ZFP451 and
the LSD1/CoREST complex and gains binding at differentiation genes, which is not
observed in RA-treated Satb2K →R cells. Thus, SATB2 SUMOylation may contribute
to the rewiring of transcriptional networks and the chromatin interactome of
ESCs in the transition of pluripotency to differentiation. |
What is PPROM? | Preterm premature(Prelabor) rupture of fetal membranes is often abbreviated as PPROM, and is defined as rupture of membranes before the onset of labor at < 37 weeks' gestation, affects approximately 3% of all pregnancies | BACKGROUND: Preterm, prelabour rupture of the fetal membranes (pPROM) is the
commonest antecedent of preterm birth, and can lead to death, neonatal disease,
and long-term disability. Previous small trials of antibiotics for pPROM
suggested some health benefits for the neonate, but the results were
inconclusive. We did a randomised multicentre trial to try to resolve this
issue.
METHODS: 4826 women with pPROM were randomly assigned 250 mg erythromycin
(n=1197), 325 mg co-amoxiclav (250 mg amoxicillin plus 125 mg clavulanic acid;
n=1212), both (n=1192), or placebo (n=1225) four times daily for 10 days or
until delivery. The primary outcome measure was a composite of neonatal death,
chronic lung disease, or major cerebral abnormality on ultrasonography before
discharge from hospital. Analysis was by intention to treat.
FINDINGS: Two women were lost to follow-up, and there were 15 protocol
violations. Among all 2415 infants born to women allocated erythromycin only or
placebo, fewer had the primary composite outcome in the erythromycin group (151
of 1190 [12.7%] vs 186 of 1225 [15.2%], p=0.08) than in the placebo group. Among
the 2260 singletons in this comparison, significantly fewer had the composite
primary outcome in the erythromycin group (125 of 1111 [11.2%] vs 166 of 1149
[14.4%], p=0.02). Co-amoxiclav only and co-amoxiclav plus erythromycin had no
benefit over placebo with regard to this outcome in all infants or in singletons
only. Use of erythromycin was also associated with prolongation of pregcy,
reductions in neonatal treatment with surfactant, decreases in oxygen dependence
at 28 days of age and older, fewer major cerebral abnormalities on
ultrasonography before discharge, and fewer positive blood cultures. Although
co-amoxiclav only and co-amoxiclav plus erythromycin were associated with
prolongation of pregcy, they were also associated with a significantly higher
rate of neonatal necrotising enterocolitis.
INTERPRETATION: Erythromycin for women with pPROM is associated with a range of
health benefits for the neonate, and thus a probable reduction in childhood
disability. However, co-amoxiclav cannot be routinely recommended for pPROM
because of its association with neonatal necrotising enterocolitis. A follow-up
study of childhood development and disability after pPROM is planned. Infection is believed to be a leading cause of preterm premature rupture of
membranes (PPROM). The bacterial cell wall component, lipopolysaccharide (LPS),
is thought to initiate tissue responses leading to PPROM in the setting of Gram
negative infection. LPS is recognized by the innate immune system, including the
proteins encoded by the CARD15 and TLR4 genes. A recently described mutation
(2936insC) in CARD15 and a polymorphism in TLR4 896 A>G impair responses to LPS.
The objective of this study was to determine if African Americans, who have a
higher incidence of PPROM than Caucasians, have different frequencies of the
mutant CARD15 allele and the TLR4 hyporesponsive variant, and if risk of PPROM
is influenced by fetal carriage of these alleles. The allele frequencies for the
CARD15 mutation and the TLR4 896G variant in African Americans were similar to
those reported for Caucasians. There was no association between the TLR4 alleles
examined and PPROM. However, the CARD15 mutation was only detected in controls
and not in PPROM cases. We conclude that the CARD15 mutation and hyporesponsive
TLR4 allele do not contribute to ethnic variation in the incidence of PPROM. Preterm prelabour rupture of the membranes (PPROM) is defined as prelabour
rupture of the membranes prior to 37 weeks of gestation. It occurs in
approximately 3% of pregcies and is responsible for one-third of all preterm
births. Effective treatment relies on accurate diagnosis, and it is gestational
age dependent because the potential complications change with gestational age.
Diagnosis itself is made by clinical suspicion, patient history and simple
testing. Studies have shown that if a combination of patient history, nitrazine
testing and ferning was used, the accuracy of at least two positive tests was
93.1%. PPROM is associated with significant maternal and neonatal morbidity and
mortality from infection, umbilical cord compression, placental abruption and
preterm birth. Subclinical uterine infection has been implicated as a major
aetiological factor in the pathogenesis and subsequent morbidity associated with
PPROM and antenatal antibiotics, together with corticosteroid therapies, have
clear benefits and should be offered to all women without contraindications.
Women with PPROM after 32 weeks should be considered for delivery, and after 34
weeks of gestation the benefits of elective delivery appear to outweigh the
risks. Here, two cases are discussed that were experienced in our unit. PROBLEM: Preterm, premature rupture of membranes (PPROM) is a dire pregcy
outcome that is frequently associated with infection by the genital mycoplasmas,
Mycoplasma hominis, Ureaplasma parvum, and U. urealyticum. One potential
mechanism by which these microorganisms may cause PPROM is by increasing the
concentration of matrix metalloproteinases (MMPs) in the membranes and amniotic
fluid. We tested this hypothesis in a well-defined model system of genital
infection with M. pulmonis, a natural reproductive pathogen of rats.
METHOD OF STUDY: Timed-pregt, specific pathogen-free, Sprague-Dawley rats
were infected with 10(7) CFU M. pulmonis at gestation day (gd) 14. Controls
received an equivalent volume (100 microL) of sterile medium. At gd 18, rats
were euthanized, and membranes and amniotic fluids were harvested and stored at
-70 degrees C until analysis. Proteinase activity of amniotic fluid and
membranes was resolved on discontinuous 7.5% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis gelatin zymography gels. Band
intensity was determined using a digital gel documentation system and the
manufacturer's software (Kodak).
RESULTS: Gelatinolytic activity associated with a band similar in molecular
weight to ProMMP-9 (92 kDa, the inactive precursor of MMP-9) was significantly
increased in amniotic fluids and membranes harvested from M. pulmonis-treated
pups at gd 18 when compared with tissues harvested from control pups. Both
ProMMP-9 and ProMMP-2 (72 kDa, the inactive precursor of MMP-2) were increased
in infected animals at gd 21.
CONCLUSION: Our study suggests that the genital mycoplasmas can increase MMP-9
production in vivo. We investigated the association between prepregcy maternal body mass index
(BMI) and preterm delivery (PTD). The study included 44,421 American women
presenting for care in Saint Louis, Missouri between 1990 and 2006. Only
singleton gestations were included. The authors examined the associations
between categories of BMI with PTD <37 and <34 weeks, respectively. A stratified
analysis by subtypes of PTD was also performed. The subtypes of PTD evaluated
included spontaneous PTD without preterm premature rupture of membranes (PPROM),
PPROM, and indicated PTD. Univariate and multivariable analyses were used to
estimate the association between maternal BMI categories and PTD <37 weeks, PTD
<34 weeks, and subtypes of PTD. Among women meeting the inclusion criteria, PTD
<37 occurred in 4783 (10.8%) and PTD <34 weeks in 1132 (2.5%). Being underweight
was associated with increased risks of PTD <37 weeks (adjusted odd ratio [OR] =
1.3, 95% confidence interval [CI]: 1.2, 1.5). Being obese was associated with
decreased risks of spontaneous PTD without PPROM <37 weeks (adjusted OR = 0.8,
95% CI: 0.7, 0.9) and increased risk of PPROM <37 weeks (adjusted OR = 1.3, 95%
CI: 1.1, 1.6) and PPROM <34 weeks (adjusted OR = 1.4, 95% CI: 1.0, 2.0).
Prepregcy obesity increases the risk of PPROM and decreases risk of
spontaneous PTD without PPROM. OBJECTIVE: To examine the incidence of preterm premature rupture of membranes
(PPROM) in pregcies affected by twin-twin transfusion syndrome (TTTS) treated
with laser photocoagulation where an absorbable gelatin sponge was used as a
chorioamnion sealant of the fetoscopic access port.
METHOD: A retrospective review was undertaken of consecutive cases undergoing
fetoscopic directed laser surgery for TTTS between October 2006 and November
2008 at Texas Children's Fetal Center, in which an absorbable gelatin sponge,
used as a chorioamnion 'plug', was placed at the conclusion of the intervention
as a possible prophylactic measure to prevent PPROM. We excluded cases that had
a failure of plug placement and those in which it was not attempted. PPROM was
defined as rupture of membranes before 34 weeks' gestation. A comparison was
performed between the PPROM group and a no-PPROM group to determine risk factors
and outcomes.
RESULTS: Successful plug placement occurred in 79 of 84 cases (94%) in which it
was attempted after laser surgery, with a rate of PPROM of 34% in these
patients. PPROM occurred at an average gestational age of 26.5 +/- 3.6 weeks,
with an average procedure-to-PPROM interval of 5.2 +/- 3.5 weeks. There were no
statistically significant differences between the PPROM group and the no-PPROM
group in maternal demographics or preoperative parameters including: amniotic
fluid volumes in the recipient twin's gestational sac, volume of amnioreduction,
and location of the placenta. The procedure-to-delivery interval for the total
cohort (n = 79) was 9.2 +/- 4.7 weeks, without a significant difference between
the two groups (P = 0.08). However, after exclusion of one PPROM outlier, the
PPROM group had an average procedure-to-delivery time 2 weeks shorter than the
group with no PPROM (P = 0.03). The live birth rates were similar in the PPROM
and no-PPROM groups, at 77 and 73%, respectively. However, the average
recipient's weight in the PPROM group was significantly lower than in the
no-PPROM group (1321 +/- 493 vs. 1705 +/- 576 g; P = 0.02).
CONCLUSION: The rate of PPROM and the mean gestational age at delivery in
pregcies in which an absorbable gelatin sponge was used as a sealant of the
fetoscopic port following laser photocoagulation for TTTS were comparable to
those that have been reported by other laser centers where membrane sealants
were not used. A randomized controlled trial should be considered to evaluate
the effect of chorioamnion plugging. The preterm premature rupture of membranes (PPROM) is a common condition in
pregt women and is associated with significant maternal and perinatal
morbidity. Most of the time, the diagnosis is done during physical examination.
However, in 10%-20% of equivocal cases, biological markers are needed to confirm
the diagnosis, especially when leakage of fluid is low or intermittent. In these
cases, a quick and reliable diagnosis is necessary for applying the appropriate
measures to reduce perinatal complications. The prognosis in PPROM is linked to
maternal inflammatory markers that might predict perinatal infection, and
therefore be helpful to decide the timing of the delivery. Nevertheless, further
research is needed to identify robust biological markers for the diagnosis of
PPROM in equivocal cases and for the prognosis. Preterm premature rupture of the membranes (PPROM) is an important etiology of
preterm birth and source of significant neonatal morbidity. We propose that
PPROM occurs in the setting of long-standing altered tissue remodeling, which
creates a vulnerable environment for the fetal membranes and pregcy. We
tested the hypothesis that PPROM is the result of tissue remodeling in the fetal
membranes, specifically the chorion, and this weakening of the chorion
compromises the protection provided to the amnion. The purpose of this study was
to quantify thickness and apoptosis in the choriodecidua of fetal membranes in
patients with PPROM, preterm labor (PTL), preterm no labor (PTNL), and women
with term labor (TERM). We conducted a retrospective evaluation of fetal
membrane samples from 86 placentas. Immunohistochemistry was performed using a
cytokeratin antibody, and mean chorion cellular thickness was compared between
each clinical group. To evaluate chorion apoptosis, fetal membranes from
patients with PPROM, PTL, and TERM were stained with the M30 antibody, and the
degree of cellular apoptosis was determined. Statistical analysis was performed
using analysis of variance with corrections for multiple comparisons. The
chorion cellular layer was thinner in patients with PPROM compared to patients
with PTNL and TERM (62, 140, and 169 µm, respectively, P < .0001), though not
significantly different from PTL (95 µm, P > .05). The percentage of apoptotic
cells within the chorion among the patients with PPROM was greater compared to
PTL and TERM (24.2%, 13.1%, and 8.4%, respectively, P < .001). The chorion
cellular layer is thinner and demonstrates increased apoptosis in PPROM compared
to patients with PTL, PTNL, and TERM, suggesting differential remodeling between
clinical phenotypes. Preterm premature rupture of membranes (PPROM) is defined as a spontaneous
membrane rupture that occurs before the onset of labor and 37 weeks gestation.
Subclinical intrauterine infection has been suggested as a very important
etiological factor in the pathogenesis and subsequent morbidity related with
PPROM. This study was performed to assess the levels of maternal
proadrenomedullin (pro-ADM) and serum amyloid A (AA) in PPROM and its
association with fetomaternal infectious morbidity. A total of 63 pregt
women, of which 43 with PPROM between 24 and 34 weeks gestation and 20 normal
pregt women without PPROM were included in the study. The study group was
separated into 2 subgroups as PPROM and PPROM-histological chorioamnionitis
(PPROM-HC). The blood samples were taken before the administration of any
medication. The mean serum interleukin-6 (IL-6), AA, and pro-ADM values in the
PPROM-HC group were significantly higher than the PPROM and control group. The
cutoff values of pro-ADM and AA were determined as 4.2 nM and 69 μg/mL,
respectively. Both of them showed similar sensitivity, specificity to IL-6 and a
better sensitivity and specificity as compared to C-reactive protein and white
blood cell count. We determined the predictive value of pro-ADM and serum AA
measurements in PPROM and PPROM with histological chorioamnionitis. We suggest
using pro-ADM and serum AA biomarkers for detecting the histological
chorioamnionitis at an earlier stage in PPROM without any clinical signs. OBJECTIVES: To determine whether chorioamniotic membrane separation from the
internal cervical os, the "moon sign," is associated with preterm premature
rupture of membranes (PPROM) in twin-twin transfusion syndrome (TTTS).
METHODS: A retrospective study of patients with TTTS treated with laser surgery
was performed. Membrane separation before and after surgery was tested against
any PPROM, PPROM within 7 days, and PPROM within 21 days. Because intrauterine
fetal demise (IUFD) was weakly associated with PPROM, these cases were studied
separately.
RESULTS: Among 304 consecutive patients, 247 patients (81.3%) had no IUFD, and
preoperative and postoperative membrane separation rates were 13.4% and 13.0%,
respectively. In 7 cases (2.8%), preoperative membrane separation disappeared
postoperatively, and in 6 cases (2.4%), membrane separation appeared
postoperatively; 26 cases (10.5%) had membrane separation at both times. Rates
of PPROM did not differ between those who did and did not have preoperative
membrane separation (30.3% versus 28.0%; P= .9511). Among those with and without
postoperative membrane separation, the rates of any PPROM were 34.4% and 27.4%,
respectively (P = .5473), and the rates of PPROM within 21 days were 15.6% and
5.6% (P = .0524). Those with postoperative membrane separation were 3 times more
likely to have PPROM within 21 days (odds ratio, 3.13; 95% confidence interval,
1.02-9.58; P= .0453). Preterm premature rupture of membranes was not associated
with preoperative or postoperative membrane separation in patients with IUFD.
CONCLUSIONS: The preoperative moon sign does not appear to be associated with
PPROM in TTTS. Postoperatively, membrane separation may be weakly associated
with PPROM at 21 days, but further research is required to confirm this
association. BACKGROUND: Preterm premature rupture of membranes (PPROM) is a challenging
complication of pregcies and an important cause of perinatal morbidity and
mortality. Management of morbidities associated with PPROM is fraught with
controversy. However, women should be informed of these complications.
OBJECTIVE: This article aimed to review the morbidities, concordance, and
predictors of PPROM over a 10-year period.
METHODS: This was a retrospective review of morbidities, concordance, and
predictors of PPROM among pregt women at the University of Nigeria Teaching
Hospital, Enugu, Nigeria between January 1, 1999, and December 31, 2008. The
morbidities, concordance, and predictors of PPROM were expressed by regression
analysis output for PPROM.
RESULTS: Primigravidae had the highest occurrence of PPROM. Increasing parity
does not significantly influence the incidence of PPROM. The concordance and
predictors of PPROM are maternal age (P < 0.000), gestational age at PROM (P <
0.000), latency period (P < 0.000), and birth weight (P < 0.001).
CONCLUSION: PPROM is a major complication of pregcies and an important cause
of perinatal morbidity and mortality. Management of these morbidities associated
with PPROM poses a great challenge. However, women should be informed of these
complications. Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture
of fetal membranes prior to 28 weeks of gestation, complicates approximately
0.4%-0.7% of all pregcies. This condition is associated with a very high
neonatal mortality rate as well as an increased risk of long- and short-term
severe neonatal morbidity. The causes of the mid-trimester PPROM are
multifactorial. Altered membrane morphology including marked swelling and
disruption of the collagen network which is seen with PPROM can be triggered by
bacterial products or/and pro-inflammatory cytokines. Activation of matrix
metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The
propagation of bacteria is an important contributing factor not only in PPROM,
but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory
mediators likely play a causative role in both disruption of fetal membrane
integrity and activation of uterine contraction. The "classic PPROM" with
oligo/an-hydramnion is associated with a short latency period and worse neonatal
outcome compared to similar gestational aged neonates delivered without
antecedent PPROM. The "high PPROM" syndrome is defined as a defect of the
chorio-amniotic membranes, which is not located over the internal cervical os.
It may be associated with either a normal or reduced amount of amniotic fluid.
It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or
IGFBP-1/alpha fetoprotein test can have a positive result without other signs of
overt ROM such as fluid leakage with Valsalva. The membrane defect following
fetoscopy also fulfils the criteria for "high PPROM" syndrome. In some cases,
the rupture of only one membrane - either the chorionic or amniotic membrane,
resulting in "pre-PPROM" could precede "classic PPROM" or "high PPROM". The
diagnosis of PPROM is classically established by identification of nitrazine
positive, fern positive watery leakage from the cervical canal observed during
in specula investigation. Other more recent diagnostic tests include the vaginal
swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some
rare cases amniocentesis and infusion of indigo carmine has been used to confirm
the diagnosis of PPROM. The management of the PPROM requires balancing the
potential neonatal benefits from prolongation of the pregcy with the risk of
intra-amniotic infection and its consequences for the mother and infant. Close
monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP,
leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to
minimize the risk of neonatal and maternal complications. In addition to delayed
delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or
macrolide and corticosteroids have been show to improve neonatal outcome
[reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal
infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)].
The positive effect of continuous amnioinfusion through the subcutaneously
implanted perinatal port system with amniotic fluid like hypo-osmotic solution
in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be
proved in future prospective randomized studies. Systemic antibiotics
administration in "pre-PPROM" without infection and hospitalization are also of
questionable benefit and needs to be further evaluated in well-designed
randomized prospective studies to evaluate if it is associated with any neonatal
benefit as well as the relationship to possible adverse effect of antibiotics on
to fetal development and neurological outcome. OBJECTIVES: Preterm premature rupture of membranes (PPROM) is a leading
complication following fetoscopic laser coagulation (FLC) for twin-twin
transfusion syndrome (TTTS). Our primary objective was to describe the impact of
improvements in surgical technique on survival and rate of PPROM over time. The
secondary objective was to assess potential risk factors for PPROM.
DESIGN AND SETTING: Single-centre retrospective observational study.
POPULATION: 1092 consecutive cases of TTTS operated by FLC between 2000 and
2016, with a 6.8% rate of loss to follow up.
METHODS: The incidence of PPROM and potential risk factors were analysed using
competing risks models.
MAIN OUTCOME MEASURES: PPROM, neonatal survival and neurological damage at 28
days.
RESULTS: PPROM <32 weeks increased from 15 to 40% between 2000 and 2016 along
with an overall improvement of perinatal outcomes: dual survival rose from 42 to
66% whereas dual losses dropped two-fold, from 19 to 9%. Gestational age at
surgery at <17 weeks was a significant risk-factor for PPROM, with an additional
risk of 10% within the first week of surgery. Although early PPROM at <20 weeks
carried a 56% risk of miscarriage, the occurrence of PPROM at >20 weeks did not
affect survival, despite an increase in preterm birth at <32 weeks.
CONCLUSIONS: With significant improvement in perinatal outcomes, possibly
related to improvements in surgical technique, postoperative complications have
shifted to non-lethal obstetric complications such as PPROM, with rather
reassuring postnatal outcomes, despite an increase in preterm birth and,
potentially, morbidity. Early surgeries (<17 weeks) are at higher risk of
postoperative PPROM.
TWEETABLE ABSTRACT: Following laser/TTTS, rates of PPROM increased with
perinatal survival; surgeries at <17 weeks are at highest risk. INTRODUCTION: Pre-term premature rupture of membranes (PPROM) is one of the
leading causes of perinatal morbidity and mortality. This complication is
diagnosed in 3% of pregt women in Kazakhstan, and it is the leading cause of
pre-term deliveries. The aim of this study was to determine the outcomes of
pregcies complicated by PPROM in gestation periods between 24 to 32 weeks
among three institutions in Kazakhstan.
METHODS: This is descriptive analysis of 154 cases with PPROM observed between
24 to 32 weeks of gestation at Perinatal Centers #2 and #3 and the National
Research Center for Maternal and Child Health, Astana, Kazakhstan. Cases were
selected on the basis of retrospective chart review where PPROM diagnosis
occurred in 2013. Descriptive statistics were utilized for data analysis.
RESULTS: The most frequent complications associated with PPROM were threat of
miscarriage (13.6% of cases) and chronic placental insufficiency (7.8%). The
mean time between PPROM and onset of spontaneous labor was 12.1 ± 2.3 days.
Spontaneous labor within 3 days after PPROM started in patients with an amniotic
fluid index of 3.0 ± 0.2 cm. Complications experienced by PPROM women during
delivery and early postpartum period included: precipitous labor (6.4%),
weakness of labor activity (16.2%), atonic hemorrhage (1.2%), and
chorioamnionitis (3.2%). 37.6% of newborns in this study were admitted to the
Intensive Care Unit. Their health complications included pneumonia (7.7%),
conjunctivitis (1.3%), omphalitis and infectious-toxic shock (3.8%),
intraventricular hemorrhage (7.8%), and respiratory distress (10.3%).
CONCLUSION: Thus, preterm rupture of membranes is associated with preterm
delivery and an increase of neonatal morbidity. Therefore, it is necessary to
find ways to effectively manage PPROM, including developing new techniques to
restore the amniotic fluid volume in women experiencing PPROM during 24 to 32
weeks of gestation. Objective: To evaluate the efficacy and safety of amniopatch in pregcies
associated with spontaneous preterm premature rupture of fetal membranes
(PPROM).Methods: A randomized controlled trial that involved 100 women diagnosed
with PPROM between 24 and 34 weeks of gestational age. Participants were
randomized equally into two groups. Group I in which amniopatch was done in
addition to the routine management. Group II was treated with routine management
including antibiotics and corticosteroids.Results: Amniopatch was successful in
complete sealing of the membrane defect in 6/50 (12%) of women while none the
control group have undergone similar sealing (p = .0144, RR = 0.88). Women in
the amniopatch group showed a significant increase of AFI compared to controls
(12 versus 0, p = .0001, RR = 0.56).Conclusion: The amniopatch procedure is a
successful technique that safely enhances sealing of fetal membranes and restore
the AFI.Clinical trial registration: NCT03473210SynopsisThe amniopatch procedure
is a successful technique that could be done safely to enhance sealing the fetal
membranes and restoring the AFI after PPROM. Background: Placental dysfunction, inflammation and degradation of fetal
membranes has been hypothesized as a cause of preterm prelabor of rupture of
membranes.Objective: To examine the effect of aspirin, an anti-inflammatory
agent, on the prevalence of preterm prelabor rupture of membranes
(PPRoMs).Methods: A retrospective analysis was conducted to examine the effect
of aspirin on the prevalence of PPRoM. Aspirin (150 mg, nocte) was prescribed to
women who were identified through a screening program at 11-13+6 weeks'
gestation as being at high risk for developing early-onset preeclampsia. Women
who were at low risk for developing preeclampsia did not receive aspirin. The
prevalence of PPRoM was compared with an observational cohort.Results: In the
observational cohort, there were 3027 women, including 32 (1.1%) cases of PPRoM.
The prevalence of PPRoM in the high risk group was 3.1% (4/128) and was
statistically significantly higher compared to the low risk group (1.0%)
(28/2899). The relative risk was 3.02 (95% CI 1.2-7.7; p= .04). In the
interventional cohort, there were 7280 women, with 114 (1.6%) cases of PPRoM.
The prevalence of PPRoM in the high risk group who were treated with aspirin was
1.8% (14/766) compared to 1.5% (100/6516) in the low risk group (p= .54). The
prevalence of PPRoM in high risk patients in the observational group (who did
not receive aspirin) compared with the high risk patients in the interventional
group (who were treated with aspirin) was not statistically significant
(p= .31).Conclusions: PPRoM is significantly associated with a description of
high risk for ePET; although, this algorithm is not a good screening tool for
predicting PPRoM. Aspirin treatment of women deemed high risk for ePET is safe
in the context of PPRoM and there may be some reduction in prevalence of PPRoM
in treated high risk women; although, this study was not powered to demonstrate
a small reduction in the prevalence of PPRoM. The findings merit further
investigation through a larger prospective study with adequate sample size. INTRODUCTION: Spontaneous preterm birth (sPTB), which predomitly presents as
spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes
(PPROM), is a syndrome that accounts for 5-10% of live births annually. The
long-term morbidity in surviving preterm infants is significantly higher than
that in full-term neonates. The causes of sPTB are complex and not fully
understood. Human placenta, the maternal and fetal interface, is an
environmental core of fetal intrauterine life, mediates fetal oxygen exchange,
nutrient uptake, and waste elimination and functions as an immune-defense organ.
In this study, the molecular signature of preterm birth placenta was assessed
and compared to full-term placenta by proteomic profiling.
MATERIALS AND METHODS: Four groups of fetal membranes (the amniochorionic
membranes), with five cases in each group in the discovery study and 30 cases in
each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term
birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal
membranes were dissected and used for proteome quantification study. Maxquant
and Perseus were used for protein quantitation and statistical analysis. Both
fetal membranes and placental villi samples were used to validate proteomic
discovery.
RESULTS: Proteomics analysis of fetal membranes identified 2,800 proteins across
four groups. Sixty-two proteins show statistical differences between the preterm
and full-term groups. Among these differentially expressed proteins are (1)
proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage
activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3)
proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular
matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and
(6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and
ACSL3), and energy biosynthesis (ATP6AP1 and CYBB).
CONCLUSION: Our molecular signature study of preterm fetal membranes revealed
inflammation as a major event, which is inconsistent with previous findings.
Proteolysis may play an important role in fetal membrane rupture. Extracellular
matrix s have been altered in preterm fetal membranes due to proteolysis.
Metabolism was also altered in preterm fetal membranes. The molecular changes in
the fetal membranes provided a significant molecular signature for PPROM in
preterm syndrome. BACKGROUND: Preterm prelabour rupture of membranes (PPROM) is a common preterm
birth antecedent. Preterm infants experience increased adverse newborn outcome
risks. Infection is a risk factor for early birth in PPROM. Current management
is antibiotic therapy, antenatal corticosteroids and to plan delivery at
37 weeks gestation. The microbiota and probiotics are potentially protective and
may improve outcomes.
AIMS: The primary aim is to evaluate whether oral probiotic therapy
(Lactobacillus fermentum CECT5716) administered during PPROM between 24 and
34 weeks gestation prolongs pregcy duration. The secondary aim is to evaluate
maternal and neonatal outcomes.
MATERIALS AND METHODS: This is a pragmatic, multicentre, double-blind,
placebo-controlled randomised controlled trial in Australia. The population will
be women with a singleton pregcy and PPROM less than 34 weeks gestation. The
intervention will be an oral probiotic therapy compared with a placebo control.
The primary outcome will be the proportion of women still pregt at seven days
following PPROM. One-to-one randomisation will occur within 24 h of PPROM. The
trial is powered (80%, alpha = 0.05) to detect an absolute percentage increase
in the primary outcome of 30%, (from expected rate of 20% up to 50%).
DISCUSSION: This trial will provide evidence for the effectiveness of the
probiotic in prolonging pregcy duration. Findings will inform the feasibility
of a larger trial to examine the effect of oral probiotics on clinically
important maternal and neonatal outcomes in PPROM. |
What is the half-life of epimutations across generations of C. elegans? | In C. elegans, epimutations typically have short half-lives of two to three generations. Nevertheless, some epimutations last at least ten generations. | |
What drugs are included in the Avandamet pill? | The combination of metformin and rosiglitazone in a single pill (Avandamet), was approved by the FDA in October 2002 for the treatment of diabetes. | Insulin resistance is a major endocrinopathy underlying the development of
hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a
biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance,
acting by different cellular mechanisms. The two agents can be used in
combination to achieve additive glucose-lowering efficacy in the treatment of
type 2 diabetes, without stimulating insulin secretion and without causing
hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and
markers, indicating a lower cardiovascular risk. Early intervention with
metformin is already known to reduce myocardial infarction and increase survival
in overweight type 2 patients. Recently, a single-tablet combination of
metformin and rosiglitazone, Avandamet, has become available. Avandamet is
suitable for type 2 diabetic patients who are inadequately controlled by
monotherapy with metformin or rosiglitazone. Patients already receiving separate
tablets of metformin and rosiglitazone may switch to the single-tablet
combination for convenience. Also, early introduction of the combination before
maximal titration of one agent can reduce side effects. Use of Avandamet
requires attention to the precautions for both metformin and rosiglitazone,
especially renal, cardiac and hepatic competence. In summary, Avandamet is a
single-tablet metformin-rosiglitazone combination that doubly targets insulin
resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes. OBJECTIVE: The long-term cost-effectiveness of using pioglitazone plus metformin
(Actoplusmet dagger) compared with rosiglitazone plus metformin (Avandamet
double dagger) in treating type 2 diabetes (T2DM) was assessed from a US
third-party payer perspective.
RESEARCH DESIGN AND METHODS: Clinical efficacy (change in HbA(1c) and lipids)
and baseline cohort parameters were extracted from a 12-month, randomized
clinical trial (Derosa et al., 2006) evaluating the efficacy and tolerability of
pioglitazone versus rosiglitazone, both in addition to metformin, in adult T2DM
patients with insufficient glucose control (n = 96). A Markov-based model was
used to project clinical and economic outcomes over 35 years, discounted at 3%
per annum. Costs for complications were taken from published sources. Base-case
assumptions were assessed through several sensitivity analyses.
MAIN OUTCOME MEASURES: Outcomes included incremental life-years,
quality-adjusted life-years (QALYs), total direct medical costs, cumulative
incidence of complications and associated costs, and incremental
cost-effectiveness ratios (ICERs).
RESULTS: Compared to rosiglitazone plus metformin, pioglitazone plus metformin
was projected to result in a modest improvement in 0.187 quality-adjusted
life-years. Over patients' lifetimes, total direct medical costs were projected
to be marginally lower with pioglitazone plus metformin (difference -$526.),
largely due to reduced CVD complication costs. While costs were higher among
renal, ulcer/amputation/neuropathy, and eye complications in the pioglitazone
plus metformin group, the cost savings for CVD complications outweighed their
economic impact. Pioglitazone plus metformin was found to be a domit
long-term treatment strategy in the US compared to rosiglitazone plus metformin.
Sensitivity analyses showed findings to be robust under almost all scenarios,
including short-term time horizons, 6% discounting, removal of individual lipid
parameters, and modifications of patient cohort to more closely represent a US
T2DM population. Pioglitazone plus metformin was no longer domit with 0%
discounting, with 25% reduction in its HbA(1c) effects, or with a 15% increase
in its acquisition price.
CONCLUSIONS: Under a range of assumptions and study limitations around cohorts,
clinical effects, and treatment patterns, this long-term analysis showed that
pioglitazone plus metformin, when compared to rosiglitazone plus metformin, was
a domit treatment strategy within the US payer setting. Results were driven
by the combination of modest differences in QALYs and modest savings in total
complication costs over 35 years. BACKGROUND: Complex diseases, such as Type 2 Diabetes, are generally caused by
multiple factors, which hamper effective drug discovery. To combat these
diseases, combination regimens or combination drugs provide an alternative way,
and are becoming the standard of treatment for complex diseases. However, most
of existing combination drugs are developed based on clinical experience or
test-and-trial strategy, which are not only time consuming but also expensive.
RESULTS: In this paper, we presented a novel network-based systems biology
approach to identify effective drug combinations by exploiting high throughput
data. We assumed that a subnetwork or pathway will be affected in the networked
cellular system after a drug is administrated. Therefore, the affected
subnetwork can be used to assess the drug's overall effect, and thereby help to
identify effective drug combinations by comparing the subnetworks affected by
individual drugs with that by the combination drug. In this work, we first
constructed a molecular interaction network by integrating protein interactions,
protein-DNA interactions, and signaling pathways. A new model was then developed
to detect subnetworks affected by drugs. Furthermore, we proposed a new score to
evaluate the overall effect of one drug by taking into account both efficacy and
side-effects. As a pilot study we applied the proposed method to identify
effective combinations of drugs used to treat Type 2 Diabetes. Our method
detected the combination of Metformin and Rosiglitazone, which is actually
Avandamet, a drug that has been successfully used to treat Type 2 Diabetes.
CONCLUSIONS: The results on real biological data demonstrate the effectiveness
and efficiency of the proposed method, which can not only detect effective
cocktail combination of drugs in an accurate manner but also significantly
reduce expensive and tedious trial-and-error experiments. AIM: The purpose of this study was to evaluate if superior glycaemic control
could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with
metformin (MET) monotherapy, and if glycaemic effects attained with AVM are
durable over 18 months of treatment. Bone mineral density (BMD) and bone
biomarkers were evaluated in a subgroup of patients.
METHODS: This was a phase IV, randomized, double-blind, multi-centre study in
688, drug naÏve, male and female patients who had an established clinical
diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 :
1 ratio either to AVM or MET.
RESULTS: As initial therapy in patients with T2DM, AVM was superior to MET in
achieving statistically significant reductions in glycated haemoglobin (HbA1c)
(p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients
reaching recommended HbA1c and FPG targets for intensive glycaemic control. The
glycaemic effects attained with AVM compared to MET monotherapy were durable
over 18 months of treatment. In the bone substudy, AVM was associated with a
significantly lower BMD in comparison with MET at week 80 in the lumbar spine
and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment
differences were not statistically significant for distal one-third of radius
BMD, femoral neck BMD or total BMD.
CONCLUSION: Superior glycaemic control was achieved with AVM compared with MET
monotherapy. The superior glycaemic effects were shown to be durable over 18
months of treatment. AVM was associated with a significantly reduced BMD in
comparison with MET at week 80 in the lumbar spine and total hip. BACKGROUND: At present, China has listed the compound tablet containing a fixed
dose of rosiglitazone and metformin, Avandamet, which may improve patient
compliance. The aim of this study was to evaluate the efficacy and safety of
Avandamet or uptitrated metformin treatment in patients with type 2 diabetes
inadequately controlled with metformin alone.
METHODS: This study was a 48-week, multicenter, randomized, open-labeled,
active-controlled trial. Patients with inadequate glycaemic control (glycated
hemoglobin [HbA1c] 7.5-9.5%) receiving a stable dose of metformin (≥1500 mg)
were recruited from 21 centers in China (from 19 November, 2009 to 15 March,
2011). The primary objective was to compare the proportion of patients who
reached the target of HbA1c ≤7% between Avandamet and metformin treatment.
RESULTS: At week 48, 83.33% of patients reached the target of HbA1c ≤7% in
Avandamet treatment and 70.00% in uptitrated metformin treatment, with
significantly difference between groups. The target of HbA1c ≤6.5% was reached
in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin
treatment. The target of fasting plasma glucose (FPG) ≤6.1 mmol/L was reached in
26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin
treatment. The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in
Avandamet treatment and 43.33% in uptitrated metformin treatment. Fasting
insulin decreased 3.24 ± 0.98 μU/ml from baseline in Avandamet treatment and
0.72 ± 1.10 μU/ml in uptitrated metformin treatment. Overall adverse event (AE)
rates and serious AE rates were similar between groups. Hypoglycaemia occurred
rarely in both groups.
CONCLUSIONS: Compared with uptitrated metformin, Avandamet treatment provided
significant improvements in key parameters of glycemic control and was generally
well tolerated.
REGISTRATION NUMBER: ChiCTR-TRC-13003776. |
What does temsirolimus inhibit? | Temsirolimus is a mTOR inhibitor | BACKGROUND: From 10% to 26% of patients with metastatic renal cell carcinoma
(mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib.
OBJECTIVE: To investigate the benefit of subsequent treatment with another
tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR)
inhibitor in such primary refractory patients.
DESIGN, SETTING, AND PARTICIPANTS: A total of 150 mRCC patients with rapidly PD
on first-line sunitinib (within two cycles, n=93, or four cycles, n=57) were
identified: median age 59yr; nephrectomy 86%; histological subtypes: clear cell
(77.8%), papillary (14%), and sarcomatoid features (18%); according to the
Memorial Sloan-Kettering Cancer Center and French classifications: good risk
(11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor
(21% and 29%, respectively).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data were retrospectively
collected by a questionnaire from 19 European oncology centers between March
2005 and March 2011. Progression-free survival (PFS) and overall survival (OS)
were calculated (Kaplan-Meier method).
RESULTS AND LIMITATIONS: Median OS from the start of first-line treatment was
7.4mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR
inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination;
three chemotherapy). Second-line PFS was not significantly different between
TKIs and mTOR inhibitors (2.0 vs 0.9mo; p=0.536). Median OS from the start of
second-line treatment was 5.0mo for mTOR inhibitors and 6.6mo for TKIs (p=0.15).
CONCLUSIONS: Treatment with further TKIs or mTOR inhibitors for mRCC patients
primarily refractory to first-line sunitinib in the observed time period
achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly
preferring alternative strategies, such as immune checkpoint inhibitors, after
PD to a treatment line including a TKI in this setting.
PATIENT SUMMARY: The present work collected data about 150 patients affected by
metastatic renal cell carcinoma, who received one of the current standard of
care as first-line treatment, namely, the antiangiogenic drug sunitinib, and
experienced rapid worsening of the disease. We investigated and described the
subsequent outcome of such patients treated with two different types of drug,
administered as second-line therapy, to better understand the best strategy to
adopt for patients who got no benefit from sunitinib and to describe the current
therapeutic approach in such cases. BACKGROUND: Temsirolimus is a mTOR inhibitor approved for the first-line
treatment of advanced or metastatic renal cell carcinoma (a/mRCC) with poor
prognosis. In treatment of a/mRCC several prognostic scoring systems are used.
We assessed the prognostic value of these scores in a large temsirolimus treated
cohort and compared the results with the physician's prognosis.
METHODS: A German multicenter registry (STAR-TOR) for a/mRCC patients
(NCT00700258) was established to evaluate the efficacy and safety of
temsirolimus 25 mg weekly in a routine clinical setting. These prospective data
were systematically analyzed and followed-up by an independent clinical research
organization to compare established prognostic scores (MSKCC, IMDC and Hudes)
with the risk assessment by treating physicians based on their medical expertise
and match them with survival outcomes.
RESULTS: This interim analysis included 547 patients between 02/2008 and 05/2015
in 87 centers. Either prognostic tool resulted in significant and clinically
meaningful differentiation between good, intermediate and poor prognosis.
However, physician's prognosis identified more patients with good prognosis
(9.1% vs. 1.3%). In patients with good physician's prognosis and intermediate
prognosis by MSKCC, overall survival was nearly doubled compared to consensual
intermediate prognosis (26.6 vs. 13.6 months), albeit without reaching
statistical significance (P=0.09). For poor prognosis assessed by the physician,
MSKCC performed statistically better for differentiation between poor and
intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months
(P<0.01).
CONCLUSIONS: Physician's prognosis may be able to identify a subset of patients
treated with temsirolimus with good prognosis when MSKCC-determines intermediate
prognosis while the MSKCC score could identify patients which were falsely
placed in the poor risk group by physicians. |
Are circular RNAs implicated in diseases of the eye? | Circular RNA (circRNA) are associated with several eye diseases. | Cystathionine-β-synthase (CBS) gene encodes L-serine hydrolyase which catalyzes
β-reaction to condense serine with homocysteine (Hcy) by pyridoxal-5'-phosphate
helps to form cystathionine which in turn is converted to cysteine. CBS resides
at the intersection of transmethylation, transsulfuration, and remethylation
pathways, thus lack of CBS fundamentally blocks Hcy degradation; an essential
step in glutathione synthesis. Redox homeostasis, free-radical detoxification
and one-carbon metabolism (Methionine-Hcy-Folate cycle) require CBS and its
deficiency leads to hyperhomocysteinemia (HHcy) causing retinovascular
thromboembolism and eye-lens dislocation along with vascular cognitive
impairment and dementia. HHcy results in retinovascular, coronary, cerebral and
peripheral vessels' dysfunction and how it causes metabolic dysregulation
predisposing patients to serious eye conditions remains unknown. HHcy
orchestrates inflammation and redox imbalance via epigenetic remodeling leading
to neurovascular pathologies. Although circular RNAs (circRNAs) are domit
players regulating their parental genes' expression dynamics, their importance
in ocular biology has not been appreciated. Progress in gene-centered analytics
via improved microarray and bioinformatics are enabling dissection of genomic
pathways however there is an acute under-representation of circular RNAs in
ocular disorders. This study undertook circRNAs' analysis in the eyes of CBS
deficient mice identifying a pool of 12532 circRNAs, 74 exhibited differential
expression profile, ∼27% were down-regulated while most were up-regulated
(∼73%). Findings also revealed several microRNAs that are specific to each
circRNA suggesting their roles in HHcy induced ocular disorders. Further
analysis of circRNAs helped identify novel parental genes that seem to influence
certain eye disease phenotypes. Long non-coding RNAs are 200 nucleotide long RNA molecules which lack or have
limited protein-coding potential. They can regulate protein formation through
several different mechanisms. Similarly, circular RNAs are reported to play a
critical role in post-transcriptional gene regulation. Changes in the expression
pattern of these molecules are established to underline various diseases,
including cancer, cardiovascular, neurological and immunological disorders.
Recent studies suggest that they are differentially expressed both in healthy
ocular tissues as well as in eye pathologies, such as neovascularization,
proliferative vitreoretinopathy, glaucoma, cataract, ocular maligcy or even
strabismus. Aetiology of ocular diseases is multifactorial and combines genetic
and environmental factors, including epigenetic and non-coding RNAs. In
addition, disorders like diabetic retinopathy or age-related macular
degeneration lack biomarkers for early detection as well as effective treatment
methods that will allow controlling the disease progression at its early stages.
The newly discovered non-coding RNAs seem to be the ideal candidate for novel
molecular markers and therapeutic strategies. In this review, we summarize
current knowledge about gene expression regulators - long non-coding and
circular RNA molecules in eye diseases. Circular RNAs (circRNAs) are being hailed as a newly rediscovered class of
covalently closed transcripts that are produced via alternative, noncanonical
pre-mRNA back-splicing events. These single-stranded RNA molecules have been
identified in organisms ranging from the worm (Cortés-López et al. 2018. BMC
Genomics, 19: 8; Ivanov et al. 2015. Cell Rep. 10: 170-177) to higher eukaryotes
(Yang et al. 2017. Cell Res. 27: 626-641) to plants (Li et al. 2017. Biochem.
Biophys. Res. Commun. 488: 382-386). At present, research on circRNAs is an
active area because of their diverse roles in development, health, and diseases.
Partly because their circularity makes them resistant to degradation, they hold
great promise as unique biomarkers for ocular and central nervous system (CNS)
disorders. We believe that further work on their applications could help in
developing them as "first-in-class" diagnostics, therapeutics, and prognostic
targets for numerous eye conditions. Interestingly, many circRNAs play key roles
in transcriptional regulation by acting as miRNAs sponges, meaning that they
serve as master regulators of RNA and protein expression. Since the retina is an
extension of the brain and is part of the CNS, we highlight the current state of
circRNA biogenesis, properties, and function and we review the crucial roles
that they play in the eye and the brain. We also discuss their regulatory roles
as miRNA sponges, regulation of their parental genes or linear mRNAs,
translation into micropeptides or proteins, and responses to cellular stress. We
posit that future advances will provide newer insights into the fields of RNA
metabolism in general and diseases of the aging eye and brain in particular.
Furthermore, in keeping pace with the rapidly evolving discipline of
RNA"omics"-centered metabolism and to achieve uniformity among researchers, we
recently introduced the term "cromics" (circular ribonucleic acids based omics)
(Singh et al. 2018. Exp. Eye Res. 174: 80-92). Author information:
(1)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The
Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
(2)Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing, China.
(3)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
(4)Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan
University, Shanghai, China.
(5)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The
Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
Electronic address: [email protected].
(6)Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing, China; Eye Institute, Eye & ENT Hospital, Shanghai Medical
College, Fudan University, Shanghai, China. Electronic address:
[email protected].
(7)Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan
University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University),
Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key
Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai,
China. Electronic address: [email protected]. Retinoblastoma (RB) is an intraocular maligcy that mainly occurs in infants
and young children under 5 years of age. Circular RNA hsa_circ_0000034
(circ_0000034) was reported to be upregulated in RB tissues. Nevertheless, the
function and mechanism of circ_0000034 in RB are unclear. Expression of
circ_0000034, microRNA-361-3p (miR-361-3p), and a disintegrin and
metalloproteinase 19 (ADAM19) was examined via quantitative real-time polymerase
chain reaction (qRT-PCR). Cell viability, migration, invasion, and apoptosis
were determined though Cell Counting Kit-8 (CCK-8), transwell, or flow cytometry
assays. Caspase-3 activity was detected using a caspase-3 activity assay kit.
Some protein levels were examined using Western blot analysis. Dual-luciferase
reporter assay, RNA immunoprecipitation (RIP) assay, or RNA pull-down assay were
performed to verify the relationship between circ_0000034 or ADAM19 and
miR-361-3p. The function of circ_0000034 in vivo was confirmed via animal
experiment. We verified that circ_0000034 expression was elevated in RB tissues
and cells. Circ_0000034 silencing reduced RB growth in vivo, repressed
viability, migration, invasion, and EMT, and induced apoptosis of RB cells in
vitro. Circ_0000034 acted as a sponge for miR-361-3p, which targeted ADAM19 in
RB cells. Furthermore, the inhibition of miR-361-3p restored circ_0000034
knockdown-mediated impacts on viability, migration, invasion, apoptosis, and EMT
of RB cells. Moreover, ADAM19 overexpression abolished the influence of
miR-361-3p mimic on viability, migration, invasion, apoptosis, and EMT of RB
cells. Circ_0000034 expedited RB progression through upregulating ADAM19 via
sponging miR-361-3p, which indicated that circ_0000034 might a target for RB
therapy. PURPOSE: This study aimed to determine whether circular RNAs (circRNAs) in whole
blood could be served as novel non-invasive biomarkers for proliferative
diabetic retinopathy (PDR).
METHODS: This retrospective cross-sectional study comprised 34 healthy
participants, 34 PDR patients and 34 non-proliferative DR (NPDR) patients.
High-throughput whole transcriptome sequencing was performed to explore the
expression profile of circRNAs in the whole blood, and the candidate circRNAs
were validated by quantitative real-time polymerase chain reaction (qRT-PCR).
Receiver operating characteristic (ROC) analysis evaluated the ability of these
candidate circRNAs in discriminating PDR patients from NPDR patients and healthy
subjects. Finally, the networks of circRNA-miRNA-mRNA based on the candidate
circRNAs were constructed.
RESULTS: Using sequencing and qRT-PCR, hsa_circ_0001953 was found to be elevated
in PDR patients in contrast with the other two groups. Statistical analysis
showed that the expression levels of hsa_circ_0001953 in PDR patients were
positively related to the duration of diabetes and HbAc1. Receiver operating
characteristic (ROC) curve analysis revealed that hsa_circ_0001953 was
associated with a high diagnostic accuracy in discriminating PDR patients from
NPDR patients and healthy controls, resulting in an area under the curve (AUC)
of 0.87 and 0.92, respectively. The circRNA-miRNA-target gene networks for
hsa_circ_0001953 showed that hsa_circ_0001953 could interact with dozens of
miRNAs and some targeted mRNAs have been potentially involved in the
pathogenesis of diabetes.
CONCLUSION: The present findings indicate that hsa_circ_0001953 in the whole
blood may serve as a novel diagnostic biomarker and potential therapeutic target
for PDR. Epigenetic memory plays crucial roles in gene regulation. It not only modulates
the expression of specific genes but also has ripple effects on transcription as
well as translation of other genes. Very often an alteration in expression
occurs either via methylation or demethylation. In this context, "1-carbon
metabolism" assumes a special significance since its dysregulation by higher
levels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct
of "1-Carbon Metabolism" during methionine biosynthesis leads to serious
implications in cardiovascular, renal, cerebrovascular systems, and a host of
other conditions. Currently, the circular RNAs (circRNAs) generated via
non-canonical back-splicing events from the pre-mRNA molecules are at the center
stage for their essential roles in diseases via their epigenetic manifestations.
We recently identified a circular RNA transcript (circGRM4) that is
significantly upregulated in the eye of cystathionine β-synthase-deficient mice.
We also discovered a concurrent over-expression of the mGLUR4 receptor in the
eyes of these mice. In brief, circGRM4 is selectively transcribed from its
parental mGLUR4 receptor gene (GRM4) functions as a "molecular-sponge" for the
miRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in
response to extremely high circulating glutamate concentration. We opine that
this epigenetic manifestation potentially predisposes HHcy people to
retinovascular malfunctioning. In diabetic patients, diabetic retinopathy (DR) is the leading cause of
blindness and seriously affects the quality of life. However, current treatment
methods of DR are not satisfactory. Advances have been made in understanding
abnormal protein interactions and signaling pathways in DR pathology, but little
is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs
(circRNAs), have been shown to be associated with DR. In this review, we
summarized the function of circRNAs and indicated their roles in the
pathogenesis of DR, which may provide new therapeutic targets for clinical
treatment. |
What happens to the expression levels of piRNAs in the case of intracranial aneurysm rupture? | piRNAs showed a substantial decrease in RNA abundance that was sustained after IA rupture. | Multiple classes of small RNAs (sRNAs) are expressed in the blood and are
involved in the regulation of pivotal cellular processes. We aimed to elucidate
the expression patterns and functional roles of sRNAs in the systemic response
to intracranial aneurysm (IA) rupture. We used next-generation sequencing to
analyze the expression of sRNAs in patients in the acute phase of IA rupture
(first 72 h), in the chronic phase (3-15 months), and controls. The patterns of
alterations in sRNA expression were analyzed in the context of clinically
relevant information regarding the biological consequences of IA rupture. We
identified 542 differentially expressed sRNAs (108 piRNAs, 99 rRNAs, 90 miRNAs,
43 scRNAs, 36 tRNAs, and 32 snoRNAs) among the studied groups with notable
differences in upregulated and downregulated sRNAs between the groups and sRNAs
categories. piRNAs and rRNAs showed a substantial decrease in RNA abundance that
was sustained after IA rupture, whereas miRNAs were largely upregulated.
Downregulated sRNA genes included piR-31080, piR-57947, 5S rRNA, LSU-rRNA, and
SSU-rRNA s. Remarkable enrichment in the representation of transcription factor
binding sites was revealed in genomic locations of the regulated sRNA. We found
strong overrepresentation of glucocorticoid receptor, retinoid x receptor alpha,
and estrogen receptor alpha binding sites at the locations of downregulated
piRNAs, tRNAs, and rRNAs. This report, although preliminary and largely
proof-of-concept, is the first to describe alterations in sRNAs abundance levels
in response to IA rupture in humans. The obtained results indicate novel
mechanisms that may constitute another level of control of the inflammatory
response. KEY MESSAGES: A total of 542 sRNAs were differentially expressed after
aneurysmal SAH comparing with controls piRNAs and rRNAs were upregulated and
miRNAs were downregulated after IA rupture The regulated sRNA showed an
enrichment in the representation of some transcription factor binding sites
piRNAs, tRNAs, and rRNAs showed an overrepresentation for GR, RXRA, and ERALPHA
binding sites. |
Lucio’s Phenomenon is characteristic to which disease? | Lucio's phenomenon is a rare but distinctive skin eruption seen in patients with diffuse lepromatous leprosy. | O Lucio's phenomenon is an uncommon type 2 reactional state occurring
exclusively in patients with diffuse lepromatous leprosy (Lucio-Latapi leprosy).
Previous case reports have been most frequent in Central America and rare in
Asia and Africa. Lucio's phenomenon is characterized by necrotic ulcerations of
the skin preferentially on the lower extremities usually in association with
ongoing Lucio lepromatosis. The purpose of this report is to describe an unusual
case of Lucio's phenomenon occurring four years after successful treatment of
diffuse lepromatous leprosy. The patient was a 51-year-old man who had presented
diffuse lepromatous leprosy ongoing since 1998. Diagnosis was documented based
on histological and bacteriologic evidence. After successful treatment using
dapsone (100 mg/d), rifadine (600 mg/month) and ethionamide (250 mg/d), the
patient was lost from follow-up for 4 years. In January 2005, he consulted again
for alteration of general status. Clinical examination showed inflammatory
livedo on the lower extremities in association with several infiltrating
maculo-papular lesions and painful erythemato-pupuric lesions on the legs and
buttocks. The patient's skin was dry, shiny and galabrous with alopecia of the
eyelashes and eyebrows. Examination of smear samples (skin and nasal) to
identify mycobacterium leprae was negative. Histological study demonstrated
epidermic necrosis with aspects of leucocytoclastic vasculitis. No Virchow cells
were detected and Ziehl staining was negative. Search for circulating immune
complexes and antiphospholipid antibodies was negative. Diagnosis of Lucio's
phenomenon was made and the patient was treated using prednisone at a dose of 1
mg/kg/d in association with rifampicine (600 mg/month) and dapsone (100 mg/d).
Outcome was favorable after one month of treatment. Lucio's phenomenon has
rarely been observed in Tunisia. To our knowledge this is the third case
reported from Tunisia and only 13 cases have been reported in the world since
1983. In all cases including the two from Tunisia, Lucio's phenomenon occurred
during the course of treatment of ongoing Lucio-Latapi lepromatous leprosy (2).
The remarkable features of our case are that Lucio's phenomenon occurred a long
time after successful treatment of lepromatous leprosy and that the patient
responded promptly to treatment. The pathogenesis of Lucio's phenomenon is often
compared with that of erythema nodosum leprosum. Discussion focuses on
pathophysiologic features and natural course of Lucio's phenomenon. Hansen's disease is a chronic granulomatous disease of infectious origin. It has
a worldwide distribution and a variety of clinical manifestations often
involving the skin, nasal mucosa, and peripheral nerves. Lepromatous leprosy
characterizes the condition of a large group of patients with little or no
resistence to the infection. Several forms of lepromatous leprosy are
recognized, including macular, nodular, and diffuse. Lucio's phenomenon is a
rare but distinctive skin eruption seen in patients with diffuse lepromatous
leprosy. The diffuse lesions of Lucio's phenomenon have a predilection for the
extremities, can include nodules, and heal with atrophic stellate scars;
histologically, a necrotizing vasculitis accompanied by a nonspecific
inflammatory reaction may be seen. We describe two patients with Lucio's
phenomenon who presented with nontender, painless, skin lesions with nodules in
part perceptible only by palpation. Both patients were treated with multidrug
therapy, and immunosuppressive doses of steroids as the suggested optimal
treatment for this reactional state. However, Lucio's phenomenon is frequently
fatal as a result of bacterial infection or sepsis, and both patients reported
here died. We call attention to this particular and unusual skin manifestation
of lepromatous leprosy, which can mimic rheumatic disease and other causes of
vasculitis. This is especially likely to be unrecognized in nonendemic countries
but cases will occasionally be seen in this age of extensive international
travel. BACKGROUND: Lucio's phenomenon is a rare and aggressive necrotising variant of
erythema nodosum leprosum that classically occur in patients with undiagnosed,
diffuse non-nodular lepromatous leprosy. It is a potentially fatal leprosy
reaction characterised by extensive, bizarrely-shaped, painful purpuric skin
lesions and ulcerations. Lucio's phenomenon is very rarely reported outside of
Mexico and Costa Rica.
METHODS: We describe 3 cases seen in Johor, Malaysia.
RESULTS: The first two cases responded to the prompt simultaneous institution of
daily rifampicin, dapsone, clofazimine and prednisolone. Case 3 continued to
have new lesions and extension of existing lesions while on dapsone and
clofazimine. The subsequent addition of rifampicin and prednisolone prevented
new lesion formation but patient succumbed to the extensive cutaneous infarcts
and consequent sepsis.
CONCLUSIONS: Early diagnosis and prompt institution of multi-drug therapy
together with prednisolone may improve the prognosis and outcome of Lucio's
phenomenon. BACKGROUND: Lucio's phenomenon is a rare leprosy reaction characterised by
bizarrely-shaped, purpuric skin lesions and ulceration. It occurs in diffuse
lepromatous leprosy and it is mainly reported in patients from Mexico and the
Caribbean.
CASE DESCRIPTION: We describe the case of a 90-year-old Aruban man with
recurrent leg ulcers and flexion contractures of the lower extremities.
Occurrence of Lucio's phenomenon led to a diagnosis of diffuse lepromatous
leprosy. Presence of Mycobacterium leprae was demonstrated in skin, bone marrow
and lymph nodes.
CONCLUSION: Lucio's phenomenon led to a diagnosis of leprosy. Leprosy is still
endemic in Aruba. Lucio's phenomenon is defined as a variant of type 2 leprosy reaction. It is a
rare event, occurring in the evolution of leprosy of Lucio and other forms of
lepromatous leprosy. It has an exacerbated proliferation of Hansen bacilli in
its pathophysiology, which invade blood vessel walls and injure endothelial
cells, causing endothelial proliferation and decreasing the vascular lumen. This
fact, associated with inflammatory reactions and changes in the coagulation
system causes vascular thrombosis, ischemia, infarction and tissue necrosis,
leading to the histopathological characteristic of the phenomenon. We report a
case of lepromatous leprosy with irregular treatment that developed Lucio's
phenomenon. Treatment with multidrug therapy, antibiotics, steroids and
thalidomide achieved a favorable outcome. The different clinical forms of leprosy are mainly related to the variety of
immunological responses to the infection. Several forms of lepromatous leprosy
are recognized, including macular, nodular, and diffuse. Lucio's phenomenon is a
rare but distinctive skin eruption seen in patients with diffuse lepromatous
leprosy. The diffuse lesions of Lucio's phenomenon have a predilection for the
extremities, can include nodules, and heal with atrophic stellate scars;
histologically, a necrotizing vasculitis accompanied by a nonspecific
inflammatory reaction may be seen. Because of its rarity and similarity with
some manifestations of the rheumatic disease and other causes of vasculitis,
Lucio's phenomenon may not be easily recognized, especially in non-endemic
countries, which leads to confusing diagnosis and loss of time for treatment. We
report five patients with vasculitis caused by Lucio's phenomenon. Lucio's phenomenon (LPh) is considered a necrotizing panvasculitis and a variant
of leprosy Type 2 reaction, clinically characterised by necrotic-haemorrhagic
lesions on the extremities and trunk. LPh is observed in diffuse lepromatous
leprosy (DLL or Lucio-Latapí leprosy). This is a distinct form of lepromatous
leprosy (LL) reported mainly in Mexico. Anti-phospholipid antibody syndrome
(APS) has been rarely described in LPh. We report a case of Lucio-Latapí leprosy
with LPh observed in a patient from the province of El Oro in Ecuador, who
presented clinical manifestations of long standing DLL (non-nodular infiltration
of the skin, collapse of the nasal pyramid, madarosis, atrophy of the earlobes),
of LPh (necrotic-haemorrhagic macules with irregular shapes) and of APS
(necrosis of the right big and second toe). Histopathology showed perineural and
periadnexal foamy macrophages with numerous bacilli (diagnostic of LL) in the
subcutis, a mild lobular panniculitis with a large subcutaneous vessel
infiltrated by macrophages in the wall (typical of LPh) and vessels of the
superficial and mid dermis occluded by thrombi but without signs of vasculitis
(typical of occlusive vasculopathy as in APS). Our observations suggest that
some cases of LPh may be associated with APS. Anti-cardiolipin antibodies (aCL)
and lupus anticoagulant (LA) should be tested in patients with LPh because this
may have therapeutic implications. BACKGROUND: Lucio's phenomenon is a rare manifestation of untreated leprosy
which is seen almost exclusively in regions surrounding the Gulf of Mexico. Its
occurrence elsewhere though documented is considered uncommon. We present a case
of Lucio's phenomenon in a previously undiagnosed leprosy patient who presented
to us with its classical skin manifestations.
CASE PRESENTATION: A 64 year old South Asian (Sri Lankan) male with a history of
chronic obstructive airway disease presented to us with fever and cough. He had
a generalized smooth and shiny skin with ulcerating skin lesions afflicting the
digits of the fingers. The lesions progressed to involve the extremities of the
body and healed with crusting. Based on the clinical and investigational
findings Tuberculosis and common vasculitic conditions were suspected and
excluded. The unusual skin manifestations prompted a biopsy, and wade fite
stained revealed Mycobacterium bacilli. In context of the clinical picture and
histological findings, Lucio's phenomenon was suspected. A clinical diagnosis of
Lucio's phenomenon occurring in the backdrop of lepromatous leprosy was made.
CONCLUSION: Though leprosy is still a prevalent disease, it has manifestations
that are not easily recognized or fully appreciated. Regional patterns of
atypical manifestations should not limit better understanding of rarer
manifestations as it will aid in clinching an early diagnosis and instituting
prompt treatment, thereby reducing morbidity and mortality. Diffuse multibacillary leprosy of Lucio and Latapí is mainly reported in Mexico
and Central America. We report a case in a 65-year-old man in Peru. He also had
Lucio's phenomenon, characterized by vascular thrombosis and invasion of blood
vessel walls by leprosy bacilli, causing extensive skin ulcers. Lucio's phenomenon (LP) is a special reactional state associated with diffuse
multibacillary leprosy; both exhibit a limitative global distribution mainly in
Mexico and Central America. We report a case of a 28-year-old female leprosy
patient in the People's Republic of China, together with LP and positive
anticardiolipin antibody, characterized by vascular thrombosis and invasion of
blood vessel walls by leprosy bacilli, causing extensive skin ulcers and
followed by a large number of atrophic scars. BACKGROUND: Leprosy is a chronic granulomatous infection caused by Mycobacterium
leprae. It is a polymorphic disease with a wide range of cutaneous and neural
manifestations. Ulcer is not a common feature in leprosy patients, except during
reactional states, Lucio's phenomenon (LP), or secondary to neuropathies.
CASES PRESENTATION: We report eight patients with multibacillary leprosy who
presented specific skin ulcers as part of their main leprosy manifestation.
Ulcers were mostly present on lower limbs (eight patients), followed by the
upper limbs (three patients), and the abdomen (one patient). Mean time from
onset of skin ulcers to diagnosis of leprosy was 17.4 months: all patients were
either misdiagnosed or had delayed diagnosis, with seven of them presenting
grade 2 disability by the time of the diagnosis. Reactional states, LP or
neuropathy as potential causes of ulcers were ruled out. Biopsy of the ulcer was
available in seven patients: histopathology showed mild to moderate
lympho-histiocytic infiltrate with vacuolized histiocytes and intact isolated
and grouped acid-fast bacilli. Eosinophils, vasculitis, vasculopathy or signs of
chronic venous insufficiency were not observed. Skin lesions improved rapidly
after multidrug therapy, without any concomitant specific treatment for ulcers.
CONCLUSIONS: This series of cases highlights the importance of recognizing
ulcers as a specific cutaneous manifestation of leprosy, allowing diagnosis and
treatment of the disease, and therefore avoiding development of disabilities and
persistence of the transmission chain of M. leprae. Leprosy is a chronic disease with clinical presentations according to the
immunologic spectrum. Lepromatous form is the most advanced, with the highest
transmissibility and risk of causing disabilities. Lucio's phenomenon is a rare
manifestation among lepromatous patients with a rapid and severe evolution and
high mortality. It is difficult to differentiate from ulcerative/necrotic
erythema nodosum leprosum and has no consensus on how it should be treated. This
article is a qualitative review of the literature after the introduction of
multidrug therapy, aiming to bring consensus related to the clinical, laboratory
and histopathological diagnostic criteria of the disease and its management. |
Where are the complexins expressed? | Complexins (CPLXs), initially identified in neuronal presynaptic terminals, are cytoplasmic proteins that interact with the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex to regulate the fusion of vesicles to the plasma membrane. | Complexins are small α-helical proteins that modulate neurotransmitter release
by binding to SNARE complexes during synaptic vesicle exocytosis. They have been
found to function as fusion clamps to inhibit spontaneous synaptic vesicle
fusion in the absence of Ca(2+), while also promoting evoked neurotransmitter
release following an action potential. Complexins consist of an N-terminal
domain and an accessory α-helix that regulates the activating and inhibitory
properties of the protein, respectively, and a central α-helix that binds the
SNARE complex and is essential for both functions. In addition, complexins
contain a largely unstructured C-terminal domain whose role in synaptic vesicle
cycling is poorly defined. Here, we demonstrate that the C-terminus of
Drosophila complexin (DmCpx) regulates localization to synapses and that
alternative splicing of the C-terminus can differentially regulate spontaneous
and evoked neurotransmitter release. Characterization of the single DmCpx gene
by mRNA analysis revealed expression of two alternatively expressed isoforms,
DmCpx7A and DmCpx7B, which encode proteins with different C-termini that contain
or lack a membrane tethering prenylation domain. The predomit isoform,
DmCpx7A, is further modified by RNA editing within this C-terminal region.
Functional analysis of the splice isoforms showed that both are similarly
localized to synaptic boutons at larval neuromuscular junctions, but have
differential effects on the regulation of evoked and spontaneous fusion. These
data indicate that the C-terminus of Drosophila complexin regulates both
spontaneous and evoked release through separate mechanisms and that alternative
splicing generates isoforms with distinct effects on the two major modes of
synaptic vesicle fusion at synapses. Ribbon synapses of tonically releasing sensory neurons must provide a large pool
of releasable vesicles for sustained release, while minimizing spontaneous
release in the absence of stimulation. Complexins are presynaptic proteins that
may accomplish this dual task at conventional synapses by interacting with the
molecular machinery of synaptic vesicle fusion at the active zone to retard
spontaneous vesicle exocytosis yet facilitate release evoked by depolarization.
However, ribbon synapses of photoreceptor cells and bipolar neurons in the
retina express distinct complexin subtypes, perhaps reflecting the special
requirements of these synapses for tonic release. To investigate the role of
ribbon-specific complexins in transmitter release, we combined presynaptic
voltage clamp, fluorescence imaging, electron microscopy, and behavioral assays
of photoreceptive function in zebrafish. Acute interference with complexin
function using a peptide derived from the SNARE-binding domain increased
spontaneous synaptic vesicle fusion at ribbon synapses of retinal bipolar
neurons without affecting release triggered by depolarization. Knockdown of
complexin by injection of an antisense morpholino into zebrafish embryos
prevented photoreceptor-driven migration of pigment in skin melanophores and
caused the pigment distribution to remain in the dark-adapted state even when
embryos were exposed to light. This suggests that loss of complexin function
elevated spontaneous release in illuminated photoreceptors sufficiently to mimic
the higher release rate normally associated with darkness, thus interfering with
visual signaling. We conclude that visual system-specific complexins are
required for proper illumination-dependent modulation of the rate of
neurotransmitter release at visual system ribbon synapses. Complexins (Cplxs) are small synaptic proteins that cooperate with
SNARE-complexes in the control of synaptic vesicle (SV) fusion. Studies
involving genetic mutation, knock-down, or knock-out indicated two key functions
of Cplx that are not mutually exclusive but cannot easily be reconciled, one in
facilitating SV fusion, and one in "clamping" SVs to prevent premature fusion.
Most studies on the role of Cplxs in mammalian synapse function have relied on
cultured neurons, heterologous expression systems, or membrane fusion assays in
vitro, whereas little is known about the function of Cplxs in native synapses.
We therefore studied consequences of genetic ablation of Cplx1 in the mouse
calyx of Held synapse, and discovered a developmentally exacerbating phenotype
of reduced spontaneous and evoked transmission but excessive asynchronous
release after stimulation, compatible with combined facilitating and clamping
functions of Cplx1. Because action potential waveforms, Ca(2+) influx, readily
releasable SV pool size, and quantal size were unaltered, the reduced synaptic
strength in the absence of Cplx1 is most likely a consequence of a decreased
release probability, which is caused, in part, by less tight coupling between
Ca(2+) channels and docked SV. We found further that the excessive asynchronous
release in Cplx1-deficient calyces triggered aberrant action potentials in their
target neurons, and slowed-down the recovery of EPSCs after depleting stimuli.
The augmented asynchronous release had a delayed onset and lasted hundreds of
milliseconds, indicating that it predomitly represents fusion of newly
recruited SVs, which remain unstable and prone to premature fusion in the
absence of Cplx1. Complexins play a critical role in the regulation of neurotransmission by
regulating SNARE-mediated exocytosis of synaptic vesicles. Complexins can exert
either a facilitatory or an inhibitory effect on neurotransmitter release,
depending on the context, and different complexin domains contribute differently
to these opposing roles. Structural characterization of the central helix domain
of complexin bound to the assembled SNARE bundle provided key insights into the
functional mechanism of this domain of complexin, which is critical for both
complexin activities, but many questions remain, particularly regarding the
roles and mechanisms of other complexin domains. Recent progress has clarified
the structural properties of these additional domains, and has led to various
proposals regarding how they contribute to complexin function. This chapter
describes spectroscopic approaches used in our laboratory and others, primarily
involving circular dichroism and solution-state NMR spectroscopy, to
characterize structure within complexins when isolated or when bound to
interaction partners. The ability to characterize complexin structure enables
structure/function studies employing in vitro or in vivo assays of complexin
function. More generally, these types of approaches can be used to study the
binding of other intrinsically disordered proteins or protein regions to
membrane surfaces or for that matter to other large physiological binding
partners. |
Please list the tests used to diagnose Allergic Rhinitis. | Diagnosis of allergic rhinitis is made by a combination of medical history, physical examination, positive methacholine challenge result or bronchodilator responsiveness, determination of IgE-mediated sensitization, and specific inhalation challenge tests as the gold standard, specific IgE screening tests include Skin prick test (SPT), Phadiatop, and nasal provocation test (NPT). | Various methods of diagnosing allergic factors in chronic rhinitis are
discussed. Among the procedures which aim at detecting specific allergens, i.e.
skin testing, RAST, and nasal provocation tests, the last mentioned, as they are
performed directly on the shock organ, have so far been found to give the most
accurate picture of clinically domit allergens and of the intensity and
character of the rhinitis. However, information obtained by analysing the
correlations between different procedures is not uimous. As long as test
techniques and allergen extracts have not been standardized, one particular test
cannot be recommended as the method of choice. After discussing the causes and immunopathology of allergic rhinitis, the
authors describe the most frequently used diagnostic tests, confirming the
validity of PRICK TEST, PRIST, RAST, and TNP. As for treatment, they stress the
special importance of vaccines for specific therapy and of drugs such as
ketotifen and sodium cromoglycate for aspecific rhinitis and for those forms
which have not benefited from vaccination. OBJECTIVE: To identify the most useful combinations of symptoms and the results
of radioallergosorbent tests (RASTs) and skin prick tests (SPTs) for the
diagnosis of allergic rhinitis.
DESIGN: A prospective comparison was made of symptoms and the results of RASTs
and SPTs with 7 different nasal allergies; the references used were the
"consensus diagnoses" provided by 3 experts.
SETTING: Nineteen general practices in The Netherlands.
PATIENTS: 365 consecutive patients aged 12 or over who visited their general
practitioner because of chronic or recurrent nasal symptoms between 1 March 1990
and 1 March 1991.
MAIN OUTCOME MEASURES: The most useful combinations of items from the history,
RASTs, and SPTs, for the diagnosis of 7 different nasal allergies; the
predictive probabilities of these combinations.
RESULTS: Diagnostic criteria could be drawn up resulting in a near-perfect
discrimination between patients diagnosed as having allergic rhinitis and
patients diagnosed as not having allergic rhinitis. Most of these criteria
combined only a single item from the history with either RAST or SPT. For nearly
all nasal allergies, both the negative predictive probabilities and the positive
predictive probabilities were 97% or more.
CONCLUSIONS: The common nasal allergies can be diagnosed with a very high
certainty with the aid of simple diagnostic criteria. Data from a strictly
limited case history combined with either RAST or SPT are sufficient. In the wide spectrum of medical practice, rhinitis is often incorrectly assumed
to be solely allergic in etiology. Consequently, other rhinitis subtypes
(nonallergic and mixed) remain under-diagnosed. This is of concern because
inaccurate diagnosis may lead to unsatisfactory treatment outcome. Contributing
to this under-diagnosis is the fact that primary care practitioners do not often
have at their disposal the same diagnostic tools as the allergist. Tools that
the allergist is more likely to use include nasal cytology, skin testing and in
vitro assays for specific immunoglobulin E. Patients with pure nonallergic
rhinitis have negative skin tests or clinically irrelevant positive results.
Mixed rhinitis refers to the presence of both allergic and nonallergic rhinitis
components within the same individual. Allergic rhinitis more commonly develops
before the age of 20, whereas nonallergic rhinitis affects an older population
and disproportionately more females. The type of nasal symptoms manifested by
the patient usually does not differentiate allergic from nonallergic rhinitis.
Vasomotor rhinitis is the most common form of nonallergic rhinitis, followed by
nonallergic rhinitis with eosinophilia and others. In terms of estimated
prevalence, allergic rhinitis affects approximately 58 million Americans, 19
million have pure nonallergic rhinitis and 26 million have mixed rhinitis. Thus
a wide spectrum of relevant epidemiologic information can be used to assist in
determining the differential diagnosis of rhinitis. Physicians are reminded to
look further and consider whether a rhinitis patient truly has pure allergic
rhinitis or whether a diagnosis of mixed rhinitis or nonallergic rhinitis is
more appropriate. Allergic rhinitis is an increasingly common disease, with a prevalence of at
least 10% to 25% in the United States. Diagnostic allergy tests, such as skin
tests and in vitro tests, can assist clinicians in determining whether nasal
symptoms are allergic in origin. In addition, safe and effective medications are
available to treat allergic rhinitis. The initial strategy should be to
determine whether patients should undergo diagnostic testing or receive
empirical treatment. This paper reviews the test characteristics of the history,
skin tests, and in vitro tests in diagnosing allergic rhinitis from the
perspective of decision thresholds. A combination of pertinent medical history
features in a practice with a high baseline prevalence of allergic rhinitis
justifies the common practice of empirical treatment since allergy medication
has minimal toxicity and side effects. The situation is more complex when the
patient needs a diagnostic test, because reported sensitivities and
specificities of skin tests and in vitro tests vary widely. As a result, it is
difficult to calculate the post-test probability of allergic rhinitis with any
confidence. The decision to initiate diagnostic testing must rely on clinical
judgment to select patients who would benefit most from determining their
allergic status while minimizing unnecessary testing and medications. Diagnosing
allergy to a specific antigen allows patients to avoid the allergen and makes
them candidates for allergen immunotherapy, which can decrease the need for
medications. Non-allergic rhinitis (NAR) is a common disorder, which can be defined as
chronic nasal inflammation, independent of systemic IgE-mediated mechanisms.
Symptoms of NAR patients mimic those of allergic rhinitis (AR) patients.
However, AR patients can easily be diagnosed with skin prick test or
allergen-specific IgE measurements in the serum, whereas NAR patients form a
heterogeneous group and are difficult to diagnose because of an extensive list
of different phenotypes, all varying in severity, underlying etiology and type
of inflammation. Characterization of those phenotypes, mechanisms and management
of NAR represents one of the major unmet needs in the field of allergic and
non-allergic diseases. This review aims at providing a comprehensive overview of
the state of the art in classifying the NAR patients and focuses on the
neuro-immune mechanisms involved in allergic and non-allergic rhinitis,
including reflections on the pathophysiology and the currently available
treatment options. BACKGROUND: Nasal provocation tests (NPTs) are indicated in confirming the
diagnosis of allergic rhinitis if the clinical history, skin tests or sIgE are
inconclusive. NPTs are time- consuming, technically difficult and expensive to
perform. Consequently, conjunctival provocation tests (CPTs), which are easier,
cheaper and safer should be considered as an alternative method. No recent study
has compared CPTs with NPTs in allergic rhinitis children.
OBJECTIVE: To compare CPTs with NPTs in allergic rhinitis children with house
dust mite sensitization
METHODS: Fifty-five children with allergic rhinitis were included. Thirty-six
children had positive skin prick tests (SPTs) to Dermatophagoides pteronyssinus
(Dp). NPTs were performed by spraying 0.1 ml of Dp extract with concentrations
of 50, 200 and 500 AU/ml to each nostril at 15 minute interval. The clinical
symptom scores, anterior rhinomanometry results and nasal peak flow testing were
performed to assess the responses. For CPTs, 0.1 ml of the same concentration of
allergen extract was droppedinto one eye and the control solution was dropped
into the other. The responses were assessed by clinical symptom scores. The
tests were stopped when the subject reported a positive response, or continued
to the maximum concentration.
RESULTS: The sensitivity, specificity, positive predictive value, negative
predictive value and accuracy of CPT compared with NPT are 97.1% (84.7-99.9),
90.5% (69.6-98.8), 94.3% (80.8-99.3), 95% (75.1-99.9) and 94.5 (84.9-98.9),
respectively in all patients. Among individual allergic rhinitis subjects the
sensitivity, specificity, PPV and NPV are 100%.
CONCLUSIONS: CPT can be an alternative test for NPT in allergic rhinitis
children with house dust mite sensitization, even if they do not have
conjunctival symptoms. Publisher: Antecedentes: la rinitis alérgica es la enfermedad alérgica más
frecuente, se distingue por rinorrea, congestión nasal y estornudos, inducidos
por una respuesta mediada por IgE. Objetivo: validar un cuestionario para
diagnóstico clínico de rinitis alérgica. Material y método: prueba de una prueba
en la que se elaboró un cuestionario para el diagnóstico clínico de rinitis
alérgica. Se incluyeron 300 pacientes de uno y otro sexo, 150 niños y 150
adultos, atendidos en consultorios de alergia, de noviembre de 2012 a febrero de
2014. La mitad fueron casos de rinitis alérgica y la mitad controles sin rinitis
alérgica. Los límites de edad fueron 2 y 70 años. En el grupo de niños de 12
años y menores, el cuestionario se aplicó a los padres. Durante este tiempo se
realizaron las pruebas de validación de los cuestionarios. Resultados: las
pruebas aplicadas a las respuestas del cuestionario mostraron en adultos y en
los niños buena concordancia en la prueba-reprueba y en la concordancia
interobservador (evaluación de dos médicos), que fue de sustancial a casi
perfecta. Las pruebas aplicadas para validez de criterio en el cuestionario de
adultos tuvieron sensibilidad de 91%, especificidad de 89%, valor predictivo
positivo de 89% y valor predictivo negativo de 92%. En el cuestionario para
padres, la sensibilidad fue de 94%, la especificidad de 93%, valor predictivo
positivo de 93% y valor predictivo negativo de 94% y los criterios para validez
de contenido y de expresión se cumplieron adecuadamente. La prueba de
homogeneidad alcanzó un puntaje de 0.7 (alfa de Cronbach). Conclusión: el
cuestionario para diagnóstico de rinitis alérgica de adultos y niños tiene buena
concordancia intra e interobservador, con alta sensibilidad y especificidad en
la validez de criterio, y puntaje aceptable en la prueba de homogeneidad. BACKGROUNDS AND OBJECTIVES: Allergic Rhinitis is a universal common disease,
especially in populated cities and urban areas. Diagnosis and treatment of
Allergic Rhinitis will improve the quality of life of allergic patients. Though
skin tests remain the gold standard test for diagnosis of allergic disorders,
clinical experts are required for accurate interpretation of test outcomes. This
work presents a clinical decision support system (CDSS) to assist junior
clinicians in the diagnosis of Allergic Rhinitis.
METHODS: Intradermal Skin tests were performed on patients who had plausible
allergic symptoms. Based on patient׳s history, 40 clinically relevant allergens
were tested. 872 patients who had allergic symptoms were considered for this
study. The rule based classification approach and the clinical test results were
used to develop and validate the CDSS. Clinical relevance of the CDSS was
compared with the Score for Allergic Rhinitis (SFAR). Tests were conducted for
junior clinicians to assess their diagnostic capability in the absence of an
expert.
RESULTS: The class based Association rule generation approach provides a concise
set of rules that is further validated by clinical experts. The interpretations
of the experts are considered as the gold standard. The CDSS diagnoses the
presence or absence of rhinitis with an accuracy of 88.31%. The allergy
specialist and the junior clinicians prefer the rule based approach for its
comprehendible knowledge model.
CONCLUSION: The Clinical Decision Support Systems with rule based classification
approach assists junior doctors and clinicians in the diagnosis of Allergic
Rhinitis to make reliable decisions based on the reports of intradermal skin
tests. BACKGROUND: Allergic rhinitis is the most common type of allergy worldwide. The
accuracy of skin testing for allergic rhinitis is still debated. This health
technology assessment had two objectives: to determine the diagnostic accuracy
of skin-prick and intradermal testing in patients with suspected allergic
rhinitis and to estimate the costs to the Ontario health system of skin testing
for allergic rhinitis.
METHODS: We searched All Ovid MEDLINE, Embase, and Cochrane Database of
Systematic Reviews, Database of Abstracts of Reviews of Effects, CRD Health
Technology Assessment Database, Cochrane Central Register of Controlled Trials,
and NHS Economic Evaluation Database for studies that evaluated the diagnostic
accuracy of skin-prick and intradermal testing for allergic rhinitis using nasal
provocation as the reference standard. For the clinical evidence review, data
extraction and quality assessment were performed using the QUADAS-2 tool. We
used the bivariate random-effects model for meta-analysis. For the economic
evidence review, we assessed studies using a modified checklist developed by the
(United Kingdom) National Institute for Health and Care Excellence. We estimated
the annual cost of skin testing for allergic rhinitis in Ontario for 2015 to
2017 using provincial data on testing volumes and costs.
RESULTS: We meta-analyzed seven studies with a total of 430 patients that
assessed the accuracy of skin-prick testing. The pooled pair of sensitivity and
specificity for skin-prick testing was 85% and 77%, respectively. We did not
perform a meta-analysis for the diagnostic accuracy of intradermal testing due
to the small number of studies (n = 4). Of these, two evaluated the accuracy of
intradermal testing in confirming negative skin-prick testing results, with
sensitivity ranging from 27% to 50% and specificity ranging from 60% to 100%.
The other two studies evaluated the accuracy of intradermal testing as a
stand-alone tool for diagnosing allergic rhinitis, with sensitivity ranging from
60% to 79% and specificity ranging from 68% to 69%. We estimated the budget
impact of continuing to publicly fund skin testing for allergic rhinitis in
Ontario to be between $2.5 million and $3.0 million per year.
CONCLUSIONS: Skin-prick testing is moderately accurate in identifying subjects
with or without allergic rhinitis. The diagnostic accuracy of intradermal
testing could not be well established from this review. Our best estimate is
that publicly funding skin testing for allergic rhinitis costs the Ontario
government approximately $2.5 million to $3.0 million per year. Many cases of AR can be miss-diagnosed due to deficiency in the conventional
laboratory tools. Detection of local Ig E immune response and allergy associated
genes may aid in diagnosis of these cases. The local immune response and the
allergy associated genes of these suspected cases must be evaluated as they may
help in their characterization. This study was conducted on 129 patients with
chronic rhinitis to determine the frequency of LAR, and analyze the association
of IgE receptor (FcεR1β) gene polymorphism with LAR. All participants were
subjected to clinical questionnaire, skin prick test, specific IgE measurement
in serum and nasal secretions and analysis of FcεR1β gene polymorphism. LAR
constituted 24.8 % of total rhinitis cases and 44.4% of non-allergic cases.
Cockroach was the main sensitizing agent in local allergic rhinitis in
comparison with allergic cases (OR =0.11; 95% CI= 0.04-0.34; P<0.001). In LAR,
nasal specific Ig E was significantly lower than that in AR patients (P <
0.001). FcεR1β genotype TT was more frequently expressed in LAR and AR than
non-allergic rhinitis (NAR) (P< 0.001). It is concluded that LAR is an emerging
allergic condition that could be diagnosed by nasal specific IgE, and that
FcεR1β polymorphism is one of the genetic factors associated with AR and LAR. Local Allergic Rhinitis (LAR) is an emerging disease. However, its incidence in
the pediatric popolution has not yet been studied. The gold standard for the
diagnosis is the nasal provocation test that is not everywhere avalaible and
difficult to apply in children. The aim of our study was to evaluate the nasal
lavage fluid IgE as a biomarker of LAR in children. 54 pediatric patients [IQR
4.0-12.0 years] were divided into 3 groups: study group (26 children with
rhinitis symptoms and without evidence of systemic atopy); allergic rhinitis
(AR) group (15 children) and 13 healty controls (HC). Every child was subjected
to nasal lavage using 2 ml/nostril of physiologic saline solution, that was
therefore analyzed by ImmunoCAP to obtain the IgE concentration. Rhinofibroscopy
and nasal cytology were performed. Our data showed the presence of higher value
of nasal lavage fluid IgE (average of 6.005 UI/ml; range: 4.47-7.74 UI/ml) in 16
out of 26 patients of the study group who therefore may be classified as
affected by LAR. We observed a statistically significant difference (P< 0.0001)
between NAR/HC group and LAR group, identifying a cut-off of 3.85 UI/ml.
Finally, we found a better response to previous AR therapy in the LAR group than
in the NAR group. Our data showed the high incidence of LAR in pediatric
patients previously classified as NAR. The measurment of IgE in nasal lavage
fluid may be considered an easy and rapid method for the diagnosis of LAR in
children. Besides, our data add confirmatory evidence about the good response of
LAR children to the classic AR therapy. BACKGROUND: Skin prick test (SPT) or Phadiatop, a multi-allergen IgE screening
test, was used as a tool for detecting aeroallergen sensitization.
OBJECTIVE: To compare SPT and Phadiatop as a tool for diagnosis allergic
rhinitis (AR) using the nasal provocation test (NPT) as a comparative standard.
METHODS: Children aged 5-18 years with rhinitis symptoms more than 6 times in
the past year were enrolled. SPT to 13 common aeroallergens, serum for
Phadiatop, and NPT to Dermatophagoides pteronyssinus (Der p) were performed. NPT
to mixed cockroach (CR) were performed in children who had CR sensitization and
negative NPT to Der p. Children who had a disagreement between the result of SPT
and Phadiatop or having negative results were evaluated for specific IgE (sIgE)
to common aeroallergens.
RESULTS: One hundred-forty children were enrolled with the mean age of 9.8 ± 3
years, 56% were male. Of 92 children (65.7%) with positive SPT to any
aeroallergens, 88 children (95.6%) were sensitized to house dust mite (HDM). NPT
showed positive results in 97 children (69.3%). Of 48 children who showed
negative SPT, 4 children (8.3%) had sIgE to aeroallergens but NPT was positive
in 1 child. Eighty-eight children (62.9%) had positive tests for Phadiatop and 4
(4.5%) of them had negative results for NPT to Der p. Among 52 children who had
negative results for Phadiatop, 4 children (7.6%) had sIgE to aeroallergens but
NPT was positive in 2 children (3.8%). SPT and Phadiatop showed 94.2% agreement:
with Kappa 0.876, p < 0.001. Using NPT as a comparative standard for diagnosis
for AR, SPT showed a sensitivity of 89.6% and specificity of 88.3% and Phadiatop
provided the sensitivity of 88.6% and specificity of 95.3%.
CONCLUSIONS: SPT to aeroallergen and Phadiatop have good and comparable
sensitivity and specificity for the diagnosis of AR in children. BACKGROUND: Three allergic phenotypes of rhinitis have been described in adults:
allergic rhinitis (AR), local allergic rhinitis (LAR), and dual allergic
rhinitis (DAR, coexistence of AR and LAR). Nevertheless, most centers follow a
diagnostic approach only based on skin prick test and serum allergen-specific
IgE (collectively called atopy tests, AT). This approach prevents the
recognition of LAR and DAR, the diagnosis of which requires a nasal allergen
challenge (NAC). Here, we investigate the existence of LAR and DAR phenotypes in
children and adolescents, and the misdiagnosis rate associated with a work-up
exclusively based on AT.
METHODS: Clinical data were obtained during physician-conducted interviews, and
AT and NAC were systematically performed in 5- to 18-year-old patients with
chronic rhinitis. The misdiagnosis rate was defined as the proportion of cases
where AT and NAC results were discordant.
RESULTS: A total of 173 patients (mean age 15.1 years, 39.9% male) completed the
study. AR (positive AT and NAC), LAR (negative AT and positive NAC), DAR
(positive AT and NAC for some allergens and negative AT and positive NAC for
other allergens), and non-allergic rhinitis (negative NAC) were diagnosed in
45.7%, 24.9%, 11.6%, and 17.9% of individuals, respectively. The clinical
profile was comparable among allergic phenotypes, but allergic patients had a
significantly earlier rhinitis onset, higher conjunctivitis prevalence, and more
severe disease than NAR individuals. A diagnostic work-up exclusively based on
AT misclassified 37.6% of patients.
CONCLUSIONS: LAR and DAR represent relevant differential diagnosis in pediatric
rhinitis. NAC increases the diagnostic accuracy of clinical algorithms for
rhinitis in children and adolescents. BACKGROUND: Screening for the existence of aeroallergens in patients with
possible allergic rhinitis using venous blood samples has become more popular,
with advantages of increased convenience and less consumption of time.
OBJECTIVE: The aim of this study was to investigate the sensitivities and
specificities of Phadiatop tests and total immunoglobulin E (IgE) levels in both
adults and children.
METHODS: This study was conducted prospectively in a tertiary center. The
process of recruitment took place from Jan 2015 to Dec 2019, and patients with
clinical symptoms that suggested persistent allergic rhinitis were recruited and
their serum samples collected. The results of the total IgE and Phadiatop tests
as well as the positive items in the ImmunoCAP assay were recorded and analyzed.
RESULTS: A total of 9174 cases with complete data were enrolled, including 576
children and 8598 adults. A positive result in the ImmunoCAP assay was
considered a positive atopic status towards aeroallergens. While using the total
IgE levels to predict positive aeroallergens, the sensitivities and
specificities were 65.7% and 85.7%, respectively, for adults and 86.3% and
77.4%, respectively, for children. When we used Phadiatop tests for allergy
screening, the sensitivities and specificities was 94.5% and 98.2%,
respectively, for the adult group and 98.5% and 96.8%, respectively, for the
pediatric group.
CONCLUSION: The Phadiatop test had better diagnostic power for aeroallergen
detection than the serum total IgE levels, or even the dual test, for both the
adult and pediatric groups in this hospital-based study. We suggest that the
Phadiatop test is more cost-effective in aeroallergen screening for patients
with suspected atopic airway diseases. Occupational allergies are among the most common recorded occupational diseases.
The skin and the upper and lower respiratory tract are the classical
manifestation organs. More than 400 occupational agents are currently documented
as being potential "respiratory sensitizers" and new reported causative agents
are reported each year. These agents may induce occupational rhinitis (OR) or
occupational asthma (OA) and can be divided into high-molecular weight (HMW) and
low-molecular weight (LMW) agents. The most common occupational HMW agents are
(glycol)proteins found in flour and grains, enzymes, laboratory animals, fish
and seafood, molds, and Hevea brasiliensis latex. Typical LMW substances are
isocyanates, metals, quaternary ammonium persulfate, acid anhydrides, and
cleaning products/disinfectants. Diagnosis of occupational respiratory allergy
is made by a combination of medical history, physical examination, positive
methacholine challenge result or bronchodilator responsiveness, determination of
IgE-mediated sensitization, and specific inhalation challenge tests as the gold
standard. Accurate diagnosis of asthma is the first step to managing OA as shown
above. Removal from the causative agent is of central importance for the
management of OA. The best strategy to avoid OA is primary prevention, ideally
by avoiding the use of and exposure to the sensitizer or substituting safer
substances for these agents. Allergic rhinitis (AR) is a global health problem: its prevalence is 23% in
Europe, although it is underestimated because as many as 45% of the cases remain
undiagnosed. Globally, almost 500 million people suffer from AR, which shows its
increasing incidences. The diagnostic course of AR is based on clinical history,
supported by anterior rhinoscopy. This inspects the anterior part of the nasal
cavity accompanied by allergic sensitivity tests (cutaneous allergic skin tests
or specific immunoglobulin E levels). The availability of standardised
diagnostic procedures is able to provide objective evaluations of inflammatory
situation, and the degree of nasal obstruction may give an advantage in reducing
the risk of underestimating the diagnosis of AR. Diagnostic tests with a high
level of accuracy are able to provide immediate results, which can sustain the
doctor in diagnostic-therapeutic framework. The development of Point of Care
Tests (POCTs) could be a useful tool. Considering that nasal obstruction is the
most common symptom in patients with AR, the rhinomanometry (RM) test is the
most indicated objective evaluation for nasal obstruction. Several studies have
also shown the practicability of such diagnostic techniques applied in children.
So far, no study has evaluated whether all the applicable requirements are
fulfilled by RM in order to be considered as a POCT. The purpose of this
perspective was to assess whether all the POCT requirements are fulfilled by RM
by conducting a narrative review of the existing literature in which RM has been
used in the diagnosis and management of AR in children. A few but encouraging
results of studies on children supported the potential use of RM in the area of
POCT. However, costs of instruments and the training of personnel involved
remain to be explored. The studies support the potential use of RM in POCTs. BACKGROUND AND AIM: Skin prick test (SPT) with a wheal diameter of >3 mm,
generally accepted as a positive, is most commonly use diagnostic tool for
Allergic rhinitis. Aim was to validate wheal size of Skin Prick Test for the
Bermuda grass, in desert environment, with positive Bermuda grass Nasal
challenge in same environment.
METHODS: In 53 adults, mean age 33.43 ± 9.36 years, both gender (females:
33.96%), SPT positive on Bermuda grass with cut off wheal longest diameter of 3
mm, Bermuda grass nasal challenge test (bgNCT) was carried out. Response was
assessed subjectively (scored) and objectively (PNIF). Safety profile was
assessed by PEF measurement.
RESULTS: Mean weal size of SPT (mm) was bigger in bgNCT positive patients (n=47;
88.68%) 8 [4, 15] vs 5 [3, 6] (p<0.0001). ROC analysis showed Bermuda Grass SPT
at the threshold of >6.5mm enabled identification of Bermuda challenge with
sensitivity of 82.98% and specificity of 100.0% (area under the curve 0.9326,
standard error 0.03528; 95% confidence interval (CI): 0.8635 to 1.002;
p=0.0006203).
CONCLUSIONS: A SPT wheal size ≥6.5mm might be considered as an appropriate
wheal size for confirming Bermuda grass allergy in adults with SAR, avoiding the
demanding, time consuming and often unavailable bgNCT, especially in patients
eligible for allergen immunotherapy. In these patients, bgNCT is recommended if
SPT wheal size is <6.5 mm. |
Can epigenetic modifications be heritable? | Epigenetic alterations (epimutations) could thus contribute to heritable variation within populations and be subject to evolutionary processes such as natural selection and drift. | |
What is the role of the AIMS65 score? | AIMS65 score is used to predict outcomes after upper GI bleeding. | INTRODUCTION: We previously derived and validated the AIMS65 score, a mortality
prognostic scale for upper GI bleeding (UGIB).
OBJECTIVE: To validate the AIMS65 score in a different patient population and
compare it with the Glasgow-Blatchford risk score (GBRS).
DESIGN: Retrospective cohort study.
PATIENTS: Adults with a primary diagnosis of UGIB.
PRIMARY OUTCOME: inpatient mortality.
SECONDARY OUTCOMES: composite clinical endpoint of inpatient mortality,
rebleeding, and endoscopic, radiologic or surgical intervention; blood
transfusion; intensive care unit admission; rebleeding; length of stay; timing
of endoscopy. The area under the receiver-operating characteristic curve (AUROC)
was calculated for each score.
RESULTS: Of the 278 study patients, 6.5% died and 35% experienced the composite
clinical endpoint. The AIMS65 score was superior in predicting inpatient
mortality (AUROC, 0.93 vs 0.68; P < .001), whereas the GBRS was superior in
predicting blood transfusions (AUROC, 0.85 vs 0.65; P < .01) The 2 scores were
similar in predicting the composite clinical endpoint (AUROC, 0.62 vs 0.68; P =
.13) as well as the secondary outcomes. A GBRS of 10 and 12 or more maximized
the sum of the sensitivity and specificity for inpatient mortality and
rebleeding, respectively. The cutoff was 2 or more for the AIMS65 score for both
outcomes.
LIMITATIONS: Retrospective, single-center study.
CONCLUSION: The AIMS65 score is superior to the GBRS in predicting inpatient
mortality from UGIB, whereas the GBRS is superior for predicting blood
transfusion. Both scores are similar in predicting the composite clinical
endpoint and other outcomes in clinical care and resource use. AIM: To evaluate the applicability of AIMS65 scores in predicting outcomes of
peptic ulcer bleeding.
METHODS: This was a retrospective study in a single center between January 2006
and December 2011. We enrolled 522 patients with upper gastrointestinal
haemorrhage who visited the emergency room. High-risk patients were regarded as
those who had re-bleeding within 30 d from the first endoscopy as well as those
who died within 30 d of visiting the Emergency room. A total of 149 patients
with peptic ulcer bleeding were analysed, and the AIMS65 score was used to
retrospectively predict the high-risk patients.
RESULTS: A total of 149 patients with peptic ulcer bleeding were analysed. The
poor outcome group comprised 28 patients [male: 23 (82.1%) vs female: 5 (10.7%)]
while the good outcome group included 121 patients [male: 93 (76.9%) vs female:
28 (23.1%)]. The mean age in each group was not significantly different. The
mean serum albumin levels in the poor outcome group were slightly lower than
those in the good outcome group (P = 0.072). For the prediction of poor outcome,
the AIMS65 score had a sensitivity of 35.5% (95%CI: 27.0-44.8) and a specificity
of 82.1% (95%CI: 63.1-93.9) at a score of 0. The AIMS65 score was insufficient
for predicting outcomes in peptic ulcer bleeding (area under curve = 0.571;
95%CI: 0.49-0.65).
CONCLUSION: The AIMS65 score may therefore not be suitable for predicting
clinical outcomes in peptic ulcer bleeding. Low albumin levels may be a risk
factor associated with high mortality in peptic ulcer bleeding. A novel upper gastrointestinal bleeding risk stratification score (AIMS65) has
recently been developed and validated. It has advantages over existing risk
scores including being easy to remember and lack of subjectivity in calculation.
We comment on a recent study that has cast doubt on the applicability of AIMS65
in the peptic ulcer disease population. Although promising, further studies are
required to evaluate the validity of AIMS65 in various populations. BACKGROUND: The AIMS65 score and the Glasgow-Blatchford risk score (GBRS) are
validated preendoscopic risk scores for upper gastrointestinal hemorrhage
(UGIH).
GOALS: To compare the 2 scores' performance in predicting important outcomes in
UGIH.
STUDY: A prospective cohort study in 2 tertiary referral centers and 1 community
teaching hospital. Adults with UGIH were included. The AIMS65 score and GBRS
were calculated for each patient. The primary outcome was inpatient mortality.
Secondary outcomes were 30-day mortality, in-hospital rebleeding, 30-day
rebleeding, length of stay, and a composite endpoint of in-hospital mortality,
transfusions, or need for intervention (endoscopic, radiologic, or surgical
treatment). The area under the receiver operating characteristic curve (AUROC)
was calculated for each score and outcome.
RESULTS: A total of 298 patients were enrolled. The AIMS65 score was superior to
the GBRS in predicting in-hospital mortality (AUROC, 0.85 vs. 0.66; P<0.01) and
length of stay (Somer's D, 0.21 vs. 0.13; P=0.04). The scores were similar in
predicting 30-day mortality (AUROC, 0.74 vs. 0.65; P=0.16), in-hospital
rebleeding (AUROC, 0.69 vs. 0.62; P=0.19), 30-day rebleeding (AUROC, 0.63 vs.
0.63; P=0.90), and the composite outcome (AUROC, 0.57 vs. 0.59; P=0.49). The
optimal cutoffs for predicting in-hospital mortality were an AIMS65 score of 3
and a GBRS score of 10. For predicting rebleeding, the optimal cutoffs were 2
and 10, respectively.
CONCLUSIONS: The AIMS65 score is superior to the GBRS for predicting in-hospital
mortality and hospital length of stay for patients with UGIH. The AIMS65 score
and GBRS are similar in predicting 30-day mortality, rebleeding, and a composite
endpoint. BACKGROUND AND AIMS: The American College of Gastroenterology recommends early
risk stratification in patients presenting with upper GI bleeding (UGIB). The
AIMS65 score is a risk stratification score previously validated to predict
inpatient mortality. The aim of this study was to validate the AIMS65 score as a
predictor of inpatient mortality in patients with acute UGIB and to compare it
with established pre- and postendoscopy risk scores.
METHODS: ICD-10 (International Classification of Diseases, Tenth Revision) codes
identified patients presenting with UGIB requiring endoscopy. All patients were
risk stratified by using the AIMS65, Glasgow-Blatchford score (GBS),
pre-endoscopy Rockall, and full Rockall scores. The primary outcome was
inpatient mortality. Secondary outcomes were a composite endpoint of inpatient
mortality, rebleeding, and endoscopic, radiologic, or surgical intervention;
blood transfusion requirement; intensive care unit (ICU) admission; rebleeding;
and hospital length of stay. The area under the receiver-operating
characteristic curve (AUROC) was calculated for each score.
RESULTS: Of the 424 study patients, 18 (4.2%) died and 69 (16%) achieved the
composite endpoint. The AIMS65 score was superior to both the GBS (AUROC, 0.80
vs 0.76, P < .027) and the pre-endoscopy Rockall score (0.74, P = .001) and
equivalent to the full Rockall score (0.78, P = .18) in predicting inpatient
mortality. The AIMS65 score was superior to all other scores in predicting the
need for ICU admission and length of hospital stay. AIMS65, GBS, and full
Rockall scores were equivalent (AUROCs, 0.63 vs 0.62 vs 0.63, respectively) and
superior to pre-endoscopy Rockall (AUROC, 0.55) in predicting the composite
endpoint. GBS was superior to all other scores for predicting blood transfusion.
CONCLUSION: The AIMS65 score is a simple risk stratification score for UGIB with
accuracy superior to that of GBS and pre-endoscopy Rockall scores in predicting
in-hospital mortality and the need for ICU admission. BACKGROUND/AIMS: To validate the AIMS65 score for predicting mortality of
patients with nonvariceal upper gastrointestinal bleeding and to evaluate the
effectiveness of urgent (<8 hours) endoscopic procedures in patients with high
AIMS65 scores.
METHODS: This was a 5-year single-center, retrospective study. Nonvariceal,
upper gastrointestinal bleeding was assessed by using the AIM65 and Rockall
scores. Scores for mortality were assessed by calculating the area under the
receiver-operating characteristic curve (AUROC). Patients with high AIMS65
scores (≥2) were allocated to either the urgent or non-urgent endoscopic
procedure group. In-hospital mortality, success of endoscopic procedure,
recurrence of bleeding, admission period, and dose of transfusion were compared
between groups.
RESULTS: A total of 634 patients were analyzed. The AIMS65 score successfully
predicted mortality (AUROC=0.943; 95% confidence interval [CI], 0.876 to 0.99)
and was superior to the Rockall score (AUROC=0.856; 95% CI, 0.743 to 0.969) in
predicting mortality. The group with high AIMS65 score included 200 patients.
The urgent endoscopic procedure group had reduced hospitalization periods
(p<0.05).
CONCLUSIONS: AIMS65 score may be useful in predicting mortality in patients with
nonvariceal upper gastrointestinal bleeding. Urgent endoscopic procedures in
patients with high scores may be related to reduced hospitalization periods. Background. The Rockall, Glasgow-Blatchford, and AIMS65 are useful and validated
scoring systems for predicting the outcomes of patients with nonvariceal
gastrointestinal bleeding. However, there are no validated evidence for using
them to predict outcomes on variceal bleeding. The aim of this study was to
evaluate and compare the prognostic accuracy of different nonvariceal bleeding
scores with other liver-specific scoring systems in cirrhotic patients.
MATERIAL AND METHODS: A retrospective multicenter study that included 160
cirrhotic patients with acute variceal bleeding. The AUROC's to predict
in-hospital mortality, and rebleeding, were analyzed for each scoring system.
RESULTS: Overall in-hospital mortality occurred in 13% and in-hospital
rebleeding in 12% of patients. The systems with the best AUROC value for
predicting mortality were MELD (0.828; 95% CI 0.748-0.909), and AIMS65 (0.817;
95% CI 0.724-0.909). The best score systems for predicting rebleeding were
Glasgow-Blatchford (0.756; 95% CI 0.640- 0.827), and Rockall (0.691; 95% CI
0.580-0.802).
CONCLUSIONS: In addition to liver-specific scores, the AIMS65 score is accurate
for predicting in-hospital mortality in cirrhotic patients with acute variceal
bleeding. Other scoring systems might be useful for predicting significant
clinical outcomes in these patients. INTRODUCTION: The early use of risk stratification scores is recommended for
patients presenting with acute non-variceal upper gastrointestinal (GI) bleeds
(ANVGIB). AIMS65 is a novel, recently derived scoring system, which has been
proposed as an alternative to the more established Glasgow-Blatchford score
(GBS).
OBJECTIVE: To validate the AIMS65 scoring system in a predomitly Caucasian
population from Scotland and compare it with the GBS.
DESIGN: Retrospective study of patients presenting to a district general
hospital in Scotland with a suspected diagnosis of ANVGIB who underwent
inpatient upper GI endoscopy between March 2008 and March 2013.
OUTCOMES: The primary outcome measure was 30-day mortality. Secondary outcome
measures were requirement for endoscopic intervention, endoscopy refractory
bleeding, blood transfusion, rebleeding and admission to high dependency unit
(HDU) and intensive care unit (ICU). The area under the receiver operating
characteristic (AUROC) curve was calculated for each score.
RESULTS: 328 patients were included. Of these 65.9% (n=216) were men and 34.1%
(n=112) women. The mean age was 65.2 years and 30-day mortality 5.2%. AIMS65 was
superior to the GBS in predicting mortality, with an AUROC of 0.87 versus 0.70
(p<0.05). The GBS was superior for blood transfusion (AUROC 0.84 vs 0.62,
p<0.05) and admission to HDU (AUROC 0.73 vs 0.62, p<0.05). There were no
significant differences between the scores with respect to requirement for
endoscopic intervention, endoscopy refractory bleeding, rebleeding and admission
to ICU.
CONCLUSIONS: AIMS65 accurately predicted mortality in a Scottish population of
patients with ANVGIB. Large prospective studies are now required to establish
the exact role of AIMS65 in triaging patients with ANVGIB. BACKGROUND AND AIM: Risk stratification is recommended in all patients with
acute variceal bleeding (AVB). It remains unclear whether liver disease severity
or upper gastrointestinal bleeding (UGIB) scoring algorithms offer superior
predictive ability. We aimed to validate the AIMS65 score as a predictor of
mortality in AVB, and to compare AIMS65 with established UGIB and liver disease
severity risk stratification scores.
METHODS: International Classification of Diseases, Tenth Revision codes
identified patients presenting with AVB to three tertiary centers over a
48-month period. Patients were risk-stratified using AIMS65, Rockall,
pre-endoscopy Rockall, Child-Pugh, Model for End-stage Liver Disease (MELD) and
United Kingdom MELD (UKELD) scores. Primary outcomes were inpatient and 6-week
mortality and inpatient rebleeding.
RESULTS: Two hundred and twenty-three patients were included. Inpatient and
6-week mortality were 13.9% and 15.5% respectively. Prediction of inpatient
mortality by AIMS65 (area under the receiver-operating characteristic curve
[AUROC: 0.84]) was equivalent to UGIB (Rockall: 0.79, pre-Rockall: 0.78) and
liver risk scores (MELD: 0.81, UKELD: 0.79, Child-Pugh: 0.78). AIMS65 score ≥3
best defined high- and low-risk groups for inpatient mortality (mortality 37.7%
vs 4.9%). AIMS65 (AUROC: 0.62) was equivalent to UGIB risk scores (pre-Rockall:
0.64, Rockall: 0.70) in predicting inpatient rebleeding and superior to liver
risk scores (MELD: 0.56, UKELD: 0.57, Child-Pugh: 0.60).
CONCLUSIONS: AIMS65 is equivalent to established UGIB and liver disease severity
risk stratification scores in predicting mortality, and superior to liver scores
in predicting rebleeding. BACKGROUND: Determining the risk stratification of nonvariceal upper
gastrointestinal bleeding (NVUGIB) plays a vital role in treating upper
gastrointestinal bleeding (UGIB). Traditional scores like Glasgow-Blatchford
score (GBS), Rockall score (RS), and AIMS65 score have been widely utilized in
UGIB practice, however exhibiting limited practical use due to relative lack of
user-friendly characters. Prealbumin as a nutritional indicator and d-dimer as a
fibrinolytic activity monitor, are generally used to evaluate the overall
nutritional and fibrinolytic condition in UGIB patients.
AIMS: Here, we explored the predictive value of these two markers in NVUGIB for
evaluating severity and prognosis including rebleeding and surgery intervention.
METHODS: One hundred and eighty-five patients suffering NVUGIB were enrolled.
Their GBS, RS, and AIMS65 score, routine laboratory test results including
prealbumin and d-dimer were determined after admission. Multivariate regression
analysis was performed to define the independent predictors of rebleeding. ROC
curves were generated to compare the suitability of prealbumin, d-dimer, and
scores for rebleeding prediction.
RESULTS: The NVUGIB patients with rebleeding exhibited higher scores, white
blood cell counts, d-dimer, CRP, proportion of surgery intervention, and longer
hospital stay, but lower hematocrit, hemoglobin, calcium, prealbumin, and
fibrinogen than those without rebleeding. The multivariate regression analysis
demonstrated that prealbumin and d-dimer were independent predictors for
rebleeding. Values of prealbumin and d-dimer were correlated with hospital stay,
ulcer degrees, and surgery demand. The ROC curve analyses showed that prealbumin
and d-dimer exhibited superior prediction value over the scoring systems.
CONCLUSIONS: Prealbumin and d-dimer are promising predictors for severity and
prognosis in NVUGIB practice. BACKGROUND/AIMS: This study aimed to determine the performance of the AIMS65
score (AIMS65), Glasgow-Blatchford score (GBS), and Rockall score (RS) in
predicting outcomes in patients with upper gastrointestinal bleeding (UGIB), and
to compare the results between patients with nonvariceal UGIB (NVUGIB) and those
with variceal UGIB (VUGIB).
METHODS: We conducted a prospective observational study between March 2016 and
December 2017. Receiver operating characteristic curve analysis was performed
for all outcomes for comparison. The associations of all three scores with
mortality were evaluated using multivariate logistic regression analysis.
RESULTS: Of the total of 337 patients with UGIB, 267 patients (79.2%) had
NVUGIB. AIMS65 was significantly associated (odds ratio [OR], 1.735; 95%
confidence interval [CI], 1.148-2.620), RS was marginally associated (OR, 1.225;
95% CI, 0.973-1.543), but GBS was not associated (OR, 1.017; 95% CI,
0.890-1.163) with mortality risk in patients with UGIB. However, all three
scores accurately predicted all other outcomes (all p<0.05) except rebleeding
(p>0.05). Only AIMS65 precisely predicted mortality, the need for blood
transfusion and the composite endpoint (all p<0.05) in patients with VUGIB.
CONCLUSION: AIMS65 is superior to GBS and RS in predicting mortality in patients
with UGIB, and also precisely predicts the need for blood transfusion and the
composite endpoint in patients with VUGIB. No scoring system could
satisfactorily predict rebleeding in all patients with UGIB. BACKGROUND AND AIM: Duodenal ulcer bleeding has a higher risk of mortality than
bleeding from other portions of the gastrointestinal tract. AIMS65 is an
effective risk-scoring system to predict prognosis of upper gastrointestinal
bleeding and can be easily calculated without endoscopic findings. In this
study, we investigate the usefulness of AIMS65 to predict prognosis of patients
with duodenal ulcer bleeding.
METHODS: Two hundred and fifty-five patients with endoscopically diagnosed
duodenal ulcer bleeding at Kurashiki Central hospital from July 2007 to June
2017 were studied. We compared AIMS65, Glasgow Blatchford score (GBS), admission
Rockall, and full Rockall scoring systems for predicting in-hospital mortality
by calculating area under the receiver operating characteristic curve (AUROC).
RESULTS: In-hospital mortality due to duodenal ulcer bleeding occurred in 17
(6.7%). Scores of all scoring systems were significantly higher in patients with
in-hospital mortality than in patients without it. AUROC values for predicting
in-hospital mortality was 0.83 in AIMS65, 0.74 in GBS, 0.76 in admission Rockall
score, and 0.82 in full Rockall score, a statistically insignificant difference
among the systems. In AIMS65, score more than or equal to 2 was an optimal value
to predict in-hospital mortality, with sensitivities of 88.2% and specificities
of 59.7%, respectively.
CONCLUSIONS: AIMS65 predicted in-hospital mortality of patients with duodenal
ulcer bleeding as accurately as did other scoring systems. Given its simplicity
of calculation, AIMS65 may be a more clinically practical system in the
management of bleeding duodenal ulcer patients. BACKGROUND AND OBJECTIVES: Acute upper gastrointestinal bleeding (UGIB) is a
common problem that can cause significant morbidity and mortality. We aimed to
compare the performance of the ABC score (ABC), the AIMS65 score (AIMS65), the
Glasgow-Blatchford score (GBS), and the pre-endoscopic Rockall score (pRS) in
predicting 90-day mortality or rebleeding among patients with acute UGIB.
METHODS: This was a prospective multicenter study conducted at 20 tertiary
hospitals in China. Data were collected between June 30, 2020 and February 10,
2021. An area under the receiver operating characteristic curve (AUC) analysis
was used to compare the performance of the four scores in predicting 90-day
mortality or rebleeding.
RESULTS: Among the 1072 patients included during the study period, the overall
90-day mortality rate was 10.91% (117/1072) and the rebleeding rate was 12.03%
(129/1072). In predicting 90-day mortality, the ABC and pRS scores performed
better with an AUC of 0.722 (95% CI 0.675-0.768; P<0.001) and 0.711 (95% CI
0.663-0.757; P<0.001), respectively, compared to the AIMS-65 (AUC, 0.672; 95%
CI, 0.624-0.721; P<0.001) and GBS (AUC, 0.624; 95% CI, 0.569-0.679; P<0.001)
scores. In predicting rebleeding in 90 days, the AUC of all scores did not
exceed 0.70.
CONCLUSION: In patients with acute UGIB, ABC and pRS performed better than
AIMS-65 and GBS in predicting 90-day mortality. The performance of each score is
not satisfactory in predicting rebleeding, however. Newer predictive models are
needed to predict rebleeding after UGIB. OBJECTIVE: Several mortality prediction scores are available for patients with
upper gastrointestinal bleeding who visited the emergency department; however,
most of the available scores include endoscopic data. Endoscopy is difficult or
impossible to access for many emergencies departments worldwide. The aim of this
study was to evaluate and compare the performance of the albumin, INR,
alteration in mental status, systolic blood pressure and age 65 score and the
Glasgow-Blatchford score in predicting mortality in patients with upper
gastrointestinal bleeding who visited the emergency department and for which
endoscopic data were not required.
METHODS: The data of patients with acute upper gastrointestinal bleeding who
visited the emergency department during the study period were retrospectively
analyzed. The data were obtained from the hospital automation system using the
international classification of disease codes via computer registration. The
prediction accuracy of AIMS65 and Glasgow-Blatchford score was compared using
the area under the receiver operating characteristic curve method.
RESULTS: There were 422 patients in total; the mean age of these patients was
68.5 while 62.6% were males. The mortality rate was 30 (7.1%). The AIMS65 score
performed better with an AUC 0.706 [95%CI 0.660-0.749; p<0.001] compared with
the Glasgow-Blatchford score (AUC 0.542; 95%CI 0.4693-0.576; p=0.11).
CONCLUSION: In this study, it was revealed that AIMS65, which is a score that
can be easily calculated only with the data in the emergency department,
outperformed Glasgow-Blatchford score in predicting mortality in patients with
acute upper gastrointestinal bleeding who visited the emergency department. |
What is the gene ABCG1 encoding? | ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. | BACKGROUND: Cholesterol metabolism is tightly regulated at the cellular level.
This study was to measure the expression levels of ATP-binding cassette
transporter A1 (ABCA1) and G1 (ABCG1), scavenger receptor class B type I (SR-BI)
and class A (SRA), and CD36 mRNAs in peripheral blood mononuclear cells (PBMCs)
in response to 100-km ultramarathon event and determine any correlation between
these ABC transporters/scavenger receptor expression levels and plasma
cholesterol homeostasis.
MATERIALS AND METHODS: Twenty-six participants were enrolled. Blood was drawn
from each individual 1 week prior, immediately after, and 24 hours after the
race. The expression levels of ABCA1, ABCG1, SR-BI, SRA and CD36 in PBMCs were
measured by using real-time quantitative reverse transcription polymerase chain
reaction.
RESULTS: Plasma triglyceride levels were significantly increased immediately
after the race and dropped at 24-hour post-race compared with pre-race values.
The 100-km ultramarathon boosted high-density lipoprotein cholesterol (HDL-C)
levels and decreased low-density lipoprotein cholesterol (LDL-C) levels 24-hour
post-race. The expression levels of ABCA1, ABCG1 and SR-BI were markedly
decreased, whereas that of CD36 was slightly but significantly upregulated in
runners' PBMCs immediately after the race. Ultramarathon resulted in immediate
large-scale stimulation of inflammatory cytokines with increased plasma
interleukin-6 and tumour necrosis factor-alpha levels. Moreover, by using in
vitro models with human monocytic cell lines, incubation of runners' plasma
immediately after the race significantly downregulated ABCA1 and ABCG1, and
upregulated CD36 expression in these cells.
CONCLUSIONS: ABCA1, ABCG1 and CD36 gene expressions in PBMCS might be associated
with endurance exercise-induced plasma cholesterol homeostasis and systemic
inflammatory response. Atherosclerosis and related cardiovascular diseases pose severe threats to human
health worldwide. There is evidence to suggest that at least 50% of foam cells
in atheromas are derived from vascular smooth muscle cells (VSMCs); the first
step in this process involves migration to human atherosclerotic lesions. Long
non‑coding RNAs (lncRNAs) have been found to play significant roles in diverse
biological processes. The present study aimed to investigate the role of lncRNAs
in VSMCs. The expression of lncRNAs or mRNAs was detected using reverse
transcription‑quantitative polymerase chain reaction. The Gene Expression
Omnibus datasets in the NCBI portal were searched using the key words
'Atherosclerosis AND tissue AND Homo sapiens' and the GSE12288 dataset. Gene
expression in circulating leukocytes was measured to identify patients with
coronary artery disease (CAD) or controls, and used to analyze the correlation
coefficient and expression profiles. The protein level of ATP‑binding cassette
sub‑family G member 1 (ABCG1) and matrix metalloproteinase (MMP)3 was determined
using immunohistochemistry and western blot analysis. The analysis of mouse
aortic roots was performed using Masson's and Oil Red O staining. The expression
of lncRNA AL355711, ABCG1 and MMP3 was found to be higher in human
atherosclerotic plaques or in patients with atherosclerotic CAD. The correlation
analysis revealed that ABCG1 may be involved in the regulation between lncRNA
AL355711 and MMP3 in atherosclerotic CAD. The knockdown of lncRNA AL355711
inhibited ABCG1 transcription and smooth muscle cell migration. In addition,
lncRNA AL355711 was found to regulate MMP3 expression through the ABCG1 pathway.
The expression of ABCG1 and MMP3 was found to be high in an animal model of
atherosclerosis. The results indicated that lncRNA AL355711 promoted VSMC
migration and atherosclerosis partly via the ABCG1/MMP3 pathway. On the whole,
the present study demonstrates that the inhibition of lncRNA AL355711 may serve
as a novel therapeutic target for atherosclerosis. lncRNA AL355711 in
circulating leukocytes may be a novel biomarker for atherosclerotic CAD. |
Febrifugine could be repositioned for what diseases? | Febrifugine exerts potent antischistosomal effects and can be expected to contribute to the development of a novel antischistosomal drug. | Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of
traditional Chinese medicine, has been characterized for its therapeutic
activity, though its molecular target has remained unknown. Febrifugine
derivatives have been used to treat malaria, cancer, fibrosis and inflammatory
disease. We recently demonstrated that halofuginone (HF), a widely studied
derivative of febrifugine, inhibits the development of T(H)17-driven
autoimmunity in a mouse model of multiple sclerosis by activating the amino acid
response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA
synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition
is reversed by the addition of exogenous proline or EPRS. We further show that
inhibition of EPRS underlies the broad bioactivities of this family of natural
product derivatives. This work both explains the molecular mechanism of a
promising family of therapeutics and highlights the AAR pathway as an important
drug target for promoting inflammatory resolution. The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product
febrifugine (also known as dichroine B) and its synthetic analogue,
halofuginone, possess antimalarial activity. More recently studies have also
shown that halofuginone acts as an agent capable of reducing fibrosis, an
indication with clinical relevance for several disease states. This review
summarizes historical isolation studies and the chemistry performed which
culminated in the correct structural elucidation of naturally occurring
febrifugine and its isomer isofebrifugine. It also includes the range of
febrifugine analogues prepared for antimalarial evaluation, including
halofuginone. Finally, a section detailing current opinion in the field of
halofuginone's human biology is included. Visceral leishmaniasis affects people from 70 countries worldwide, mostly from
Indian, African and south American continent. The increasing resistance to
antimonial, miltefosine and frequent toxicity of amphotericin B drives an urgent
need to develop an antileishmanial drug with excellent efficacy and safety
profile. In this study we have docked series of febrifugine analogues (n = 8813)
against trypanothione reductase in three sequential docking modes. Extra
precision docking resulted into 108 ligands showing better docking score as
compared to two reference ligand. Furthermore, 108 febrifugine analogues and
reference inhibitor clomipramine were subjected to ADMET, QikProp and molecular
mechanics, the generalized born model and solvent accessibility study to ensure
the toxicity caused by compounds and binding-free energy, respectively. Two best
ligands (FFG7 and FFG2) qualifying above screening parameters were further
subjected to molecular dynamics simulation. Conducting these studies, here we
confirmed that 6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxo-propyl]-7-(4-pyridyl)
quinazolin-4-one can be potential drug candidate to fight against Leishmania
donovani parasites. BACKGROUND: Reports on the antischistosomal effect of several antimalarial drugs
such as artesunate, mefloquine, and amodiaquine suggest that febrifugine, which
exerts an antimalarial effect, can also be expected to possess antischistosomal
potential. The present study investigates the antischistosomal effects of
febrifugine.
METHODS: In experiment 1, Schistosoma mansoni adult worm pairs were incubated in
a medium alone as a control or supplemented with febrifugine at 0.05, 0.1, 0.2,
and 0.5 μg/ml for 14 days. The morphology of the worms and the egg production of
the female worms were observed simultaneously. In experiment 2, the incubation
was conducted as in experiment 1, except that the febrifugine concentrations
were reduced to 0.005, 0.01, and 0.02 μg/ml. In addition, S. mansoni adult worms
were incubated with either 0.5 μg/ml febrifugine or none as a control for 5 days
and stained with neutral red dye.
RESULTS: Febrifugine significantly reduced the survival of S. mansoni male and
female worms at concentrations of 0.02-0.5 μg/ml following incubation for 14
days and remarkably inhibited the daily egg output of the female worms. The
non-treated male and female worms remained morphologically normal within the
period of 14 days, whereas male and female worms treated with febrifugine at
different concentrations gradually twisted and subsequently died. In addition,
S. mansoni adult worms were incubated with either 0.5 μg/ml febrifugine or none
as a control for 5 days and stained with neutral red dye. Non-treated male worms
were morphologically normal and stained dark red with neutral red, while
febrifugine-treated male worms appeared similar to those in the control group
and were stained at a slightly lower level of dark red than the non-treated male
worms. Non-treated female worms were morphologically normal, and their
intestinal tract and vitellaria were stained deep red and dark red,
respectively. In contrast, febrifugine-treated female worms were morphologically
damaged, and their intestinal tract and vitellaria remained mostly unstained and
stained dark red, respectively.
CONCLUSION: Febrifugine exerts potent antischistosomal effects and can be
expected to contribute to the development of a novel antischistosomal drug. BACKGROUND: 5-aminolevulinic acid-mediated PDT (ALA-PDT) has been used in a
variety of skin diseases including cSCC (cutaneous squamous cell carcinoma).
Halofuginone (HL) is a less-toxic febrifugine derivative and has inhibitory
effects on a variety of cancer cells. For now, there are no published study
focusing on the combination use of ALA-PDT with HL to improve clinical efficacy
of cSCC.
OBJECTIVE: In this study, we will examine the effectiveness of combined
treatment of ALA-PDT and HL in cSCC as well as its underlying mechanism.
METHODS: The human epidermoid carcinoma cell line SCL-1 was treated with ALA-PDT
or/ and HL, and cell viability, cell migration, ROS production, apoptosis were
evaluated by CCK-8, colony formation, scratch assay, DCFH-DA probe, flow
cytometry, respectively. The protein expression of NRF2 signaling was examined
by western blot.
RESULTS: HL strengthened ALA-PDT's inhibition of SCL-1 cell viability,
migration, as well as NRF2 related β-catenin, p-Erk1/2, p-Akt and p-S6K1
expression. Overexpression of NRF2 conferred resistance to co-treatment's
effects on c-Myc, Cyclin D1, Bcl-2, as well as cell proliferation. HL also
strengthened ALA-PDT's inhibition of tumor volume in cSCC mouse model and
elevated ROS generation of ALA-PDT.
CONCLUSION: HL enhances the anti-tumor effect of ALA-PDT in vitro and in vivo.
HL has the potential to enhance the anti-tumor effect of ALA-PDT in cSCC via
inhibiting NRF2 signaling. |
When was Volanesorsen approved in the EU? | In May 2019, volanesorsen was approved in the EU for the treatment of adult patients with familial chylomicronemia syndrome. | |
Is Belimumab used for lupus nephritis? | Yes, Belimumab can be used for lupus nephritis. | The treatment of lupus nephritis has seen significant advances during the past
decade mainly due to the publication of well-designed randomized clinical trials
(RCTs). The choice of treatment is guided by the histopathologic classification
but is also influenced by demographic, clinical, and laboratory characteristics
that allow for the identification of patients at risk for more aggressive
disease. For the induction arm, low-dose cyclophosphamide regimens and
mycophenolate mofetil have been validated as alternatives to the established
National Institutes of Health regimen of high-dose cyclophosphamide; for the
maintece phase, azathioprine and mycophenolate compete for treatment of first
choice. Rituximab is efficacious in real-life clinical practice but ineffective
in clinical trials. The role of recently approved belimumab in lupus nephritis
eagerly awaits further documentation. Aggressive management of comorbid
conditions, such as hypertension and dyslipidemia, is of utmost importance.
Here, we review the latest advances in lupus nephritis therapy with a focus on
recent RCTs as well as new biologic agents under development. Furthermore, we
propose a therapeutic algorithm in an effort to facilitate clinical
decision-making in this gradually changing landscape. Upcoming European and
American recommendations should provide further clarification. Recently introduced into the market, belimumab (Benlysta) is a monoclonal
antibody that has potential clinically efficacious applications for the
treatment of lupus nephritis. Lupus nephritis is a major complication of
systemic lupus erythematosus (SLE) that can lead to significant illness or even
death without proper intervention and treatment. With vast implications through
a novel mechanism, belimumab offers a new standard of treatment for physicians
in the complications associated with SLE, specifically lupus nephritis. By
targeting B cell signaling and maturation, belimumab is able to mitigate the
underlying pathological complications surrounding SLE. Phase 3 clinical trials
with belimumab have depicted clinically efficacious applications, suggesting
belimumab as a revolutionary breakthrough in the treatment armamentarium for
practicing clinicians. This article explains the precise mechanism of action of
belimumab on the soluble protein BlyS that plays a major role in the
pathogenesis of lupus nephritis. In addition, the extensive pharmacokinetics and
clinical implications are exemplified in this review with belimumab's comparison
with standard therapeutic guidelines for the treatment of lupus nephritis. BACKGROUND: The treatment of Lupus Nephritis (LN) is an unmet need in the
management of patients with Systemic Lupus Erythematosus (SLE).
CASE PRESENTATION : We report two cases of women affected by Lupus Nephritis
(LN) ISN/RNP Class IV with serological active disease, high disease activity and
marked fatigue. In both cases, Mycophenolate mofetil (MMF), as induction
therapy, was poorly tolerated because of gastrointestinal toxicity. Belimumab,
together with low-doses of MMF, was effective as induction treatment leading to
early achievement of complete renal response in these two selected cases of LN.
CONCLUSIONS: We also report a literature review concerning the efficacy and
safety of Belimumab in Lupus Nephritis. Further studies are needed to evaluate
the use of Belimumab to manage the renal involvement in patients with Systemic
Lupus Erythematosus, waiting for the results of ongoing randomized clinical
trials. Despite advancements in the care of lupus nephritis, a considerable proportion
of patients may respond poorly or flare while on conventional immunosuppressive
agents. Studies in murine and human lupus have illustrated a pathogenic role for
several cytokines by enhancing T- and B-cell activation, autoantibodies
production and affecting the function of kidney resident cells, therefore
supporting their potential therapeutic targeting. To this end, there is limited
post-hoc randomized evidence to suggest beneficial effect of belimumab,
administered on top of standard-of-care, during maintece therapy in lupus
nephritis. Type I interferon receptor blockade has yielded promising results in
preliminary SLE trials yet data on renal activity are unavailable. Conversely,
targeting interleukin-6 and interferon-γ both failed to demonstrate a
significant renal effect. For several other targets, preclinical data are
encouraging but will require confirmation. We envision that high-throughput
technologies will enable accurate patient stratification, thus offering the
opportunity for personalized implementation of cytokine-targeting therapies. BACKGROUND: Belimumab (Benlysta) is currently approved for the treatment of
active Lupus despite standard therapy. Few data are available on the efficacy of
this drug in lupus nephritis (LN).
METHODS: 17 LN female followed in two Nephrology Italian Unit received belimumab
for a median period of 36 months (range 6-42 months). The indications were:
arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in
8, and the need to reduce steroids for severe side effects in 4. Of interest, 1
patient started therapy during Peritoneal Dialysis and continued after kidney
transplantation due to non-responsive arthralgias.
RESULTS: Arthralgia and skin manifestations resolved in all patients.
Proteinuria normalized in three patients and stabilized in all but one of the
others. Steroids were indefinitely stopped in six patients (35%) and reduced to
around 40% of the basal dosage in the other patients. During belimumab therapy,
three extrarenal and one renal SLE flares were diagnosed accounting for a rate
of renal flares of 0.02/patient/year. No major adverse events leading to therapy
withdrawal occurred.
CLINICAL CASE: Arthralgia resolved, immunological parameters improved and
prednisone could be reduced within few months in the patient who started
belimumab during peritoneal dialysis. After kidney transplantation belimumab was
stopped but due to arthralgias unresponsive to standard immunosuppressive
therapy it was restarted with success.
CONCLUSIONS: Belimumab allows the achievement of complete response together with
the withdrawal or the reduction of corticosteroids in almost all our patients.
Of interest its satisfactory use in a patient in peritoneal dialysis and after
kidney transplantation. PURPOSE OF REVIEW: Despite ground-breaking innovations for most autoimmune
diseases, the treatment of lupus nephritis has remained largely the same for
decades because none of the tested drugs demonstrated superiority over
standard-of-care in randomized controlled clinical trials.
RECENT FINDINGS: Recently, the Belimumab in Subjects with Systemic Lupus
Erythematosus - Lupus Nephritis trial tested belimumab, an inhibitor of B-cell
activating factor, as an add-on therapy to steroids and either mycophenolate
mofetil (MMF) or cyclophosphamide when given IV monthly over a period of 104
weeks at an effect size of 11% for a Primary Efficacy Renal Response. The
NOBILITY trial reported positive results for the B-cell-depleting agent
obinutuzumab as an add-on therapy to steroids and MMF when given IV every 6
months over a period of 76 weeks at an effect size of 22% for a complete renal
response (CRR). The AURORA trial reported positive results for the calcineurin
inhibitor voclosporin as an oral add-on therapy to low dose steroids and MMF
when given twice daily over a period of 52 weeks at an effect size of 18.5% for
a CRR.
SUMMARY: These studies will change the treatment landscape of lupus nephritis.
In which way is discussed in this article. Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a
multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is
characterized by simultaneous or sequential organ and system involvement, with
unpredictable flare and high levels of morbidity and mortality. Racial/ethnic
background, socioeconomic status, cost of medications, difficulty accessing
health care, and poor adherence seem to impact lupus outcomes and treatment
response. In this article, the management of cSLE patients is updated. Regarding
pathogenesis, a number of potential targets for drugs have been studied.
However, most treatments in pediatric patients are off-label drugs with
recommendations based on inadequately powered studies, therapeutic consensus
guidelines, or case series. Management practices for cSLE patients include
evaluations of disease activity and cumulative damage scores, routine non-live
vaccinations, physical activity, and addressing mental health issues.
Antimalarials and glucocorticoids are still the most common drugs used to treat
cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients.
Disease-modifying antirheumatic drugs (DMARDs) should be standardized for each
patient, based on disease flare and cSLE severity. Mycophenolate mofetil or
intravenous cyclophosphamide is suggested as induction therapy for lupus
nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus,
voclosporin) appear to be another good option for cSLE patients with lupus
nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for
refractory lupus nephritis patients in combination with another DMARD, and
belimumab was recently approved by the US Food and Drug Administration for cSLE
treatment in children aged > 5 years. New therapies targeting CD20, such as
atacicept and telitacicept, seem to be promising drugs for SLE patients.
Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial
results in phase II randomized control trials in adult SLE patients, as have
some Janus kinase inhibitors, and these could be alternative treatments for
pediatric patients with severe interferon-mediated inflammatory disease in the
future. In addition, strict control of proteinuria and blood pressure is
required in cSLE, especially with angiotensin-converting enzyme inhibitor and
angiotensin receptor blocker use. The current treatment paradigm in lupus nephritis consists of an initial phase
aimed at inducing remission and a subsequent remission maintece phase. With
this so-called sequential treatment approach, complete renal response is
achieved in a disappointing proportion of 20-30% of the patients within 6-12
months, and 5-20% develop end-stage kidney disease within 10 years.
Treat-to-target approaches are detained owing to uncertainty as to whether the
target should be determined based on clinical, histopathological, or
immunopathological features. Until reliable non-invasive biomarkers exist,
tissue-based evaluation remains the gold standard, necessitating repeat kidney
biopsies for treatment evaluation and therapeutic decision-making. In this
viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on
agents to standard therapy, the first drugs to be licenced for lupus nephritis
after recent successful randomised phase III clinical trials. We also discuss
the prospect of obinutuzumab and anifrolumab, also on top of standard
immunosuppression, currently tested in phase III trials after initial auspicious
signals. Undoubtably, the treatment landscape in lupus nephritis is changing,
with combination treatment regimens challenging the sequential concept.
Meanwhile, the enrichment of the treatment armamentarium shifts the need from
lack of therapies to the challenge of how to select the right treatment for the
right patient. This has to be addressed in biomarker surveys along with
tissue-level mapping of inflammatory phenotypes, which will ultimately lead to
person-centred therapeutic approaches. After many years of trial failures, we
may now anticipate a heartening future for patients with lupus nephritis. We performed a post hoc analysis of the Belimumab International Study in Lupus
Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in
which 448 patients with lupus nephritis were randomized to receive intravenous
belimumab 10 mg/kg or placebo with standard therapy
(cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was
found to be most effective in improving the primary efficacy kidney response and
complete kidney response in patients with proliferative lupus nephritis and a
baseline urine protein/creatinine ratio under 3 g/g. However, there was no
observed improvement in the kidney response with belimumab treatment in patients
with lupus nephritis and sub-epithelial deposits or with a baseline
protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the
risk of kidney-related events or death and lupus nephritis flare in the overall
population. Belimumab reduced the risk of a sustained 30% or 40% decline in
estimated glomerular filtration rate (eGFR) versus standard treatment alone and
attenuated the annual rate of eGFR decline in patients who remained on-study.
Thus, our data suggest that the addition of belimumab to standard therapy could
attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum
of patients with lupus nephritis. |
Is SOX10 expressed in melanoma cells? | Yes,
The most commonly used melanocytic markers include S100, Melan-A, HMB45 and SOX10 | AIMS: The diagnosis of metastatic cutaneous melanoma (CM) on lymph node fine
needle aspiration samples may be challenging and usually requires confirmation
by immunocytochemistry. However, the cytological material could be too scant to
order a broad panel of markers. In this case, the pathologist is forced to
choose the most advantageous antibodies. The most commonly used melanocytic
markers include S100, Melan-A, HMB45 and SOX10 but their diagnostic yield on
cytological samples has been poorly studied. The current work aimed to evaluate
the diagnostic performance of melanocytic markers when applied to cell blocks
obtained from fine needle aspiration cytology (FNAC) of lymph node metastases
from CM.
METHODS: S100, Melan-A, HMB45 and SOX10 were tested on cell block sections of 38
lymphnode metastases from CM diagnosed by cytology. A combined score was built
to evaluate each immunostaining, considering the intensity of the staining and
the percentage of stained neoplastic cells.
RESULTS: S100 and SOX10 revealed a higher sensitivity (100%) than Melan-A and
HMB45 for the diagnosis of metastatic CM. Furthermore, SOX10 emerged as the
melanocytic marker with the best staining performance.
CONCLUSION: SOX10 has a 100% detection rate and the most easily interpretable
staining pattern compared with other melanocytic markers. Therefore, it is
strongly recommended that SOX10 is included in the minimal immunocytochemical
panel for the diagnostic evaluation of lymph node FNAC in patients with
suspected CM metastasis. PURPOSE: Melanoma is a serious and maligt disease worldwide. Seeking
diagnostic markers and potential therapeutic targets is urgent for melanoma
treatment. SOX10, a member of the SoxE family of genes, is a transcription
factor which can regulate the transcription of a wide variety of genes in
multiple cellular processes.
METHODS: The mRNA level and protein expression of SOX10 is confirmed by
bioinformatic analysis and IHC staining. MTT, clone formation and EdU analysis
showed that SOX10 knockdown (KD) could significantly inhibit melanoma cell
proliferation. FACS analysis showed that SOX10 KD could markedly enhance the
level of cell apoptosis. The downstream target signaling pathway is predicted by
RNA-seq based on the public GEO database. The activation of Notch signaling
mediated by SOX10 is tested by qPCR and Western blot.
RESULTS: Ectopic upregulation of SOX10 was found in melanoma patient tissues
compared to normal nevus tissues in mRNA and protein levels. Furthermore, both
mRNA and protein level of SOX10 were negatively correlated with melanoma
patient's prognosis. SOX10 knockdown could obviously suppress the proliferation
ability of melanoma cells by inactivating Notch signaling pathway.
CONCLUSION: Our study confirmed that SOX10 is an oncogene and activate Notch
signaling pathway, which suggests the potential treatment for melanoma patients
by target SOX10/Notch axis. |
How many copies of LBX are found in teleosts? | In teleosts, that have undergone an additional genome duplication, 8 Lbx paralogons (three of which retain Lbx genes) were found. | BACKGROUND: Lbx/ladybird genes originated as part of the metazoan cluster of Nk
homeobox genes. In all animals investigated so far, both the protostome genes
and the vertebrate Lbx1 genes were found to play crucial roles in neural and
muscle development. Recently however, additional Lbx genes with divergent
expression patterns were discovered in amniotes. Early in the evolution of
vertebrates, two rounds of whole genome duplication are thought to have
occurred, during which 4 Lbx genes were generated. Which of these genes were
maintained in extant vertebrates, and how these genes and their functions
evolved, is not known.
RESULTS: Here we searched vertebrate genomes for Lbx genes and discovered novel
members of this gene family. We also identified signature genes linked to
particular Lbx loci and traced the remts of 4 Lbx paralogons (two of which
retain Lbx genes) in amniotes. In teleosts, that have undergone an additional
genome duplication, 8 Lbx paralogons (three of which retain Lbx genes) were
found. Phylogenetic analyses of Lbx and Lbx-associated genes show that in
extant, bony vertebrates only Lbx1- and Lbx2-type genes are maintained. Of
these, some Lbx2 sequences evolved faster and were probably subject to
neofunctionalisation, while Lbx1 genes may have retained more features of the
ancestral Lbx gene. Genes at Lbx1 and former Lbx4 loci are more closely related,
as are genes at Lbx2 and former Lbx3 loci. This suggests that during the second
vertebrate genome duplication, Lbx1/4 and Lbx2/3 paralogons were generated from
the duplicated Lbx loci created during the first duplication event.
CONCLUSION: Our study establishes for the first time the evolutionary history of
Lbx genes in bony vertebrates, including the order of gene duplication events,
gene loss and phylogenetic relationships. Moreover, we identified genetic
hallmarks for each of the Lbx paralogons that can be used to trace Lbx genes as
other vertebrate genomes become available. Significantly, we show that bony
vertebrates only retained copies of Lbx1 and Lbx2 genes, with some Lbx2 genes
being highly divergent. Thus, we have established a base on which the evolution
of Lbx gene function in vertebrate development can be evaluated. |
Which organizations approved Tagsedi in 2018? | In 2018 Tagsedi was approved by the United States Food and Drug Agency, Health Canada, and European Commission. | |
What is the use of the CAHP score? | CAHP (cardiac arrest hospital prognosis) score is used to evaluate prognosis after cardiac arrest. | AIMS: Survival after out-of-hospital cardiac arrest (OHCA) remains
disappointingly low. Among patients admitted alive, early prognostication
remains challenging. This study aims to establish a stratification score for
patients admitted in intensive care unit (ICU) after OHCA, according to their
neurological outcome.
METHODS AND RESULTS: The CAHP (Cardiac Arrest Hospital Prognosis) score was
developed from the Sudden Death Expertise Center registry (Paris, France). The
primary outcome was poor neurological outcome defined as Cerebral Performance
Category 3, 4, or 5 at hospital discharge. Independent prognostic factors were
identified using logistic regression analysis and thresholds defined to stratify
low-, moderate-, and high-risk groups. The CAHP score was validated in both a
prospective and an external data set (Parisian Cardiac Arrest Registry). The
developmental data set included 819 patients admitted from May 2011 to December
2012. After multivariate analysis, seven variables were independently associated
with poor neurological outcome and subsequently included in the CAHP score (age,
non-shockable rhythm, time from collapse to basic life support, time from basic
life support to return of spontaneous circulation, location of cardiac arrest,
epinephrine dose, and arterial pH). Three risks groups were identified: low risk
(score ≤150, 39% of unfavourable outcome), medium risk (score 150-200, 81% of
unfavourable outcome) and high-risk group (score ≥200, 100% of unfavourable
outcome). The AUC of the CAHP score were 0.93, and the discrimination value in
the validation data sets was consistent (respectively, AUC 0.91 and 0.85).
CONCLUSION: The CAHP score represents a simple tool for early stratification of
patients admitted in ICU after OHCA. A high-risk category of patients with very
poor prognosis can be easily identified. PURPOSE: Although guidelines on post-resuscitation care recommend the use of
short-acting agents for sedation during targeted temperature management (TTM)
after cardiac arrest (CA), the potential advantages of this strategy have not
been clinically demonstrated.
METHODS: We compared two sedation regimens (propofol-remifentanil, period P2, vs
midazolam-fentanyl, period P1) among comatose TTM-treated CA survivors.
Management protocol, apart from sedation and neuromuscular blockers use, did not
change between the two periods. Baseline severity was assessed with
Cardiac-Arrest-Hospital-Prognosis (CAHP) score. Time to awakening was measured
starting from discontinuation of sedation at the end of rewarming. Awakening was
defined as delayed when it occurred after more than 48 h.
RESULTS: 460 patients (134 in P2, 326 in P1) were included. CAHP score did not
significantly differ between P2 and P1 (P = 0.93). Sixty percent of patients
awoke in both periods (81/134 vs. 194/326, P = 0.85). Median time to awakening
was 2.5 (IQR 1-9) hours in P2 vs. 17 (IQR 7-60) hours in P1. Awakening was
delayed in 6% of patients in P2 vs. 29% in P1 (p < 0.001). After adjustment, P2
was associated with significantly lower odds of delayed awakening (OR 0.08, 95%
CI 0.03-0.2; P < 0.001). Patients in P2 had significantly more ventilator-free
days (25 vs. 24 days; P = 0.007), and lower catecholamine-free days within day
28. Survival and favorable neurologic outcome at discharge did not differ across
periods.
CONCLUSIONS: During TTM following resuscitation from CA, sedation with
propofol-remifentanil was associated with significantly earlier awakening and
more ventilator-free days as compared with midazolam-fentanyl. BACKGROUND: Older age is associated with worse outcome after out-of-hospital
cardiac arrest (OHCA). Therefore, we tested the performance of CAHP score, to
predict neurological outcome in elderly OHCA patients and to select patients
most likely to benefit from coronary angiogram (CAG).
MATERIALS AND METHODS: The present study was a retrospective multicentre
observational study at 3 non-university hospitals and 1 university hospital.
CAHP score was calculated, and its performance to predict outcomes was
evaluated. Factors associated with the use of CAG were analysed and the rate of
CAG across each CAHP score risk group reported.
RESULTS: One hundred seventy-six patients fulfilled inclusion criteria (median
age of 81, [79-84]), among which a cardiac cause was presumed for 99 patients.
The hospital unfavourable outcome was 91%. The ROC-AUC values for hospital
neurological outcome prediction of CAHP score was 0.81 [0.68-0.94], showing good
discrimination performance. ST-segment elevation in ECG and initial shockable
rhythm were independent factors for performing early CAG, whereas age and
distance from the percutaneous coronary intervention centre were independently
associated with the absence of early CAG. The percentages of patients receiving
early CAG in the low, medium and high CAHP score risk groups were 64%, 33% and
34%, respectively, and differed significantly between low CAHP score risk group
and other groups (p = 0.02).
CONCLUSIONS: The CAHP score exhibited a good discrimination performance to
predict neurological outcome in elderly OHCA patients. This score could
represent a helpful tool for treatment allocation. A simple prognostication
score could permit avoiding unnecessary procedures in patients with minimal
chances of survival. OBJECTIVE: The aim of this study in out-of-hospital cardiac arrest (OHCA)
patients treated with targeted temperature management (TTM) was to evaluate the
prognostic value of OHCA, C-GRApH, and CAHP scores with initial neurologic
examinations for predicting neurologic outcomes.
METHODS: This retrospective study included OHCA patients treated with TTM from
2009 to 2017. We calculated three cardiac arrest (CA)-specific risk scores
(OHCA, C-GRApH, and CAHP) at the time of admission. The initial neurologic
examination included an evaluation of the Full Outline of UnResponsiveness
brainstem reflexes (FOUR_B) and Glasgow Coma Scale motor (GCS_M) scores. The
primary outcome was the neurologic outcome at hospital discharge.
RESULTS: Of 311 subjects, 99 (31.8%) had a good neurologic outcome at hospital
discharge. The OHCA score had an area under the receiver operating
characteristic curve (AUROC) of 0.844 (95% confidence interval (CI):
0.798-0.884), the C-GRApH score had an AUROC of 0.779 (95% CI: 0.728-0.824), and
the CAHP score had an AUROC of 0.872 (95% CI: 0.830-0.907). The addition of the
FOUR_B or GCS_M score to the OHCA score improved the prediction of poor
neurologic outcome (with FOUR_B: AUROC = 0.899, p = 0.001; with GCS_M: AUROC =
0.880, p = 0.004). The results were similar with the C-GRApH and CAHP scores in
predicting poor neurologic outcome.
CONCLUSIONS: This study confirms the good prognostic performance of CA-specific
scores to predict neurologic outcomes in OHCA patients treated with TTM. By
adding new variables associated with the initial neurologic examinations, the
prognoses of neurologic outcomes improved compared to the existing scoring
models. AIM: We assessed the ability of the Out-of-Hospital Cardiac Arrest (OHCA) and
the Cardiac Arrest Hospital Prognosis (CAHP) scores to predict neurological
outcome following in-hospital cardiac arrest (IHCA).
METHODS: Retrospective review of a seven-year French multicentric database
including ten intensive care units. Primary endpoint was the outcome at hospital
discharge using the Cerebral Performance Category score (CPC) in all IHCA
patients. OHCA and CAHP scores, sequential organ failure assessment (SOFA) score
and the simplified acute physiological score 2 (SAPS-2) were compared using area
under ROC curves (AUROC) and Delong tests.
RESULTS: Among 381 included patients, 125 (33%) were discharged alive with
favourable outcome (CPC 1-2). Among 256 patients (77%) with unfavourable outcome
(CPC 3-5), 10 were discharged alive with CPC 3 (4%), 130 died from withdrawal of
life sustaining therapies because of severe neurological impairment (51%), 107
died from multiorgan failure (42%) and 9 died after discharge from complications
and comorbidities (3%). OHCA and CAHP scores were independently associated with
unfavourable outcome. The AUROCs to predict unfavourable outcome for OHCA, CAHP,
SAPS-2 and SOFA scores were 0.76 [0.70-0.80], 0.74 [0.69-0.79], 0.72
[0.67-0.77], and 0.69 [0.64-0.74] respectively, with a significant difference
observed only between OHCA and SOFA scores AUROCs (p = 0.04).
CONCLUSION: In parallel with CAHP score, OHCA score could be used to early
predict outcome at hospital discharge after IHCA. However, prediction accuracy
for all scores remains modest, suggesting the use of other dedicated means to
early predict IHCA patients' outcome. BACKGROUND: The novel simplified out-of-hospital cardiac arrest (sOHCA) and
simplified cardiac arrest hospital prognosis (sCAHP) scores used for
prognostication of hospitalised patients have not been externally validated.
Therefore, this study aimed to externally validate the sOHCA and sCAHP scores in
a Japanese population.
METHODS: We retrospectively analysed data from a prospectively maintained
Japanese database (January 2012 to March 2013). We identified adult patients who
had been resuscitated and hospitalised after intrinsic out-of-hospital cardiac
arrest (OHCA) (n=2428, age ≥18 years). We validated the sOHCA and sCAHP scores
with reference to the original scores in predicting 1-month unfavourable
neurological outcomes (cerebral performance categories 3-5) based on the
discrimination and calibration measures of area under the receiver operating
characteristic curves (AUCs) and a Hosmer-Lemeshow goodness-of-fit test with a
calibration plot, respectively.
RESULTS: In total, 1985/2484 (82%) patients had a 1-month unfavourable
neurological outcome. The original OHCA, sOHCA, original cardiac arrest hospital
prognosis (CAHP) and sCAHP scores were available for 855/2428 (35%), 1359/2428
(56%), 1130/2428 (47%) and 1834/2428 (76%) patients, respectively. The AUCs of
simplified scores did not differ significantly from those of the original
scores, whereas the AUC of the sCAHP score was significantly higher than that of
the sOHCA score (0.88 vs 0.81, p<0.001). The goodness of fit was poor in the
sOHCA score (ν=8, χ2=19.1 and Hosmer-Lemeshow test: p=0.014) but not in the
sCAHP score (ν=8, χ2=13.5 and Hosmer-Lemeshow test: p=0.10).
CONCLUSION: The performances of the original and simplified OHCA and CAHP scores
in predicting neurological outcomes in successfully resuscitated OHCA patients
were acceptable. With the highest availability, similar discrimination and good
calibration, the sCAHP score has promising potential for clinical
implementation, although further validation studies to evaluate its clinical
acceptance are necessary. |
What is the drug Aduhelm approved for? | he Food and Drug Administration (FDA) granted approval for Aduhelm (aducanumab) for the treatment of Alzheimer's disease under its accelerated approval program | On June 7th 2021, the Food and Drug Administration (FDA) granted approval for
Aduhelm (aducanumab) for the treatment of Alzheimer's disease under its
accelerated approval program. Aducanumab is the first putative disease-modifying
therapy (DMT) approved for the treatment of AD with a great potential for
clinical benefit over current symptomatic therapies. The scientific community
has been largely confounded by this historical decision since this has been
based on the reduction of a surrogate marker (amyloid beta) and not on data
showing clinical efficacy. Here we provide a regulatory perspective on the topic
and discuss potential similarities and differences between the FDA's and EMA's
evaluative processes. Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since
2003, has received accelerated approval from the Food and Drug Administration
(FDA).This drug's approval has been highly contentious in the medical and
scientific community owing to contradictory study findings and the FDA's
advisory panel not recommending its approval. According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer
drug, reduces the level of cerebral amyloid plaques-a hallmark finding in
patients with Alzheimer's disease-and this will result in a reduction in
clinical decline. The authors of this article are not convinced that amyloid
deposits are a hallmark of Alzheimer's disease and are of the opinion that the
apparent reduction in amyloid accumulation following aducanumab treatment is
likely instead a result of continued and advanced cerebral cell death and, thus,
not a sign of improvement but of an even more advanced disease. |
What are the 4 histological types of lung cancer? | Lung cancer is broadly subclassified on the basis of histological features into squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma. | The Edinburgh Lung Cancer Group registered 3070 new patients with lung cancer in
the five years 1981-5 from a catchment population of 950,000. After review only
74 (2%) were classified as lifelong non-smokers. They differed significantly
from the 2996 smokers with lung cancer in that far more were female (77% v 26%)
and their mean age was higher (75.4 v 68.0 years). More were in the worst
Karnofsky performance categories and fewer patients underwent surgery. The
stages of disease were similarly distributed in the two groups and the five year
survival was equally poor (5%). Histological cell type was determined in 59 of
the 74 patients. All histological cell types were present. More non-smokers had
adenocarcinoma than smokers (42% v 13%) and fewer had squamous cell carcinoma
(32% v 49%) or small cell carcinoma (15% v 24%). Lung cancer in lifelong
non-smokers is uncommon and the diagnosis should therefore always be questioned. To evaluate the clinical significance of monoclonal antibody against human
pulmonary surfactant apoprotein (S-AP), surgically resected lung cancer from 122
patients was studied. Paraffin embedded tissues were used for the
immunohistochemical study by the avidin-biotin-peroxidase complex method. The
results were as follows. 1. Adenocarcinoma showed highest immunoreactivity for
S-AP compared to the other histologic types. Among subtypes of adenocarcinoma,
type II alveolar epithelial type, clara cell type and mixed type of these two
types were strongly positive (100%, 77.8% and 66.7% respectively). These results
indicate that this antibody may be a good marker for the subtyping of
adenocarcinoma. 2. There were some positive cases in other histologic types
especially in peripheral type of squamous cell carcinoma. These findings suggest
that this antibody was useful for the histological differentiation of lung
cancer. 3. As to the immunohistochemical reactivity there was a good correlation
between tissue and cytological specimens, which indicate cytological studies may
be adequate for this kind of histopathological studies. 4. In our study, there
were no patients with S-AP positive carcinomas other than patients with lung
cancer. These results indicate that this antibody could be used for the
differential diagnosis between primary and secondary lung cancer. A review of 119 patients (88 males and 31 females) with carcinoma of the lung
seen at the Hospital University Sains Malaysia (HUSM) from 1984 to 1989 was
done. The mean age of the patients was 60.3 years with a high proportion (76.6%)
of them were between 41 and 70 years. Seventy five percent of patients (84% of
men and 26% of women) were smokers. The Chinese have a significantly higher
preponderance to carcinoma of the lung. The commonest histological type found
was squamous cell carcinoma in men and adenocarcinoma in women. Small cell
carcinoma was uncommon. Squamous cell and large cell/undifferentiated type of
carcinoma were significantly associated with smoking behaviour of the patients. From January 1981 through December 1989, 15 patients with small advanced lung
cancer were treated surgically at the Tenri Hospital. In these cases, the
diameter of peripheral lung cancer did not exceed 3.0 cm (T1) and mediastinal
lymph nodes were proved to be N2 postoperatively by lymph node dissection or
sampling. The histological types were as follows: 8 adenocarcinoma, 4 large cell
carcinoma, 1 squamous cell carcinoma, 1 small cell carcinoma, and 1
adenosquamous carcinoma. All but one patient were received postoperative
chemotherapy and/or radiotherapy. The survival rate was 44.5% at 3 years, and
median survival time was 36 months. The mediastinal lymph node metastasis with
small peripheral lung cancer (T1N2) was ominous, and it should be said that
complete mediastinal lymph node dissection and adjuvant therapy were
indispensable to small advanced adenocarcinoma of lung. Lung cancer tissues from 68 patients were examined for epidermal growth factor
(EGF) receptor levels and EGF receptor gene copy numbers. Histologic cell types
of these lung cancer tissues included squamous-cell carcinoma (n = 30),
adenocarcinoma (n = 28), large-cell carcinoma (n = 4), and small-cell carcinoma
(n = 6). Tissues of squamous-cell carcinoma exhibited exceptionally high
125I-EGF binding activity, and those of small-cell carcinoma showed no EGF
binding activity. Southern blot hybridization analysis revealed EGF receptor
gene amplification in the squamous-cell carcinomas with high EGF binding
activity. The EGF receptor levels in squamous-cell carcinomas and
adenocarcinomas were compared with their pathological staging grouping and
pathological findings, including degree of differentiation, diameter of tumor,
and lymph node metastasis. However, unlike previous reports on breast and
bladder cancers, there was no obvious correlation between these pathological
characteristics and the EGF receptor levels of lung cancer. It is well known that the biological behavior of lung cancer varies according to
histological type and growth pattern. Therefore, more precise analysis of
various morphologic features affecting prognosis are needed based on tumor
histology. Lung cancer is mainly classified into 4 major histological types;
squamous cell carcinoma, small cell carcinoma, adenocarcinoma and large cell
carcinoma. Recently lung cancer has been subclassified into small cell carcinoma
and non-small cell carcinoma on the basis of responsiveness to chemotherapy and
radiation therapy. In small cell carcinoma, combination of chemotherapy and
radiation therapy is the main modality for treatment, and the most important
prognostic factor is LD and ED stage classification. Even so, a new histological
classification is proposed according to the responsiveness to chemotherapy and
radiation therapy. On the other hand, surgical therapy is the first choice for
the treatment of non-small cell lung cancer and the most important prognostic
factor is TNM and related stage classification. In squamous cell carcinoma,
moreover, extended resection is sometimes tried because of its local
invasiveness. Early lung cancer of hilar type is mostly squamous cell carcinoma
and highly curative by resection. The biological behavior of adenocarcinoma is
the most variable among lung cancers. In the histopathological study of
surgically resected cases, moreover, histological differentiation, nuclear
atypia of tumor cells, mitotic frequency, grades of scarring associated with a
tumor, and degrees of infiltration of T-zone histiocytes is closely related to
prognosis. Scoring of these factors may help a clinician to reach a decision on
the necessity and type of postoperative adjuvant chemotherapy, particularly in
cases of Stage I adenocarcinoma. Most cases of large cell carcinoma including
giant cell carcinoma ultrastructurally reveal features of differentiation toward
adenocarcinoma and/or squamous cell carcinoma. Giant cell carcinoma shows the
most unfavorable prognosis because of its rapid growth. However, among operable
cases of giant cell carcinoma, some long-term survivors do exist. Evaluating
these forms of biological behavior according to tumor histology at the time of
treatment, it is easier to decide whether or not adjuvant therapy is necessary. Seventeen well-characterized human lung cancer cell lines were examined for the
presence of specific membrane receptors for epidermal growth factor (EGF) and
nerve growth factor (NGF) as well as for the production of diffusible factors
capable of stimulating soft agar growth. These cell lines represented all four
major histological types of human lung cancer including small cell carcinoma of
the lung (SCCL) and the three types of non-SCCL (epidermoid, large cell, and
adenocarcinoma). The SCCL lines included three lines referred to as "converters"
because they had lost SCCL morphological and biochemical properties during
prolonged passage in vitro. Specific receptors for EGF and NGF were detected by
measuring the binding of 125I-radiolabeled growth factor to the cell surface.
These assays revealed that EGF receptors are found on five of six non-SCCL cell
lines and are not found on any of the SCCL lines. In contract, NGF binding was
detected at low levels on three of eight SCCL lines and on all three SCCL
converters but was not observed for non-SCCL lines. Thus, SCCL and SCCL
converter cell lines are distinguished from non-SCCL by the pattern of membrane
receptors for EGF and NGF. Such differences may ultimately prove useful as
biological markers for the different histological types of lung cancer.
Moreover, the majority of SCCL cells and all of the non-SCCL cells tested were
found to produce diffusible growth factors which can stimulate soft agar growth
of nontransformed normal rat kidney fibroblasts. Although some correlation
between soft agar growth factor production and the absence of EGF receptors may
exist for SCCL cells, the production of transforming growth factors appears to
be a general property of human lung cancer cells in vitro and is independent of
EGF receptor expression. Two hundred and eleven surgically resected primary lung tumors were studied
immunohistochemically. According to histologic type, they were 129
adenocarcinomas, 56 squamous cell carcinomas, 4 small cell carcinomas, 8 large
cell carcinomas, 8 adenosquamous cell carcinomas, 5 so-called carcinosarcomas
and 2 other tumors. Immunohistochemical expression of p53 and bcl-2 was studied
in relation to the disease-free survival. Among the 211 patients with lung
cancer, 109 were positive for p53 expression, and there was no significant
relationship between p53 expression and sex, or clinicopathological stage and
size of the tumor, although the patients with squamous cell carcinoma had a
significantly higher frequency of p53 expression than those with
adenocarcinomas. The frequency of p53 expression was significantly higher in the
patients with poorly differentiated adenocarcinomas than in those with other
histologic types. Seventy four of the 211 patients were positive for bcl-2
expression and bcl-2 expression was higher in the stage I patients and patients
with small lung tumors 2cm or less in diameter than in the other patients. The
patients with adenocarcinoma had a higher frequency of expression than those
with squamous cell carcinoma but no difference was found in the histological
differentiation of the tumor. The 5-year survival of patients positive for p53
expression was poorer than that of those with negative expression and the
survival rate was higher in the patients positive for bcl-2 expression than in
those with negative expression. These findings suggested that the expression of
p53 and bcl-2 is a useful marker of follow-up and prognosis, but will require
more data concerning the mechanism of carcinogenesis. Seven cases of primary
lung cancer were examined for genetic abnormality of the p53 gene. cDNA was
synthesized from total RNA of primary tissues of lung cancer using oligo (dT)
primer and reverse transcriptase and polymerase chain reaction (RT-PCR), and
PCR-single strand conformation polymorphism (SSCP) analysis were performed. Five
patients gave a positive result upon PCR-SSCP analysis of the p53 gene. To
confirm the results of PCR-SSCP analysis, their nucleotide sequences were
further analyzed and four of them had point mutations at different codons (154,
176, 207, 236) and one had deletion of one nucleotide (245) in exon 5 and 8.
Fifteen percent of 26 patients with small peripheral lung adenocarcinomas less
than 2cm in diameter were already advanced in stage and various factors such as
vascular invasion, pleural involvement and degree of scar grade were higher than
in patients with clinicopathological stage I. In advanced cases, the frequencies
of p53 expression was higher than in stage I cases. Concerning the relationship
of the degree of scar grade to PDGF-B expression, we demonstrated the production
of PDGF-B protein immunohistochemically and the expression of PDGF-B-mRNA by In
situ hybridization in the adenocarcinoma cells and macrophages of the lung
tumors. However, no significant correlation was observed between the degree of
PDGF-B expression and collagen production in the fibrotic focus. Metastasis is the major obstacle in cancer therapy. Lung cancer is divided into
4 histological groups, such as small cell carcinoma, squamous cell carcinoma,
adenocarcinoma and large cell carcinoma, representing different clinical
behaviors. Novel metastasis models of human lung cancer cells to the liver,
kidneys and lymph nodes were established in SCID mice depleted of NK cells. In
the model under study, small-cell carcinoma cells mainly formed lymph-node
metastases, while squamous cell carcinoma cells mainly metastasized to the liver
and kidneys. Moreover, adenocarcinoma cells formed lung metastases and maligt
pleural effusion. These findings suggest that our model reflects clinical
behavior of metastatic lung cancer and is useful for evaluation of
antimetastatic modalities. Lung cancer has increased in incidence throughout the twentieth century and is
now the most common cancer in the Western World. It has a poor prognosis, only
10-15% of patients survive 5 years or longer. Outcome is dependent on clinical
stage and cancer cell type. Lung cancer is broadly subclassified on the basis of
histological features into squamous cell carcinoma, adenocarcinoma, large cell
carcinoma and small cell carcinoma. The histopathological type of lung cancer
correlates with tumour behaviour and prognosis. Staging based on prognosis is
essential in clinical trials comparing different management strategies, and
enables universal communication regarding the efficacy of different treatments
in specific patient groups. The anatomic extent of disease determined either
preoperatively using imaging supplemented by invasive procedures such as
mediastinoscopy, and anterior mediastinotomy or following resection are
described according to the T-primary tumour, N-regional lymph nodes, M-distant
metastasis classification. The International System for Staging Lung Cancer
attempts to group together patients with similar prognosis and treatment
options. Various combinations of T, N, and M define different clinical or
surgical-pathological stages (IA-IV) characterised by different survival
characteristics. Refinements in staging based on imaging findings have enabled
clinical staging to more accurately reflect the surgical-pathological stage and
therefore more accurately predict prognosis. Recent advances including the use
of positron emission tomography in combination with conventional staging
promises to increase the accuracy of staging and therefore to reduce the number
of invasive staging procedures and inappropriate thoracotomies. The incidence of lung cancer has been increasing over recent decades. Previous
studies showed that polymorphisms of the genes involved in
carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors
for lung cancer. Recent observations revealed that the growth hormone receptor
(GHR) might play important roles in carcinogenesis and Rudd et al. found that
the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk
in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity).
To test whether this variant of GHR would modify the risk of lung cancer in
Chinese population, we compared the polymorphism between 778 lung cancer
patients and 781 healthy control subjects. Our results indicate that the
frequency of 495Thr (2.8%) allele in cases was significantly higher than in
controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele
might be a risk factor for lung cancer. Further analyses revealed Thr495Pro
variant was associated with lung cancer in the subpopulation with higher risk
for lung cancer: male subpopulation, still-smokers subpopulation and the
subpopulation with familial history of cancer. In different histological types
of lung cancer, Thr495Pro SNP was significantly associated with small cell and
squamous cell lung cancer, but not with adenocarcinoma, which suggested a
potential interaction between this polymorphism and metabolic pathways related
to smoking. The potential gene-environment interaction on lung cancer risk was
evaluated using MDR software. A significant redundant interaction between
Thr495Pro polymorphism and smoking dose and familial history of cancer was
identified and the combination of genetic factors and smoking status or familial
history of cancer barely increased the cancer risk prediction accuracy. In
conclusion, our results suggested that the Thr495Pro polymorphism of GHR was
associated with the risk of lung cancer in a redundant interaction with smoking
and familial history of cancer. BACKGROUND: The magnitude of the link between cigarette smoking and lung cancer
may vary by histological type.
METHODS: We used polytomous logistic regression to evaluate whether aspects of
smoking have different effects across four histological types in the Nurses'
Health Study.
RESULTS: From 1976 to 2002, we identified 1062 cases of lung cancer: squamous
cell (n = 201), small cell (n = 236), adenocarcinoma (n = 543) and large cell
carcinoma (n = 82), among 65 560 current or former smokers. Risk reduction after
quitting ranged from an 8% reduction (relative risk (RR): 0.92, 95% CI 0.91 to
0.94) to a 17% reduction (RR: 0.83, 95% CI 0.80 to 0.86) per year for
adenocarcinoma and small cell carcinoma, respectively, with a 9% reduction
observed for large cell carcinoma and an 11% reduction observed for squamous
cell carcinoma. The association of age at smoking initiation and former
cigarette smoking was similar across types, while the association of smoking
duration differed. The risk of adenocarcinoma increased by 6% per year of
smoking, compared to 7% for large cell, 10% for squamous cell and 12% for small
cell. The 6% difference between adenocarcinoma and small cell carcinoma is
equivalent to a 3.2 to 9.7-fold increase in risk for 20 years of smoking.
CONCLUSIONS: The effects of the number of cigarettes smoked per day and years
since quitting smoking are different across the major types of lung cancer,
which are fully appreciated at long durations of smoking and smoking cessation.
Smoking prevention and cessation should continue to be the focus of public
health efforts to reduce lung cancer incidence and mortality. The four major histological types of lung cancer are adenocarcinoma, squamous
cell carcinoma (SQ), large cell carcinoma and small cell carcinoma. Over the
past few decades, the incidence of lung adenocarcinoma has increased gradually
in most countries as the most frequently occurring histological type, displacing
SQ. Adenocarcinoma is the predomit type of lung cancer among lifelong
non-smokers and among females. Especially in East Asian countries, the cause(s)
of the increase in adenocarcinomas are not clear. Several genetic mutations
specific to lung adenocarcinomas have been found, representing attractive
targets for molecular therapy. Recently, the pathological classification of lung
adenocarcinoma was revised by integrating the newer clinical and biological
knowledge concerning this prevailing type. Additional epidemiological,
pathological and genetic studies are required to better understand this type of
lung cancer. BACKGROUND AND OBJECTIVE: Lung cancer remains the leading cause of cancer deaths
worldwide. The aim of this study was to examine the trend in the incidence of
lung cancer, validated by histology in Tianjin, the third largest municipal city
in China, during the period from 1981 to 2005.
METHODS: New lung cancer cases, crude incidence rates and age-adjusted rates by
histological type were analysed using the data from the Tianjin Cancer Registry,
which covers a population of 4 million urban residents.
RESULTS: The most common histological types of lung cancer were squamous cell
carcinoma (SQCC) in men and adenocarcinoma (ADC) in women. During the 25-year
period, the constitutive pattern of the histological types changed gradually,
ADC increased by 31.4%, but SQCC decreased by 25.6% among women. For SQCC, ADC
or small cell carcinoma (SMCC), both the new cases and crude incidences per year
increased among men and women. However, the age-adjusted incidences of all types
of lung cancer showed an initial increase, which then levelled off or declined
in recent years. The birth-cohort incidence analyses revealed that SQCC declined
sharply, while ADC still increased among the younger age groups.
CONCLUSION: The incidences of lung cancer by histological type changed during
the 25-year period in Tianjin. Tailored strategies on prevention and control
should be developed to meet the needs for various populations. INTRODUCTION: Histologically lung cancer is classified into four major types:
adenocarcinoma (Ad), squamous cell carcinoma (SqCC), large cell carcinoma (LCC),
and small cell lung cancer (SCLC). Presently, our understanding of cellular
metabolism among them is still not clear.
OBJECTIVES: The goal of this study was to assess the cellular metabolic profiles
across these four types of lung cancer using an untargeted metabolomics
approach.
METHODS: Six lung cancer cell lines, viz., Ad (A549 and HCC827), SqCC (NCl-H226
and NCl-H520), LCC (NCl-H460), and SCLC (NCl-H526), were analyzed using liquid
chromatography quadrupole time-of-flight mass spectrometry, with normal human
small airway epithelial cells (SAEC) as the control group. The principal
component analysis (PCA) was performed to identify the metabolic signatures that
had characteristic alterations in each histological type. Further, a metabolite
set enrichment analysis was performed for pathway analysis.
RESULTS: Compared to the SAEC, 31, 27, 34, 34, 32, and 39 differential
metabolites mainly in relation to nucleotides, amino acid, and fatty acid
metabolism were identified in A549, HCC827, NCl-H226, NCl-H520, NCl-H460, and
NCl-H526 cells, respectively. The metabolic signatures allowed the six cancerous
cell lines to be clearly separated in a PCA score plot.
CONCLUSION: The metabolic signatures are unique to each histological type, and
appeared to be related to their cell-of-origin and mutation status. The changes
are useful for assessing the metabolic characteristics of lung cancer, and offer
potential for the establishment of novel diagnostic tools for different origin
and oncogenic mutation of lung cancer. The differentiation between major histological types of lung cancer, such as
adenocarcinoma (ADC), squamous cell carcinoma (SCC), and small-cell lung cancer
(SCLC) is of crucial importance for determining optimum cancer treatment.
Hematoxylin and Eosin (H&E)-stained slides of small transbronchial lung biopsy
(TBLB) are one of the primary sources for making a diagnosis; however, a subset
of cases present a challenge for pathologists to diagnose from H&E-stained
slides alone, and these either require further immunohistochemistry or are
deferred to surgical resection for definitive diagnosis. We trained a deep
learning model to classify H&E-stained Whole Slide Images of TBLB specimens into
ADC, SCC, SCLC, and non-neoplastic using a training set of 579 WSIs. The trained
model was capable of classifying an independent test set of 83 challenging
indeterminate cases with a receiver operator curve area under the curve (AUC) of
0.99. We further evaluated the model on four independent test sets-one TBLB and
three surgical, with combined total of 2407 WSIs-demonstrating highly promising
results with AUCs ranging from 0.94 to 0.99. |
What is F105-P? | F105-P is a protamine-antibody fusion protein designed to deliver siRNA to HIV-infected or envelope-transfected cells. In specific, it was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. | Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to
their therapeutic application. We designed a protamine-antibody fusion protein
to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion
protein (F105-P) was designed with the protamine coding sequence linked to the C
terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs
bound to F105-P induced silencing only in cells expressing HIV-1 envelope.
Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV
replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or
intravenous injection of F105-P-complexed siRNAs into mice targeted HIV
envelope-expressing B16 melanoma cells, but not normal tissue or
envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc,
MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors.
Furthermore, an ErbB2 single-chain antibody fused with protamine delivered
siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates
the potential for systemic, cell-type specific, antibody-mediated siRNA
delivery. |
Should edasalonexent be used for Duchenne muscular dystrophy patients? | No. In phase 3 clinical trial edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of Duchenne muscular dystrophy. However, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. | BACKGROUND: Edasalonexent (CAT-1004) is an orally-administered novel small
molecule drug designed to inhibit NF-κB and potentially reduce inflammation and
fibrosis to improve muscle function and thereby slow disease progression and
muscle decline in Duchenne muscular dystrophy (DMD).
OBJECTIVE: This international, randomized 2 : 1, placebo-controlled, phase 3
study in patients ≥4 - < 8 years old with DMD due to any dystrophin mutation
examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52
weeks.
METHODS: Endpoints were changes in the North Star Ambulatory Assessment (NSAA;
primary) and timed function tests (TFTs; secondary). Assessment of
health-related function used the Pediatric Outcomes Data Collection tool
(PODCI).
RESULTS: One hundred thirty one patients received edasalonexent (n = 88) and
placebo (n = 43). At week 52, differences between edasalonexent and placebo for
NSAA total score and TFTs were not statistically significant, although there
were consistently less functional declines in the edasalonexent group. A
pre-specified analysis by age demonstrated that younger patients (≤6.0 years)
showed more robust and statistically significant differences between
edasalonexent and placebo for some assessments. Treatment was well-tolerated and
the majority of adverse events were mild, and most commonly involved the
gastrointestinal system (primarily diarrhea).
CONCLUSIONS: Edasalonexent was generally well-tolerated with a manageable safety
profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve
statistical significance for improvement in primary and secondary functional
endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent
may slow disease progression if initiated before 6 years of age. (NCT03703882). |
What disease is presenilin involved in? | Loss-of-function mutations in PSEN1/2 genes are the leading cause of familial Alzheimer's disease (fAD). | Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly.
Few cases are familial (FAD), due to autosomal domit mutations in
presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP). The
three proteins are involved in the generation of amyloid-beta (Aβ) peptides,
providing genetic support to the hypothesis of Aβ pathogenicity. However,
clinical trials focused on the Aβ pathway failed in their attempt to modify
disease progression, suggesting the existence of additional pathogenic
mechanisms. Ca2+ dysregulation is a feature of cerebral aging, with an increased
frequency and anticipated age of onset in several forms of neurodegeneration,
including AD. Interestingly, FAD-linked PS1 and PS2 mutants alter multiple key
cellular pathways, including Ca2+ signaling. By generating novel tools for
measuring Ca2+ in living cells, and combining different approaches, we showed
that FAD-linked PS2 mutants significantly alter cell Ca2+ signaling and brain
network activity, as summarized below. The presenilin genes (PSEN1 and PSEN2) are mainly responsible for causing
early-onset familial Alzheimer's disease, harboring ~300 causative mutations,
and representing ~90% of all mutations associated with a very aggressive disease
form. Presenilin 1 is the catalytic core of the γ-secretase complex that
conducts the intramembranous proteolytic excision of multiple transmembrane
proteins like the amyloid precursor protein, Notch-1, N- and E-cadherin, LRP,
Syndecan, Delta, Jagged, CD44, ErbB4, and Nectin1a. Presenilin 1 plays an
essential role in neural progenitor maintece, neurogenesis, neurite
outgrowth, synaptic function, neuronal function, myelination, and plasticity.
Therefore, an imbalance caused by mutations in presenilin 1/γ-secretase might
cause aberrant signaling, synaptic dysfunction, memory impairment, and increased
Aβ42/Aβ40 ratio, contributing to neurodegeneration during the initial stages of
Alzheimer's disease pathogenesis. This review focuses on the neuronal
differentiation dysregulation mediated by PSEN1 mutations in Alzheimer's
disease. Furthermore, we emphasize the importance of Alzheimer's disease-induced
pluripotent stem cells models in analyzing PSEN1 mutations implication over the
early stages of the Alzheimer's disease pathogenesis throughout neuronal
differentiation impairment. Presenilins (PS) form the active subunit of the gamma-secretase complex, which
mediates the proteolytic clearance of a broad variety of type-I plasma membrane
proteins. Loss-of-function mutations in PSEN1/2 genes are the leading cause of
familial Alzheimer's disease (fAD). However, the PS/gamma-secretase substrates
relevant for the neuronal deficits associated with a loss of PS function are not
completely known. The members of the neurexin (Nrxn) family of presynaptic
plasma membrane proteins are candidates to mediate aspects of the synaptic and
memory deficits associated with a loss of PS function. Previous work has shown
that fAD-linked PS mutants or inactivation of PS by genetic and pharmacological
approaches failed to clear Nrxn C-terminal fragments (NrxnCTF), leading to its
abnormal accumulation at presynaptic terminals. Here, we generated transgenic
mice that selectively recreate the presynaptic accumulation of NrxnCTF in adult
forebrain neurons, leaving unaltered the function of PS/gamma-secretase complex
towards other substrates. Behavioral characterization identified selective
impairments in NrxnCTF mice, including decreased fear-conditioning memory.
Electrophysiological recordings in medial prefrontal cortex-basolateral amygdala
(mPFC-BLA) of behaving mice showed normal synaptic transmission and uncovered
specific defects in synaptic facilitation. These data functionally link the
accumulation of NrxnCTF with defects in associative memory and short-term
synaptic plasticity, pointing at impaired clearance of NrxnCTF as a new mediator
in AD. |
In what part of the body is the masseter muscle located? | In human anatomy, the masseter is one of the muscles of mastication and is located in the jaw. | Since experimental and clinical evidence supports some role of musculature in
determining the form and size of facial bones during the active periods of
growth after birth, this study addresses the same basic relationships between
muscle and bone during the periods of active growth before birth. The
relationship between the masseter muscle and the mandible, including its ramal
and body components, was chosen as the model for study in nineteen human fetuses
(ages 16 to 36 weeks). Cross-sectional cephalometric data indicated that,
although increases in the size of the muscle and mandible were linearly related
to increasing age, the ramal portion of the mandible was more closely related to
changes in the masseter muscle than to changes in the mandibular body. Moreover,
it appears that reorientation of the muscle anteriorly and downward precedes a
similar reorientation of the ramus, with the combination of both fetal events
leading to the typical relationships of the two structures expected after birth.
Although this study does not get to cause-and-effect relationships, and although
the fetal specimens cannot be monitored longitudinally over time, the
parallelisms between our prenatal findings and those reported for postnatal
periods certainly lend further support to the observation that many aspects of
morphogenesis and growth are continual processes spanning the periods on either
side of birth. Benign hypertrophy of the masseter muscle is an uncommon entity important in the
differential diagnosis of head and neck masses, particularly a unilateral mass
located in the cheek. Ten cases of benign masseteric hypertrophy are reviewed,
current surgical treatment is described, and the pertinent literature is
summarized. The growth of the masseter muscle in eight infant, juvenile, and adolescent
female rhesus monkeys (M. mulatta) was examined over a 2.5 year period using
serial radiographic cephalometric techniques with the aid of radiopaque muscle
markers. The radiopaque markers, which are composed of small pieces of root
canal broach inserted into the muscle belly, make it possible to determine
longitudinal masseter muscle growth as well as migration of the masseter muscle
relative to the mandible. It was found that the masseter muscle increased in
length by 64% during the total growth period, most of which occurred between 6
and 18 months of age. Relative to the cranium, the masseter muscle grew markedly
inferiorly and only slightly posteriorly. Relative to the mandible, the masseter
migrated in a posterior and slightly superior direction, keeping pace with the
ramus and condyle as they grew posteriorly and posterosuperiorly throughout the
study period. It was concluded that: 1) radiopaque muscle markers are a valuable
tool for analysis of muscle growth and alteration of muscle location; 2) the
masseter muscle in the rhesus monkey undergoes elongation, probably due to
addition of sarcomeres at the fiber-tendon junctions; and 3) posterior migration
of the masseter muscle relative to the corpus of the mandible, probably due to
the nature of its periosteal attachment, results in a stability of the
anteroposterior position of the masseter muscle despite the anterior
displacement of the mandible. Masticatory and bite forces, when applied to the teeth, generate tremendous
compressive energy in the temporomandibular joint (TMJ). Excessive 'TMJ
loading', if left untreated, deteriorates articular functions. Normally, it is
controlled, to a certain extent, by stomatognathic means. In an attempt to
clarify this control mechanism, we analyzed the relationship between TMJ loading
and the activities of the masticatory muscles, by employing a static
two-dimensional jaw model. This comprises two rigid bodies, the upper and lower
jaws, including three domit muscles, i.e. the masseter, the anterior portion
of the temporalis and the lateral pterygoid. Static equilibrium analyses
determined that TMJ loading can be minimized, under controlled bite conditions,
by pointing the loading vector in a direction solely indicated by individual
morphological factors, such as the position and orientation of the masseter and
the temporalis. This theoretically optimum direction of TMJ loading was also
anatomically acceptable, because the load is applied exactly to those portions
of the articular disk and mandibular head that can most easily sustain it.
Interestingly, this factor was absolutely independent of both the activities of
the lateral pterygoid and the direction of bite force. Consequently. TMI loading
can be minimized, by coordinating the activities of the masseter and the
anterior portion of the temporalis. Structure and function are reviewed in the masticatory muscles and in the
muscles of the lower face and tongue. The enormous strength of jaw closure is in
large part due to the pinnated arrangement of the muscle fibres in the masseter.
This muscle, like other masticatory muscles, is unusual in that the cell bodies
of the muscle spindle afferents lie in the brain stem rather than in an external
ganglion; spindles are absent in the lower facial muscles. Although few data are
available, the numbers of motor units in the masticatory muscles, and probably
in the lower facial muscles also, appear to be much greater than in limb
muscles. The motor units in the facial and tongue muscles are largely composed
of histochemical type II ('fast-twitch') fibres, but in the masticatory muscles
there are substantial numbers of fibres intermediate between type I ('slow
twitch') and type II, and fibre type grouping is present. In comparison with
limb muscles, there is little information on ageing changes in oro-facial
muscles. The masticatory muscles do, however, show some atrophy and loss of
X-ray density, while motor unit twitches are prolonged. Strength is reduced in
the tongue and masticatory muscles. It is known that limb muscle properties are
largely governed by their innervation, both through the pattern and amount of
impulse activity, and the delivery of trophic messengers; the situation for
oro-facial muscles is unclear. The structural and functional differences between
the two types of muscle indicate the need for conducting ageing studies on the
oro-facial muscles, rather than relying on extrapolations from limb muscles. In the giraffe (Giraffa camelopardalis), the masseter muscle was divided into
several layers. The superficial and more medial (second) tendinous sheets of the
masseter muscle fused with each other at the dorso-caudal part and a fleshy
portion was located between these tendinous sheets. In the rostral part, the
most superficial tendinous sheet turned around as a compact tendon and attached
to the facial crest (Crista facialis). The turned tendinous sheet, however,
never fused with the second tendinous sheet and this layer of the masseter
muscle, that originated from the facial crest with the turned sheet, was
inserted into the mandible with its fleshy portion. In the cattle, goat, sheep
and Sika deer, the rostral layer of the masseter muscle arises from the facial
crest with its fleshy portion and is inserted into the tubercle on the mandible
through the strong tendinous sheet. In this study, the takin also showed the
same structure of the masseter muscle. In the giraffe, however, the rostral
layer inserted into the mandible through the strong tendinous sheet could not be
distinguished, thus, there was no conspicuous tubercle on the mandible. Moreover
in the masseteric region of the skull.,the giraffe was similar to the Sika deer
in several ways. However, it is suggested that the giraffe exerts smaller forces
on the cheek teeth than does the Sika deer because of its longer Margo
interalveolaris. Nodular fasciitis (NF) is a benign, reactive proliferation of fibroblasts in
subcutaneous tissues which commonly occurs in the deep fascia. It can only be
diagnosed by histopathological examination of a biopsy. A total of 23 orofacial
NF patients was analysed, including those reported in the English language
literature and six new patients from the files of this hospital. All patients
were treated between 1994 and 2005. The reported lesions were located in cheek
masseter muscle, parotid gland, upper neck, upper gingiva and body of
mandibular. The clinical and histological features and differential diagnoses
are discussed. All lesions were removed under general or local anaesthesia and
no recurrence of the lesions was found. The masseter muscle is an integral part of the oral facial complex and one of
the muscles of mastication. It functions with the other masticatory muscles in
moving and posturing the mandible and in verbalizing, eating and swallowing.
When a patient has temporomandibular dysfunction (TMD) or a myogenic disorder,
the integrity of the masseter muscle can be compromised resulting in pain,
malfunction, inflammation and/or swelling. A careful evaluation of the masseter
muscles is necessary in facial pain patients since the pain can originate from a
distant site and be referred to this area. One of the little known disorders
involving the masseter and its tendinous origin is tenomyositis, in which an
inflammation of the muscle and its tendon occurs. In this retrospective study,
the charts of 114 consecutive patients (N = 114) were evaluated to determine the
prevalence of this disorder and the reported etiology. Facial musculature is divided into masticatory muscles, i.e. M. masseter and M.
buccalis, with bony insertions and smaller facial muscles involved in facial
expression, which insert into bone and skin. There are four fixed osteocutaneous
points of the face, i.e. zygomatic (Mac Gregor), mandibular (Furnas), orbital
(Psillakis), and masseteric with an antigravitational effect and functional role
in facial expression (1,2). In other body parts, the direct insertion of muscle
fibers into skin has not been reported. In the neck-shoulder region, direct
insertion of skeletal muscles into the skin can be observed during surgery in
this area. We observed this phenomenon in 3 adult male patients (51-65 years
old) during lipoma surgery. In our case series, lipomas were of the superficial
subcutaneous type. After local anesthesia with 1% ropivacain, a fusiform skin
incision was followed by en bloc resection of the lipoma. During resection, we
became aware that muscle fibers of M. levator scapulae inserted into the back
skin (Figure 1). This has practical implications for surgery because of possible
pain when these fibers need to be cut to deliver a lipoma or other subcutaneous
tumors. Lipomas are a common benign tumor of the subcutaneous adipose tissue,
known as the superficial type. However, lipomas may occur intramuscularly,
intermuscularly, parostealy and intra-osseously (3). In the deep subtypes of
lipoma, pain and discomfort may be a leading clinical symptom whereas
superficial lipomas often are asymptomatic (4,5). Surgery is the treatment of
choice, while liposuction and laser-lipolysis are alternatives (6). During
surgery of lipomas of the shoulder/neck region, direct insertion of muscle
fibers of M. levator scapulae into skin was noted - an observation possibly
underreported in surgical literature. Muscle spindles in the jaw-closing muscles, which are innervated by trigeminal
mesencephalic neurons (MesV neurons), control the strength of occlusion and the
position of the mandible. The mechanisms underlying cortical processing of
proprioceptive information are critical to understanding how sensory information
from the masticatory muscles regulates orofacial motor function. However, these
mechanisms are mostly unknown. The present study aimed to identify the regions
that process proprioception of the jaw-closing muscles using in vivo optical
imaging with a voltage-sensitive dye in rats under urethane anesthesia. First,
jaw opening that was produced by mechanically pulling down the mandible evoked
an optical response, which reflects neural excitation, in two cortical regions:
the most rostroventral part of the primary somatosensory cortex (S1) and the
border between the ventral part of the secondary somatosensory cortex (S2) and
the insular oral region (IOR). The kinetics of the optical signal, including the
latency, amplitude, rise time, decay time and half duration, in the S1 region
for the response with the largest amplitude were comparable to those in the
region with the largest response in S2/IOR. Second, we visualized the regions
responding to electrical stimulation of the masseter nerve, which activates both
motor efferent fibers and somatosensory afferent fibers, including those that
transmit nociceptive and proprioceptive information. Masseter nerve stimulation
initially excited the rostral part of the S2/IOR region, and an adjacent region
responded to jaw opening. The caudal part of the region showing the maximum
response overlapped with the region responding to jaw opening, whereas the
rostral part overlapped with the region responding to electrical stimulation of
the maxillary and mandibular molar pulps. These findings suggest that
proprioception of the masseter is processed in S1 and S2/IOR. Other sensory
information, such as nociception, is processed in a region that is adjacent to
these pulpal regions and is located in the rostral part of S2/IOR, which
receives nociceptive inputs from the molar pulps. The spatial proximity of these
regions may be associated with the mechanisms by which masseter muscle pain is
incorrectly perceived as dental pain. A macroscopic and microscopic study of the mandibular organ of the silky
anteater (Cyclopes didactylus) was carried out. The organ extends from below the
zygomatic bone line to the middle of the mandible body, between the skin and the
masseter muscle, on both sides of the animal. It has an average length of 11.7
mm and a width of 6.3 mm. In the mesoscopic analysis, it was observed that the
organ presents in yellowish color due to the high amount of sebaceous content.
In the histological analysis, the mandibular organ was observed to be composed
of innumerable alveoli of the specialized sebaceous gland, surrounded by a layer
of adventitia tunica. Scanning electron microscopy (SEM), revealed an apparent
alveolar division with what appeared to be a sulcus at its center. The
information here presented regarding the constitution and location of this
structure has not been previously explored for other species and differs with
respect to other descriptions for anteaters. Based on the present study, it is
suggested that the mandibular organ is involved in social interaction in this
species. PURPOSE: Masticatory myofascial trigger points (TrP) are one of the major causes
of nondental pain in the orofacial region. Intramuscular injections are
considered the first-line treatment for myofascial TrPs. The objectives of this
study were to evaluate and compare the effectiveness of local anesthesia (LA),
botulinum toxin (BTX), and platelet-rich plasma (PRP) injections for the
treatment of myofascial TrPs in the masseter muscle.
METHODS: In this retrospective study, the sample was composed of patients with
myofascial TrPs in masseter muscle who were treated between 2016 and 2019.
Patients were divided into 3 groups according to treatment methods: group I (LA
injection), group II (BTX injection), and group III (PRP injection). Primary
outcome variable was the average pain level at rest and while chewing, and
pressure pain intensity (PPI), Jaw Functional Limitation Scale (JFLS) value, and
quality-of-life (measured using Oral Health Impact Profile-14 (OHIP-14)) were
secondary outcomes. The outcome variables were assessed at diagnosis, and 1, 3,
and 6 months post-treatment.
RESULTS: The study consisted of 82 patients (group I, 27; group II, 26; group
III, 29). At 1 and 3 months, improvement in all parameters was recorded in all
groups. Groups I and II showed superior improvement in all parameters compared
with group III at 3 months. Improvements in VAS pain, JFLS, and OHIP-14 values
were significantly better in group II than group I at 3 months (P = .009;
P = .004; P = .002). At 6 months, significant improvement in VAS pain, JFLS, and
OHIP-14 (P = .008; P < .001; P < .01) values was recorded only in group II.
CONCLUSIONS: All procedures successfully improved the symptoms of TrPs in the
masseter muscle at 1 and 3 months. However, BTX injection seemed superior at the
3-month follow-up and remained effective up to 6 months. Intramuscular hemangiomas of the masseter muscle are uncommon tumors and
therefore can be difficult to accurately diagnose preoperatively, due to the
unfamiliar presentation and deep location in the lateral face. A case of
intramuscular hemangioma of the masseter muscle in a 66-yearold woman is
presented. Doppler ultrasonography showed a 34× 15 mm hypoechoic and
hypervascular soft tissue mass in the left masseter muscle, suggesting
hemangioma. The mass was excised via a lateral cervical incision near the
posterior border of the mandibular ramus. The surgical wound healed well without
complications. |
Which endothelial cell migration pathways were modulated at the gene expression level by rHDL-apoE3? | The most pronounced effect was observed for EC migration, with 42/198 genes being involved in the following EC migration-related pathways: 1) MEK/ERK, 2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, and 4) integrin. | INTRODUCTION: Atherosclerotic Coronary Artery Disease (ASCAD) is the leading
cause of mortality worldwide. Novel therapeutic approaches aiming to improve the
atheroprotective functions of High Density Lipoprotein (HDL) include the use of
reconstituted HDL forms containing human apolipoprotein A-I (rHDL-apoA-I). Given
the strong atheroprotective properties of apolipoprotein E3 (apoE3), rHDL-apoE3
may represent an attractive yet largely unexplored therapeutic agent.
OBJECTIVE: To evaluate the atheroprotective potential of rHDL-apoE3 starting
with the unbiased assessment of global transcriptome effects and focusing on
endothelial cell (EC) migration as a critical process in re-endothelialization
and atherosclerosis prevention. The cellular, molecular and functional effects
of rHDL-apoE3 on EC migration-associated pathways were assessed, as well as the
potential translatability of these findings in vivo.
METHODS: Human Aortic ECs (HAEC) were treated with rHDL-apoE3 and total RNA was
analyzed by whole genome microarrays. Expression and phosphorylation changes of
key EC migration-associated molecules were validated by qRT-PCR and Western blot
analysis in primary HAEC, Human Coronary Artery ECs (HCAEC) and the human
EA.hy926 EC line. The capacity of rHDL-apoE3 to stimulate EC migration was
assessed by wound healing and transwell migration assays. The contribution of
MEK1/2, PI3K and the transcription factor ID1 in rHDL-apoE3-induced EC migration
and activation of EC migration-related effectors was assessed using specific
inhibitors (PD98059: MEK1/2, LY294002: PI3K) and siRNA-mediated gene silencing,
respectively. The capacity of rHDL-apoE3 to improve vascular permeability and
hypercholesterolemia in vivo was tested in a mouse model of hypercholesterolemia
(apoE KO mice) using Evans Blue assays and lipid/lipoprotein analysis in the
serum, respectively.
RESULTS: rHDL-apoE3 induced significant expression changes in 198 genes of HAEC
mainly involved in re-endothelialization and atherosclerosis-associated
functions. The most pronounced effect was observed for EC migration, with 42/198
genes being involved in the following EC migration-related pathways: 1) MEK/ERK,
2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, 4) integrin. rHDL-apoE3 induced changes
in 24 representative transcripts of these pathways in HAEC, increasing the
expression of their key proteins PIK3CG, EFNB2, ID1 and FLT1 in HCAEC and
EA.hy926 cells. In addition, rHDL-apoE3 stimulated migration of HCAEC and
EA.hy926 cells, and the migration was markedly attenuated in the presence of
PD98059 or LY294002. rHDL-apoE3 also increased the phosphorylation of ERK1/2,
AKT, eNOS and p38 MAPK in these cells, while PD98059 and LY294002 inhibited
rHDL-apoE3-induced phosphorylation of ERK1/2, AKT and p38 MAPK, respectively. LY
had no effect on rHDL-apoE3-mediated eNOS phosphorylation. ID1 siRNA markedly
decreased EA.hy926 cell migration by inhibiting rHDL-apoE3-triggered ERK1/2 and
AKT phosphorylation. Finally, administration of a single dose of rHDL-apoE3 in
apoE KO mice markedly improved vascular permeability as demonstrated by the
reduced concentration of Evans Blue dye in tissues such as the stomach, the
tongue and the urinary bladder and ameliorated hypercholesterolemia.
CONCLUSIONS: rHDL-apoE3 significantly enhanced EC migration in vitro,
predomitly via overexpression of ID1 and subsequent activation of MEK1/2 and
PI3K, and their downstream targets ERK1/2, AKT and p38 MAPK, respectively, and
improved vascular permeability in vivo. These novel insights into the rHDL-apoE3
functions suggest a potential clinical use to promote re-endothelialization and
retard development of atherosclerosis. |
Is tivantinib effective for MET-high hepatocellular carcinoma? | No. In phase 3 clinical trials Tivantinib did not improve overall survival compared with placebo in patients with MET-high hepatocellular carcinoma despite promising phase 2 trial results. | Author information:
(1)Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
(2)Service d'Oncologie Médicale, CHRU Saint Eloi, Montpellier, France.
(3)Department of Internal Medicine III, Section of Gastroenterology/Hepatology,
Medizinische Universitaet Wien, Wien, Austria; Department of Internal Medicine
and Gastroenterology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.
(4)Centre Eugène Marquis et CH Saint Malo, Rennes, France.
(5)Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto
Institute of Oncology-IRCCS, Padua, Italy.
(6)Service des Maladies de l'Appareil Digestif, Hôpital Claude Huriez, Lille
Cedex, France.
(7)Oncologia Medica, AO Papa Giovanni XXIII Hospital, Bergamo, Italy.
(8)IRCCS San Matteo University Hospital Foundation, Pavia, Italy.
(9)Department of Oncology and Medical Oncology Unit, AO G Rummo Hospital,
Benevento, Italy.
(10)Department of Medical and Surgical Sciences, University of Bologna, Bologna,
Italy; Center for Applied Biomedical Research, Sant'Orsola-Malpighi Hospital,
Bologna, Italy.
(11)Department of Gastro-Intestinal Surgery and Liver Transplantation,
University of Milan, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei
Tumori, Milan, Italy.
(12)University of Washington School of Medicine, Seattle, WA, USA.
(13)Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA,
USA.
(14)Department of Oncology, Santa Maria del Prato Hospital, Feltre, Italy.
(15)Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University
of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades
Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
(16)Solid Tumor Medical Oncology, McCain Centre for Pancreatic Cancer,
University Health Network, Princess Margaret Cancer Center at the OPG, Toronto,
ON, Canada.
(17)Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
(18)Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt, Germany.
(19)Medical Oncology Department, Hospital Universitario Marqués de Valdecilla,
Santander, Spain.
(20)Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of
Medical Biotechnology and Translational Medicine, University of Milan, Milan,
Italy.
(21)Institute for Advanced Biosciences-INSERM U1209, CNRS UMR 5309 and
Department of Hepatogastroenterology Université Grenoble-Alpes, Grenoble,
France; Clinique Universitaire d'Hépato-gastroentérologie, Pôle Digidune, Centre
Hospitalier Universitaire Grenoble-Alpes, La Tronche, France.
(22)Department of Internal Medicine III, Section of Gastroenterology/Hepatology,
Medizinische Universitaet Wien, Wien, Austria.
(23)ArQule Inc, Burlington, MA, USA.
(24)Daiichi Sankyo Inc, Basking Ridge, NJ, USA.
(25)Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of
Biomedical Sciences, Humanitas University, Milan, Italy.
(26)Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University
of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades
Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Electronic address:
[email protected]. There is no available effective systemic treatment for patients with advanced
hepatocellular carcinoma (HCC) who are intolerant of sorafenib or who have
disease that has progressed on sorafenib. In Phase I and II studies, tivantinib
(ARQ 197), an oral inhibitor of MET, demonstrated promising antitumor activity
in patients with HCC, both as monotherapy and in combination with sorafenib. A
randomized Phase II trial in second-line HCC showed improved overall survival
(hazard ratio: 0.38; p = 0.01) in patients with MET-high tumors, as demonstrated
by immunohistochemistry, treated with tivantinib versus placebo. Here we present
the treatment rationale and study design of the METIV-HCC Phase III study. This
randomized, double-blind study will investigate tivantinib monotherapy as
second-line treatment in patients with advanced, pretreated, MET-high HCC.
Approximately 303 patients will be randomized 2:1 to tivantinib or placebo for
the purpose of analyzing the primary end point. Tivantinib will be dosed at 120
mg twice daily, and treatment will continue until disease progression,
unacceptable toxicity, patient or physician decision to discontinue, or death.
The primary end point of this study is overall survival, while secondary end
points include progression-free survival and safety. All patients will be tested
for biomarkers. If the primary objective is achieved, this study will provide
the first effective therapy for a biologically selected patient population in
HCC. Conflict of interest statement: The study was designed under the responsibility
of Kyowa Kirin Co., Ltd. The study was funded by Kyowa Kirin Co., Ltd. Study
drug was provided by Kyowa Kirin Co., Ltd; Kyowa Kirin Co., Ltd collected and
analyzed the data and contributed to the interpretation of the study. All
authors had full access to all of the data in the study and had final
responsibility for the decision to submit for publication. Masatoshi Kudo has
received honoraria, research funds and/or grants from Abbvie, Bayer,
Bristol‐Myers Squibb, EA Pharma, Eisai, Eli Lilly, Gilead, MSD, Ono
Pharmaceutical, Otsuka Pharmaceutical, Roche, Sumitomo Dainippon Pharma, Taiho
Pharmaceutical, and Takeda Pharmaceutical. Manabu Morimoto has received research
funds from MSD, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly,
AstraZeneca, and Takeda Pharmaceutical. Namiki Izumi and Michihisa Moriguchi
have received honoraria from Bayer and Eisai. Tetsuji Takayama has received
grants from Abbvie, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Eli Lilly,
Bayer, Teijin Pharma, and Zeria Pharmaceutical. Keisuke Hino has received
honoraria and/or grants from MSD, Abbvie, Gilead, Sumitomo Dainippon Pharma, and
Otsuka Pharmaceutical. Hitoshi Yoshiji, Tetsuhiro Chiba, Junko Kato and Kentaro
Yasuchika have no conflicts of interest to declare. Kenta Motomura has received
honoraria from Eisai. Akio Ido has received honoraria, research funds and/or
grants from Gilead, Abbvie, Bristol‐Myers Squibb, EA Pharma, Fujifilm, Otsuka
Pharmaceutical, Eisai, and SNBL, and belongs to an endowed chair funded by
Eisai. Takashi Sato and Daisuke Nakashima have been employees of Kyowa Kirin.
Kazuomi Ueshima has received honoraria from Eisai, Bayer, and Eli Lilly.
Masafumi Ikeda has received honoraria and/or research funds from Bayer, Eisai,
Eli Lilly, Novartis, Taiho Pharmaceutical; Bristol‐Myers Squibb, AstraZeneca,
Chugai Pharmaceutical, MSD, Ono Pharmaceuticals, Yakult Honsha, Aslan
Pharmaceutical, Merck Serono, and J‐Pharma. Takuji Okusaka has received research
funds from AstraZeneca, Chugai Pharmaceutical, Eisai, Novartis, and
Bristol‐Myers Squibb. Kazuo Tamura has received remuneration from AC Medical.
Junji Furuse has received honoraria and/or research funds from Bayer, Ono
Pharmaceutical, Eisai, Taiho Pharmaceutical, Fujifilm, Chugai Pharmaceutical,
Astellas Pharma, Novartis, Yakult Honsha, Teijin Pharma, MSD, Sumitomo Dainippon
Pharma, J‐Pharma, and AstraZeneca. |
What is the function of the protein SLC26A5? | SLC26A5 transporter prestin is fundamental for the higher hearing sensitivity and frequency selectivity of mammals. Prestin is a voltage-dependent transporter found in the cochlear outer hair cells responsible for their electromotility. | Author information:
(1)Division of Cardiovascular Medicine, University of California, Davis, Davis,
CA 95616, USA; Department of Veterans Affairs, VA Northern California Health
Care System, Mather, CA 95655, USA. Electronic address: [email protected].
(2)Division of Cardiovascular Medicine, University of California, Davis, Davis,
CA 95616, USA.
(3)Department of Physiology and Cell Biology, University of Nevada, Reno School
of Medicine, Reno, NV 89557, USA.
(4)Department of Pathology and Laboratory Medicine, University of California,
Davis, Davis, CA 95817, USA.
(5)Department of Biomedical Sciences, Creighton University, Omaha, NE 68178,
USA.
(6)Department of Physiology and Cell Biology, University of Nevada, Reno School
of Medicine, Reno, NV 89557, USA. Electronic address: [email protected].
(7)Division of Cardiovascular Medicine, University of California, Davis, Davis,
CA 95616, USA; Department of Veterans Affairs, VA Northern California Health
Care System, Mather, CA 95655, USA. Electronic address:
[email protected]. BACKGROUND: Prestin (SLC26A5) is responsible for acute sensitivity and frequency
selectivity in the vertebrate auditory system. Limited knowledge of prestin is
from experiments using site-directed mutagenesis or domain-swapping techniques
after the amino acid residues were identified by comparing the sequence of
prestin to those of its paralogs and orthologs. Frog prestin is the only
representative in amphibian lineage and the studies of it were quite rare with
only one species identified.
RESULTS: Here we report a new coding sequence of SLC26A5 for a frog species,
Rana catesbeiana (the American bullfrog). In our study, the SLC26A5 gene of Rana
has been mapped, sequenced and cloned successively using RNA-Seq. We measured
the nonlinear capacitance (NLC) of prestin both in the hair cells of Rana's
inner ear and HEK293T cells transfected with this new coding gene. HEK293T cells
expressing Rana prestin showed electrophysiological features similar to that of
hair cells from its inner ear. Comparative studies of zebrafish, chick, Rana and
an ancient frog species showed that chick and zebrafish prestin lacked NLC.
Ancient frog's prestin was functionally different from Rana.
CONCLUSIONS: We mapped and sequenced the SLC26A5 of the Rana catesbeiana from
its inner ear cDNA using RNA-Seq. The Rana SLC26A5 cDNA was 2292 bp long,
encoding a polypeptide of 763 amino acid residues, with 40% identity to mammals.
This new coding gene could encode a functionally active protein conferring NLC
to both frog HCs and the mammalian cell line. While comparing to its orthologs,
the amphibian prestin has been evolutionarily changing its function and becomes
more advanced than avian and teleost prestin. The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin
(SLC26a5), in high density, whose charge movement is evidenced as a nonlinear
capacitance (NLC). NLC is bell-shaped, with its peak occurring at a voltage, Vh,
where sensor charge is equally distributed across the plasma membrane. Thus, Vh
provides information on the conformational state of prestin. Vh is sensitive to
membrane tension, shifting to positive voltage as tension increases and is the
basis for considering prestin piezoelectric (PZE). NLC can be deconstructed into
real and imaginary components that report on charge movements in phase or 90
degrees out of phase with AC voltage. Here we show in membrane macro-patches of
the OHC that there is a partial trade-off in the magnitude of real and imaginary
components as interrogation frequency increases, as predicted by a recent PZE
model (Rabbitt in Proc Natl Acad Sci USA 17:21880-21888, 2020). However, we find
similar behavior in a simple 2-state voltage-dependent kinetic model of prestin
that lacks piezoelectric coupling. At a particular frequency, Fis, the complex
component magnitudes intersect. Using this metric, Fis, which depends on the
frequency response of each complex component, we find that initial Vh influences
Fis; thus, by categorizing patches into groups of different Vh, (above and
below - 30 mV) we find that Fis is lower for the negative Vh group. We also find
that the effect of membrane tension on complex NLC is dependent, but
differentially so, on initial Vh. Whereas the negative group exhibits shifts to
higher frequencies for increasing tension, the opposite occurs for the positive
group. Despite complex component trade-offs, the low-pass roll-off in absolute
magnitude of NLC, which varies little with our perturbations and is indicative
of diminishing total charge movement, poses a challenge for a role of
voltage-driven prestin in cochlear amplification at very high frequencies. |
Is EuroQol 5-Dimension Health Assessment (EQ-5D) [a widely used, simple instrument that monitors the general health-related quality of life (HRQoL) in chronic disease] a 5 question assessment? | The 6-question EuroQol 5-Dimension Health Assessment (EQ-5D) is a widely used, simple instrument that monitors general health-related quality of life (HRQoL) in chronic disease. | OBJECTIVE: The 6-question EuroQol 5-Dimension Health Assessment (EQ-5D) is a
widely used, simple instrument that monitors general health-related quality of
life (HRQoL) in chronic disease. It has not previously been applied to US
patients undergoing endoscopic sinus surgery (ESS).
STUDY DESIGN: Prospective cohort study.
SETTING: Academic Medical Center.
SUBJECTS AND METHODS: The study population consisted of 267 patients with
chronic rhinosinusitis (CRS) who completed 2 disease-specific instruments-the
Chronic Sinusitis Survey (CSS) and the Sinonasal Outcomes Test-22 (SNOT-22)-and
1 general health-related quality-of-life instrument-the EQ-5D-before and after
ESS for CRS. Baseline scores were compared to those collected 3 and 12 months
after surgery and to the general US population.
RESULTS: Surveys were completed at all time points by 186 patients, for a
response rate of 69.7%. Patients with CRS, when compared to the US population,
reported more problems in the domains of pain/discomfort (73.1% vs 40.8%, P <
.01), anxiety/depression (50.5% vs 26.4%, P < .01), and usual activities (30.6%
vs 15.0%, P < .01). One year following ESS, there was a significant decrease in
patients who reported problems with pain/discomfort (54.3%, P < .001),
anxiety/depression (30.6%, P < .001), and usual activities (21.5%, P < .01).
After surgery, CRS anxiety/depression scores were no different from those of the
US general population. Chronic Sinusitis Survey and SNOT-22 scores demonstrated
similar postoperative improvements.
CONCLUSION: The EQ-5D assessment provides meaningful general health outcomes
data with low patient burden. Application of this instrument demonstrated
long-term improvement in the quality of life of patients who undergo sinus
surgery. |
What are piRNAs? | PIWI-interacting RNAs (piRNAs) are germline-specific small RNAs that form effector complexes with PIWI proteins (Piwi-piRNA complexes) and play critical roles for preserving genomic integrity by repressing transposable elements (TEs). | |
Bimekizumab is used for treatment of which disease? | Bimekizumab is used for psoriasis. | AIMS: To assess safety, pharmacokinetics (PK) and clinical efficacy of
bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual
inhibitor of interleukin (IL)-17A and IL-17F, in subjects with mild plaque
psoriasis.
METHODS: Randomized, double-blind, first-in-human study of bimekizumab in 39
subjects who received single-dose intravenous bimekizumab (8-640 mg) or placebo
(NCT02529956).
RESULTS: Bimekizumab demonstrated dose-proportional linear PK and was tolerated
across the dose range assessed. No subject discontinued due to
treatment-emergent adverse events and no severe adverse events were reported.
Bimekizumab demonstrated fast onset of clinically-meaningful effects on skin of
patients with mild psoriasis as early as Week 2. Maximal improvements (100% or
near 100% reductions from baseline) in all measures of disease activity were
observed between Weeks 8-12 in subjects receiving 160-640 mg bimekizumab. The
duration of effect at doses ≥160 mg was evident up to Weeks 12-20 after a single
intravenous dose, dependent on endpoint.
CONCLUSIONS: This is the first study to demonstrate the safety, tolerability and
clinical efficacy of a dual IL-17A and IL-17F inhibitor, in subjects with mild
psoriasis. Bimekizumab showed fast onset of clinically-meaningful efficacy by
Week 2, with a maximal or near-maximal magnitude of response that was maintained
up to study Weeks 12-20. These findings support the continued clinical
development of bimekizumab for diseases mediated by both IL-17A and IL-17F,
including psoriasis. Psoriasis and psoriatic arthritis are common diseases with significant physical
and emotional burden. Several biologics are FDA-approved to treat psoriasis and
psoriatic arthritis, though some patients remain refractory to, or have lost
response to, therapy and/or cannot tolerate the associated risks and side
effects. Bimekizumab is a new biologic that inhibits both IL-17A and IL-17F. It
is currently in phase III clinical trials. To date, phase II studies show
promise in its ability to rapidly resolve symptoms while remaining safe and
well-tolerated. Areas covered: This review serves to summarize the literature
regarding the use of bimekizumab for psoriasis and psoriatic arthritis.
Bimekizumab has undergone phase I and phase II clinical trials with results
showing significant disease improvement or resolution, as well as safety and
tolerability. Phase III studies are now actively enrolling. Expert opinion:
Bimekizumab is a burgeoning biologic offering significant promise through its
unique bispecific targeting of both IL-17A and IL-17F. Clinical trials have
shown the potential of rapid symptom improvement after treatment with
bimekizumab, with some patients seeing improvement after only two weeks. To
date, bimekizumab has been shown to be safe and well-tolerated by patients,
without any associated significant adverse events. Plaque psoriasis (PsO) is a chronic inflammatory skin disorder that may be
associated with several comorbidities, including arthritis. The increasing
knowledge of psoriasis pathogenesis led to the identification of novel targeted
therapeutic interventions. Among them, anti-IL-17A and anti-IL-17F antibodies
are currently being investigated for the treatment of PsO and/or psoriatic
arthritis (PsA). Bimekizumab is one of these agents, capable ofsimultaneously
neutralizing both IL-17A and IL-17F cytokines. In this review we included
preclinical and clinical data related to this highly promising agent that shows
a peculiar molecular structure differing from other bispecific agents. Psoriatic arthritis is a complex and heterogeneous disease with potential
significant disability and impaired quality of life. Although in the last
decades new treatment options have led to a better management of this disease,
there are still significant unmet therapeutic needs. Dual inhibitor antibodies
target two different cytokines simultaneously, potentially offering a better
disease control. In psoriatic arthritis, there is evidence for a pathogenic role
not only of IL-17A but also the structurally homologous IL-17F. It is postulated
that differential expression of both in several targets of PsA could account for
disparities in clinical response to IL-17A inhibition alone (such as with
secukinumab or ixekizumab). Here we review the evidence so far for the use in
psoriatic arthritis of bimekizumab, the first humanized monoclonal IgG1 antibody
that selectively neutralizes both IL-17A and IL-17F. A Phase 2b trial reports
better outcomes over both placebo and IL-17A inhibition alone. Very recently
encouraging results from open-label extensions with regards to both safety and
maintece of response were presented. Phase III trials are ongoing with the
first results awaited in 2021. INTRODUCTION: Plaque psoriasis can significantly impact patients' quality of
life. We assessed psychometric properties of the Psoriasis Symptoms and Impacts
Measure (P-SIM), developed to capture patients' experiences of signs, symptoms
and impacts of psoriasis.
METHODS: Pooled, blinded, 16-week data from 1002 patients in the BE VIVID and
BE READY bimekizumab phase 3 trials were analysed. The suitability of the P-SIM
missing score rule (weekly scores considered missing if ≥ 4 daily scores were
missing) was assessed. Test-retest reliability was evaluated using intraclass
correlation coefficients (ICCs). Convergent validity was assessed between P-SIM
and relevant patient-reported outcome (PRO) (Dermatology Life Quality Index
[DLQI], DLQI item 1 [skin symptoms], Patient Global Assessment of Psoriasis) and
clinician-reported outcome (ClinRO) scores (Psoriasis Area and Severity Index
[PASI], Investigator's Global Assessment [IGA]) at baseline and week 16.
Known-groups validity was assessed, comparing P-SIM scores between patient
subgroups predefined using PASI/IGA scores. Sensitivity to change over 16 weeks
was evaluated; responder definition (RD) thresholds were explored.
RESULTS: The missing score rule used did not impact P-SIM scores. Test-retest
reliability analyses demonstrated excellent score reproducibility (ICC
0.91-0.98). Inter-item correlations at baseline and week 16 were strong (> 0.5),
apart from "choice of clothing" with "skin pain" and "burning" at baseline (both
0.49). All P-SIM scores were moderately to strongly correlated with other
outcomes, demonstrating convergent validity, apart from ClinROs (PASI, IGA) at
baseline that had low variability. P-SIM scores discriminated known groups at
week 16, confirming known-groups validity. Changes from baseline to week 16 in
P-SIM and other clinically relevant outcomes were strongly correlated (> 0.5;
weaker with ClinROs), establishing sensitivity to change. Anchor-based RD
analyses determined a four-point P-SIM item score decrease as indicative of
marked clinically meaningful improvement.
CONCLUSION: P-SIM scores demonstrated good reliability, validity and sensitivity
to change. A four-point RD threshold could be used to assess 16-week treatment
effects.
TRIAL REGISTRATION: BE VIVID: NCT03370133; BE READY: NCT03410992. INTRODUCTION: Interleukin (IL)-17 is critical in the pathogenesis of psoriasis
and psoriatic arthritis (PsA) with most data suggesting that IL-17A alone was
the key cytokine. However, in vitro and in vivo studies have suggested dual
blockade of IL-17A and IL-17 F may be more effective than IL-17 A blockade
alone. Bimekizumab is the first human monoclonal antibody to exert simultaneous
specific inhibition of IL-17A and IL-17 F, and has been studied in several phase
II/III trials for psoriasis and PsA.
AREAS COVERED: Bimekizumab is not currently licensed for use. A literature
search identified clinical trials examining the efficacy and safety of
bimekizumab for psoriasis and PsA, and these were critically appraised.
EXPERT OPINION: Clinical trials of bimekizumab have been promising,
demonstrating a rapid onset of response and superior efficacy compared to three
currently licensed biologics: secukinumab, ustekinumab, and adalimumab.
Bimekizumab maintains a high level of efficacy with maintece dosing intervals
of 8 weeks, compared with 4 weeks for currently licensed IL-17A antagonists. No
unexpected adverse events have been identified, although mild-to-moderate fungal
infections occur in approximately 10%. Studies over longer time periods
involving additional active comparators would be valuable in further defining
the role of bimekizumab amongst currently available treatments. Conflict of interest statement: Conflict of interest statement: H. Iznardo does
not have any potential conflicts of interest involving the work under
consideration for publication. L. Puig has perceived consultancy/speaker’s
honoraria from and/or participated in clinical trials sponsored by Abbvie,
Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen,
JS BIOCAD, Leo-Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer,
Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi, and UCB. Receipt of
grants/research supports or participation in clinical trials (paid to
institution): Abbvie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen,
Leo-Pharma, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB. Receipt of
honoraria or consultation fees (paid to myself): Abbvie, Almirall, Amgen,
Baxalta, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene,
Fresenius-Kabi, Janssen, JS BIOCAD, Leo-Pharma, Lilly, Mylan, Novartis, Pfizer,
Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi, UCB. Participation in a
company sponsored speaker’s bureau: Celgene, Janssen, Lilly, Novartis, Pfizer.
Stock shareholder: None. Other support (please specify): None. INTRODUCTION: This analysis assessed the psychometric properties of the
Psoriasis Symptoms and Impacts Measure (P-SIM), a novel patient-reported outcome
(PRO) tool designed to capture patient experiences of the signs, symptoms and
impacts of psoriasis.
METHODS: Blinded data from the BE RADIANT phase 3b trial of bimekizumab were
analysed. In BE RADIANT, patients were randomised 1:1 to bimekizumab 320 mg
every 4 weeks (Q4W) or secukinumab 300 mg (weekly until Week 4, then Q4W). Three
items (itching, skin pain and scaling) of the P-SIM were electronically assessed
throughout the trial and were scored from 0 to 10 (none to very severe
signs/symptoms/impacts). Test-retest reliability was determined using intraclass
correlations. Convergent validity was assessed between P-SIM and other relevant
PRO and clinician-reported outcome (ClinRO) scores. Known-groups validity was
assessed by comparing mean P-SIM item scores between patient subgroups based on
the Psoriasis Area and Severity Index (PASI)/Investigator's Global Assessment
(IGA) scores. Responsiveness was assessed via correlations between changes from
baseline in P-SIM item scores and other relevant PRO and ClinRO scores.
Anchor-based responder analyses and empirical cumulative distribution function
(eCDF) curves determined responder thresholds.
RESULTS: The three P-SIM items yielded high intraclass coefficients (> 0.70). By
Week 48, the three P-SIM items had moderate (> 0.30 and ≤ 0.50) to strong
(> 0.50) correlations with other PROs and weaker correlations with ClinROs,
demonstrating good convergent validity. For almost all known-group comparisons,
statistically significant between-subgroup score differences were seen across
all three P-SIM items. Changes from baseline in the P-SIM and other relevant
outcomes were above the acceptable threshold of ≤ 0.30, demonstrating
sensitivity to change. Anchor-based analyses determined a ≥ four-point reduction
from baseline to indicate marked clinically meaningful improvement for the
P-SIM.
CONCLUSION: These results support the validity, reliability and sensitivity to
change of the P-SIM in assessing key symptoms (itching, skin pain and scaling)
in patients with moderate to severe plaque psoriasis.
TRIAL REGISTRATION: NCT03536884. Psoriasis is a chronic, systemic, immune-mediated disease, with prominent skin
and joint manifestations, associated with several comorbidities. In the past few
decades, advances in the knowledge of psoriasis pathogenesis have driven the
development of highly effective targeted biologic therapies, transforming the
treatment landscape of psoriasis. Bimekizumab is a humanized antibody that
selectively binds and neutralizes the biologic functions of interleukin (IL)-17A
and IL-17F. This article reviews the current knowledge about bimekizumab in
psoriasis treatment. The results obtained in the phase 3 studies (BE VIVID, BE
READY, BE RADIANT, BE SURE) corroborate the high levels of efficacy of
bimekizumab seen in previous studies, and show superior efficacy over
adalimumab, ustekinumab, and secukinumab in direct comparative studies. In all
phase 3 trials, bimekizumab was also well tolerated, with a safety profile
similar to the other biologic drugs tested, except for a higher frequency of
oral candidiasis. Dual inhibition of IL-17A and IL-17F is a highly effective
therapeutic option for the treatment of psoriasis, both for naïve patients and
for those resistant to previous biologic treatments. BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both
interleukin (IL)-17A and IL-17F, which is currently under investigation for
treatment of moderate-to-severe plaque psoriasis. Maintece dosing every
4 weeks is well established with IL-17 inhibitors for psoriasis.
OBJECTIVES: To investigate the possible dosing interval during bimekizumab
maintece therapy to maintain clear skin, to inform phase III studies.
METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received
bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg
(n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity
and biopsy transcriptomic analyses were assessed to week 28.
RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in
Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12
(8 weeks after the second dose) before decreasing. In those who received
bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at
week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week
8 transcriptional signature observed in lesional psoriatic skin rapidly
normalized to levels consistent with nonlesional skin, resulting in molecular
remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif
chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif
chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated
with nonlesional skin.
CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid,
deep clinical responses. Additionally, profound normalization of keratinocyte
biology and the psoriatic transcriptome was observed, including normalization of
both IL17 and IL23 gene expression by week 8. These data provide evidence to
support evaluation of bimekizumab maintece dosing both every 8 and every
4 weeks in phase III clinical trials. |
What is the white mutation in Drosophila affecting? | Βeyond the classical eye-color phenotype, mutations in Drosophila white gene could impair several biological functions affecting parameters like mobility, life span and stress tolerance. | The classic eye-color gene white (w) in Drosophila melanogaster (fruitfly) has
unexpected behavioral consequences. How w affects locomotion of adult flies is
largely unknown. Here, we show that a mutant allele (w1118 ) selectively
increases locomotor components at relatively high frequencies (> 0.1 Hz). The
w1118 flies had reduced transcripts of w+ from the 5' end of the gene. Male
flies of w1118 walked continuously in circular arenas while the wildtype
Canton-S walked intermittently. Through careful control of genetic and
cytoplasmic backgrounds, we found that the w1118 locus was associated with
continuous walking. w1118 -carrying male flies showed increased median values of
path length per second (PPS) and 5-min path length compared with w+ -carrying
males. Additionally, flies carrying 2-4 genomic copies of mini-white+ (mw+ ) in
the w1118 background showed suppressed median PPSs and decreased 5-min path
length compared with controls, and the suppression was dependent on the copy
number of mw+ . Analysis of the time-series (i.e., PPSs over time) by Fourier
transform indicated that w1118 was associated with increased locomotor
components at relatively high frequencies (> 0.1 Hz). The addition of multiple
genomic copies of mw+ (2-4 copies) suppressed the high-frequency components.
Lastly, the downregulation of w+ in neurons but not glial cells resulted in
increased high-frequency components. We concluded that mutation of w modified
the locomotion in adult flies by selectively increasing high-frequency locomotor
components. |
Austrian syndrome is a rare entity characterized by Osler's triad. Please list the 3 components of Osler's triad. | Austrian syndrome, which is also known as Osler's triad, is a rare aggressive pathology consisting of pneumonia, endocarditis, and meningitis caused by Streptococcus pneumoniae | This report describes two cases of Osler's triad of pneumonia, meningitis, and
endocarditis, as a result of Streptococcus pneumoniae infection, also called
Austrian's syndrome. In the first patient, a 51 year old non-alcoholic man, the
aortic valve was affected and needed to be replaced in an emergency operation.
The mitral valve was affected in a 70 year old woman without underlying disease,
who only benefited from medical treatment. Both patients received
corticosteroids, either dexamethasone followed by low doses of hydrocortisone
and fludrocortisone, or only hydrocortisone and fludrocortisone, at the onset of
the illness, and their outcome was favourable. These case reports focus on the
presentation, prognosis, and therapeutic options for this severe syndrome. The triad of pneumonia, meningitis, and endocarditis due to Streptococcus
pneumoniae is known as Austrian syndrome. We report a case with an aortic-right
atrium fistula in a 39-year-old woman who had undergone splenectomy for
Hodgkin's lymphoma. The review of literature shows that the prevalence of
Austrian syndrome is decreasing from 19% to 3% of patients with pneumococcal
endocarditis in recent years. This case emphasizes that diagnosis of
endocarditis should be considered early in every patient with pneumococcal
meningitis or bacteremia, particularly in immunocompromised patients. Austrian's triad is a rare complication of disseminated Streptococcus pneumoniae
infection consisting of pneumonia, meningitis, and endocarditis. We report what
we believe to be the first case of Austrian's triad further complicated by
purulent pericarditis and cardiac tamponade, and review the relevant literature. In this report, we describe the case of a 64-year-old male patient, with no
history of alcohol consumption, who presented the Osler's triad, which is the
association of endocarditis, pneumonia, and meningitis caused by a single agent.
This syndrome is called Austrian syndrome, when the infection is caused by
Streptococcus pneumoniae. We discuss the clinical manifestations, the
pathophysiology, and the therapeutic approach to this condition. Given the
rarity of the condition and its high morbidity and mortality, the importance of
an early diagnosis and an appropriate treatment to reduce the complications
associated with this disease will be emphasized. Bi-valvular pneumococcal endocarditis in Austrian syndrome, which includes a
triad of pneumococcal endocarditis, pneumonia, and meningitis, is a rare but
life-threatening disease. We present a case of a woman found to have Austrian
syndrome who presented to the emergency department (ED) with dehydration and
radiographical signs of lobar pneumonia and quickly deteriorated to fulmit
cardiogenic shock in less than four hours. An early echocardiogram in the ED
confirmed a diagnosis of bi-valvular endocarditis with severe aortic and mitral
valve insufficiency and large vegetations on the valve leaflets requiring
emergent surgical intervention with double valve replacement. Assumed meningitis
as a part of the triad of Austrian syndrome was confirmed by imaging the day
after hospital admission. Early diagnosis of endocarditis by obtaining the
echocardiogram in the ED along with emergent surgical intervention allowed for a
favorable outcome for the patient. We herein describe the case of a 65-year-old male patient who presented with
Osler's triad, which is the combination of endocarditis, pneumonia, and
meningitis. This report is even more unusual since the pathogen isolated was the
invasive and virulent strain of Streptococcus pneumoniae serotype 3. The
clinical entity described is also called Austrian syndrome. Even though rare in
this antibiotic era, the syndrome remains one of high morbidity and mortality.
This particular case is of paramount importance for the clinician reader. First,
it documents the clinical features associated with invasive pneumococcal disease
and the Austrian syndrome. Second, and equally important, it highlights why
following the Surviving Sepsis Campaign guidelines saves lives. For this case,
the following steps were taken: 1. As a surrogate for perfusion, early and
aggressive fluid resuscitation therapy (guided by lactic acid levels) was
instituted; 2. also early in the treatment, broad spectrum antibiotics were
administered; 3. to guide antibiotic therapy, microbiological cultures were
obtained. The patient subsequently improved and was transferred to the internal
medicine ward to complete 4 weeks of antibiotic therapy. BACKGROUND: Known also as Osler's triad, Austrian syndrome is a complex
pathology which consists of pneumonia, meningitis and endocarditis, all caused
by the haematogenous dissemination of Streptococcus pneumoniae. The
multivalvular lesions are responsible for a severe and potential lethal outcome.
CASE REPORT: The case of a 51-year-old female patient, with a past medical
history of splenectomy, is presented. She developed bronchopneumonia, acute
meningitis and infective endocarditis as a result of Streptococcus pneumoniae
infection and subsequently developed multiple organ dysfunction syndromes which
led to a fatal outcome. Bacteriological tests did not reveal the etiological
agent. The histopathological examination showed a severe multivalvular
endocarditis, while a PCR based molecular analysis from formalin fixed valvular
tissue identified Streptococcus pneumoniae as the etiologic agent.
CONCLUSIONS: The presented case shows a rare syndrome with a high risk of
morbidity and mortality. Following the broad-spectrum treatment and intensive
therapeutic support, the patient made unfavourable progress which raised
differential diagnosis problems. In this case, the post-mortem diagnosis
demonstrated multiple valvular lesions occurred as a result of endocarditis. El síndrome de Austrian es una patología producida por la infección diseminada
de Streptococcus pneumoniae y caracterizada por la tríada de neumonía,
endocarditis y meningitis Tiene una incidencia estimada de 0,9-7,8 casos por
diez millones de habitantes y año y una mortalidad del 32%. El consumo de
alcohol, como principal factor de riesgo, aparece solamente en cuatro de cada
diez pacientes. Un 14% no presentan factores de riesgo. Dos de cada tres
enfermos son varones y ocurre en la época media de la vida. Asienta sobre
válvula nativa, lesionándose la aorta en la mitad de los afectados. Presentan
regurgitación severa dos de cada tres pacientes. El tratamiento antimicrobiano
apropiado y la cirugía temprana de la endocarditis disminuyen la mortalidad. Es
posible que la epidemiología del síndrome de Austrian esté cambiando por la
introducción de la vacuna antineumocócica conjugada 13-valente en el calendario
infantil. Austrian syndrome is a rare triad of meningitis, pneumonia, and endocarditis
caused by Streptococcus pneumoniae. We present a case of the Austrian syndrome
in the oldest patient in the reviewed literature, with no other classically
described risk factors. She had an unusual initial presentation
and microorganism portal of entry. Her hospital course was complicated by
the diagnosis of monoclonal gammopathy, septic knee joint, septic brain
emboli and respiratory failure. We also provide an extensive review of available
literature of this commonly unrecognized entity. BACKGROUND: Austrian syndrome, which is also known as Osler's triad, is a rare
aggressive pathology consisting of pneumonia, endocarditis, and meningitis
caused by Streptococcus pneumoniae and carries drastic complications.
CASE PRESENTATION: A case of a 68-year-old female with a past medical history of
hypertension and had a recent viral influenza is presented. She developed
bacterial pneumonia, endocarditis with mitral and aortic vegetations and
perforation, meningitis, and right sternoclavicular septic arthritis. Two prior
case reports have described sternoclavicular septic arthritis as part of
Austrian syndrome. Our case is the third case; however, it is the first case to
have this tetrad in an immunocompetent patient with no risk factors, i.e.,
males, chronic alcoholism, immunosuppression, and splenectomy.
CONCLUSIONS: Clinicians should maintain a high index of suspicion for the
possibility of sternoclavicular joint septic arthritis as a complication of
Austrian syndrome in immunocompetent patients. Author information:
(1)Department of Internal Medicine, St. Barnabas Hospital Bronx, Bronx, NY,
United States.
(2)School of Medicine, University of El Salvador, San Salvador, El Salvador.
(3)Department of Radiology, St. Barnabas Hospital Bronx, Bronx, NY, United
States.
(4)Department of Medicine, Creighton University, Omaha, NE, United States.
(5)Division of Infectious Diseases, Department of Internal Medicine, St.
Barnabas Hospital Bronx, Bronx, NY, United States. Austrian syndrome is a rare triad of endocarditis, meningitis, and pneumonia
caused by Streptococcus pneumonia described by Robert Austrian in 1956. The
incidence has reduced since the introduction of beta-lactam therapy in the early
1940s. Additionally, the introduction of the pneumococcal vaccination in 1977
further decreased the incidence of infection. Streptococcal endocarditis could
potentially be very aggressive and life threatening despite appropriate therapy.
It has a high mortality rate nearing 30 % even after proper antibiotics and
surgical intervention. Therefore, an early recognition is crucial for early
intervention and mortality reduction. We present a patient with Austrian
syndrome who had a poor outcome despite proper management that is attributed to
late presentation and delayed treatment. |
What is the rate of epimutations in C. elegans? | In C. elegans epimutations arise spontaneously at a rate approximately 25 times greater than DNA sequence changes. | |
Is sacituzumab govitecan effective for breast cancer? | Yes. Sacituzumab Govitecan is a new and available treatment for metastatic triple-negative breast cancer. | Results from a phase I/II trial suggest that an antibody-drug conjugate,
sacituzumab govitecan, is active against refractory, metastatic triple-negative
breast cancer. A phase III trial is under way to compare its safety and efficacy
with that of standard chemotherapy. Introduction: Triple negative breast cancer (TNBC) is an aggressive breast
cancer subtype associated with an increased risk of recurrence and
cancer-related death. Unlike hormone receptor-positive or HER2-positive breast
cancers, there are limited targeted therapies available to treat TNBC and
cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan
(IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and
selectively delivering SN-38, an active metabolite of irinotecan. Areas covered:
This review covers the mechanism of action, safety and efficacy of sacituzumab
govitecan in patients with previously treated, metastatic TNBC. Additionally,
efficacy data in other epithelial maligcies is included based on a PubMed
search for 'sacituzumab govitecan' and 'clinical trial'. Expert opinion:
Sacituzumab govitecan has promising anti-cancer activity in patients with
metastatic TNBC previously treated with at least two prior lines of systemic
therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase
III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable
side effect profile, with the most common adverse events being nausea,
neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends
beyond TNBC with promising early efficacy data in many other epithelial cancers,
including hormone receptor-positive breast cancer. Sacituzumab govitecan (sacituzumab govitecan-hziy; Trodelvy™) is a
Trop-2-directed antibody conjugated to a topoisomerase I inhibitor (SN-38) that
is being developed by Immunomedics for the treatment of solid tumours, including
breast cancer. In April 2020, sacituzumab govitecan received accelerated
approval in the USA for the treatment of adult patients with metastatic
triple-negative breast cancer (mTNBC) who have received at least two prior
therapies for metastatic disease. Sacituzumab govitecan is undergoing phase III
development for breast cancer in the USA and EU, and phase II development for
urothelial cancer. It is also being explored for brain metastases, glioblastoma,
endometrial cancer and prostate cancer. This article summarizes the milestones
in the development of sacituzumab govitecan leading to this first approval for
mTNBC. Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein
and an epithelial cell adhesion molecule (EpCAM) family member. Although
initially identified as a transmembrane protein, other subcellular localizations
and processed forms were described. Its congenital mutations cause a gelatinous
drop-like corneal dystrophy, a disease characterized by loss of barrier function
in corneal epithelial cells. Trop2 is considered a stem cell marker and its
expression associates with regenerative capacity in various tissues. Trop2
overexpression was described in tumors of different origins; however, functional
studies revealed both oncogenic and tumor suppressor roles. Nevertheless,
therapeutic potential of Trop2 was recognized and clinical studies with
drug-antibody conjugates have been initiated in various cancer types. One of
these agents, sacituzumab govitecan, has been recently granted an accelerated
approval for therapy of metastatic triple-negative breast cancer. In this
article, we review the current knowledge about the yet controversial function of
Trop2 in homeostasis and pathology. Prostate cancer remains the second leading cause of cancer-associated deaths
amongst American men. Trop2, a cell surface glycoprotein, correlates with poor
clinical outcome and is highly expressed in metastatic, treatment-resistant
prostate cancer. High levels of Trop2 are prognostic for biochemical recurrence.
Trop2 regulates tumor growth and metastatic ability of prostate cancer.
Moreover, overexpression of Trop2 drives the transdifferentiation to
neuroendocrine phenotype in prostate cancer. In addition, Trop2 is overexpressed
across epithelial cancers and has emerged as a promising therapeutic target in
various solid epithelial cancers. The FDA (Food and Drug Administration)
recently approved the use of a Trop2-targeting ADC (antibody-drug conjugate),
Sacituzumab Govitecan (IMMU-132), for metastatic, triple-negative breast cancer
with at least two prior therapies. Here, we review the role of Trop2 in prostate
tumorigenesis and its potential as a promising biomarker and therapeutic target
for prostate cancer. BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor
prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an
antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which
is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase
I inhibitor) through a proprietary hydrolyzable linker.
METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan
as compared with single-agent chemotherapy of the physician's choice (eribulin,
vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or
refractory metastatic triple-negative breast cancer. The primary end point was
progression-free survival (as determined by blinded independent central review)
among patients without brain metastases.
RESULTS: A total of 468 patients without brain metastases were randomly assigned
to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients).
The median age was 54 years; all the patients had previous use of taxanes. The
median progression-free survival was 5.6 months (95% confidence interval [CI],
4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5
to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or
death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was
12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months
(95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI,
0.38 to 0.59; P<0.001). The percentage of patients with an objective response
was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of
key treatment-related adverse events of grade 3 or higher were neutropenia (51%
with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%),
diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%).
There were three deaths owing to adverse events in each group; no deaths were
considered to be related to sacituzumab govitecan treatment.
CONCLUSIONS: Progression-free and overall survival were significantly longer
with sacituzumab govitecan than with single-agent chemotherapy among patients
with metastatic triple-negative breast cancer. Myelosuppression and diarrhea
were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT
ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.). Conflict of interest statement: S. Sun reports grants from NCI, Terri Brodeur
Breast Cancer Foundation, and Massachusetts General Hospital during the conduct
of the study. I. Leshchiner reports personal fees from PACT Pharma, Inc and
Enov1, LLC outside the submitted work. A. Kambadakone reports grants from
Philips Healthcare, GE Healthcare, PanCAN, personal fees from Bayer, and other
support from Siemens Healthcare outside the submitted work. S.J. Isakoff reports
personal fees from Immunomedics, Mylan, Myriad, Puma, Novartis, Seattle
Genetics, grants and personal fees from OncoPep and AbbVie, grants from Merck,
AstraZeneca, and Genentech outside the submitted work. D. Juric reports grants
and personal fees from Novartis, Genentech, Syros, grants from Pfizer, Takeda,
personal fees from Relay, PIC Therapeutics, Mapkure, Vibliome, grants and
personal fees from Eisai, grants from InventisBio, Arvinas, Ribon Therapeutics,
and Infinity Pharmaceuticals outside the submitted work. G. Getz reports grants
from IBM during the conduct of the study; and receives research funds from
Pharmacyclics. G. Getz is a founder, consultant, and holds privately held equity
in Scorpion Therapeutics. A. Bardia reports grants from Genentech, Novartis,
Pfizer, Merck, Sanofi, Radius Health, Immunomedics, and Diiachi
Pharma/AstraZeneca, and personal fees from Pfizer, Novartis, Genentech, Merck,
Radius Health, Immunomedics, Taiho, Sanofi, Diiachi Pharma/AstraZeneca, Puma;
Biothernostics Inc., Phillips, Eli Lilly, Foundation Medicine, during the
conduct of the study; personal fees from Pfizer, Novartis, Genentech, Merck,
Radius Health, Immunomedics, Taiho, Sanofi, Diiachi Pharma/AstraZeneca, Puma;
Biothernostics Inc., Phillips, Eli Lilly, Foundation Medicine, and grants from
Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, and
Diiachi Pharma/AstraZeneca outside the submitted work. L.W. Ellisen reports
grants from DOD/CDMRP and other support from Tracey Davis Memorial Fund during
the conduct of the study; and sacituzumab (drug only) provided by the sponsor
for in vitro experiments as acknowledged in the manuscript. No disclosures were
reported by the other authors. Introduction Metastatic triple-negative breast cancer (TNBC) is an aggressive
cancer with poor survival that is difficult to treat due to a lack of targeted
options. Conventional therapies targeting hormone receptors (HR) and human
epidermal growth factor 2 (HER2) are ineffective and often chemotherapy is
standard-of-care. Sacituzumab govitecan is an antibody drug conjugate (ADC)
comprised of an active metabolite of irinotecan, SN-38, bound to a humanized
monoclonal antibody targeting trophoblastic cell-surface antigen 2 (Trop-2).
Trop-2 is highly expressed on the surface of TNBC cells, making it an attractive
target. Areas covered We explore the mechanism, pharmacology, efficacy, safety,
and tolerability of sacituzumab govitecan. A literature search was conducted via
PubMed using keywords such as 'sacituzumab govitecan,' and 'metastatic TNBC.'
Expert opinion Sacituzumab govitecan has promising survival benefits in patients
with previously treated mTNBC based on data from the ASCENT trial. Common
adverse effects were neutropenia, diarrhea, and nausea, however these effects
were manageable with supportive care. Sacituzumab govitecan has shown promise in
cancers outside of TNBC, such as urothelial and lung and is being evaluated in
HR-positive breast cancers. It is likely we will see this therapy used in
combination with other novel targeted agents as current clinical trials mature. Sacituzumab govitecan was initially approved in April 2020 under accelerated
approval for the treatment of patients with metastatic triple-negative breast
cancer who received at least two prior therapies for metastatic disease. A
confirmatory phase III trial evaluating sacituzumab govitecan vs. chemotherapy
of the provider's choice was published in April 2021. Based on this trial, the
FDA granted sacituzumab govitecan full regulatory approval. This antibody-drug
conjugate is composed of a monoclonal antibody targeted at Trop-2 and contains
the active metabolite of irinotecan, SN-38, as a cytotoxic side moiety. In a
phase III clinical trial, sacituzumab govitecan demonstrated a median
progression-free survival of 5.7 months vs. 1.7 months with chemotherapy. It is
now an additional option for patients with metastatic triple-negative breast
cancer who received at least two prior therapies for metastatic disease. The ASCENT trial reports impressive results with a median overall survival (OS)
increased from 6.7 months to 12.1 months with sacituzumab govitecan over
single-agent chemotherapy, in metastatic triple negative breast cancer (TNBC)
patients in second and subsequent line of therapy. We described design features
in the ASCENT trial casting doubt on the extrapolation of the reported results
to real world patients. First, the open-label design may exaggerate the effect
of the experimental arm. Second, the choice of progression-free-survival (PFS)
as a primary endpoint, debatable in metastatic TNBC, can lead to biases: early
stopping rules may exaggerate efficacy results and informative censoring can
bias PFS results interpretation. Third, the control arm was not a complete
"physician's choice": it was restricted, preventing from using effective agents
in this setting, and leading to a substandard control arm. Fourth and lastly,
dose reduction and supportive care recommendations for the experimental drug
were different between the trial protocol and the FDA labels, and favored the
experimental arm as compared with the control arm. In conclusion, we described
four design features in the ASCENT trial having the potential to favor the
experimental arm or to penalize the control arm. It thus remains uncertain in
which extent the reported outcomes will translate in the real world. Efforts
should be made to avoid trial biases that will eventually prevent to conclude
about their true impact in patients when applied broadly. INTRODUCTION: Sacituzumab govitecan-hziy, approved in 2020 for treatment of
metastatic triple-negative breast cancer, provides a new option for a population
with a historically poor prognosis with standard chemotherapy. Uridine
diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at
increased risk for profound neutropenia. This case discusses clinical
implications of the uridine diphosphate glucuronosyltransferase family 1 member
A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy.
CASE REPORT: A 38-year-old otherwise healthy pre-menopausal female of South
Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and
human epidermal growth factor receptor 2-negative breast cancer. This was
treated with neoadjuvant chemotherapy and multiple lines of subsequent
therapies. Upon finding bone metastasis, an additional six lines of therapy
ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was
started for disease transformation to triple-negative status.
MANAGEMENT AND OUTCOME: Sacituzumab govitecan-hziy was initiated at the Food and
Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle.
Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified
the patient as a uridine diphosphate glucuronosyltransferase family 1 member
A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and
granulocyte colony-stimulating factor was administered due to the severity of
neutropenia. The patient continued on sacituzumab govitecan-hziy until disease
progression.
DISCUSSION: Sacituzumab govitecan-hziy's propensity to cause neutropenia is
multifactorial. Although incidence of all-grade neutropenia from sacituzumab
govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase
family 1 member A1*28 homozygous expressors, this does not translate to
increased risk for febrile neutropenia. Detailed guidance is lacking regarding
empiric dose adjustments or prophylactic granulocyte colony-stimulating factor
for these patients.1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics
testing to identify uridine diphosphate glucuronosyltransferase family 1 member
A1 poor metabolizers is not recommended, and the cost-effectiveness of this
approach is unclear. |
What is Upadacitinib? | Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). | This phase 1 study characterized the effect of multiple doses of upadacitinib,
an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the
cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22)
received a single oral dose of bupropion 150 mg alone (study period 1) and on
day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2).
Serial blood samples for measurement of bupropion and hydroxybupropion plasma
concentrations were collected in each study period. The central values (90%
confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for
bupropion maximum plasma concentration (Cmax ), 0.92 (0.87-0.98) for bupropion
area under the plasma-concentration time curve from time 0 to infinity (AUCinf
), 0.78 (0.72-0.85) for hydroxybupropion Cmax , and 0.72 (0.67-0.78) for
hydroxybupropion AUCinf when administered with, relative to when administered
without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg
once daily, upadacitinib mean ± SD AUC0-24 was 641 ± 177 ng·h/mL, and Cmax was
83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant
effect on pharmacokinetics of substrates metabolized by CYP2B6. BACKGROUND AND AIMS: A number of Janus kinase (JAK) inhibitors (tofacitinib,
filgotinib, upadacitinib) have been tested for moderate and severe Crohn's
disease (CD) in randomized control trials (RCTs). However, data on their
comparative efficacy and tolerability is lacking. We aimed to study their
performance comparatively, by means of network meta-analysis (NWM).
METHODS: We searched the Pubmed/Medline, EMBASE, and Cochrane Library databases
for relevant RCTs through March 2021 and data was extracted. A bayesian NWM was
performed to investigate the efficacy and tolerability of the above JAK
inhibitors and to explore their rank order in treating moderate and severe CD
patients. The cumulative ranking probability for each intervention at the end of
treatment period, was evaluated by means of surfaces under cumulative ranking
(SUCRA) values.
RESULTS: Four RCTs were entered into this NWM. They included 811 patients
totally, randomized to 11 interventions, i.e. placebo, tofacitinib (1mg BID, 5mg
BID, 10mg BID, 15mg BID), filgotinib 200 OD and upadacitinib (3 mg BID, 6 mg
BID, 12 mg BID, 24 mg BID and 24mg OD). Two upadacitinib doses (6 mg BID and 24
mg BID) and filgotinib 200 OD, performed best as judged by the relevant forest
plots, league matrixes, rankograms, SUCRA values (96.7%, 84,6 %and 78,7%,
respectively) and the clustered ranking plots for efficacy and tolerability.
CONCLUSIONS: Upadacitinib 6 mg BID, upadacitinib 24 mg BID and filgotinib 200 OD
performed better as induction therapies in comparison to control therapies.
Consequently, these regimens may play a therapeutic role in CD and therefore
they merit further evaluation with well-designed RCTs. |
Please list the difference between Pyoderma gangrenosum versus chronic venous ulceration? | Even when other body sites are affected, pyoderma gangrenosum usually affects the upper and lower legs and feet or peristomal sites compared with chronic venous ulcers that are limited to the lower legs and feet. (2) Pyoderma gangrenosum can be associated with systemic diseases, especially inflammatory bowel disease. (4) Crater-like holes or cribriform scarring is commonly seen in pyoderma gangrenosum but not in chronic venous ulcers. | Pyoderma gangrenosum is a skin disease characterized by wounds with
blue-to-purple undermined borders surrounding purulent necrotic bases. This
article reports on a patient with a circumferential, full-thickness, and
partially necrotic lower-extremity ulceration of unknown etiology. Results of
laboratory tests and arterial and venous imaging studies were found to be within
normal limits. The diagnosis of pyoderma gangrenosum was made on the basis of
the histologic appearance of the wound tissue after biopsy as a diagnosis of
exclusion. Negative pressure wound therapy was undertaken, which saved the
patient's leg from amputation. Although negative pressure wound therapy has
demonstrated efficacy in the treatment of chronic wounds in a variety of
circumstances, this is the first documented use of this technique to treat an
ulceration secondary to pyoderma gangrenosum. BACKGROUND: Diagnosis of pyoderma gangrenosum can be difficult, leading to
overdiagnosis or underdiagnosis.
OBJECTIVE: To identify clinical features helpful in establishing a diagnosis of
pyoderma gangrenosum and to compare the characteristics of patients with
pyoderma gangrenosum with those of patients with chronic venous ulcers.
METHOD: A retrospective chart review was performed in 28 patients with typical
pyoderma gangrenosum and compared with the clinical features in 28 patients with
chronic venous ulcers.
RESULTS: (1) Even when other body sites are affected, pyoderma gangrenosum
usually affects the upper and lower legs and feet or peristomal sites compared
with chronic venous ulcers that are limited to the lower legs and feet. (2)
Pyoderma gangrenosum can be associated with systemic diseases, especially
inflammatory bowel disease. (3) Pustules and purulent discharge are features of
pyoderma gangrenosum but not of chronic venous ulcers. (4) Crater-like holes or
cribriform scarring is commonly seen in pyoderma gangrenosum but not in chronic
venous ulcers. (5) Pathergy is a specific but not sensitive finding of pyoderma
gangrenosum. It does not occur in patients with chronic venous ulcers.
CONCLUSIONS: Diagnosis of pyoderma gangrenosum should be considered in patients
with purulent ulcers affecting the legs or peristomal sites. To confirm the
diagnosis, specific features should be sought, including pathergy, crater-like
holes or cribriform scarring, and association with inflammatory bowel disease.
Other causes of ulceration should be excluded. |
What is Mobilome-seq? | Mobilome-seq is a method for selectively amplifying and sequencing eccDNAs. It relies on linear digestion of genomic DNA followed by rolling circle amplification of circular DNA. Both active DNA transposons and retrotransposons can be identified using this technique. | Retrotransposons are mobile genetic elements abundant in plant and animal
genomes. While efficiently silenced by the epigenetic machinery, they can be
reactivated upon stress or during development. Their level of transcription not
reflecting their transposition ability, it is thus difficult to evaluate their
contribution to the active mobilome. Here we applied a simple methodology based
on the high throughput sequencing of extrachromosomal circular DNA (eccDNA)
forms of active retrotransposons to characterize the repertoire of mobile
retrotransposons in plants. This method successfully identified known active
retrotransposons in both Arabidopsis and rice material where the epigenome is
destabilized. When applying mobilome-seq to developmental stages in wild type
rice, we identified PopRice as a highly active retrotransposon producing eccDNA
forms in the wild type endosperm. The mobilome-seq strategy opens new routes for
the characterization of a yet unexplored fraction of plant genomes. Active transposable elements (TEs) generate insertion polymorphisms that can be
detected through genome resequencing strategies. However, these techniques may
have limitations for organisms with large genomes or for somatic insertions.
Here, we present a method that takes advantage of the extrachromosomal circular
DNA (eccDNA) forms of actively transposing TEs in order to detect and
characterize active TEs in any plant or animal tissue. Mobilome-seq consists in
selectively amplifying and sequencing eccDNAs. It relies on linear digestion of
genomic DNA followed by rolling circle amplification of circular DNA. Both
active DNA transposons and retrotransposons can be identified using this
technique. Transposable elements (TEs) are the main component of eukaryotic genomes.
Besides their impact on genome size, TEs are also functionally important as they
can alter gene expression and influence phenotypic variation. In plants, most
top-down studies focus on extremely clear phenotypes such as the shape or the
color of individuals and do not explore fully the role of TEs in evolution.
Assessing the impact of TEs in a more systematic manner, however, requires
identifying active TEs to further study their impact on phenotypes. In this
chapter, we describe an in planta approach that consists in activating TEs by
interfering with pathways involved in their silencing. It enables to directly
investigate the functional impact of single TE families at low cost. |
Which variables are included in the ALT-70 Score for cellulitis? | ALT-70 cellulitis score includes: Asymmetry (3 points), Leukocytosis (1 point), Tachycardia (1 point), and age ≥70 (2 points). | BACKGROUND: Cellulitis has many clinical mimickers (pseudocellulitis), which
leads to frequent misdiagnosis.
OBJECTIVE: To create a model for predicting the likelihood of lower extremity
cellulitis.
METHODS: A cross-sectional review was performed of all patients admitted with a
diagnosis of lower extremity cellulitis through the emergency department at a
large hospital between 2010 and 2012. Patients discharged with diagnosis of
cellulitis were categorized as having cellulitis, while those given an
alternative diagnosis were considered to have pseudocellulitis. Bivariate
associations between predictor variables and final diagnosis were assessed to
develop a 4-variable model.
RESULTS: In total, 79 (30.5%) of 259 patients were misdiagnosed with lower
extremity cellulitis. Of the variables associated with true cellulitis, the 4 in
the final model were asymmetry (unilateral involvement), leukocytosis (white
blood cell count ≥10,000/uL), tachycardia (heart rate ≥90 bpm), and age
≥70 years. We converted these variables into a points system to create the
ALT-70 cellulitis score as follows: Asymmetry (3 points), Leukocytosis (1
point), Tachycardia (1 point), and age ≥70 (2 points). With this score, 0-2
points indicate ≥83.3% likelihood of pseudocellulitis, and ≥5 points indicate
≥82.2% likelihood of true cellulitis.
LIMITATIONS: Prospective validation of this model is needed before widespread
clinical use.
CONCLUSION: Asymmetry, leukocytosis, tachycardia, and age ≥70 are predictive of
lower extremity cellulitis. This model might facilitate more accurate diagnosis
and improve patient care. |
List biomarkers for sepsis. | HCK, PRKCD, SIRPA, DOK3, ITGAM, LTB4R, MAPK14, MALT1, NLRC3, LCK
C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin 6 (IL-6)
sTM | PURPOSE: Neonatal sepsis is an important public health concern worldwide due to
its immediate lethality and long-term morbidity rates, Clinical evaluation and
laboratory analyses are indispensable for diagnosis of neonatal sepsis. However,
assessing multiple biomarkers in neonates is difficult due to limited blood
availability. The aim is to investigate if the neonatal sepsis in preterm could
be identified by multiparameter analysis with flow cytometry.
MATERIALS AND METHODS: The expression of activation-related molecules was
evaluated by flow cytometry in newborn with or without risk factors for sepsis.
RESULTS: Our analysis revealed that several markers could be useful for sepsis
diagnosis, such as CD45RA, CD45RO, or CD71 on T cells; HLA-DR on NKT or classic
monocytes, and TREM-1 on non-classic monocytes or neutrophils. However, ROC
analysis shows that the expression of CD45RO on T lymphocytes is the only useful
biomarker for diagnosis of neonatal late-onset sepsis. Also, decision tree
analyses showed that CD45RO plus CD27 could help differentiate the preterm
septic neonates from those with risk factors.
CONCLUSIONS: Our study shows a complementary and practical strategy for
biomarker assessment in neonatal sepsis. BACKGROUND: The increased oxidative stress resulting from the inflammatory
responses in sepsis initiates changes in mitochondrial function which may result
in organ damage, the most common cause of death in the intensive care unit
(ICU). Deficiency of coenzyme Q10 (CoQ10), a key cofactor in the mitochondrial
respiratory chain, could potentially disturb mitochondrial bioenergetics and
oxidative stress, and may serve as a biomarker of mitochondrial dysfunction.
Hence, we aimed to investigate in initially non-septic patients whether CoQ10
levels are decreased in sepsis and septic shock compared to ICU admission, and
to evaluate its associations with severity scores, inflammatory biomarkers, and
ICU outcomes.
METHODS: Observational retrospective analysis on 86 mechanically-ventilated,
initially non-septic, ICU patients. CoQ10 was sequentially measured on ICU
admission, sepsis, septic shock or at ICU discharge. CoQ10 was additionally
measured in 25 healthy controls. Inflammatory biomarkers were determined at
baseline and sepsis.
RESULTS: On admission, ICU patients who developed sepsis had lower CoQ10 levels
compared to healthy controls (0.89 vs. 1.04 µg/ml, p < 0.05), while at sepsis
and septic shock CoQ10 levels decreased further (0.63 µg/ml; p < 0.001 and 0.42
µg/ml; p < 0.0001, respectively, from admission). In ICU patients who did not
develop sepsis, admission CoQ10 levels were also lower than healthy subjects
(0.81 µg/ml; p < 0.001) and were maintained at the same levels until discharge.
CONCLUSION: CoQ10 levels in critically-ill patients are low on ICU admission
compared to healthy controls and exhibit a further decrease in sepsis and septic
shock. These results suggest that sepsis severity leads to CoQ10 depletion. Procalcitonin (PCT) is useful for differentiating between viral and bacterial
infections and for reducing the unnecessary use of antibiotics. As the rise of
antimicrobial resistance reaches "alarming" levels according to the World Health
Organization, the importance of using biomarkers, such as PCT to limit
unnecessary antibiotic exposure has further increased. Randomized trials in
patients with respiratory tract infections have shown that PCT has prognostic
implications and its use, embedded in stewardship protocols, leads to reductions
in the use of antibiotics in different clinical settings without compromising
clinical outcomes. However, available data are heterogeneous and recent trials
found no significant benefit. Still, from these trials, we have learned several
key considerations for the optimal use of PCT, which depend on the clinical
setting, severity of presentation, and pretest probability for bacterial
infection. For patients with respiratory infections and sepsis, PCT can be used
to determine whether to initiate antimicrobial therapy in low-risk settings and,
together with clinical data, whether to discontinue antimicrobial therapy in
certain high-risk settings. There is also increasing evidence regarding
PCT-guided therapy in patients with coronavirus disease 2019 (COVID-19). This
review provides an up-to-date overview of the use of PCT in different clinical
settings and diseases, including a discussion about its potential to improve the
care of patients with COVID-19. PURPOSE: Blood culture contamination is still a frequently observed event and
may lead to unnecessary antibiotic prescriptions and additional hazards and
costs. However, in patients hospitalized in tertiary care, true bacteremias for
pathogens that are classically considered as contamits can be observed. We
assessed the diagnostic accuracy of procalcitonin for differentiating blood
culture contamination from bacteremia in patients with positive blood cultures
for potential contamits.
METHODS: We carried out a retrospective, cross-sectional, observational study on
consecutive patients hospitalized between January 2016 and May 2019 at the
University Hospital of Nancy and who had a positive peripheral blood culture for
a pathogen classically considered as a potential contamit.
RESULTS: During the study period, 156 patients were screened, and 154 were
retained in the analysis. Among the variables that were significantly associated
with a diagnosis of blood culture contamination in univariate analyses, four
were maintained in multivariate logistic regression analysis: a number of
positive blood culture bottles ≤ 2 (OR 23.76; 95% CI 1.94-291.12; P = 0.01),
procalcitonin < 0.1 ng/mL (OR 14.88; 95% CI 1.62-136.47; P = 0.02),
non-infection-related admission (OR 13.00; 95% CI 2.17-77.73; P = 0.005), and a
percentage of positive blood culture bottles ≤ 25% (OR 12.15; 95% CI 2.02-73.15;
P = 0.006).
CONCLUSIONS: These data provide new evidence on the usefulness of plasma
procalcitonin as a reliable diagnostic biomarker in the diagnostic algorithm of
peripheral blood culture contamination among patients hospitalized in tertiary
care.
CLINICAL TRIAL: ClinicalTrials.gov #NCT04573894. BACKGROUND: Endothelium injury and coagulation dysfunction play an important
role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), tissue
plasminogen activator-inhibitor complex (t-PAIC), thrombin-antithrombin complex
(TAT) and α2-plasmin inhibitor-plasmin complex (PIC) are biomarkers of
endothelium injury and coagulation dysfunction. This study aimed to explore the
prognostic values and diagnostic performance for septic shock and sepsis-induced
disseminated intravascular coagulation (DIC) of endothelial biomarkers.
METHODS: We conducted an observational study on patients with sepsis admitted to
intensive care unit (ICU) at a teaching hospital from January 2016 to December
2018. Levels of sTM, t-PAIC, TAT and PIC were measured at admission day and day
5-7 after admission and detected by qualitative chemiluminescence enzyme
immunoassay performed on HISCL automated analyzers.
RESULTS: A total of 179 septic patients and 125 non-septic ICU controls were
enrolled. The level of sTM was higher in septic patients compared to ICU
controls (OR =1.093, 95% CI: 1.045-1.151, P<0.001). Moreover, higher levels of
sTM and t-PAIC were independent predictors of poor 60-day prognosis for septic
patients (HR =1.012, 95% CI: 1.003-1.022, P=0.012; HR =1.014, P=0.009). Level of
sTM was also higher in patients with septic shock as revealed by multivariate
analysis (OR =1.049, 95% CI: 1.020-1.078, P=0.001), as well as in patients with
sepsis-induced DIC (OR =1.109, 95% CI: 1.065-1.158, P<0.001). sTM was considered
as a sensitive biomarker for the early prediction of septic shock and
sepsis-induced DIC, with AUC up to 0.765 (0.687-0.842) and 0.864 (0.794-0.935)
of receiver operating characteristic curve.
CONCLUSIONS: Most patients developed coagulopathy which was closely linked to
endothelial injury in initial phase of sepsis, which was demonstrated by
abnormalities in endothelial biomarkers and their strong association with poor
60-day prognosis and development of septic shock and sepsis-induced DIC. BACKGROUND: Over-activation of the NLRP3 inflammasome can lead to sepsis. NLRP3
is an essential protein in the classical pathway of pyroptosis. This study
assessed the use of serum NLRP3 level as a potential inflammatory biomarker in
septic patients.
METHODS: Patients were categorized into five groups: healthy controls (n = 30),
ICU controls (n = 22), infection (n = 19), septic non-shock (n = 33), and septic
shock (n = 83). Serum NLRP3 levels were measured by enzyme-linked immunosorbent
assay for all patients upon enrollment. Clinical parameters and laboratory test
data (APACHE II, SOFA, and lactate) were also assessed. Moreover, the ability of
serum NLRP3 levels to predict sepsis was determined by the area under the curve
(AUC) analysis.
RESULTS: The NLRP3 levels in the septic shock group was significantly higher
(431.89, 386.61-460.21 pg/mL) than that in the healthy control group (23.24,
9.38-49.73 pg/mL), ICU control group (74.82, 62.71-85.93 pg/mL), infection group
(114.34, 99.21-122.56 pg/mL), and septic non-shock group (136.99,
128.80-146.98 pg/mL; P＜0.001 for all comparisons). Additionally, the AUC
indicated that the ability of serum NLRP3 levels to predict sepsis and septic
shock incidences was not lower than that of the SOFA score. Patients with higher
NLRP3 serum levels (>147.72 pg/mL) had significantly increased 30-day mortality
rate.
CONCLUSIONS: NLRP3 is useful for the early identification of high-risk septic
patients, particularly septic shock patients. Moreover, elevated NRLP3 levels
could result in poor septic prediction outcomes. |
Is Acute Necrotizing Encephalopathy (ANE) which typically affects young, healthy children usually triggered by exposure to air pollution? | Acute necrotizing encephalopathy (ANE) is a recently identified, uncommon encephalopathy affecting children. Acute necrotizing encephalopathy (ANE) is a specific type of encephalopathy usually followed by febrile infection | Acute necrotizing encephalopathy of childhood represents a novel entity of acute
encephalophathy, predomitly affecting infants and young children living in
Taiwan and Japan. It manifests with symptoms of coma, convulsions, and
hyperpyrexia after 2 to 4 days of respiratory tract infections in previously
healthy children. The hallmark of acute necrotizing encephalopathy of childhood
consists of multifocal and symmetric brain lesions affecting the bilateral
thalami, brainstem tegmentum, cerebral periventricular white matter, or
cerebellar medulla. The etiology and pathogenesis of this kind of acute
encephalopathy remain unknown, and there is no specific therapy or prevention.
The prognosis is usually poor, and less than 10% of patients recover completely.
We report a 3-year-old previously healthy girl presenting with acute necrotizing
encephalopathy of childhood associated with influenza type B virus infection,
which resulted in severe neurologic sequelae. We also review the current
knowledge of the clinical, neuroimaging, and pathologic aspects of acute
necrotizing encephalopathy of childhood. Acute necrotizing encephalopathy (ANE) typically affects young, healthy children
who develop rapid-onset severe encephalopathy triggered by viral infections.
This disease is more commonly reported in Japan but occurs worldwide, although
it remains under-recognized in Western countries. An autosomal domit form,
ANE1, was recently identified. We report the details of a 9-year-old Caucasian
female who experienced recurrent ANE episodes at the ages of 9 months and 9
years. Brain magnetic resoce imaging findings were characteristic of ANE
during both episodes, although more extensive in the recent episode, which
resulted in severe neurological sequelae; influenza A was identified on
bronchoalveolar lavage during this episode. Interestingly, there was evidence of
peripheral polyneuropathy during the recent episode, which has not previously
been described in sporadic ANE. Both the patient and her mother, who had also
had postviral polyneuritis in the past, harbour a mutation in Ran-binding
protein 2 (RANBP2); this occurred de novo in the mother and confers genetic
susceptibility to ANE. Our case suggests that recurrent disease and/or an
expanded clinical phenotype raises the possibility of ANE1; positive family
history, although supportive, is not necessary as the mutation can occur de
novo. Increased awareness may lead to earlier recognition and better treatment
options. In 2009 a novel swine-origin Influenza A H1N1 virus was identified in Mexico and
Southern California. Since it was first recognized, neurological complications
including acute necrotizing encephalopathy (ANE) have been globally documented
in association with this viral infection. ANE is mostly known to occur in the
paediatric population. We describe a fatal case of ANE in a previously healthy
40-year-old man infected with influenza A H1N1 virus presenting with severe
neurologic decline. Computed tomography (CT) scan and magnetic resoce imaging
(MRI) findings were consistent with ANE. CT and MR findings typically documented
in paediatric cases of ANE - including bilateral thalamic necrosis with
petechial hemorrhage - have been seldom described in adulthood. Acute necrotizing encephalopathy of childhood (ANEC) is a disease characterized
by respiratory or gastrointestinal infection and high fever accompanying with
rapid alteration of consciousness and seizures. This disease is nearly
exclusively seen in East Asian infants and children who had previously been
completely healthy. Serial magnetic resoce imaging examinations have
demonstrated symmetric lesions involving the thalami, brainstem, cerebellum, and
white matter in this disease. The condition accompanies a poor prognosis with
high morbidity and mortality rates. A 22-month-old toddler with ANEC
hospitalized in Amirkola Children Hospital is being reviewed. Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute
encephalopathy with global distribution. Occurrence of ANE is usually preceded
by a virus-associated febrile illness and ensued by rapid deterioration.
However, the causal relationship between viral infections and ANE and the exact
pathogenesis of ANE remain unclear; both environmental and host factors might be
involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or
sporadic ANE; however, few cases are recurrent and with familial episodes. The
recurrent and familial forms of ANE were found to be incompletely
autosomal-domit. Further the missense mutations in the gene encoding the
nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although
the clinical course and the prognosis of ANE are diverse, the hallmark of
neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which
are demonstrated by computed tomography (CT) or magnetic resoce imaging
(MRI). The treatment of ANE is still under investigation. We summarize the
up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better
treatment of this rare but fatal disease. Acute necrotizing encephalopathy (ANE) is a rapidly progressing neurologic
disorder that occurs in children after common viral infections of the
respiratory or gastrointestinal systems. This disease is commonly seen in East
Asia. Normal healthy infants and children can get affected. The condition
carries a poor prognosis with high morbidity and mortality rates. We report here
a case of a 23-year-old female with ANE and describe its neuroimaging findings.
Magnetic resoce imaging examination performed showed symmetric lesions
involving the thalami, brainstem, and cerebellum. Acute necrotizing encephalopathy of childhood (ANEC) is a disease, characterized
by a respiratory or gastrointestinal infection, accompanied with fever, rapid
alteration of consciousness, and seizures. The clinical characteristics of ANEC
include acute encephalopathy following a viral infection, seizure, altered
consciousness, and absence of cerebrospinal fluid (CSF) pleocytosis, with an
occasional increase in the level of proteins. This disease is almost exclusively
seen in previously healthy infants and children from East Asia. Serial magnetic
resoce imaging (MRI) examinations have demonstrated symmetric lesions
involving the thalami, brainstem, cerebellum, and white matter. ANEC has a poor
prognosis with high morbidity and mortality rates. Herein, we present three
cases of ANEC, who were referred to Bu-Ali Hospital of Ardabil, Iran during two
weeks. Report of these three cases promoted the idea of an epidemic. The purpose
of this case series was to raise the issue that ANEC may occur as an epidemic. BACKGROUND: Among the influenza-associated encephalopathies, acute necrotizing
encephalopathy (ANE) has a particularly poor prognosis. While it usually
progresses within 48 h, we encountered a rapidly evolving case with the patient
falling into coma from lucidity within 10 min.
CASE PRESENTATION: A 71-year-old man was found unconscious after taking a 10-min
bath and brought to the emergency room. The head computed tomography (HCT) was
normal, and he was diagnosed with heatstroke as a complication of influenza A.
Despite effective therapy to correct his temperature, his consciousness did not
improve, and within 24 h he progressed to multiple organ injury. Repeat HCT and
subsequent magnetic resoce imaging revealed irreparably progressed ANE.
CONCLUSION: To effectively treat ANE, early recognition and diagnosis are
critical. Our case suggests that ANE should be considered and added to the
differential diagnosis for adult patients with rapid cognitive deterioration. RATIONALE: Acute necrotizing encephalopathy (ANE) is a specific type of
encephalopathy usually followed by febrile infection. It has an aggressive
clinical course; however, it usually does not recur after recovery in cases of
spontaneous ANE. Nevertheless, there are several studies reporting recurrences
in familial ANE with RAN-binding protein 2 (RANBP2) mutation. There are few
cases of familial ANE with RANBP2 mutation in Asian populations.
PATIENTS CONCERNS: A 21-month-old Korean boy who was previously healthy,
presented with seizure following parainfluenza - a virus and bocavirus
infection, followed by 2 recurrent seizure episodes and encephalitis after
febrile respiratory illnesses. Meanwhile, his 3-year-old sister had focal brain
lesions on neuroimaging studies when evaluated for head trauma. The siblings
also had an older brother who presented status epilepticus after febrile
respiratory illness at the age of 10 months old.
DIAGNOSIS: Brain magnetic resoce imaging was performed to evaluate the
seizure and neurologic symptoms. Imaging findings showed variable spectrum -
from non-specific diffuse white matter injury pattern to typical "tricolor
pattern" of the ANE on diffusion-weighted images. The other 2 siblings showed
focal lesions in both external capsules and severe diffuse brain edema. Genetic
tests identified a heterozygous missense mutation in the RANBP2 [c.1754C>T
(p.Thr585Met)] in 2 siblings and their mother.
INTERVENTIONS: Patients were treated conservatively with anticonvulsive agents,
intravascular immunoglobulin, and steroids.
OUTCOMES: Among the 3 siblings, 2 male siblings died from familial ANE, whereas
the female sibling was asymptomatic.
LESSONS: These cases highlight the radiological aspects of familial ANE with
incomplete penetrance of the RANBP2 gene in 3 family members, showing variable
involvements of the brain and natural history on magnetic resoce images.
Radiologists should be aware of the typical and atypical imaging findings of
familial ANE for prompt management of affected patients. BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rapidly progressive
encephalopathy seen commonly in children triggered by various prodromal viral
infections, most common being influenza virus and Human herpes virus-6.
OBJECTIVE: We report two rare cases of ANE preceded by Chikungunya infection.
CASES: A 13-year old girl presented with a three-day history of headache, fever,
seizures, and altered sensorium. Another 42-year old man presented with two days
history of fever and altered sensorium. Both were suspected to have viral
encephalitis. Evaluation revealed serum positivity for Chikungunya virus. In
both cases, diagnosis was clinched by characteristic bilateral symmetrical
thalamic lesions with central necrosis and hemorrhage along with lesions in
cerebral white matter, brainstem, and cerebellum.
CONCLUSIONS: ANE is reported to have high morbidity and mortality. To the best
of our knowledge, this is the first report of ANE post-Chikungunya infection.
Apart from being rare etiologically, the patients had excellent response to
steroids. Objective: To investigate the risk factors for death in children with acute
necrotizing encephalopathy (ANE) in pediatric intensive care unit (PICU).
Methods: This was a multicenter retrospective study. Thirty-nine children with
ANE were from PICUs in 4 centers from December 1, 2014 to December 1, 2020. The
4 participating centers were Beijing Children's Hospital, Shengjing Hospital of
China Medical University, Hebei Children's Hospital, and Bao'an Maternity &
Child Health Hospital. Patients were divided into survival and non-survival
groups by the outcome at discharge, and the differences in clinical data between
the two groups were compared. Risk factors for death in children with ANE and
the odds ratios (OR) were analyzed by univariable Logistic regression. Results:
Thirty-nine children with ANE were included. There were 18 males and 21 females.
The median onset age was 30 months. The mortality at discharge was 41% (16/39).
The onset age of most patients (74%, 29/39) was younger than 4 years old.
Influenza virus was the most common precursor infection (80%, 20/25). Patients
with shock at PICU admission were more common in the non-survival group (12/16
vs. 17% (4/23), P=0.001). Glasgow coma score (GCS) at PICU admission was
significantly lower in the non-survival group than survival group (3 (3, 6) vs.
6 (5, 7), Z=-2.598, P=0.009). The optimal cut-off value was 4. The proportion of
patients with GCS ≤ 4 at PICU admission was higher in the non-survival group
(10/16 vs. 22% (5/23), P=0.018). ANE severity score (ANE-SS) at PICU admission
was significantly higher in the non-survival group (5 (2, 6) vs. 2 (1, 4),
Z=-2.436, P=0.015). The proportion of patients with high risk ANE-SS was higher
in non-survival group than the survival group (9/16 vs. 22% (5/23), P=0.043).
The proportion of application of high-dose methylprednisolone (20 mg/(kg·d)) was
significantly higher in survival group than non-survival group (43% (10/23) vs.
1/13, P=0.031). Univariable Logistic regression indicated that risk factors for
death in children with ANE were shock (OR=14.250, 95%CI 2.985-68.018, P=0.001),
GCS≤4 (OR=6.000, 95%CI 1.456-24.733, P=0.013) and high risk ANE-SS (OR=4.629,
95%CI 1.142-18.752, P=0.032) at PICU admission. Conclusions: ANE usually occurs
in children under 4 years old after influenza infection. Shock, GCS≤4 and high
risk ANE-SS at PICU admission were risk factors for death in children with ANE.
High-dose methylprednisolone may improve the prognosis of children with ANE. |
What is Waylivra? | Volanesorsen (Waylivra®), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA to treat familial chylomicronemia syndrome (FCS), hypertriglyceridemia and familial partial lipodystrophy (FPL). | |
Which disease can be prevented with PfSPZ Vaccine? | PfSPZ Vaccine is used for prevention of malaria. | An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ
Vaccine, is highly protective against controlled human malaria infection (CHMI)
3 weeks after immunization, but the durability of protection is unknown. We
assessed how vaccine dosage, regimen, and route of administration affected
durable protection in malaria-naive adults. After four intravenous immunizations
with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without
parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic
subjects from this dosage group underwent repeat CHMI at 59 weeks, and none
developed parasitemia. Although Pf-specific serum antibody levels correlated
with protection up to 21-25 weeks after immunization, antibody levels waned
substantially by 59 weeks. Pf-specific T cell responses also declined in blood
by 59 weeks. To determine whether T cell responses in blood reflected responses
in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific
interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies
in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred
durable protection to malaria through long-lived tissue-resident T cells and
that administration of higher doses may further enhance protection. BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ)
malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against
homologous Pf (same strain as in the vaccine) controlled human malaria infection
(CHMI) 3 weeks after 5 doses administered intravenously. The next step was to
assess protective efficacy against heterologous Pf (different from Pf in the
vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed
tolerability, safety, immunogenicity, and protective efficacy of direct venous
inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects.
RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ
protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous
CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 ×
105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI.
Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10
(70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6])
against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5,
76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ
Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell
responses correlated with protection. CONCLUSIONS: We have demonstrated for the
first time to our knowledge that PfSPZ Vaccine can protect against a 3-week
heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose
regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%,
respectively) in this population. These results provide a foundation for
developing an optimized immunization regimen for preventing malaria. TRIAL
REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided
through the US Army Medical Research and Development Command, Military
Infectious Diseases Research Program, and the Naval Medical Research Center's
Advanced Medical Development Program. A highly protective malaria vaccine would greatly facilitate the prevention and
elimination of malaria and containment of drug-resistant parasites. A high level
(more than 90%) of protection against malaria in humans has previously been
achieved only by immunization with radiation-attenuated Plasmodium falciparum
(Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of
aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine');
or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine
or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by
direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated
PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking
chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as
PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day
intervals were well tolerated and safe, and prevented infection in 9 out of 9
(100%) volunteers who underwent controlled human malaria infection ten weeks
after the last dose (group III). Protective efficacy was dependent on dose and
regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ
protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three
doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%)
volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was
associated with protection. On a 7,455 peptide Pf proteome array, immune sera
from at least 5 out of 9 group III vaccinees recognized each of 22 proteins.
PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to
optimize the immunization regimen (dose, interval between doses, and drug
partner), this vaccine could be used for combination mass drug administration
and a mass vaccination program approach to eliminate malaria from geographically
defined areas. BACKGROUND: Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically
active, non-replicating, whole malaria sporozoite vaccine that has been reported
to be safe and protective against P falciparum controlled human malaria
infection in malaria-naive individuals. We aimed to assess the safety and
protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in
malaria-experienced adults in Mali.
METHODS: After an open-label dose-escalation study in a pilot safety cohort, we
did a double-blind, randomised, placebo-controlled trial based in Donéguébougou
and surrounding villages in Mali. We recruited 18-35-year-old healthy adults who
were randomly assigned (1:1) in a double-blind manner, with stratification by
village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ
or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January
to July inclusive). Participants and investigators were masked to group
assignments, which were unmasked at the final study visit, 6 months after
receipt of the last vaccination. Participants received combined artemether and
lumefantrine (four tablets, each containing 20 mg artemether and 120 mg
lumefantrine, given twice per day over 3 days for a total of six doses) to
eliminate P falciparum before the first and last vaccinations. We collected
blood smears every 2 weeks and during any illness for 24 weeks after the fifth
vaccination. The primary outcome was the safety and tolerability of the vaccine,
assessed as local and systemic reactogenicity and adverse events. The sample
size was calculated for the exploratory efficacy endpoint of time to first P
falciparum infection beginning 28 days after the fifth vaccination. The safety
analysis included all participants who received at least one dose of
investigational product, whereas the efficacy analyses included only
participants who received all five vaccinations. This trial is registered at
ClinicalTrials.gov, number NCT01988636.
FINDINGS: Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the
main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned
placebo, all of whom were evaluable for safety. We detected no significant
differences in local or systemic adverse events or laboratory abnormalities
between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or
systemic adverse events occurred in both groups. The most common solicited
systemic adverse event in the vaccine and placebo groups was headache (three
[7%] people in the vaccine group vs four [9%] in the placebo group) followed by
fatigue (one [2%] person in the placebo group), fever (one [2%] person in the
placebo group), and myalgia (one [2%] person in each group). The exploratory
efficacy analysis included 41 participants from the vaccine group and 40 from
the placebo group. Of these participants, 37 (93%) from the placebo group and 27
(66%) from the vaccine group developed P falciparum infection. The hazard ratio
for vaccine efficacy was 0·517 (95% CI 0·313-0·856) by time-to-infection
analysis (log-rank p=0·01), and 0·712 (0·528-0·918) by proportional analysis
(p=0·006).
INTERPRETATION: PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed
significant protection in African adults against P falciparum infection
throughout an entire malaria season.
FUNDING: US National Institutes of Health Intramural Research Program, Sanaria. A live-attenuated malaria vaccine, Plasmodium falciparum sporozoite vaccine
(PfSPZ Vaccine), confers sterile protection against controlled human malaria
infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the
vaccine strain up to 14 mo after final vaccination. No injectable malaria
vaccine has demonstrated long-term protection against CHMI using Pf parasites
heterologous to the vaccine strain. Here, we conducted an open-label trial with
PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk
intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19
wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated
volunteers remained without parasitemia compared with none of six nonvaccinated
controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat
CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five
(83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of
six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were
detected in all vaccine recipients. Cytokine production by T cells from
vaccinated subjects after in vitro stimulation with homologous (NF54) or
heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific
T-cell responses in the blood peaked after the first immunization and were not
enhanced by subsequent immunizations. Collectively, these data suggest durable
protection against homologous and heterologous Pf parasites can be achieved with
PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be
enhanced by additional alterations in the vaccine dose and number of
immunizations. Malaria is a severe infectious disease with relatively high mortality, thus
having been a scourge of humanity. There are a few candidate malaria vaccines
that have shown a protective efficacy in humans against malaria. One of the
candidate human malaria vaccines, which is based on human malaria sporozoites
and called PfSPZ Vaccine, has been shown to protect a significant proportion of
vaccine recipients from getting malaria. PfSPZ Vaccine elicits a potent response
of hepatic CD8+ T cells that are specific for malaria antigens in non-human
primates. To further characterize hepatic CD8+ T cells induced by the
sporozoite-based malaria vaccine in a mouse model, we have used a cutting-edge
Single-cell Barcode (SCBC) assay, a recently emerged approach/method for
investigating the nature of T-cells responses during infection or cancer. Using
the SCBC technology, we have identified a population of hepatic CD8+ T cells
that are polyfunctional at a single cell level only in a group of vaccinated
mice upon malaria challenge. The cytokines/chemokines secreted by these
polyfunctional CD8+ T-cell subsets include MIP-1α, RANTES, IFN-γ, and/or IL-17A,
which have shown to be associated with protective T-cell responses against
certain pathogens. Therefore, a successful induction of such polyfunctional
hepatic CD8+ T cells may be a key to the development of effective human malaria
vaccine. In addition, the SCBC technology could provide a new level of
diagnostic that will allow for a more accurate determination of vaccine
efficacy. BACKGROUND: Whole parasite vaccines provide a unique opportunity for dissecting
immune mechanisms and identify antigens that are targeted by immune responses
which have the potential to mediate sterile protection against malaria
infections. The radiation attenuated sporozoite (PfSPZ) vaccine has been
considered the gold standard for malaria vaccines because of its unparalleled
efficacy. The immunogenicity of this and other vaccines continues to be
evaluated by using recombit proteins or peptides of known sporozoite
antigens. This approach, however, has significant limitations by relying solely
on a limited number of known pathogen-associated immune epitopes. Using the full
range of antigens expressed by the sporozoite will enable the comprehensive
immune-profiling of humoral immune responses induced by whole parasite vaccines.
To address this challenge, a novel ELISA based on sporozoites was developed.
RESULTS: The SPZ-ELISA method described in this report can be performed with
either freshly dissected sporozoites or with cryopreserved sporozoite lysates.
The use of a fixative for reproducible coating is not required. The SPZ-ELISA
was first validated using monoclonal antibodies specific for CSP and TRAP and
then used for the characterization of immune sera from radiation attenuated
sporozoite vaccinees.
CONCLUSION: Applying this simple and highly reproducible approach to assess
immune responses induced by malaria vaccines, both recombit and whole
parasite vaccines, (1) will help in the evaluation of immune responses induced
by antigenically complex malaria vaccines such as the irradiated SPZ-vaccine,
(2) will facilitate and accelerate the identification of immune correlates of
protection, and (3) can also be a valuable assessment tool for antigen discovery
as well as down-selection of vaccine formulations and, thereby, guide vaccine
design. BACKGROUND: The assessment of antibody responses after immunization with
radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum
sporozoites (Sanaria PfSPZ Vaccine) has focused on IgG isotype antibodies. Here,
we aimed to investigate if P. falciparum sporozoite binding and
invasion-inhibitory IgM antibodies are induced following immunization of
malaria-preexposed volunteers with PfSPZ Vaccine.
METHODS: Using serum from volunteers immunized with PfSPZ, we measured
vaccine-induced IgG and IgM antibodies to P. falciparum circumsporozoite protein
(PfCSP) via ELISA. Function of this serum as well as IgM antibody fractions was
measured via in vitro in an inhibition of sporozoite invasion assay. These IgM
antibody fractions were also measured for binding to sporozoites by
immunofluorescence assay and complement fixation on whole sporozoites.
RESULTS: We found that in addition to anti-PfCSP IgG, malaria-preexposed
volunteers developed anti-PfCSP IgM antibodies after immunization with PfSPZ
Vaccine and that these IgM antibodies inhibited P. falciparum sporozoite
invasion of hepatocytes in vitro. These IgM plasma fractions also fixed
complement to whole P. falciparum sporozoites.
CONCLUSIONS: This is the first finding that PfCSP and P. falciparum
sporozoite-binding IgM antibodies are induced following immunization of PfSPZ
Vaccine in malaria-preexposed individuals and that IgM antibodies can inhibit P.
falciparum sporozoite invasion into hepatocytes in vitro and fix complement on
sporozoites. These findings indicate that the immunological assessment of PfSPZ
Vaccine-induced antibody responses could be more sensitive if they include
parasite-specific IgM in addition to IgG antibodies.
CLINICAL TRIALS REGISTRATION: NCT02132299. Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been
shown to be protective against malaria, but the features of the antibody
response induced by this treatment remain unclear. To investigate this response
in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian
volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine
and who were found to be protected from controlled human malaria infection with
infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P.
falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in
its N terminus, NANP-repeat region, and C terminus. Strikingly, the most
effective antibodies, as determined in a humanized mouse model, bound not only
to the repeat region, but also to a minimal peptide at the PfCSP N-terminal
junction that is not in the RTS,S vaccine. These dual-specific antibodies were
isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that
encode tryptophan or arginine at position 52. Using structural and mutational
data, we describe the elements required for germline recognition and affinity
maturation. Our study provides potent neutralizing antibodies and relevant
information for lineage-targeted vaccine design and immunization strategies. We are using controlled human malaria infection (CHMI) by direct venous
inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf)
sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of
developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five
doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65%
vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and
52% (time to event) or 29% (proportional) VE over 24 weeks against naturally
transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians
for VE against PfSPZ Challenge. Twenty- to thirty-year-old men were randomized
to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial.
Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar
in vaccinees and controls. Antibody responses to Pf circumsporozoite protein
were significantly lower than in malaria-naïve Americans, but significantly
higher than in Malians. All 18 controls developed Pf parasitemia after CHMI.
Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by
time to event, P = 0.543 by proportional analysis) and all four (100%) were
uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by
time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well
tolerated, and induced durable VE in four subjects. Controlled human malaria
infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than
mosquito bite CHMI in United States or natural exposure in Malian adults,
thereby providing a rigorous test of VE in Africa. PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified,
cryopreserved Plasmodium falciparum sporozoites, is administered by direct
venous inoculation (DVI) for maximal efficacy against malaria. A critical issue
for advancing vaccines that are administered intravenously is the ability to
efficiently administer them across multiple age groups. As part of a pediatric
safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the
feasibility and tolerability of DVI, including ease of venous access, injection
time, and crying during the procedure across age groups. Part 1 was an age
de-escalation, dose escalation trial in children aged 13 months-5 years and
infants aged 5-12 months; part 2 was a vaccine efficacy trial including only
infants, using the most skilled injectors from part 1. Injectors could use a
vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were
initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were
13-59-month-olds, and 410 infants). The complete volume was injected in
1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI.
474/511 (92.8%) participants received only complete injections, 27/511 (5.3%)
received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous
access was not obtained. The rate of complete injections by single DVI for
infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in
51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in
13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean
administration time ranged from 2.6 to 4.6 minutes and was longer for younger
age groups. These data show that vaccination by DVI was feasible and well
tolerated in infants and children in this rural hospital in western Kenya, when
performed by skilled injectors. We also report that shipping and storage in
liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov
NCT02687373). BACKGROUND: A live-attenuated Plasmodium falciparum sporozoite (SPZ) vaccine
(PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria
infection (CHMI) using homologous parasites (same P. falciparum strain as in the
vaccine). Using a more stringent CHMI, with heterologous parasites (different P.
falciparum strain), we assessed the impact of higher PfSPZ doses, a novel
multi-dose prime regimen, and a delayed vaccine boost upon vaccine efficacy
(VE).
METHODS: We immunized 4 groups that each contained 15 healthy, malaria-naive
adults. Group 1 received 5 doses of 4.5 x 105 PfSPZ (Days 1, 3, 5, and 7; Week
16). Groups 2, 3, and 4 received 3 doses (Weeks 0, 8, and 16), with Group 2
receiving 9.0 × 105/doses; Group 3 receiving 18.0 × 105/doses; and Group 4
receiving 27.0 × 105 for dose 1 and 9.0 × 105 for doses 2 and 3. VE was assessed
by heterologous CHMI after 12 or 24 weeks. Volunteers not protected at 12 weeks
were boosted prior to repeat CHMI at 24 weeks.
RESULTS: At 12-week CHMI, 6/15 (40%) participants in Group 1 (P = .04) and 3/15
(20%) participants in Group 2 remained aparasitemic, as compared to 0/8
controls. At 24-week CHMI, 3/13 (23%) participants in Group 3 and 3/14 (21%)
participants in Group 4 remained aparasitemic, versus 0/8 controls (Groups 2-4,
VE not significant). Postboost, 9/14 (64%) participants versus 0/8 controls
remained aparasitemic (3/6 in Group 1, P = .025; 6/8 in Group 2, P = .002).
CONCLUSIONS: Administering 4 stacked priming injections (multi-dose priming)
resulted in 40% VE against heterologous CHMI, while dose escalation of PfSPZ
using single-dose priming was not significantly protective. Boosting unprotected
subjects improved VE at 24 weeks, to 64%.
CLINICAL TRIALS REGISTRATION: NCT02601716. Plasmodium falciparum sporozoite (PfSPZ) Vaccine (radiation-attenuated, aseptic,
purified, cryopreserved PfSPZ) and PfSPZ-CVac (infectious, aseptic, purified,
cryopreserved PfSPZ administered to subjects taking weekly chloroquine
chemoprophylaxis) have shown vaccine efficacies (VEs) of 100% against homologous
controlled human malaria infection (CHMI) in nonimmune adults. Plasmodium
falciparum sporozoite-CVac has never been assessed against CHMI in African
vaccinees. We assessed the safety, immunogenicity, and VE against homologous
CHMI of three doses of 2.7 × 106 PfSPZ of PfSPZ Vaccine at 8-week intervals and
three doses of 1.0 × 105 PfSPZ of PfSPZ-CVac at 4-week intervals with each arm
randomized, double-blind, placebo-controlled, and conducted in parallel. There
were no differences in solicited adverse events between vaccinees and normal
saline controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6
days after administration of investigational product. However, from days 7-13,
PfSPZ-CVac recipients had significantly more AEs, probably because of Pf
parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine
recipients than PfSPZ-CVac recipients at time of CHMI. Vaccine efficacy at a
median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, P = 0.051) and
at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, P =
0.32). The higher VE in PfSPZ-CVac recipients of 55% with a 27-fold lower dose
was likely a result of later stage parasite maturation in the liver, leading to
induction of cellular immunity against a greater quantity and broader array of
antigens. Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis
(PfSPZ-CVac) is the most efficacious approach to malaria vaccination.
Implementation is hampered by a complex chemoprophylaxis regimen and missing
evidence for efficacy against heterologous infection. We report the results of a
double-blinded, randomized, placebo-controlled trial of a simplified, condensed
immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36).
Participants are immunized by direct venous inoculation of 1.1 × 105 aseptic,
purified, cryopreserved PfSPZ (PfSPZ Challenge) of the PfNF54 strain or normal
saline (placebo) on days 1, 6 and 29, with simultaneous oral administration of
10 mg/kg chloroquine base. Primary endpoints are vaccine efficacy tested by
controlled human malaria infection (CHMI) using the highly divergent,
heterologous strain Pf7G8 and safety. Twelve weeks following immunization, 10/13
participants in the vaccine group are sterilely protected against heterologous
CHMI, while (5/5) participants receiving placebo develop parasitemia (risk
difference: 77%, p = 0.004, Boschloo's test). Immunization is well tolerated
with self-limiting grade 1-2 headaches, pyrexia and fatigue that diminish with
each vaccination. Immunization induces 18-fold higher anti-Pf circumsporozoite
protein (PfCSP) antibody levels in protected than in unprotected vaccinees
(p = 0.028). In addition anti-PfMSP2 antibodies are strongly
protection-associated by protein microarray assessment. This PfSPZ-CVac regimen
is highly efficacious, simple, safe, well tolerated and highly immunogenic. The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine
provides protection against P. falciparum infection in malaria-naïve adults.
Preclinical studies show that T cell-mediated immunity is required for
protection and is readily induced in humans after vaccination. However, previous
malaria exposure can limit immune responses and vaccine efficacy (VE) in adults.
We hypothesized that infants with less previous exposure to malaria would have
improved immunity and protection. We conducted a multi-arm, randomized,
double-blind, placebo-controlled trial in 336 infants aged 5-12 months to
determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ
Vaccine in infants in a high-transmission malaria setting in western Kenya (
NCT02687373 ). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or
1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine
was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in
the placebo group experienced related solicited adverse events (AEs) within 28 d
postvaccination and most were mild. There was 1 grade 3-related solicited AE in
the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more
common in the highest-dose group (14.3%) compared to 6.0% of controls, with most
being attributed to malaria. There was no significant protection against P.
falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose
group = -6.5%, P = 0.598, the primary statistical end point of the study). VE
against clinical malaria 3 months after the last dose in the highest-dose group
was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent
increase in antibody responses that correlated with VE at 6 months in the
lowest- and highest-dose groups. T cell responses were undetectable across all
dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with
induction of PfSPZ Vaccine T cell immunity and protection in adults, were
infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is
age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there
was no significant VE at 6 months in these infants, these vaccine regimens will
likely not be pursued further in this age group. |
Is Phospholemman a membrane protein? | Yes, FXYD1 (encoding phospholemman) is a transmembrane protein. | Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by
mutations in the MECP2. Several genes have been shown to be MECP2 targets. We
previously identified FXYD1 (encoding phospholemman; a protein containing the
motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane
modulator of the Na, K-ATPase (NKA) enzyme, as one of them. In the absence of
MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT
patients and Mecp2(Bird) null mice. Here, we show that Fxyd1 mRNA levels are
also increased in the FC and hippocampus (HC) of male mice carrying a truncating
mutation of the Mecp2 gene (Mecp2(308)). To test the hypothesis that some of the
behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by
genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1
null male mice with Mecp2(308) heterozygous females and behaviorally tested the
adult male offspring. Mecp2(308) mice had impaired HC-dependent novel location
recognition, and this impairment was rescued by deletion of both Fxyd1 alleles.
No other behavioral or sensorimotor impairments were rescued. These results
indicate that reducing FXYD1 levels improves a specific cognitive impairment in
MECP2-deficient mice. Phospholemman (FXYD1) is a single-transmembrane protein regulator of
Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and
phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively.
Binding of FXYD1 reduces Na,K-ATPase activity, and phosphorylation at Ser-68 or
Ser-63 relieves the inhibition. Despite the accumulated information on
physiological effects, whole cell studies provide only limited information on
molecular mechanisms. As a complementary approach, we utilized purified human
Na,K-ATPase (α1β1 and α2β1) reconstituted with FXYD1 or mutants S63E, S68E, and
S63E,S68E that mimic phosphorylation at Ser-63 and Ser-68. Compared with control
α1β1, FXYD1 reduces Vmax and turnover rate and raises K0.5Na. The phosphomimetic
mutants reverse these effects and reduce K0.5Na below control K0.5Na. Effects on
α2β1 are similar but smaller. Experiments in proteoliposomes reconstituted with
α1β1 show analogous effects of FXYD1 on K0.5Na, which are abolished by
phosphomimetic mutants and also by increasing mole fractions of DOPS in the
proteoliposomes. Stopped-flow experiments using the dye RH421 show that FXYD1
slows the conformational transition E2(2K)ATP → E1(3Na)ATP but does not affect
3NaE1P → E2P3Na. This regulatory effect is explained simply by molecular
modeling, which indicates that a cytoplasmic helix (residues 60-70) docks
between the αN and αP domains in the E2 conformation, but docking is weaker in
E1 (also for phosphomimetic mutants). Taken together with previous work showing
that FXYD1 also raises binding affinity for the Na(+)-selective site III, these
results provide a rather comprehensive picture of the regulatory mechanism of
FXYD1 that complements the physiological studies. |
What is MACE in the context of cardiotoxicity? | MACE is an acronym for Major Adverse Cardiovascular Events. | CONTEXT: Percutaneous coronary intervention (PCI) is associated with excellent
short-term improvements in ischemic symptoms, yet only three fifths of PCI
patients at 5 years and one third of patients at 10 years remain free of major
adverse cardiac events (MACE).
OBJECTIVE: To determine whether treatment with fluvastatin reduces MACE in
patients who have undergone PCI.
DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted
at 77 referral centers in Europe, Canada, and Brazil.
PATIENTS: A total of 1677 patients (aged 18-80 years) recruited between April
1996 and October 1998 with stable or unstable angina or silent ischemia
following successful completion of their first PCI who had baseline total
cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting
triglyceride levels of less than 400 mg/dL (4.5 mmol/L).
INTERVENTIONS: Patients were randomly assigned to receive treatment with
fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital
discharge for 3 to 4 years.
MAIN OUTCOME MEASURE: Survival time free of MACE, defined as cardiac death,
nonfatal myocardial infarction, or reintervention procedure, compared between
the treatment and placebo groups.
RESULTS: Median time between PCI and first dose of study medication was 2.0
days, and median follow-up was 3.9 years. MACE-free survival time was
significantly longer in the fluvastatin group (P =.01). One hundred eighty-one
(21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients
in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95%
confidence interval [CI], 0.64-0.95; P =.01). This result was independent of
baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below
[RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of
MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI,
0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95%
CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received
placebo. There were no instances of creatine phosphokinase elevations 10 or more
times the upper limit of normal or rhabdomyolysis in the fluvastatin group.
CONCLUSION: Fluvastatin treatment in patients with average cholesterol levels
undergoing their first successful PCI significantly reduces the risk of major
adverse cardiac events. OBJECTIVES: The purpose of this study was to investigate the impact of
everolimus-eluting stents (EES) in comparison with bare-metal stents (BMS),
sirolimus-eluting stents (SES), and paclitaxel-eluting stents (PES) on the
6-month clinical outcomes in an all-comer population.
BACKGROUND: EES have been shown to be effective in the context of randomized
trials with selected patients. The effect of EES implantation in more complex,
unselected patients cannot be directly extrapolated from these findings.
METHODS: In total, 649 consecutive unselected patients treated exclusively with
EES were enrolled. Six-month clinical end points were compared with 3 historical
cohorts (BMS, n = 450; SES, n = 508; and PES, n = 576). Major adverse cardiac
events (MACE) were defined as a composite of all-cause mortality, myocardial
infarction, or target vessel revascularization (TVR).
RESULTS: The patients treated with EES were older, presented more frequently
with acute myocardial infarction, and had more complicated lesions than the
other groups. The EES group demonstrated a higher incidence of all-cause
mortality than the SES group and a lower incidence of TVR than the BMS group.
Multivariate adjustment demonstrated that BMS was associated with higher TVR and
MACE risk than EES (adjusted hazard ratio [HR] for TVR: 2.02 [95% confidence
interval (CI): 1.11 to 3.67]; adjusted HR for MACE: 2.15 [95% CI: 1.36 to
3.42]); that SES had a clinical outcome similar to that of EES, and that PES had
a higher risk of MACE than did EES (adjusted HR: 1.57 [95% CI: 1.02 to 2.44]).
CONCLUSIONS: This study suggests that the use of EES in an unselected population
may be as safe as and more effective than BMS, may be as safe and effective as
SES, may be as safe as PES, and may be more effective than PES. Renal transplantation is the treatment of choice in patients with end-stage
renal disease. Major adverse cardiac events (MACE) are common after renal
transplant, especially in the perioperative period, leading to excess morbidity
and mortality. The predictors and long-term prognostic implications of MACE are
poorly understood. We analyzed predictors and implications of MACE in a cohort
of 321 consecutive adult patients, who received renal allograft transplantation
between 1995 and 2003 at our institution. The characteristics of 321 patients
were: age at transplant 44 ± 13 years, 60% male, 36% diabetes mellitus (DM),
left ventricular ejection fraction (LVEF) 60 ± 16%. MACE occurred in 21 patients
with cumulative rate of 6.5% over 3 years after renal transplant, 57% occurring
within 30 days, 67% within 90 days, and 86% within 180 days. MACE was not
predicted by any clinical or pharmacological variables including age, gender,
hypertension, DM, prior myocardial infarction, smoking, duration of dialysis,
LVEF, or therapy with β-blockers (BB), angiotensin converting enzyme inhibitors,
or calcium channel blockers. However, a clinical decision to perform a stress
test or a coronary angiogram was predictive of higher MACE rate. MACE,
irrespective of type, was independently associated with higher mortality over a
period up to 15 years and this seemed to be blunted by BB therapy. MACE rate
after renal transplantation decreases over time, most occurring in the first 90
days and is not predicted by any of the traditional risk factors or drug
therapies. It is associated with higher long-term mortality. Author information:
(1)Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands;
Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
(2)Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands.
(3)Medical Clinic II-Cardiology/Angiology/Intensive Care Medicine, University
Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
(4)Department of Cardiology, Heart Center Bad Segeberg, Bad Segeberg, Germany.
(5)Departments of Nuclear Medicine and Cardiology, Centre Georges-François
Leclerc, Dijon, France.
(6)Department of Cardiology, University Hospital of Dijon, Dijon, France.
(7)Department of Cardiology, Division of Medicine, Oslo University Hospital
Ulleval, and Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
(8)Department of Cardiology, University Hospital Basel, Basel, Switzerland.
(9)Departments of Medicine and Radiology, Division of Cardiology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois.
(10)Department of Cardiology, University of Valencia, Valencia, Spain.
(11)Department of Cardiology, University Clinic of Internal Medicine II,
Innsbruck Medical University, Innsbruck, Austria.
(12)Department of Cardiology, Amsterdam Medical Center, Amsterdam, the
Netherlands.
(13)Department of Internal Medicine, University of Ulm, Ulm, Germany.
(14)Department of Cardiology, Erasmus Medical Center, Rotterdam, the
Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the
Netherlands. Electronic address: [email protected]. CONTEXT: The correlation among metabolic syndrome, lower urinary tract symptoms
(LUTS), and cardiovascular disease (CVD) is well established. In particular, CVD
has been proposed as a potential risk factor for both LUTS progression and
severity.
OBJECTIVE: To evaluate whether LUTS severity can be considered as a significant
risk factor of major adverse cardiac events (MACE) in the male population.
EVIDENCE ACQUISITION: A systematic literature search was performed using PubMed,
Google Scholar, and Scopus. The combination of the following keywords was
adopted in a free-text strategy: benign prostatic hyperplasia (BPH) or lower
urinary tract symptoms (LUTS) and cardiovascular, cardio, major adverse cardiac
events, MACE, heart disease, heart, myocardial infarction, myocardial,
infarction, stroke, ischemic events, ischemic, cardiac death, coronary syndrome.
We included all cross-sectional and longitudinal trials enrolling men and
comparing the prevalence or incidence of MACE in men with moderate to severe
LUTS compared with those without LUTS or with mild LUTS. The studies in which
only nocturia was evaluated were excluded from the analysis.
EVIDENCE SYNTHESIS: Of 477 retrieved articles, 5 trials longitudinally reported
the incidence of MACE in patients with moderate to severe LUTS in comparisons to
those with mild or no LUTS and 10 studies reported the prevalence of history of
MACE at enrollment. All were included in the present meta-analysis. Among
cross-sectional studies, 38 218 patients and 2527 MACE were included in the
meta-analysis. The mean age of enrolled patients was 62.2±8.0 yr. Presence of
moderate to severe LUTS significantly increased the risk of reported history of
MACE (p<0.001). Metaregression analyses showed that the risk of MACE was lower
in older patients and higher in those with diabetes. The association between
LUTS-related MACE and diabetes was confirmed in a multivariate regression model
after adjusting for age (adjusted r=0.498; p<0.0001). Longitudinal trials
included 25 494 patients and 2291 MACE. The mean age of enrolled patients was
52.5±5.5 yr, and mean follow-up was 86.8±22.1 mo. Presence of moderate to severe
LUTS was associated with an increased incidence of MACE compared with the rest
of the sample (odds ratio: 1.68; 95% confidence interval, 1.13-2.50; p=0.01).
CONCLUSIONS: Men with moderate to severe LUTS seem to have an increased risk of
MACE. A holistic approach in considering the morbidities of aging men should be
strongly encouraged and represents an important role for the practicing
urologist.
PATIENT SUMMARY: We evaluated whether the severity of lower urinary tract
symptoms could be considered as a significant risk factor for major adverse
cardiac events (MACE) in the male population. We demonstrated that men with
moderate to severe LUTS have an increased risk of MACE. BACKGROUND: Main adverse cardiac events (MACE) are essentially composite
endpoints for assessing safety and efficacy of treatment processes of acute
coronary syndrome (ACS) patients. Timely prediction of MACE is highly valuable
for improving the effects of ACS treatments. Most existing tools are specific to
predict MACE by mainly using static patient features and neglecting dynamic
treatment information during learning.
METHODS: We address this challenge by developing a deep learning-based approach
to utilize a large volume of heterogeneous electronic health record (EHR) for
predicting MACE after ACS. Specifically, we obtain the deep representation of
dynamic treatment features from EHR data, using the bidirectional recurrent
neural network. And then, the extracted latent representation of treatment
features can be utilized to predict whether a patient occurs MACE in his or her
hospitalization.
RESULTS: We validate the effectiveness of our approach on a clinical dataset
containing 2930 ACS patient samples with 232 static feature types and 2194
dynamic feature types. The performance of our best model for predicting MACE
after ACS remains robust and reaches 0.713 and 0.764 in terms of AUC and
Accuracy, respectively, and has over 11.9% (1.2%) and 1.9% (7.5%) performance
gain of AUC (Accuracy) in comparison with both logistic regression and a boosted
resampling model presented in our previous work, respectively. The results are
statistically significant.
CONCLUSIONS: We hypothesize that our proposed model adapted to leverage dynamic
treatment information in EHR data appears to boost the performance of MACE
prediction for ACS, and can readily meet the demand clinical prediction of other
diseases, from a large volume of EHR in an open-ended fashion. The study aimed to determine whether high sensitivity C-reactive protein to
prealbumin (hs-CRP/PAB) ratio could be used to predict in-hospital major adverse
cardiac events (MACE) in patients with acute coronary syndrome (ACS). A total of
659 patients with ACS were included in the study. Patients were divided into two
groups: high hs-CRP/PAB ratio group (hs-CRP/PAB ≥0.010) and low hs-CRP/PAB ratio
group (hs-CRP/PAB <0.010). MACE was defined as death, cardiogenic shock,
re-infarction and acute heart failure. Logistic regression was performed and the
receiver operating characteristic curve (ROC) was generated to evaluate the
correlation of hs-CRP/PAB ratio and MACE in patients with ACS. The occurrence
rate of MACE was significantly higher in high hs-CRP/PAB ratio group when
compared with that in low hs-CRP/PAB ratio group (P < 0.001). Multivariable
analysis determined that hs-CRP/PAB ratio was an independent predictor of MACE
(adjusted odds ratio: 1.276, 95% confidence interval: 1.106-1.471, P = 0.001).
Moreover, the area under the curve value of hs-CRP/PAB ratio for predicting MACE
was higher than hs-CRP and equal to PAB. High hs-CRP/PAB ratio was considered as
a prognostic parameter of MACE in ACS patients, with the predictive power equal
to PAB but greater than hs-CRP. OBJECTIVES: Cancer survivorship status among patients evaluated for chest pain
at the emergency department (ED) warrants high degree of suspicion. However, it
remains unclear whether cancer survivorship is associated with different risk of
major adverse cardiac events (MACE) compared to those with no history of cancer.
Furthermore, while HEART score is widely used in ED evaluation, it is unclear
whether it can adequately triage chest pain events in cancer survivors. We
sought to compare the rate of MACE in patients with a recent history of cancer
in remission evaluated for acute chest pain at the ED to those with no history
of cancer, and compare the performance of a common chest pain risk
stratification score (HEART) between the two groups.
METHODS: We performed a secondary analysis of a prospective observational cohort
study of chest pain patients presenting to the EDs of three tertiary care
hospitals in the USA. Cancer survivorship status, HEART scores, and the presence
of MACE within 30 days of admission were retrospectively adjudicated from the
charts. We defined patients with recent history of cancer in remission as those
with a past history of cancer of less than 10 years, and currently cured or in
remission.
RESULTS: The sample included 750 patients (age: 59 ± 17; 42% females, 40%
Black), while 69 patients (9.1%) had recent history of cancer in remission. A
cancer in remission status was associated with a higher comorbidity burden,
older age, and female sex. There was no difference in risk of MACE between those
with a cancer in remission and their counterparts in both univariate [17.4 vs.
19.5%, odds ratio (OR) = 0.87 (95% confidence interval (CI), 0.45-1.66], P =
0.67] and multivariable analysis adjusting for demographics and comorbidities
[OR = 0.62 (95% CI, 0.31-1.25), P = 0.18]. Patients with cancer in remission had
higher HEART score (4.6 ± 1.8 vs. 3.9 ± 2.0, P = 0.006), and a higher proportion
triaged as intermediate risk [68 vs. 56%, OR = 1.67 (95% CI, 1.00-2.84), P =
0.05]; however, no difference in the performance of HEART score existed between
the groups (area under the curve = 0.86 vs. 0.84, P = 0.76).
CONCLUSIONS: There was no difference in rate of MACE between those with recent
history of cancer in remission compared to their counterparts. A higher
proportion of patients with cancer in remission was triaged as intermediate risk
by the HEART score, but we found no difference in the performance of the HEART
score between the groups. Author information:
(1)Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center,
Division of Cardiology, Toronto General Hospital, University of Toronto,
Toronto, Ontario, Canada. Electronic address: [email protected].
(2)Cardio-Oncology Program, Division of Cardiology, Department of Medicine,
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York,
USA.
(3)Cardiovascular Imaging Research Center, Division of Cardiology and Department
of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
(4)Cardiovascular Imaging Research Center, Division of Cardiology and Department
of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA; Heart
and Vascular Center, Semmelweis University, Budapest, Hungary.
(5)Cardiology Division, NewYork-Presbyterian Hospital, Weill Cornell Medical
Center, New York, New York, USA.
(6)Department of Cardiology or Diagnostic Radiology, Jewish General Hospital,
McGill University, Montreal, Quebec, Canada.
(7)Cardiovascular Imaging Research Center, Division of Cardiology and Department
of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA;
Cardio-Oncology Program, Division of Cardiology, Department of Medicine,
Massachusetts General Hospital, Boston, Massachusetts, USA.
(8)Cardio-Oncology Program, Division of Cardiology, Department of Medicine,
Brigham and Women's Hospital, Boston, Massachusetts, USA.
(9)University Mediterranean Center of Cardio-Oncology, Nord Hospital,
Aix-Marseille University, Marseille, France; Groupe Méditerranéen de
Cardio-Oncologie, Marseille, France; Center for CardioVascular and Nutrition
Research, INRA 1260, INSERM 1263, Aix-Marseille University, Marseille, France.
(10)Department of Dermatology, University Hospital Erlangen,
Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department
of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of
Munich, Munich, Germany.
(11)Cardio-Oncology Program, MedStar Heart and Vascular Institute, Georgetown
University, Washington, DC, USA.
(12)Division of Oncology and Hematology, Department of Medicine, Massachusetts
General Hospital, Boston, Massachusetts, USA.
(13)Cardiology Division, Memorial Sloan Kettering Cancer Center, Weill Cornell
Medical College, New York, New York, USA.
(14)Department of Dermatology, University Hospital Erlangen,
Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
(15)Cardiology Division, NewYork-Presbyterian Hospital, Weill Cornell Medical
Center, New York, New York, USA; Cardiology Division, Memorial Sloan Kettering
Cancer Center, Weill Cornell Medical College, New York, New York, USA.
(16)Division of Oncology and Hematology, Department of Medicine, Lehigh Valley
Hospital, Allentown, Pennsylvania, USA.
(17)Cardiovascular Institute, Mount Sinai Hospital, New York, New York, USA.
(18)Hospital General Universitario Gregorio Marañón, CIBERCV, Instituto de Salud
Carlos III, Universidad Complutense de Madrid, Madrid, Spain.
(19)Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
(20)Cardio-Oncology Program, Division of Cardiovascular Medicine, Lahey Hospital
and Medical Center, Burlington, Massachusetts, USA.
(21)Cardio-Oncology Program, Department of Cardiology, Clínica Universidad de
Navarra, Pamplona and Madrid, Spain.
(22)Cardiovascular Imaging Program, Cardiovascular Division and Department of
Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
(23)Cardiology Division, State University of Campinas, Campinas, Brazil.
(24)Cardiovascular Research Centre and Cardiovascular Magnetic Resoce Unit,
Royal Brompton Hospital, National Heart and Lung Institute, Imperial College
London, London, United Kingdom.
(25)Department of Medical Imaging, Toronto General Hospital, University Health
Network, University of Toronto, Toronto, Ontario, Canada.
(26)Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center,
Division of Cardiology, Toronto General Hospital, University of Toronto,
Toronto, Ontario, Canada.
(27)Cardio-Oncology Program, Division of Cardiology, Hôpitaux Universitaires Est
Parisien, Paris, France.
(28)UCLA Cardio-Oncology Program, Division of Cardiology, Department of
Medicine, University of California, Los Angeles, Los Angeles, California, USA.
(29)Cardio-Oncology Program, Royal Brompton Hospital, Imperial College London,
London, United Kingdom.
(30)Cardio-Oncology Center of Excellence, Division of Cardiology, Department of
Medicine, Perelman School of Medicine at the University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
(31)Cardiovascular Imaging Research Center, Division of Cardiology and
Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts,
USA; Cardio-Oncology Program, Division of Cardiology, Department of Medicine,
Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:
[email protected]. BACKGROUND AND AIMS: The effectiveness of systemic treatment in advanced
hepatocellular carcinoma (HCC) depends on the selection of patients, management
of cirrhosis complications and expertise to treat adverse events. The aims of
the study are to assess the frequency and management of cardiovascular events in
HCC patients treated with sorafenib (SOR) and to create a scale to predict the
onset of major adverse cardiovascular events (MACE).
METHOD: Observational retrospective study with consecutive HCC patients treated
with SOR between 2007 and 2019 in a western centre. In order to classify
cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age,
hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other
adverse events, dosing and outcome data were collected during a homogeneous
protocolled follow-up.
RESULTS: Two hundred ninety-nine patients were included (219 BCLC-C). The median
overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was
7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to
cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11
acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular
ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81).
Age was the only independent factor associated to MACE (HR 1.07; 95% CI
1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of
patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04).
CONCLUSION: The incidence of cardiovascular events in HCC patients treated with
SOR is higher than expected. Multidisciplinary approach and clinical tools like
CARDIOSOR scale could be helpful to manage these patients. OBJECTIVES: The purpose of this study was to evaluate whether immune checkpoint
inhibitors (ICIs) are associated with an increased risk of major adverse
cardiovascular events (MACE) compared with non-ICI therapies in patients with
lung cancer.
BACKGROUND: ICIs activate the host immune system to target cancer cells. Though
uncommon, cardiovascular immune-related adverse events can be life-threatening.
METHODS: A retrospective single-institution cohort study of 252 patients with
pathologically confirmed lung cancer who received ICI or non-ICI therapy was
analyzed. The primary endpoint was MACE, defined as a composite of
cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and
hospitalization for heart failure.
RESULTS: During a median follow-up of 6 months, MACE occurred in 13.3% of
ICI-treated patients, with a median time to event of 51 days, compared with
10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE
(hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66)
in a univariable Fine-Gray regression analysis incorporating noncardiovascular
death as a competing risk. Multivariable regression analyses determined that
patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27;
95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100
pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE.
Patients pre-treated or receiving combined immunotherapy with ICIs and vascular
endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors
(TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04).
CONCLUSIONS: ICIs were not independently associated with an increased risk of
MACE in patients with lung cancer, although power is an important limitation in
these analyses. ICI-associated cardiotoxicity was associated with elevations in
serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future
studies are needed to further define the role of cardiac biomarkers as a
monitoring strategy with ICI therapy. BACKGROUND: Immune checkpoint inhibitor (ICI)-related cardiotoxicity (iRC) is
uncommon but can be fatal. There have been few reports of iRC from a rural
cancer population and few data for iRC and inflammatory biomarkers.
OBJECTIVES: The purpose of this study was to characterize major adverse cardiac
events (MACE) in ICI-treated lung cancer patients based in a rural setting and
to assess the utility of C-reactive protein (CRP) and neutrophil-lymphocyte
ratio (NLR) in the diagnosis of iRC.
METHODS: Patients with lung cancer treated with ICIs at Vidant Medical
Center/East Carolina University (VMC/ECU) between 2015 and 2018 were
retrospectively identified. MACE included myocarditis, non-ST-segment elevated
myocardial infarction (NSTEMI), supraventricular tachycardia (SVT), and
pericardial disorders. Medical history, laboratory values, pre-ICI
electrocardiography (ECG), and echocardiography results were compared in
patients with and without MACE.
RESULTS: Among 196 ICI-treated patients, 23 patients (11%) developed MACE at a
median of 46 days from the first ICI infusion (interquartile range [IQR]: 17 to
83 days). Patients who developed MACE experienced myocarditis (n = 9), NSTEMI
(n = 3), SVT (n = 7), and pericardial disorders (n = 4). Ejection fraction was
not significantly different at the time of MACE compared to that at baseline
(p = 0.495). Compared to baseline values, NLR (10.9 ± 8.3 vs. 20.7 ± 4.2,
respectively; p = 0.032) and CRP (42.1 ± 10.1 mg/l vs. 109.9 ± 15.6 mg/l,
respectively; p = 0.010) were significantly elevated at the time of MACE.
CONCLUSIONS: NLR and CRP were significantly elevated at the time of MACE
compared to baseline values in ICI-treated patients. Larger datasets are needed
to validate these findings and identify predictors of MACE that can be used in
the diagnosis and management of ICI-related iRC. BACKGROUND: Plasma ghrelin levels can be elevated in patients with acute heart
failure (AHF). This study aimed to analyze the temporal changes and prognostic
value of ghrelin levels in patients with AHF.
METHODS: This prospective study included patients with AHF at the Cardiology
Department, Weifang People's Hospital (May 2018-October 2019), and age- and
sex-matched healthy controls. Plasma ghrelin levels were measured. Multivariable
logistic regression and receiver operating characteristic (ROC) curve analyses
were used to evaluate whether ghrelin levels could predict major cardiac adverse
events (MACEs) during a 1-year follow-up.
RESULTS: Finally, 92 patients with AHF and 50 healthy controls were enrolled.
Ghrelin levels were higher in patients with AHF at 1, 3, 12, and 24 h compared
with controls (all P < 0.01). Ghrelin levels in the AHF group were higher at 3
and 12 h than at 1 and 24 h (P < 0.001). Ghrelin level at 3 h in patients with
AHF was negatively correlated with the left ventricular end-diastolic diameter
and left ventricular ejection fraction (both P < 0.05). MACEs occurred in 48
patients with AHF. Ghrelin levels were higher in the MACE group than in the
non-MACE group at 1 (P = 0.011) and 3 h (P = 0.034). Multivariable regression
showed that ghrelin level at 3 h was independently associated with MACEs
[OR = 0.629, 95% confidence interval (CI): 0.515-0.742, P = 0.010], but the area
under the ROC curve was only 0.629 (95% CI 0.515-0.742).
CONCLUSIONS: Plasma ghrelin levels are elevated in AHF and patients with MACEs
during follow-up. |
Which clinical trials led to the first approval of Volanesorsen by the EU? | The approval of Volanesorsen by the EU was based on the positive results from the multinational, phase III APPROACH and COMPASS studies. | |
Can Isradipine slow progression of Early Parkinson Disease? | No. In a multicenter, randomized, parallel-group, double-blind, placebo-controlled trial Isradipine did not slow progression of Early Parkinson Disease. | OBJECTIVES: Isradipine is a dihydropyridine calcium channel inhibitor that has
demonstrated concentration-dependent neuroprotective effects in animal models of
Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical
trial. The objectives of this study were to model the plasma pharmacokinetics of
isradipine in study participants from the phase 3 trial; and, to investigate
associations between drug exposure and longitudinal clinical outcome measures of
PD progression.
METHODS: Plasma samples from nearly all study participants randomized to
immediate-release isradipine 5-mg twice daily (166 of 170) were collected for
population pharmacokinetic modeling. Estimates of isradipine exposure included
apparent oral clearance and area under the concentration-time curve. Isradipine
exposure parameters were tested for correlations with 36-month changes in
disease severity clinical assessment scores, and time-to-event analyses for
initiation of antiparkinson therapy.
RESULTS: Isradipine exposures did not correlate with the primary clinical
outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's
Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation
coefficient, rs : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month
36 was weakly correlated with isradipine plasma clearance (rs : 0.18,
P = 0.035). This correlation was sex dependent and significant in males, but not
females. Those with higher isradipine exposure had decreased risk of needing
antiparkinson treatment over 36 months compared with placebo (hazard ratio:
0.87, 95% CI: 0.78-0.98, P = 0.02).
INTERPRETATION: In this clinical trial, higher isradipine plasma exposure did
not affect clinical assessment measures of PD severity but modestly decreased
cumulative levodopa equivalent dose and the time needed for antiparkinson
treatment initiation.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02168842. The loss of dopamine (DA)-producing neurons in the substantia nigra pars
compacta (SN) underlies the core motor symptoms of the progressive movement
disorder Parkinson's disease (PD). To date, no treatment to prevent or slow SN
DA neurodegeneration exists; thus, the identification of the underlying factors
contributing to the high vulnerability of these neurons represents the basis for
the development of novel therapies. Disrupted Ca2+ homeostasis and mitochondrial
dysfunction seem to be key players in the pathophysiology of PD. The autonomous
pacemaker activity of SN DA neurons, in combination with low cytosolic Ca2+
buffering, leads to large somatodendritic fluctuations of intracellular Ca2+
levels that are linked to elevated mitochondrial oxidant stress. L-type
voltage-gated Ca2+ channels (LTCCs) contribute to these Ca2+ oscillations in
dendrites, and LTCC inhibition was beneficial in cellular and in vivo animal
models of PD. However, in a recently completed phase 3 clinical trial, the
dihydropyridine (DHP) LTCC inhibitor isradipine failed to slow disease
progression in early PD patients, questioning the feasibility of DHPs for PD
therapy. Novel evidence also suggests that R- and T-type Ca2+ channels (RTCCs
and TTCCs, respectively) represent potential PD drug targets. This short review
aims to (re)evaluate the therapeutic potential of LTCC, RTCC, and TTCC
inhibition in light of novel preclinical and clinical data and the feasibility
of available Ca2+ channel blockers to modify PD disease progression. I also
summarize their cell-specific roles for SN DA neuron function and describe how
their gating properties allow activity (and thus their contribution to stressful
Ca2+ oscillations) during pacemaking. BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial
data concluded that early-stage Parkinson's disease (PD) participants who had
longer exposure to isradipine had a significant delay in their need for
symptomatic medication, as well as a lower medication burden at the end of the
trial. These findings suggest that greater exposure to isradipine might slow
disease progression.
OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine
clinical trial, in which an extended-release (ER) formulation of the drug was
used, was re-examined.
METHODS: The re-analysis of the STEADY-PD II data was restricted to participants
assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or
less). The effect of isradipine treatment was assessed by Unified Parkinson's
Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by
last observation carried forward at the beginning of symptomatic therapy.
RESULTS: Participant cohorts were well-matched for baseline disability, initial
disease progression, and time to initiation of symptomatic therapy. Participants
given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS
scores at the end of the trial than did the placebo cohort. Post hoc adjustment
for symptomatic therapy diminished the statistical significance of these
differences. In those participants not taking a monoamine oxidase B inhibitor,
the progression in UPDRS scores also was significantly reduced.
CONCLUSIONS: These results are consistent with the recent secondary analysis of
the STEADY-PD III clinical trial-suggesting that clinically attainable brain
exposure to isradipine may slow early-stage PD progression. © 2021 International
Parkinson and Movement Disorder Society. |
Is neurofilament light marker for disease? | Yes,
Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury leading to numerous diseases such as frontotemporal dementia (FTD) and Multiple sclerosis (MS). | BACKGROUND: Increased blood brain barrier (BBB) permeability, CNS inflammation
and neuroaxonal damage are pathological hallmarks in early multiple sclerosis
(MS).
OBJECTIVE: To investigate the associations of neurofilament light chain (NfL)
levels with measures of BBB integrity and central nervous system (CNS)
inflammation in MS during the first demyelinating event.
METHODS: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald
2017) treatment-naive patients from the SET study (63% female; age:
29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G
(IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples.
Albumin quotient was computed as a marker of BBB integrity. Immune cell subset
counts in CSF were measured using flow cytometry. MS risk factors, such as Human
leukocyte antigen DRB1 locus gene (HLA DRB1)*1501, anti-Epstein-Barr virus (EBV)
antibodies, and 25-hydroxy vitamin D3, were also measured.
RESULTS: Higher serum NfL (sNfL) levels were associated with higher albumin
quotient (p < 0.001), CSF CD80+ (p = 0.012), and CD80+ CD19+ (p = 0.015) cell
frequency. sNfL levels were also associated with contrast-enhancing and T2
lesions on brain magnetic resoce imaging (MRI; all p ⩽ 0.001). Albumin
quotient was not associated with any of the MS risk factors assessed. sNfL
levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels
(p = 0.0026).
CONCLUSION: sNfL levels during the first demyelinating event of MS are
associated with greater impairment of BBB integrity, immune cell extravasation,
and brain lesion activity on MRI. Frontotemporal dementia (FTD) is the second most frequent dementia, after
Alzheimer's, in patients under the age of 65. It encompasses clinical entities
characterized by behavioral, language, and executive control dysfunction.
Neurofilament light chain (NfL) is a new, non-disease specific, widely studied
biomarker indicative of axonal injury and degeneration. Various studies have
previously explored the role of NfL in the diagnostic process, monitoring, and
prognosis of dementia. The current systematic review and meta-analysis include
all the available data concerning the role of NfL in frontotemporal dementia and
its use as a potential biomarker in differentiating patients with FTD from (a)
healthy individuals, (b) Alzheimer's dementia, (c) Dementia with Lewy bodies,
(d) Motor Neuron disease, (e) Parkinsonian syndromes, and (f) psychiatric
disorders. We also analyze the utility of NfL in distinguishing specific FTD
subgroups. Neurofilament light chain has a potential role in differentiating
patients with frontotemporal dementia from healthy controls, patients with
Alzheimer's dementia, and psychiatric disorders. Higher NfL levels were also
noted in patients with semantic primary progressive aphasia (PPA) when compared
with behavioral FTD and non-fluent PPA patients. Further studies exploring the
use of NfL in frontotemporal dementia are needed. BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been
proposed as a promising biomarker in frontotemporal dementia (FTD). We
investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL
with detailed neuropsychological data and cognitive decline in a cohort of
sporadic and familial FTD.
METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD)
biomarkers (Aβ42, t-Tau, p-Tau181), were determined in 63 FTD patients (30
sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome
9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and
31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals.
Correlations between baseline CSF and serum NfL levels, standardized
neuropsychological tests, and the rate of cognitive decline in FTD patients were
assessed.
RESULTS: CSF and serum NfL presented with significantly higher levels in FTD
than in AD patients and both control groups. Within FTD subtypes, genetic cases,
and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant
correlations between NfL levels and overall cognitive function, abstract
reasoning (CSF and serum), executive functions, memory, and language (serum)
were found. A relationship between increased baseline CSF and serum NfL and a
decay in cognitive performance over time was also observed.
CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful
surrogate end point of disease severity in upcoming targeted treatments. |
Is resistance training usually associated with increasing muscle hypertrophy? | Traditional resistance exercises have been widely used to promote muscle strength and hypertrophy. | We conducted a 12-wk resistance training program in elderly women [mean age 69
+/- 1.0 (SE) yr] to determine whether increases in muscle strength are
associated with changes in cross-sectional fiber area of the vastus lateralis
muscle. Twenty-seven healthy women were randomly assigned to either a control or
exercise group. The program was satisfactorily completed and adequate biopsy
material obtained from 6 controls and 13 exercisers. After initial testing of
baseline maximal strength, exercisers began a training regimen consisting of
seven exercises that stressed primary muscle groups of the lower extremities. No
active intervention was prescribed for the controls. Increases in muscle
strength of the exercising subjects were significant compared with baseline
values (28-115%) in all muscle groups. No significant strength changes were
observed in the controls. Cross-sectional area of type II muscle fibers
significantly increased in the exercisers (20.1 +/- 6.8%, P = 0.02) compared
with baseline. In contrast, no significant change in type II fiber area was
observed in the controls. No significant changes in type I fiber area were found
in either group. We conclude that a program of resistance exercise can be safely
carried out by elderly women, such a program significantly increases muscle
strength, and such gains are due, at least in part, to muscle hypertrophy. Heavy resistance training is associated with increased body weight, lean body
mass, and muscle cross-sectional area. The increased muscle cross-sectional area
is mainly brought about by hypertrophy of individual muscle fibers. There is a
greater increase in the area of fast twitch fibers compared to slow twitch
fibers. In addition, long-term heavy resistance training may produce fiber
proliferation. Mitochondrial volume density decreases in proportion to muscle
hypertrophy in response to training. Typically, no capillary neoformation occurs
during strength training. Therefore, capillary density decreases consequent to
heavy resistance training. It appears, though, that bodybuilders, relying on a
high repetition training system, in contrast to Olympic weight- and power
lifters, display a small increase in number of capillaries per fiber. Enzyme
activities, reflecting oxidative potential; decrease during long-term heavy
resistance training, resulting in muscle hypertrophy. Although glycogen storage
capacity is enhanced in strength trained athletes, enzyme activities reflecting
anaerobic metabolism do not increase in response to heavy resistance exercise. Skeletal muscle tissue is sensitive to the acute and chronic stresses associated
with resistance training. These responses are influenced by the structure of
resistance activity (i.e. frequency, load and recovery) as well as the training
history of the individuals involved. There are histochemical and biochemical
data which suggest that resistance training alters the expression of myosin
heavy chains (MHCs). Specifically, chronic exposure to bodybuilding and power
lifting type activity produces shifts towards the MHC I and IIb isoforms,
respectively. However, it is not yet clear which training parameters trigger
these differential expressions of MHC isoforms. Interestingly, many programmes
undertaken by athletes appear to cause a shift towards the MHC I isoform.
Increments in the cross-sectional area of muscle after resistance training can
be primarily attributed to fibre hypertrophy. However, there may be an upper
limit to this hypertrophy. Furthermore, significant fibre hypertrophy appears to
follow the sequence of fast twitch fibre hypertrophy preceding slow twitch fibre
hypertrophy. Whilst some indirect measures of fibre number in living humans
suggest that there is no interindividual variation, postmortem evidence suggests
that there is. There are also animal data arising from investigations using
resistance training protocols which suggest that chronic exercise can increase
fibre number. Furthermore, satellite cell activity has been linked to myotube
formation in the human. However, other animal models (i.e. compensatory
hypertrophy) do not support the notion of fibre hyperplasia. Even if hyperplasia
does occur, its effect on the cross-sectional area of muscle appears to be
small. Phosphagen and glycogen metabolism, whilst important during resistance
activity appear not to normally limit the performance of resistance activity.
Phosphagen and related enzyme adaptations are affected by the type, structure
and duration of resistance training. Whilst endogenous glycogen reserves may be
increased with prolonged training, typical isotonic training for less than 6
months does not seem to increase glycolytic enzyme activity. Lipid metabolism
may be of some significance in bodybuilding type activity. Thus, not
surprisingly, oxidative enzyme adaptations appear to be affected by the
structure and perhaps the modality of resistance training. The dilution of
mitochondrial volume and endogenous lipid densities appears mainly because of
fibre hypertrophy. In resistance training, it has been empirically accepted that muscle hypertrophy
is developed by low intensity and high volume training, while muscle strength
and power are developed by high intensity and low volume training. The purpose
of the present study was to investigate the influence of two different modes of
resistance training on isokinetic strength and muscle cross-sectional area (CSA)
in females. Eleven females, who had no experience in resistance training,
participated in this study and were randomly divided into two groups. The former
consisted of 4-5 sets of 15-20 RM (repetition maximum) with sufficient rest
between sets (Group H), while the latter consisted of 8-9 sets of 4-6R M with 90
s of rest between sets (Group S). The former was assumed to be appropriate for
muscle hypertrophy and the latter muscle strength, respectively. All subjects
completed isotonic knee extension exercise three times a week for 8 weeks.
Measurements were made on quadriceps muscle cross-sectional area (CSA) and
isokinetic torques at 0, 60, 180, and approximately 300 degrees before training,
at the fifth week and the end of training period. Muscle CSA was defined as the
sum of CSA measured at 30, 50 and 70% of femur length. After training, muscle
CSA had significantly increased in both groups: 3.3 +/- 0.7% (p < .05) for group
H and 3.6 +/- 1.1% (p < .05) for group S, respectively. While the changes in
isokinetic torque were 43.4 +/- 47.5% (p < .05) for group H and 27.4 +/- 31.3%
(p < .05) for group S, respectively. In both groups the percentage changes of
the isokinetic strength were significantly higher than those of the CSA. No
significant difference in these variables were found between the two groups.
These results suggest that during the early phase of resistance training two
different modes of resistance training may have similar effects on muscle CSA
and isokinetic strength in untrained females. High-intensity resistance (HIR) training has been associated with muscle
hypertrophy and decreased microvascular density that might produce a blood flow
limitation. The effect of HIR training on lower leg maximal blood flow and
minimum vascular resistance (Rmin) during reactive hyperemia were investigated
in 7 healthy males. The gastrocnemius-soleus muscles of one leg were trained
using maximal isokinetic concentric contractions for 4 weeks; the nontrained leg
was the control. Lower leg blood flow was measured by venous occlusion
plethysmography. Lower leg muscle volume was determined using magnetic resoce
imaging. Peak isokinetic torque increased in both the trained (T) and nontrained
(NT) legs (p < .05). Lower leg muscle volume increased by 2% in the T leg only
(p < .05). In the T leg, maximal blood flow decreased and Rmin increased (p <
.05); no hemodynamic change was detected in the NT leg. It is concluded that HIR
training of the calf muscles is associated with a decrease in hyperemia-induced
blood flow; thereby, indicating a blood flow limitation to the calf muscles. Chronic resistance training induces increases in muscle fibre cross-sectional
area (CSA), otherwise known as hypertrophy. This is due to an increased volume
percentage of myofibrillarproteins within a given fibre. The exact time-course
for muscle fibre hypertrophy is not well-documented but appears to require at
least 6-7 weeks of regular resistive training at reasonably high intensity
before increases in fibre CSA are deemed significant. Proposed training-induced
changes in neural drive are hypothesized to increase strength due to increased
synchrony of motor unit firing, reducedant agonist muscle activity, and/or a
reduction in any bilateral strength deficit. Nonetheless, increases in muscle
protein synthesis were observed following an isolated bout of resistance
exercise. In addition, muscle balance was positive, following resistance
exercise when amino acids were infused/ingested. This showed that protein
accretion occurred during the postexercise period. The implications of this
hypothesis for training-induced increases in strength are discussed. In the past decade strength training has been investigated extensively as a
means of reversing the muscle mass loss that occurs with aging (sarcopenia).
High intensity resistance training (HIRT) has led to increased protein
synthesis, along with muscle hypertrophy measured at the whole body, whole
muscle, and muscle fibre levels, in older adults. Typically, the strength
increments associated with HIRT have been much larger than the hypertrophic
response. However, most HIRT periods have been quite short. Less is known about
the long-term hypertrophic response to HIRT in older adults. In order to lessen
the effects of sarcopenia, HIRT should continue over the long term in older
adults, to improve functional performance and health. Resistance training (RT) is a popular method of conditioning to enhance sport
performance as well as an effective form of exercise to attenuate the
age-mediated decline in muscle strength and mass. Although the benefits of RT on
skeletal muscle morphology and function are well established, its effect on left
ventricular (LV) morphology remains equivocal. Some investigations have found
that RT is associated with an obligatory increase in LV wall thickness and mass
with minimal alteration in LV internal cavity dimension, an effect called
concentric hypertrophy. However, others report that short- (<5 years) to
long-term (>18 years) RT does not alter LV morphology, arguing that concentric
hypertrophy is not an obligatory adaptation secondary to this form of exertion.
This disparity between studies on whether RT consistently results in cardiac
hypertrophy could be caused by: (i) acute cardiopulmonary mechanisms that
minimise the increase in transmural pressure (i.e. ventricular pressure minus
intrathoracic pressure) and LV wall stress during exercise; (ii) the underlying
use of anabolic steroids by the athletes; or (iii) the specific type of RT
performed. We propose that when LV geometry is altered after RT, the pattern is
usually concentric hypertrophy in Olympic weightlifters. However, the pattern of
eccentric hypertrophy (increased LV mass secondary to an increase in diastolic
internal cavity dimension and wall thickness) is not uncommon in bodybuilders.
Of particular interest, nearly 40% of all RT athletes have normal LV geometry,
and these athletes are typically powerlifters. RT athletes who use anabolic
steroids have been shown to have significantly higher LV mass compared with
drug-free sport-matched athletes. This brief review will sort out some of the
factors that may affect the acute and chronic outcome of RT on LV morphology. In
addition, a conceptual framework is offered to help explain why cardiac
hypertrophy is not always found in RT athletes. Muscle hypertrophy is the product of increased drive through protein synthetic
pathways and the incorporation of newly divided satellite cells. Gains in muscle
mass and strength can be achieved through exercise regimens that include
resistance training. Increased insulin-like growth factor-I (IGF-I) can also
promote hypertrophy through increased protein synthesis and satellite cell
proliferation. However, it is not known whether the combined effect of IGF-I and
resistance training results in an additive hypertrophic response. Therefore,
rats in which viral administration of IGF-I was directed to one limb were
subjected to ladder climbing to test the interaction of each intervention on
muscle mass and strength. After 8 wk of resistance training, a 23.3% increase in
muscle mass and a 14.4% increase in peak tetanic tension (P(o)) were observed in
the flexor hallucis longus (FHL). Viral expression of IGF-I without resistance
training produced a 14.8% increase in mass and a 16.6% increase in P(o) in the
FHL. The combined interventions produced a 31.8% increase in muscle mass and a
28.3% increase in P(o) in the FHL. Therefore, the combination of resistance
training and overexpression of IGF-I induced greater hypertrophy than either
treatment alone. The effect of increased IGF-I expression on the loss of muscle
mass associated with detraining was also addressed. FHL muscles treated with
IGF-I lost only 4.8% after detraining, whereas the untreated FHL lost 8.3%
muscle mass. These results suggest that a combination of resistance training and
overexpression of IGF-I could be an effective measure for attenuating the loss
of training-induced adaptations. This paper was prepared in partial fulfillment for Doctoral Degree in Physical
Therapy at Texas Woman's University in Houston, TX. Resistance training is
frequently used in rehabilitation to improve musculoskeletal function. The
increased ability of skeletal muscle to generate force following resistance
training results from two important changes: 1) the adaptation of the muscle
fiber, and 2) the extent to which the motor unit can activate the muscle (neural
adaption). The purpose of this article is to provide a review of research
investigating the effects of resistance training on muscle fibers and on nervous
system input. Muscle fiber adaptations caused by resistance training include
increased cross-sectional area of the muscle (hypertrophy, hyperplasia, or
both), selective hypertrophy of fast twitch fibers, decreased or maintained
mitochondrial number and capillary density of muscle, and possible changes in
energy sources. Changes in nervous system input resulting from resistance
training include recruitment of an increased number and firing rate of motor
units, increased reflex potentiation, and improved synchronization. An
understanding of the adaptations occurring in muscle in response to resistance
training provides a fundamental basis for which appropriate clinical exercise
training programs can be developed for the rehabilitation of patients. J Orthop
Sports Phys Ther 1990;12(6):248-255. We determined muscle fiber type-specific hypertrophy and changes in satellite
cell (SC) content following a 12-week resistance training program in 13 healthy,
elderly men (72 +/- 2 years). Leg strength and body composition (dual-energy
X-ray absorptiometry and computed tomography) were assessed, and muscle biopsy
samples were collected. Leg strength increased 25%-30% after training (p <
.001). Leg lean mass and quadriceps cross-sectional area increased 6%-9% (p <
.001). At baseline, mean fiber area and SC content were smaller in the Type II
versus Type I muscle fibers (p < .01). Following training, Type II muscle fiber
area increased from 5,438 +/- 319 to 6,982 +/- 503 microm(2) (p < .01). Type II
muscle fiber SC content increased from 0.048 +/- 0.003 to 0.084 +/- 0.008 SCs
per fiber (p < .001). No changes were observed in the Type I muscle fibers. In
older adults, skeletal muscle tissue is still capable of inducing SC
proliferation and differentiation, resulting in Type II muscle fiber
hypertrophy. Low-intensity blood flow restricted (LI-BFR) resistance training has been shown
to produce comparable increases in muscle hypertrophy to traditional
high-intensity (HI) resistance training. However, a comparison of the acute
vascular responses between the two types of exercise has not been made. The
purpose of this study is to compare the acute vascular responses of HI,
low-intensity (LI), and LI-BFR resistance exercise. Using a randomized,
cross-over design, 11 young (28 ± 5 years) males completed three acute
resistance exercise bouts (HI, LI and LI-BFR). Before (Pre), and starting at 15-
and 45-min after each exercise bout, large (LAEI) and small (SAEI) artery
compliance and calf blood flow were assessed. Calf blood flow was normalized per
unit pressure as calf vascular conductance (CVC). Repeated measures (condition ×
time) ANOVA revealed a main time effect for LAEI and a main condition effect for
SAEI. LAEI increased following exercise but returned to baseline at 45-min post.
SAEI was greater during the HI condition compared to the LI or LI-BFR
conditions. There was a significant condition × time interaction for CVC. CVC
was elevated at 15- and 45-min post during the HI condition and at 15-min
following the LI condition. CVC was not altered following the LI-BFR condition.
These results suggest that HI, LI, and LI-BFR resistance exercise cause similar
acute increases in large artery compliance but HI causes greater increases in
small artery compliance and calf vascular conductance than LI or LI-BFR
resistance exercise. BACKGROUND: Resistance training in combination with practical blood flow
restriction (pBFR) is thought to stimulate muscle hypertrophy by increasing
muscle activation and muscle swelling. Most previous studies used the KAATSU
device; however, little long-term research has been completed using pBFR.
OBJECTIVE: To investigate the effects of pBFR on muscle hypertrophy.
METHODS: Twenty college-aged male participants with a minimum of 1 year of
resistance training experience were recruited for this study. Our study
consisted of a randomized, crossover protocol consisting of individuals either
using pBFR for the elbow flexors during the first 4 weeks (BFR-HI) or the second
4 weeks (HI-BFR) of an 8-week resistance training programme. Direct
ultrasound-determined bicep muscle thickness was assessed collectively at
baseline and at the end of weeks 4 and 8.
RESULTS: There were no differences in muscle thickness between groups at
baseline (P = 0·52). There were time (P<0·01, ES = 0·99) but no condition by
time effects (P = 0·58, ES = 0·80) for muscle thickness in which the combined
values of both groups increased on average from week 0 (3·66 ± 0·06) to week 4
(3·95 ± 0·05) to week 8 (4·11 ± 0·07). However, both the BFR-HI and HI-BFR
increased significantly from baseline to week 4 (6·9% and 8·6%, P<0·01) and from
weeks 4 to 8 (4·1%, 4·0%, P<0·01), respectively.
CONCLUSION: The results of this study suggest that pBFR can stimulate muscle
hypertrophy to the same degree to that of high-intensity resistance training. The aim of the study was to determine whether it is possible to improve both
maximum and rapid force production using resistance training that is typically
used to induce muscle hypertrophy in previously untrained older men. Subjects
(60-72 years) performed 20 weeks of "hypertrophic" resistance training twice
weekly (n = 27) or control (n = 11). Maximum dynamic and isometric leg press, as
well as isometric force over 0-100 ms, and maximum concentric power tests were
performed pre- and post-intervention. Muscle activity was assessed during these
tests by surface electromyogram of the vastus lateralis and medialis muscles.
Muscle hypertrophy was assessed by panoramic ultrasound of the vastus lateralis.
The intervention group increased their maximum isometric (from 2268 ± 544 to
2538 ± 701 N) and dynamic force production (from 137 ± 24 to 165 ± 29 kg), and
these changes were significantly different to control (isometric 12 ± 16 vs. 1 ±
9 %; dynamic 21 ± 12 vs. 2 ± 4 %). No within- or between-group differences were
observed in rapid isometric force or concentric power. Relative increases in
vastus lateralis cross-sectional area trended to be statistically greater in the
intervention group (10 ± 8 vs. 3 ± 6 %, P = 0.061). It is recommendable that
resistance training programs for older individuals integrate protocols
emphasizing maximum force/muscle hypertrophy and rapid force production in order
to induce comprehensive health-related and functionally important improvements
in this population. The possible muscular strength, hypertrophy, and muscle power benefits of
resistance training under environmental conditions of hypoxia are currently
being investigated.Nowadays, resistance training in hypoxia constitutes a
promising new training strategy for strength and muscle gains. The main
mechanisms responsible for these effects seem to be related to increased
metabolite accumulation due to hypoxia. However, no data are reported in the
literature to describe and compare the efficacy of the different hypertrophic
resistance training strategies in hypoxia.Moreover, improvements in sprinting,
jumping, or throwing performance have also been described at terrestrial
altitude, encouraging research into the speed of explosive movements at
altitude. It has been suggested that the reduction in the aerodynamic resistance
and/or the increase in the anaerobic metabolism at higher altitudes can
influence the metabolic cost, increase the take-off velocities, or improve the
motor unit recruitment patterns, which may explain these improvements. Despite
these findings, the applicability of altitude conditions in improving muscle
power by resistance training remains to be clarified.This review examines
current knowledge regarding resistance training in different types of hypoxia,
focusing on strategies designed to improve muscle hypertrophy as well as power
for explosive movements. It has been proposed that protein supplementation during resistance exercise
training enhances muscle hypertrophy. The degree of hypertrophy during training
is controlled in part through the activation of satellite cells and myonuclear
accretion.
PURPOSE: This study aimed to determine the efficacy of protein supplementation
(and the type of protein) during traditional resistance training on myofiber
cross-sectional area, satellite cell content, and myonuclear addition.
METHODS: Healthy young men participated in supervised whole-body progressive
resistance training 3 d·wk for 12 wk. Participants were randomized to one of
three groups ingesting a daily 22-g macronutrient dose of soy-dairy protein
blend (PB, n = 22), whey protein isolate (WP, n = 15), or an isocaloric
maltodextrin placebo (MDP, n = 17). Lean mass, vastus lateralis
myofiber-type-specific cross-sectional area, satellite cell content, and
myonuclear addition were assessed before and after resistance training.
RESULTS: PB and the pooled protein treatments (PB + WP = PRO) exhibited a
greater whole-body lean mass %change compared with MDP (P = 0.057 for PB) and (P
= 0.050 for PRO), respectively. All treatments demonstrated similar leg muscle
hypertrophy and vastus lateralis myofiber-type-specific cross-sectional area (P
< 0.05). Increases in myosin heavy chain I and II myofiber satellite cell
content and myonuclei content were also detected after exercise training (P <
0.05).
CONCLUSION: Protein supplementation during resistance training has a modest
effect on whole-body lean mass as compared with exercise training without
protein supplementation, and there was no effect on any outcome between protein
supplement types (blend vs whey). However, protein supplementation did not
enhance resistance exercise-induced increases in myofiber hypertrophy, satellite
cell content, or myonuclear addition in young healthy men. We propose that as
long as protein intake is adequate during muscle overload, the adaptations in
muscle growth and function will not be influenced by protein supplementation. Resistance training of healthy young men typically results in muscle hypertrophy
and a shift in vastus lateralis composition away from type IIx fibers to an
increase in IIa fiber content. Our previous studies of 8 wk of resistance
training found that many metabolic syndrome men and women paradoxically
increased IIx fibers with a decrease in IIa fibers. To confirm the hypothesis
that obese subjects might have muscle remodeling after resistance training very
different from healthy lean subjects, we subjected a group of nine obese male
volunteers to progressive resistance training for a total of 16 wk. In these
studies, weight loss was discouraged so that muscle changes would be attributed
to the training alone. Detailed assessments included comparisons of histological
examinations of needle biopsies of vastus lateralis muscle pretraining and at 8
and 16 wk. Prolonging the training from 8 to 16 wk resulted in increased
strength, improved body composition, and more muscle fiber hypertrophy, but
euglycemic clamp-quantified insulin responsiveness did not improve. Similar to
prior studies, muscle fiber composition shifted toward more fast-twitch type IIx
fibers (23 to 42%). Eight weeks of resistance training increased the muscle
expression of phosphorylated Akt2 and mTOR. Muscle GLUT4 expression increased,
although insulin receptor and IRS-1 expression did not change. We conclude that
resistance training of prediabetic obese subjects is effective at changing
muscle, resulting in fiber hypertrophy and increased type IIx fiber content, and
these changes continue up to 16 wk of training.NEW & NOTEWORTHY Obese,
insulin-resistant men responded to 16 wk of progressive resistance training with
muscle hypertrophy and increased strength and a shift in muscle fiber
composition toward fast-twitch, type IIx fibers. Activation of muscle mTOR was
increased by 8 wk but did not increase further at 16 wk despite continued
augmentation of peak power and rate of force generation. Franco, CMC, Carneiro, MAS, de Sousa, JFR, Gomes, GK, and Orsatti, FL. Influence
of high- and low-frequency resistance training on lean body mass and muscle
strength gains in untrained men. J Strength Cond Res 35(8): 2089-2094, 2021-The
aim of this study was to investigate whether high-frequency resistance training
(HFRT) performs better in lean body mass (LBM) and muscle strength gains when
compared with low-frequency resistance training (LFRT). Eighteen untrained males
(height: 1.76 ± 0.05 m, body mass: 78.3 ± 13.5 kg, and age: 22.1 ± 2.2 years)
were randomly allocated into HFRT (n = 9) and LFRT (n = 9). Muscle strength {1
repetition maximum (RM) (bench press [BP] and unilateral leg extension [LE])}
and LBM (DXA) were assessed at before and after 8 weeks of training. Both groups
performed 7 whole-body resistance exercises, standardized to 10 sets per week,
8-12 maximal repetitions, and 90-120 seconds of rest in a 5-day resistance
training routine. The LFRT performed a split-body routine, training each
specific muscle group once a week. The HFRT performed a total-body routine,
training all muscle groups every session and progressed from a training
frequency of once per week to a training frequency of 5 times per week. Lean
body mass increased without differences between groups (HFRT = 1.0 kg vs. LFRT =
1.5 kg; p = 0.377). Similarly, 1RM increased without differences between groups
(right LE, HFRT = 21.2 kg vs. LFRT = 19.7 kg, p = 0.782; BP, HFRT = 7.1 kg vs.
LFRT = 4.5 kg, p = 0.293). These findings suggest that in young untrained men,
progressing from a training frequency of once per week to a training frequency
of 5 times per week with equated volume produces similar gains in LBM and muscle
strength as a constant training frequency of once per week, over an 8-week
training period. BACKGROUND: While traditional resistance exercises have been widely used to
promote muscle strength and hypertrophy in the elderly, few studies have
reported the use of a functional approach in which common patterns for daily
activities are considered the primary stimulus.
OBJECTIVE: Investigate whether functional training has similar effects the
traditional on body composition and muscle strength components in physically
active older women.
METHODS: Forty-seven older women completed a randomized and crossover clinical
trial, distributed in three groups: Functional or Traditional Training
(FUNCT/TRAD: n = 32; 65.28 ± 4.96 years) and Stretching Group (STRETCH: n = 15;
64.40 ± 3.68 years). Maximal dynamic strength was verified with the 1 repetition
maximum (RM) test in the leg press and rowing machines. Muscular power was
analyzed using 50% of the maximum load, speed was determined using a linear
encoder, and isometric strength was analyzed with hand and lumbar dynamometers.
ANOVA for repeated measures was applied for comparisons.
RESULTS: The FUNCT showed a significant decrease in fat percentage (p = 0.015,
3.51%) and the TRAD a significant increase in lean mass (p = 0.008, 2.92%). Both
FUNCT and TRAD generated significant increases in all components of muscle
strength compared to baseline whereas STRETCH showed declines in these
variables. No statistically significant differences were observed between the
experimental groups in body composition.
CONCLUSION: Functional and traditional training are equally efficient in
improving strength components in physically active older women and, therefore,
they may be complementary to combat some of the deleterious effects of
senescence. This trial was registered at Brazilian Registry of Clinical Trials
(RBR-9Y8KJQ). Mannarino, P, Matta, T, Lima, J, Simão, R, and Freitas de Salles, B.
Single-Joint Exercise Results in Higher Hypertrophy of Elbow Flexors Than
Multijoint Exercise. J Strength Cond Res 35(10): 2677-2681, 2021-Recent data
suggest that single-joint exercises are unnecessary to maximize the resistance
training (RT) results in novice to advanced individuals. However, the present
literature is still inconsistent on this topic and controversy arises. The aim
of this study was to compare the effects of the unilateral dumbbell row (DR)
(multiple-joint) vs. unilateral biceps curl (BC) (single-joint) exercises on
strength and elbow flexors muscle thickness (MT). Ten untrained men were
assigned to an 8-week RT program for elbow flexors, one arm performing DR and
the other performing BC in a within-subject design. After a familiarization,
pretraining MT was measured using an ultrasound (US) technique, and strength was
tested using 10 repetition maximum (10RM) tests. After pretesting, 8 weeks of RT
(4-6 sets, 8-12 repetitions to concentric failure, 2 sessions per week) was
performed. Post-testing was conducted in the same order as pretesting 48 and 72
hours after the last session. Single-joint BC exercise resulted in higher
hypertrophy of elbow flexors (11.06%) than the DR (5.16%) multijoint exercise
after 8 weeks of RT (p = 0.009). The 10RM improvement was higher for DR in
DR-trained arm, whereas 10RM for BC was higher in BC-trained arm. The
single-joint exercise resulted in higher hypertrophy of the elbow flexors than
multijoint exercise after 8 weeks of RT, whereas strength improvements were
greater in accordance with specificity of RT exercise. Therefore, in RT
prescription for elbow flexors hypertrophy, single-joint exercises such as BC
should be emphasized. Resistance training is commonly prescribed to enhance strength/power qualities
and is achieved via improved neuromuscular recruitment, fiber type transition,
and/ or skeletal muscle hypertrophy. The rate and amount of muscle hypertrophy
associated with resistance training is influenced by a wide array of variables
including the training program, plus training experience, gender, genetic
predisposition, and nutritional status of the individual. Various dietary
interventions have been proposed to influence muscle hypertrophy, including
manipulation of protein intake, specific supplement prescription, and creation
of an energy surplus. While recent research has provided significant insight
into optimization of dietary protein intake and application of evidence based
supplements, the specific energy surplus required to facilitate muscle
hypertrophy is unknown. However, there is clear evidence of an anabolic stimulus
possible from an energy surplus, even independent of resistance training. Common
textbook recommendations are often based solely on the assumed energy stored
within the tissue being assimilated. Unfortunately, such guidance likely fails
to account for other energetically expensive processes associated with muscle
hypertrophy, the acute metabolic adjustments that occur in response to an energy
surplus, or individual nuances like training experience and energy status of the
individual. Given the ambiguous nature of these calculations, it is not
surprising to see broad ranging guidance on energy needs. These estimates have
never been validated in a resistance training population to confirm the "sweet
spot" for an energy surplus that facilitates optimal rates of muscle gain
relative to fat mass. This review not only addresses the influence of an energy
surplus on resistance training outcomes, but also explores other pertinent
issues, including "how much should energy intake be increased," "where should
this extra energy come from," and "when should this extra energy be consumed."
Several gaps in the literature are identified, with the hope this will stimulate
further research interest in this area. Having a broader appreciation of these
issues will assist practitioners in the establishment of dietary strategies that
facilitate resistance training adaptations while also addressing other important
nutrition related issues such as optimization of fuelling and recovery goals.
Practical issues like the management of satiety when attempting to increase
energy intake are also addressed. It is universally accepted that resistance training promotes increases in muscle
strength and hypertrophy in younger and older populations. Although less
investigated, studies largely suggest resistance training results in lower
skeletal muscle mitochondrial volume; a phenomenon which has been described as a
"dilution of the mitochondrial volume" via resistance training. While this
phenomenon is poorly understood, it is likely a result of muscle fiber
hypertrophy outpacing mitochondrial biogenesis. Critically, there is no evidence
to suggest resistance training promotes a net loss in mitochondria. Further,
given the numerous reports suggesting resistance training does not decrease and
may even increase VO2max in previously untrained individuals, it is plausible
certain aspects of mitochondrial function may be enhanced with resistance
training, and this area warrants further research consideration. Finally, there
are emerging data suggesting resistance training may affect mitochondrial
dynamics. The current review will provide an in-depth discussion of these topics
and posit future research directions which can further our understanding of how
resistance training may affect skeletal muscle mitochondrial physiology. |
Which company developed Waylivra? | Waylivra is being developed by Ionis Pharmaceuticals through its subsidiary company, Akcea Therapeutics. | |
Is nerinetide effective for ischaemic stroke? | No. Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. | |
What is known about FANK1? | Fank1 encodes a protein containing a fibronectin type III domain in the amino terminus and five ankyrin repeats in its carboxyl terminus. FANK1 displays a high degree of sequence conservation in 11 vertebrate species during evolution. Bioinformatic and experimental analyses revealed that Fank1 was exclusively expressed in the testis in both mice and humans.
Consistent with its nuclear localization, a gene ontology analysis suggests that FANK1 has a DNA binding activity and thus may function as a transcription factor. | In our effort to identify testis-specific genes we found Fank1, which encodes a
protein containing a fibronectin type III domain in the amino terminus and five
ankyrin repeats in its carboxyl terminus. FANK1 displays a high degree of
sequence conservation in 11 vertebrate species during evolution. Bioinformatic
and experimental analyses revealed that Fank1 was exclusively expressed in the
testis in both mice and humans. Fank1 mRNA was expressed in mid to late
pachytene spermatocytes as well as spermatids in steps 1-14. FANK1 protein was
localized in the nuclei of the same cells within the seminiferous epithelium.
Consistent with its nuclear localization, a gene ontology analysis suggests that
FANK1 has a DNA binding activity and thus may function as a transcription
factor. Given the highly restricted expression of FANK1, it may have a role in
regulating gene expression in the transition from the meiotic phase to the
haploid phase during spermatogenesis. Regulation of apoptosis at various stages of differentiation plays an important
role in spermatogenesis. Therefore, the identification and characterisation of
highly expressed genes in the testis that are involved in apoptosis is of great
value to delineate the mechanism of spermatogenesis. Here, we reported that
Fank1, a novel gene highly expressed in testis, functioned as an anti-apoptotic
protein that activated the activator protein 1 (AP-1) pathway. We found that
Jab1 (Jun activation domain-binding protein 1), a co-activator of AP-1,
specifically interacted with Fank1. Reporter analyses showed that Fank1
activated AP-1 pathway in a Jab1-dependent manner. Fank1 overexpression also
increased the expression and activation of endogenous c-Jun. Further study
showed that Fank1 inhibited cell apoptosis by upregulating and activating
endogenous c-Jun and its downstream target, Bcl-3. This process was shown to be
Jab1 dependent. Taken together, our results indicated that by interacting with
Jab1, Fank1 could suppress cell apoptosis by activating the AP-1-induced
anti-apoptotic pathway. BACKGROUND: The fibronectin type 3 and ankyrin repeat domains 1 gene, Fank1, is
an ancient, evolutionarily conserved gene present in vertebrates. Short-hairpin
RNA (shRNA)-based knockdown transgenic mice have oligospermia caused by an
increase in apoptotic germ cells. In this study, we investigated the in vivo
function of Fank1.
METHODS: In this study, we generated Fank1-knockout mice using the CRISPR/Cas9
system. We then investigated the phenotype and in vivo function of Fank1. Testes
and epididymis tissues were analyzed by histological and immunofluorescence
staining. Apoptotic cells were analyzed in terminal deoxynucleotidyl transferase
dUTP nick end-labeling assays. Fertility and sperm counts were also evaluated.
The GTEx database were used to assess gene expression quantitative trait loci
and mRNA expression of candidate genes and genes neighboring single nucleotide
polymorphisms was analyzed by quantitative RT-PCR.
RESULTS: In contrast to the Fank1-knockdown model, no significant changes in
epididymal sperm content and the number of apoptotic cells were observed in
Fank1-/- homozygotes. In addition, a different pattern of Dusp1, Klk1b21 and
Klk1b27 mRNA expression was detected in Fank1-knockout testis. These results
reveal differences in the molecular changes between Fank1-knockdown mice and
Fank1-knockout mice and provide a basic resource for population genetics
studies. |
Please list the drugs associated with Drug-Induced Hypophosphatemia. | Drug induced hypophosphatemia can occur with iron therapy as well a treatment with ferric carboxymaltose, elotuzumab, cemiplimab, Temsirolimus, capecitabine, panobinostat, bendamustine, ofatumumab, carboplatin and etoposide (BOCE) | Serum phosphorus levels (Ps), dietary intake of phosphorus, and renal phosphate
handling indexes were evaluated in 158 patients with chronic obstructive
pulmonary disease (COPD) of varying degrees of severity; moreover, skeletal
muscle phosphorus content (Pm) was measured in muscle samples obtained by
quadriceps femoris needle biopsy in 14 of the same patients. Hypophosphatemia
(Ps less than or equal to 2.5 mg/dl) was found in 34 (21.5 percent) of 158
patients without differences between groups of COPD patients presenting
increasing severity of respiratory illness. No relationship was found between
serum levels and dietary intake of phosphorus; hypophosphatemia was associated
with low renal phosphate threshold (TmPO4/GFR) values in 31 (91 percent) of 34
patients. The prevalence of hypophosphatemia was significantly higher among COPD
patients taking one or more drugs commonly used in COPD and known as negatively
influencing renal phosphate handling: xanthine derivatives, corticosteroids,
loop diuretics, and beta 2-adrenergic bronchodilators. Short-term administration
of therapeutic doses of these drugs in COPD patients previously not taking any
drug reduced TmPO4/GFR values; phosphaturic effect of short-term theophylline
administration on renal phosphate handling was additive to that of long-term
assumption of the drug. Muscle phosphorus content was both reduced in COPD
patients as compared with control subjects and significantly correlated to serum
phosphorus levels and to TmPO4/GFR values. The present investigation revealed a
high prevalence of hypophosphatemia among COPD patients as well as a defect in
renal phosphate reabsorption secondary, at least in part, to pharmacologic
therapy. Moreover, it also suggests that in COPD patients muscle phosphorus
content is likely to be reduced in presence of hypophosphatemia. OBJECTIVE: To provide an outline of the drugs and nutritional therapy that could
contribute to the development of hypophosphatemia in the critically ill patient.
DATA SOURCES: Computerized abstracting services, references to primary
literature articles, and review publications were screened for references to
drug- or nutrition-related hypophosphatemia.
STUDY SELECTION: Studies primarily describing responses in adults were selected.
Animal research is described that illustrates findings in humans.
DATA EXTRACTION: Information was abstracted from the findings of individual case
reports and clinical trials.
DATA SYNTHESIS: Data are organized by mechanism of possible effect on serum
phosphate concentration. No reference is made to drugs that do not have an
effect on phosphate metabolism.
CONCLUSIONS: Hypophosphatemia can have significant effects that would hinder
recovery of the critically ill patient. Antacids, catecholamines,
beta-adrenergic agonists, sodium bicarbonate, and acetazolamide are commonly
used therapeutic agents that could contribute significantly to the development
of hypophosphatemia. Provision of nutrition to the chronically malnourished
individual or chronic administration of phosphate-depleted parenteral nutrition
could produce symptoms associated with hypophosphatemia. Other drugs could have
a mild effect on lowering serum phosphate concentrations, but would be unlikely
to produce symptoms unless combined with other etiologies of hypophosphatemia. Imatinib is the drug of first choice for most patients with chronic phase
chronic myeloid leukemia (CML). Although it is generally well tolerated, a
number of hematological and nonhematological side-effects have been described.
We report here that imatinib induces hypophosphatemia in a high proportion of
our series of CML patients previously treated with interferon alpha, and that
this previously unreported side effect is associated with response. Hypophosphatemia (serum phosphorus concentration <2.5 mg/dl, 0.8 mmol/l),
although rare in the general population, is commonly observed in hospitalized
patients and may be associated with drug therapy. In fact, hypophosphatemia
frequently develops in the course of treatment with drugs used in every-day
clinical practice including diuretics and bisphosphonates. Proper diagnostic
approach of patients with low serum phosphorus concentrations should involve a
detailed medical history with special attention to the recent use of
medications. The clinical manifestations of drug-induced hypophosphatemia are
usually mild but might also be severe and potentially life-threatening. This
review aims at a thorough understanding of the underlying pathophysiological
mechanisms and risk factors of drug therapy-related hypophosphatemia thus
allowing prevention and effective intervention strategies. The use of anticancer drugs is beneficial for patients with maligcies but is
frequently associated with the occurrence of electrolyte disorders, which can be
hazardous and in many cases fatal. The review presents the electrolyte
abnormalities that can occur with the use of anticancer drugs and provides the
related mechanisms. Platinum-containing anticancer drugs induce hypomagnesemia,
hypokalemia and hypocalcemia. Moreover, platinum-containing drugs are associated
with hyponatremia, especially when combined with large volumes of hypotonic
fluids aiming to prevent nephrotoxicity. Alkylating agents have been linked with
the occurrence of hyponatremia [due to syndrome of inappropriate antidiuretic
hormone secretion (SIADH)] and Fanconi's syndrome (hypophosphatemia,
aminoaciduria, hypouricemia and/or glucosuria). Vinca alkaloids are associated
with hyponatremia due to SIADH. Epidermal growth factor receptor monoclonal
antibody inhibitors induce hypomagnesemia, hypokalemia and hypocalcemia. Other,
monoclonal antibodies, such as cixutumumab, cause hyponatremia due to SIADH.
Tyrosine kinase inhibitors are linked to hyponatremia and hypophosphatemia.
Mammalian target of rapamycin inhibitors induce hyponatremia (due to aldosterone
resistance), hypokalemia and hypophosphatemia. Other drugs such as
immunomodulators or methotrexate have been also associated with hyponatremia.
The administration of estrogens at high doses, streptozocin, azacitidine and
suramin may induce hypophosphatemia. Finally, the drug-related tumor lysis
syndrome is associated with hyperphosphatemia, hyperkalemia and hypocalcemia.
The prevention of electrolyte derangements may lead to reduction of adverse
events during the administration of anticancer drugs. INTRODUCTION: Tenofovir disoproxil fumarate (TDF) -containing regimens have been
associated with nephrotoxicity and hypophosphatemia in HIV-infected patients.
The objective of this study was to assess the possible risk factors for
hypophosphatemia and evaluate the relationship between fractional excretion of
filtered phosphate (FePi) and hypophosphatemia in TDF users.
PATIENT AND METHODS: Patients were enrolled in a prospective cohort study
between January 2011 and December 2014. We classified experienced HIV-infected
patients (individuals maintained on antiretroviral therapy (ART) for 6 months or
more) and naïve patients into 3 treatment groups: TDF-containing ART (group 1),
non-TDF-containing ART (never received TDF or had not received TDF in the past 6
months; group 2) and naive to antiretroviral therapy (group 3). Specimens from
each individual were assessed for serum phosphate, serum creatinine, urine
phosphate, and urine creatinine. Multivariable logistic regression was performed
to control for the following variables measured at baseline: eGFR, age, sex,
sexual orientation, injection drug use (IDUs), HIV-RNA viral load, and CD4 cell
count.
RESULTS: The frequency of hypophosphatemia in groups 1, 2, and 3 was 20.2%,
7.2%, and 14.6%, respectively (P = 0.002). FePi above 10% also was significantly
associated with hypophosphatemia (P = 0.003; adjusted odds ratio = 2.54).
Patients with elevated CD4 cell counts (>500 cells/μL) exhibited a lower risk of
hypophosphatemia (P = 0.002; adjusted odds ratio = 0.35).
CONCLUSIONS: Hypophosphatemia is a multifactorial etiology; FePi was confirmed
as a suggested method to predict the risk of hypophosphatemia in TDF users.
Clinical Trial Number: TYGH103011. Phosphate is actively involved in many important biochemical pathways, such as
energy and nucleic acid metabolism, cellular signaling, and bone formation.
Hypophosphatemia, defined as serum phosphate levels below 2.5 mg/dL
(0.81 mmol/L), is frequently observed in the course of treatment with commonly
used drugs, such as diuretics, bisphosphonates, antibiotics, insulin, and
antacids. Furthermore, this undesired effect may complicate the use of several
novel medications, including teriparatide, denosumab, parenteral iron, and
antiviral and antineoplastic agents. This review addresses drug-associated
hypophosphatemia, focusing on underlying mechanisms and the most recent
knowledge on this topic, in order to increase the insight of clinicians, with
reference to early diagnosis and appropriate management. Administration of intravenous ferric carboxymaltose (FCM) for iron-deficient
patients suffering heart failure with reduced ejection fraction (HFrEF) has been
associated with transient hypophosphatemia. We sought to investigate and model
the effect of intravenous FCM on phosphate levels in iron-deficient patients
with HFrEF. In this single-center retrospective study, serum phosphate levels,
recorded for clinical reasons, were collected out to 60 days following
intravenous FCM. Hypophosphatemia was defined as a nadir serum phosphate level
<0.64 mmol/L. This was further categorized as severe (0.4 to <0.64 mmol/L) and
extreme (<0.4 mmol/L). Factors associated with hypophosphatemia and change in
serum phosphate over time were explored. Of 173 patients included, 47 (27%)
experienced hypophosphatemia, 44 (25%) were classified as severe, and 3 (2%)
extreme. Risk of hypophosphatemia was increased for patients with a creatinine
clearance between 60 and <90 mL/min (odds ratio, 2.3; 95% confidence interval,
1.0-5.5), while <60 mL/min was protective. The median time to nadir in patients
who experienced hypophosphatemia was 8 (interquartile range, 4-16) days, with a
return to baseline levels at 6 weeks. Biochemically relevant hypophosphatemia is
common following a single dose of intravenous FCM. The median time to nadir was
8 days, and creatinine clearance may influence phosphate levels following
intravenous FCM. These observations support the need to increase awareness among
clinicians administering intravenous FCM to iron-deficient patients with HFrEF. The purpose of this single-center retrospective study was to determine the
incidence of decreased blood phosphorus levels and hypophosphatemia among
multiple myeloma (MM) patients treated with elotuzumab. Hypophosphatemia, which
is defined as a serum phosphorus concentration < 2.5 mg/dL, leads to
complications ranging from muscle weakness and disorientation to seizures and
heart failure. A total of 23 MM patients receiving care in a clinic specializing
in treatment of MM from July 2018 to March 2020 and treated with an
elotuzumab-containing therapy were evaluated, and 9 were investigated for this
study. Elotuzumab was given at 10 mg/kg weekly for the first two treatment
cycles (28 days/cycle), followed by 10 mg/kg every other week for all subsequent
cycles. Four different elotuzumab combination therapies were administered: 1)
elotuzumab and dexamethasone 2) elotuzumab, lenalidomide and dexamethasone 3)
elotuzumab, pomalidomide and dexamethasone and 4) elotuzumab, carfilzomib,
pomalidomide, and dexamethasone. Phosphorous levels were determined at a median
of every 13 days at intervals ranging from once weekly to once monthly until a
phosphate supplement was prescribed to the patient or when elotuzumab treatment
was discontinued. We found that regardless of elotuzumab combination therapy,
all patients treated showed decreased phosphorus levels after initiating
elotuzumab treatment with reductions ranging from 12.5% to 44.1% below baseline.
Six participants (67%) demonstrated an average serum phosphorus at or below
2.5 mg/dL after starting elotuzumab therapy. This retrospective study suggests
that hypophosphatemia commonly occurs among MM patients receiving
elotuzumab-containing therapies. Additional therapeutic options are needed for relapsed and refractory multiple
myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation
study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range:
50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory
disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib
[50%]). Patients received a median of six cycles (range: 1-74) of panobinostat
(10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg
(pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were
reported (mostly hematological); maximum tolerated dose of panobinostat (primary
endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and
peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of
patients and included decreased neutrophil (45%), platelet (25%) and white blood
cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related
discontinuations or mortality occurred. In evaluable patients (n = 18), overall
response rate was 44%, and clinical benefit rate was 61%. Median duration of
response was 9.2 months; progression-free survival was 7.4 months; overall
survival was not reached. Pano-RVd proved generally well-tolerated and
demonstrated potential to overcome lenalidomide and/or bortezomib resistance. BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy.
Preclinical data suggest greater anticancer effect when mTOR inhibitors are
combined with cytotoxic chemotherapy. We performed a Phase I assessment of the
combination of temsirolimus and capecitabine in patients with advanced solid
tumors.
METHODS: Patients were enrolled in an alternating dose escalation of
temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and
1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the
recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven
patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine
triplet combination safety and efficacy.
RESULTS: Forty-five patients were enrolled and 41 were evaluable for
dose-limiting toxicities (DLTs). The most common adverse events (AEs) were
mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were
hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia,
mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine
1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2 (Q3). Of the 38
patients evaluable for response, one had a partial response (PR) and 19 had
stable disease (SD). The overall disease control rate was 52%. Five of the 20
patients with SD/PR maintained disease control for >6 months.
CONCLUSIONS: The combination of temsirolimus and capecitabine is safe on both a
Q2-week and a Q3-week schedule. The combination demonstrated promising evidence
of disease control in this highly refractory population and could be considered
for testing in disease-specific phase II trials. Contemporary intravenous iron formulations allow administration of high doses of
elemental iron and enable correction of total iron deficit in one or two
infusions. An important but underappreciated complication of certain
formulations is hypophosphatemia caused by increased secretion of the
phosphaturic hormone, fibroblast growth factor 23 (FGF23). The pathophysiology
of FGF23-induced hypophosphatemia due to certain intravenous iron formulations
has been recently investigated in prospective clinical trials. To reach the
correct diagnosis, clinicians must recognize the typical clinical manifestations
of intravenous iron-induced hypophosphatemia and identify a specific pattern of
biochemical changes (hyperphosphaturic hypophosphatemia triggered by high FGF23
that causes low 1,25 (OH)2 vitamin D, hypocalcemia and secondary
hyperparathyroidism). Physicians and patients should be aware of
hypophosphatemia as a common complication of intravenous iron therapy and
monitor serum phosphate concentrations in patients receiving repeated doses of
specific intravenous iron formulations. Symptoms of hypophosphatemia are
associated with severity and duration. Persistent hypophosphatemia can occur
with iron therapy and can cause debilitating diseases including myopathy,
osteomalacia and fractures. This review summarizes the current understanding of
the iron-phosphate axis as well as complications of intravenous iron-induced
hypophosphatemia. |
Is Algenpantucel-L effective for pancreatic cancer? | No. In phase 3 clinical trial Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable pancreatic cancer receiving SOC neoadjuvant chemotherapy and chemoradiation. | BACKGROUND: Despite continued investigation, limited progress has been made in
the adjuvant treatment of resected pancreatic cancer. Novel or targeted
therapies are needed.
METHODS: Multi-institutional, open-label, dose-finding, phase 2 trial evaluating
the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA)
immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant
setting for resected pancreatic cancer (ClinicalTrials.gov identifier,
NCT00569387). The primary outcome was 12-month disease-free survival. Secondary
outcomes included overall survival and toxicity.
RESULTS: Seventy patients were treated with gemcitabine and 5-fluorouracil-based
chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1-14). After
a median follow-up of 21 months, the 12-month disease-free survival was 62 %,
and the 12-month overall survival was 86 %. The most common adverse events were
injection site pain and induration.
CONCLUSIONS: The addition of algenpantucel-L to standard adjuvant therapy for
resected pancreatic cancer may improve survival. A multi-institutional, phase 3
study is ongoing (ClinicalTrials.gov identifier, NCT01072981). OBJECTIVES: To compare the efficacy and safety of algenpantucel-L
[HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined
with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy
and chemoradiation therapy alone in patients with borderline resectable or
locally advanced pancreatic ductal adenocarcinoma (PDAC).
SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit
patients with borderline resectable or locally advanced unresectable PDAC. HAPa
is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered
to express the murine α(1,3)GT gene.
METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients
with borderline resectable or locally advanced unresectable PDAC. Patients
received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel)
followed by chemoradiation (standard group) or the same standard neoadjuvant
regimen combined with HAPa immunotherapy (experimental group). The primary
outcome was overall survival.
RESULTS: Between May 2013 and December 2015, 303 patients were randomized from
32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8)
months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the
experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals
0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the
standard group and 12.4 months in the experimental group (HR 1.33, 95%
confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events
occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142
patients (81%) in the experimental group (P > 0.05).
CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients
with borderline resectable or locally advanced unresectable PDAC receiving SOC
neoadjuvant chemotherapy and chemoradiation.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432. |
Is Mical an oxidoreductase? | Yes,
MICAL is an oxidoreductase | |
What is the most frequent evolution (next stage) when Aortic intramural hematoma (IMH) is not treated? | Aortic intramural hematoma (IMH) evolves very dynamically in the short-term to regression, dissection, or aortic rupture | BACKGROUND: It has been reported that early surgery should be required for
patients with type A aortic intramural hematoma (IMH) because it tends to
develop classic aortic dissection or rupture. However, the anatomic features of
type A IMH that develops dissection or rupture are unknown. The purpose of this
study was to investigate the predictors of progression or regression of type A
IMH by computed tomography (CT).
METHODS AND RESULTS: Twenty-two consecutive patients with type A IMH were
studied by serial CT images. Aortic diameter and aortic wall thickness of the
ascending aorta were estimated in CT images at 3 levels on admission and at
follow-up (mean 37 days). We defined patients who showed increased maximum
aortic wall thickness in the follow-up CT (n=9) or died of rupture (n=1) as the
progression group (n=10). The other 12 patients, who all showed decreased
maximum wall thickness, were categorized as the regression group. In the
progression group, the maximum aortic diameter in the initial CT was
significantly greater than that in the regression group (55+/-6 vs 47+/-3 mm,
P=0.001). A Cox regression analysis revealed that the maximum aortic diameter
was the strongest predictor for progression of type A IMH. We considered the
optimal cutoff value to be 50 mm for the maximum aortic diameter to predict
progression (positive predictive value 83%, negative predictive value 100%).
CONCLUSIONS: Maximum aortic diameter estimated by the initial CT images is
predictive for progression of type A IMH. BACKGROUND: Aortic intramural hematoma (IMH) evolves very dynamically in the
short-term to regression, dissection, or aortic rupture. The aim of the present
study was to assess the long-term clinical and morphological evolution of
medically treated IMH.
METHODS AND RESULTS: Fifty of 68 consecutive patients with aortic IMH monitored
clinically and by imaging techniques at 3, 6, and 12 months and annually
thereafter were prospectively studied. Mean follow-up was 45+/-31 months. In the
first 6 months, total IMH regression was observed in 14 and progression to
aortic dissection in 18 patients; in 14 of these, the dissection was localized,
and 12 later developed pseudoaneurysm. At the end of follow-up, the IMH had
regressed completely without dilatation in 17 patients (34%), progressed to
classical dissection in 6 (12%), evolved to fusiform aneurysm in 11 (22%),
evolved to saccular aneurysm in 4 (8%), and evolved to pseudoaneurysm in 12
(24%). Evolution to dissection was related to echolucency (P<0.02) and to
longitudinal extension of IMH (P<0.01). Multivariate analysis showed an
independent association between regression and smaller maximum aortic diameter
and between aneurysm formation and atherosclerotic ulcerated plaque and absence
of echolucent areas in IMH.
CONCLUSIONS: The most frequent long-term evolution of IMH is to aortic aneurysm
or pseudoaneurysm. Complete regression without changes in aorta size is observed
in one third of cases, and progression to classical dissection is less common. A
normal aortic diameter in the acute phase is the best predictor of IMH
regression without complications, and absence of echolucent areas and
atherosclerotic ulcerated plaque are associated with evolution to aortic
aneurysm. This review article is written so as to present the pathophysiology, the
symptomatology and the ways of diagnosis and treatment of a rather rare aortic
disease called Intra-Mural Haematoma (IMH). Intramural haematoma is a quite
uncommon but potentially lethal aortic disease that can strike as a primary
occurrence in hypertensive and atherosclerotic patients to whom there is
spontaneous bleeding from vasa vasorum into the aortic wall (media) or less
frequently, as the evolution of a penetrating atherosclerotic ulcer (PAU). IMH
displays a typical of dissection progress, and could be considered as a
precursor of classic aortic dissection. IMH enfeebles the aortic wall and may
progress to either outward rupture of the aorta or inward disruption of the
intima layer, which ultimately results in aortic dissection. Chest and back
acute penetrating pain is the most commonly noticed symptom at patients with
IMH. Apart from a transesophageal echocardiography (TEE), a tomographic imaging
such as a chest computed tomography (CT), a magnetic resoce (MRI) and most
lately a multy detector computed tomography (MDCT) can ensure a quick and
accurate diagnosis of IMH. Similar to type A and B aortic dissection, surgery is
indicated at patients with type-A IMH, as well as at patients with a persistent
and/or recurrent pain. For any other patient (with type-B IMH without an
incessant pain and/or without complications), medical treatment is suggested, as
applied in the case of aortic dissection. The outcome of IMH in ascending aorta
(type A) appears favourable after immediate (emergent or urgent) surgical
intervention, but according to international bibliography patients with IMH of
the descending aorta (type B) show similar mortality rates to those being
subjected to conservative medical or surgical treatment. Endovascular surgery
and stent-graft placement is currently indicated in type B IMH. Aortic intramural hematoma (IMH) is an acute aortic syndrome characterized by
bleeding into the media of the aortic wall without intimal disruption or the
classic flap formation. Its natural history is variable and still poorly
understood, so strategies for therapeutic management are not fully established.
In some cases there is partial or complete regression of the hematoma under
medical treatment, but most progress to dissection, aneurysmal dilatation or
aortic rupture. The authors present the case of a 44-year-old hypertensive male
patient admitted with a diagnosis of IMH of the descending aorta. Despite
initial symptom resolution and optimal medical therapy, the IMH evolved to a
pseudoaneurysm, which was successfully treated by an endovascular approach. Thoracic aortic dissection (AD) is one of the most common aortic emergencies. It
can be fatal if not promptly diagnosed and treated. Intramural hematoma (IMH) of
the aorta is recognized as distinct from classic (double-barreled) AD. IMH also
frequently leads to aortic emergency, which can be fatal unless rapidly
diagnosed and treated. Recently, thoracic endovascular aortic repair (TEVAR) has
been used for the treatment of complications caused by AD. TEVAR is also a
viable option for the treatment of complicated IHM. In this article, we review
the details of TEVAR as treatment options for AD and IMH, including the
indications for TEVAR, imaging, and follow-up. INTRODUCTION: Aortic intramural hematoma (IMH) is described as "dissection
without intimal tear" due to rupture of vasa vasorum, which results in bleeding
within the tunica media in the absence of intimal disruption or blood flow
communication. The aim of our study is to validate perioperative evidence of
intimal entry tear in patients with IMH and to suggest that this entity may
represent a part of a disease and not a separate disease.
PRESENTATION OF CASES: We report two patients admitted to our institution with
sudden onset thoracic pain. A CT scan showed an aneurysm of the ascending aorta
complicated by type A IMH. The patients underwent open operation. Surgical
set-up has included right axillary artery as arterial inflow, no cross-clamp
before hypothermic circulatory arrest and Kazui protocol for selective antegrade
cerebral perfusion. We found no evidence of intimal flap, but we identified an
intimal tear in both patients. A hemiarch procedure associated with root
replacement, using two-grafts techniques was performed in both cases. The
postoperative course was uneventful and the patients were discharged home.
DISCUSSION: Recent data are emerging from the radiologic literature about the
evidence of intimal lesions in IMH, but surgical reports are scant. The evidence
of intimal tears contributes to consider as questionable the etiological role of
vasa vasorum and it may justify updates in the management.
CONCLUSION: We consider that IMH may represent a part of a disease (aortic
dissection), depicted by radiological images in a specific single instant of its
clinical evolution. BACKGROUND: Intramural hematomas (IMHs) are reported to dynamically evolve into
different clinical outcomes ranging from regression to aortic rupture, but no
practice guidelines are available in China.
OBJECTIVE: To determine the evolution of IMHs after long-term follow-up and to
identify the predictive factors of IMH outcomes in the Chinese population.
METHODS: A total of 123 IMH patients with clinical and imaging follow-up data
were retrospectively studied. The primary endpoints were aortic disease-related
death, aortic dissection, penetrating aortic ulcer (PAU), thickening of the
aortic hematoma and aortic complications requiring surgical or endovascular
treatment.
RESULTS: All 123 IMH patients were monitored clinically. The follow-up duration
ranged from 1.4 to 107 months (median, 20 months). Thirty-nine patients had type
A IMH, and 84 had type B. The multivariate analysis showed that a baseline
MAD ≥ 44.75 mm (2.9% vs 61.4%, P < 0.001) and acute PAUs (2.9% vs 34.1%,
P = 0.008) were independent predictors of aorta-related events.
CONCLUSIONS: Medication and short-term imaging are recommended for Chinese IMH
patients with a hematoma thickness < 10.45 mm and a baseline MAD < 44.75 mm.
Rigorous medical observation should also be performed during the acute phase of
IMH. Within the spectrum of acute aortic syndromes, intramural hematoma (IMH) is a
distinct lesion that is characterized by crescentic or circumferential
thickening of the aortic wall in the absence of an intimal defect. The reported
incidence of IMH among all type A acute aortic syndromes ranges from 3.5% to
28.3%. As compared with acute aortic dissection, IMH is a disease of the
elderly, and it tends to have reduced rates of malperfusion syndromes, aortic
insufficiency, and root dilation, yet also tends to have increased rates of
pericardial effusion, cardiac tamponade, and periaortic hematoma. With respect
to natural history, IMH may progress to classic dissection, frank rupture, or
aneurysmal dilation; yet, IMH may also regress and be completely resorbed.
However, studies disagree over the rates of progression or regression; as such,
few studies agree on the short-term and long-term prognosis associated with IMH.
American and European guidelines advocate emergent surgery for all acutely
presenting type A IMH. At a minimum, supracoronary replacement of the aorta with
hemiarch reconstruction is the preferred extent of operative repair to reduce
rates of long-term reintervention for disease progression. However, valve and/or
root procedures may be necessary proximally, while total arch reconstruction or
hybrid procedures for the descending aorta may be necessary distally. Much
remains unknown for IMH, including the ideal extent of aortic repair,
risk-stratification for elderly patients, and the optimal treatment paradigm for
stable, uncomplicated IMH. As such, IMH remains a diagnostic and therapeutic
challenge for the cardiovascular surgeon. Type B acute aortic dissection (AAD) and intramural hematoma (IMH) can both
present as potentially catastrophic lesions of the descending aorta. IMH is
distinguished from AAD by the absence of an intimal tear and flap. With
short-term outcomes being similar to type B AAD, IMH is treated identically to
AAD in the corresponding segment of the aorta. While all patients with any acute
aortic syndrome of the descending aorta receive prompt anti-impulse therapy,
thoracic endovascular aortic repair (TEVAR) is reserved for patients presenting
with certain complications, namely malperfusion, rupture, or periaortic
hematoma. Technical aspects of TEVAR for IMH include maximal endograft
oversizing of 10% with 20 mm landing zones of the healthy aorta,
revascularization of the left subclavian artery when covered, use of
cerebrospinal fluid drainage with extensive coverage, and restoration of branch
vessel perfusion. With respect to disease evolution, IMH may progress to classic
AD, frank rupture, or aneurysmal dilation; yet, IMH may also regress and be
completely resorbed. However, since the natural history of IMH is unpredictable,
TEVAR is being used more aggressively to improve long-term survival, rates of
secondary reintervention, and positive aortic remodeling. Much remains unknown
for acute type B IMH, including the use of prophylactic TEVAR for stable
uncomplicated presentations, as well as the optimal timing of intervention and
certain technical aspects of TEVAR. As such, IMH remains a diagnostic and
therapeutic challenge for cardiovascular surgeons. |
Which drugs are included in the Qtern pill? | Qtern pill includes saxagliptin and dapagliflozin. It is indicated in the EU for the improvement of glycaemic control in adults with type 2 diabetes mellitus. | OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and
place in therapy of the fixed-dose combination (FDC) product, QTERN
(dapagliflozin/saxagliptin) tablets.
DATA SOURCES: Searches of MEDLINE (1946 to July 1, 2017) were conducted using
the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were
obtained from the prescribing information, the product dossier, and
Clinicaltrials.gov .
STUDY SELECTION AND DATA EXTRACTION: All English language articles related to
pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy
in human subjects were reviewed.
DATA SYNTHESIS: The pharmacokinetics of saxagliptin and dapagliflozin were not
affected significantly when administered as an FDC product. Saxagliptin may
suppress the increased secretion of glucagon associated with dapagliflozin. The
combination dapagliflozin/saxagliptin has been studied as add-on therapy to
metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The
difference in hemoglobin A1C (A1C) between saxagliptin + dapagliflozin +
metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81
to -0.37, P < 0.0001), and the difference between triple therapy and
dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The
combination was well tolerated when added to metformin.
CONCLUSION: QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option
for patients with T2DM not controlled on metformin, but cost, insurance
coverage, and a lackluster reduction in A1C will likely limit its use until more
data regarding its effects on complications of diabetes and cardiovascular
outcomes become available. Author information:
(1)Geoffrey Mospan is an assistant professor of pharmacy at Wingate University
School of Pharmacy, Wingate, N.C. Cortney Mospan is an assistant professor of
pharmacy at Wingate University School of Pharmacy, Wingate, N.C. Shayna Vance is
a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate,
N.C. Alyssa Bradshaw is a 4th year PharmD candidate at Wingate University School
of Pharmacy, Wingate, N.C. Kalyn Meosky is a 4th year PharmD candidate at
Wingate University School of Pharmacy, Wingate, N.C. Kirklin Bowles is a 4th
year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C. OBJECTIVES: The fixed dose combination of saxagliptin and dapagliflozin is a
recently approved antidiabetic medication. It is marketed under the brand name
Qtern. The aim of this study was to develop a simple, rapid, sensitive, and
validated isocratic reversed phase-high performance liquid chromatography
(RP-HPLC) method for the simultaneous estimation of saxagliptin and
dapagliflozin in human plasma using linagliptin as internal standard as per
US-Food and Drug Administration guidelines.
MATERIALS AND METHODS: The method was performed on a Waters 2695 HPLC equipped
with a quaternary pump. The analyte separation was achieved using an Eclipse XDB
C18 (150 × 4.6 mm × 5 µm) column with a mobile phase consisting of 0.1% ortho
phosphoric acid and acetonitrile (50:50) with pH adjusted to 5.0 at 1 mL/min
flow rate.
RESULTS: The analyte was detected at 254 nm. The retention time of the internal
standard, saxagliptin, and dapagliflozin was 2.746, 5.173, and 7.218 min,
respectively. The peaks were found to be free of interference. The method was
validated over a dynamic linear range of 0.01 to 0.5 μg/mL and 0.05 to 2 μg/mL
for saxagliptin and dapagliflozin, respectively, with a correlation coefficient
of 0.998. The precision and accuracy of samples of six replicate measurements at
lower limits of quantification level were within the limits. The analytes were
found to be stable in human plasma at -28°C for 37 days.
CONCLUSION: The stability, sensitivity, specificity, and reproducibility of this
method make it appropriate for the determination of saxagliptin and
dapagliflozin in human plasma. |
List SLE-related autoantibodies. | Serum autoantibodies analyzed included lupus anticoagulant (LAC), anticardiolipine (aCL) IgG and IgM (first 3 also grouped into antiphospholipid autoantibodies (aPL)), anti-dsDNA, anti-SSA, anti-SSB, anti-RNP, and anti-Sm (the latter 5 grouped into SLE-related autoantibodies).
Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. | The association of anti-nuclear antigen (ANA) and anti-cardiolipin (CL)
antibodies is often observed during systemic lupus erythematosus (SLE) or the
primary anti-phospholipid syndrome, thereby raising the possibility of a
relationship between these two autoantibody populations. To determine whether
ANA and anti-CL antibodies can overlap, we derived, from a male (NZW x BXSB)F1
mouse, 14 hybridomas selected based on their capacities to react with CL and to
label HEp-2 cell nuclei. Four of these anti-CL were IgG and bound to CL and
phosphatidylserine in a cofactor-dependent manner and reacted strongly with
nucleosomes. Variable region sequence analysis indicated that these four
monoclonal antibodies (mAb) were derived from three independent B cell clones
that used recurrent heavy and/or light chain immunoglobulin rearrangements, as
assessed by comparison with each other and prototypic anti-CL mAb previously
derived from different lupus mouse strains. These results indicate that anti-CL
mAb can have overlapping cross-reactivities with nucleosomes, thereby defining a
new category of SLE-related autoantibodies characterized by their capacities to
recognize distinct supramolecular complexes, formed by the association of an
anionic structure and a protein, that exert a strong selective pressure on
autoreactive B cell clones. Objective: To analyze the clinical significance of anti- ubiquitin C-terminal
hydrolase L1(UCHL-1)autoantibodies in neuropsychiatric systemic lupus
erythematosus (NPSLE). Methods: Autoantibodies in cerebrospinal fluid specimen
of 56 inpatients were detected by using indirect enzyme-linked immunosorbent
assay (ELISA) and the fullmedical history and clinical manifestations were
analyzed retrospectively. Results: The levels of anti-UCHL-1 autoantibodies in
NPSLE group were significant higher than that in other controls (P<0.05). The
positive rate of anti-UCHL-1 autoantibodies in NPSLE group was 23.7% (9/38),
which was higher than that in the control groups (0%). A significant difference
of anti-UCHL-1 autoantibodies was observed in the patients with blood system
involvement (P=0.012). The positive rates of anti-UCHL autoantibodies in the
patients with negative SLE related autoantibodies including AnuA, anti-dsDNA,
Acl, anti-nRNP, anti-rRNP and anti-Smantibody negative were 41.7%, 29.4%, 29.2%,
25.9%, 25.0%, 25.0%, respectively.The levels of anti-UCHL-1 autoantibodies had a
positive correlation with 24-hours proteinuria (r=0.361, P=0.039). Conclusion:
Anti-UCHL-1 autoantibodies had promising value in the diagnosis of
neuropsychiatric systemic lupus erythematosus. Systemic lupus erythematosus (SLE) is a common autoimmune disease. Many
autoantibodies are closely associated with SLE. However, the specific epitopes
recognized and bound by these autoantibodies are still unclear. This study
screened the binding epitopes of SLE-related autoantibodies using a
high-throughput screening method. Epitope prediction on 12 SLE-related
autoantigens was performed using the Immune Epitope Database and Analysis
Resource (IEDB) software. The predicted epitopes were synthesized into peptides
and developed into a peptide array. Serum IgG from 50 SLE patients and 25
healthy controls was detected using the peptide array. The results were then
validated using an enzyme-linked immunosorbent assay (ELISA). The diagnostic
efficiency of each epitope was analyzed using a ROC curve. Seventy-three
potential epitopes were screened for using the IEDB software after the epitopes
on the 12 SLE-related autoantigens were analyzed. Peptide array screening
revealed that the levels of the autoantibodies recognized and bound by 4 peptide
antigens were significantly upregulated in the serum of SLE patients (P < 0.05).
The ELISA results showed that the 4 antigens with significantly increased serum
autoantibodies levels in SLE patients were acidic ribosomal phosphoprotein
(P0)-4, acidic ribosomal phosphoprotein (P0)-11, DNA topoisomerase 1 (full
length)-1, and U1-SnRNP 68/70 KDa-1 (P < 0.05), and the areas under the ROC
curve for diagnosing SLE on the basis of these peptides were 0.91, 0.90, 0.93,
and 0.91, respectively. Many autoantibodies specifically expressed in the serum
of patients with SLE can be detected by specific peptide fragments and may be
used as markers in clinical auxiliary diagnoses. OBJECTIVE: Clinical diagnosis of SLE is currently challenging due to its
heterogeneity. Many autoantibodies are associated with SLE and are considered
potential diagnostic markers, but systematic screening and validation of such
autoantibodies is lacking. This study aimed to systematically discover new
autoantibodies that may be good biomarkers for use in SLE diagnosis.
METHODS: Sera from 15 SLE patients and 5 healthy volunteers were analysed using
human proteome microarrays to identify candidate SLE-related autoantibodies. The
results were validated by screening of sera from 107 SLE patients, 94 healthy
volunteers and 60 disease controls using focussed arrays comprised of
autoantigens corresponding to the identified candidate antibodies. Logistic
regression was used to derive and validate autoantibody panels that can
discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE
patients and 461 controls was performed to validate one of the newly discovered
autoantibodies.
RESULTS: A total of 31, 11 and 18 autoantibodies were identified to be expressed
at significantly higher levels in the SLE group than in the healthy volunteers,
disease controls and healthy volunteers plus disease control groups,
respectively, with 25, 7 and 13 of these differentially expressed autoantibodies
being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC
and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were
selected. Performance of the newly discovered anti-MAK16 autoantibody was
confirmed by ELISA. Some associations were seen with clinical characteristics of
SLE patients, such as disease activity with the level of anti-PARP1 and rash
with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A.
CONCLUSION: The combined autoantibody panels identified here show promise for
the diagnosis of SLE and for differential diagnosis of other major rheumatic
immune diseases. |
What is nephropathic cystinosis? | Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by abnormal accumulation of intracellular cystine in various tissues including the brain, kidneys, bones, and eyes. | Nephropathic cystinosis is an autosomal recessive inborn error of metabolism
characterized by the lysosomal storage of the disulphide amino acid cystine. It
produces a variety of clinical manifestations including failure to thrive, the
renal Fanconi syndrome, eye findings, and end-stage renal disease. A variety of
phenotypes are known; however, the molecular defect underlying any of the forms
has not yet been identified. Therapy of cystinosis with cysteamine averts the
otherwise inevitable renal failure, but systemic therapy does not improve the
corneal keratopathy. A number of presentations in this review detail approaches
to gene identification, systemic therapy with cysteamine, measurement of
cystine, and pathophysiological effects at the cellular and clinical level. Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused
by a defect in the transport of cystine across the lysosomal membrane and
characterized by early onset of renal proximal tubular dysfunction. Late-onset
cystinosis, a rarer form of the disorder, is characterized by onset of symptoms
between 12 and 15 years of age. We previously characterized the cystinosis gene,
CTNS, and identified pathogenic mutations in patients with infantile
nephropathic cystinosis, including a common, approximately 65 kb deletion which
encompasses exons 1-10. Structure predictions suggested that the gene product,
cystinosin, is a novel integral lysosomal membrane protein. We now examine the
predicted effect of mutations on this model of cystinosin. In this study, we
screened patients with infantile nephropathic cystinosis, those with late-onset
cystinosis and patients whose phenotype does not fit the classical definitions.
We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25
patients with infantile nephropathic cystinosis, 12 have two severely truncating
mutations, which is consistent with a loss of functional protein, and 13 have
missense or in-frame deletions, which would result in disruption of
transmembrane domains and loss of protein function. Mutations found in two
late-onset patients affect functionally unimportant regions of cystinosin, which
accounts for their milder phenotype. For three patients, the age of onset of
cystinosis was <7 years but the course of the disease was milder than the
infantile nephropathic form. This suggests that the missense mutations found in
these individuals allow production of functional protein and may also indicate
regions of cystinosin which are not functionally important. Ocular nonnephropathic cystinosis, a variant of the classic nephropathic type of
cystinosis, is an autosomal recessive lysosomal storage disorder characterized
by photophobia due to corneal cystine crystals but absence of renal disease. We
determined the molecular basis for ocular cystinosis in four individuals. All
had mutations in the cystinosis gene CTNS, indicating that ocular cystinosis is
allelic with classic nephropathic cystinosis. The ocular cystinosis patients
each had one severe mutation and one mild mutation, the latter consisting of
either a 928 G-->A (G197R) mutation or an IVS10-3 C-->G splicing mutation
resulting in the insertion of 182 bp of IVS10 into the CTNS mRNA. The mild
mutations appear to allow for residual CTNS mRNA production, significant amounts
of lysosomal cystine transport, and lower levels of cellular cystine compared
with those in nephropathic cystinosis. The lack of kidney involvement in ocular
cystinosis may be explained by two different mechanisms. On the one hand (e.g.
the G197R mutation), significant residual cystinosin activity may be present in
every tissue. On the other hand (e.g. the IVS 10-3 C-->G mutation), substantial
cystinosin activity may exist in the kidney because of that tissue's specific
expression of factors that promote splicing of a normal CTNS transcript. Each of
these mechanisms could result in minimally reduced lysosomal cystine transport
in the kidneys. Nephropathic cystinosis is an autosomal recessive disorder caused by the
defective transport of cystine out of lysosomes. Recently, the causative gene
(CTNS) was identified and presumed to encode an integral membrane protein called
cystinosin. Many of the disease-associated mutations in CTNS are deletions,
including one >55 kb in size that represents the most common cystinosis allele
encountered to date. In an effort to determine the precise genomic organization
of CTNS and to gain sequence-based insight about the DNA within and flanking
cystinosis-associated deletions, we mapped and sequenced the region of human
chromosome 17p13 encompassing CTNS. Specifically, a bacterial artificial
chromosome (BAC)-based physical map spanning CTNS was constructed by
sequence-tagged site (STS)-content mapping. The resulting BAC contig provided
the relative order of 43 STSs. Two overlapping BACs, which together contain all
of the CTNS exons as well as extensive amounts of flanking DNA, were selected
and subjected to shotgun sequencing. A total of 200,237 bp of contiguous,
high-accuracy sequence was generated. Analysis of the resulting data revealed a
number of interesting features about this genomic region, including the
long-range organization of CTNS, insight about the breakpoints and intervening
DNA associated with the common cystinosis-causing deletion, and structural
information about five genes neighboring CTNS (human ortholog of rat vanilloid
receptor subtype 1 gene, CARKL, TIP-1, P2X5, and HUMINAE). In particular,
sequence analysis detected the presence of a novel gene (CARKL) residing within
the most common cystinosis-causing deletion. This gene encodes a previously
unknown protein that is predicted to function as a carbohydrate kinase.
Interestingly, both CTNS and CARKL are absent in nearly half of all cystinosis
patients (i.e., those homozygous for the common deletion). [The sequence data
described in this paper have been submitted to the GenBank data library under
accession nos. AF168787 and AF163573.] The autosomal recessive lysosomal storage disorder, nephropathic cystinosis is
characterized by impaired transport of free cystine out of lysosomes. The gene
responsible for cystinosis, CTNS, consists of 12 exons and encodes a 55 kDa
putative lysosomal membrane protein, called cystinosin. Up to now more than 55
different CTNS mutations have been described in cystinosis. We have analyzed the
mutation pattern in a population of 40 cystinosis patients from 35 families of
German and Swiss origin. CTNS mutations in 68 out of 70 alleles were identified.
The common 57-kb deletion accounted for 65% of the alleles. In five patients we
found a known GACT deletion at position 18-21. In two patients we identified a
nucleotide substitution at codon 339 and one patient showed a CG insertion at
position 697-698. In five patients we observed a G insertion at position
926-927. Moreover, five novel mutations including two deletions involving exon 3
(61-61+2delGGT) and exon 6 (280delG), two insertions in exon 6 (292-293insA) and
exon 7 (684insCACTT) and one nucleotide substitution in exon 11 (923G>T) have
been identified. These data provide a basis for routine molecular diagnosis of
cystinosis in the central European population, especially in cystinosis patients
of German and Swiss origin. BACKGROUND: Nephropathic cystinosis is characterized by an accumulation of
cystine crystals within most body tissues. Renal transplantation and oral
cysteamine have improved the general prognosis of the disease, and ocular
manifestations are now the most common complication. This long-term follow-up
study describes the sequence of ocular manifestations in patients with
nephropathic cystinosis treated with oral and topical cysteamine.
METHODS: Data were recorded for all patients with cystinosis examined between
1980 and 2000. For each patient, photophobia and visual acuity were evaluated
and slit-lamp and fundus examinations were performed. For some patients, an
electroretinogram was also performed.
RESULTS: Twenty-nine patients were observed during this period. They received
oral and topical cysteamine. Photophobia and loss of visual acuity generally
began by 10 years of age but were severe only after 15 years of age. Peripheral
corneal epithelial infiltration appeared in the first few years of life.
Infiltration evolved toward the depth and center of the cornea during the second
decade of life. Retinopathy was present in 51.7% of the patients, with 3 cases
of maculopathy and 3 cases of flattening on electroretinogram.
CONCLUSIONS: Photophobia and corneal infiltration, although generally severe
after 15 years of age, could be treated with topical cysteamine and corneal
transplantation. Retinal infiltration, previously described as frequent and
potentially blinding, is currently observed in only half of these patients, with
mild visual impairment. This could be related to the treatment with oral
cysteamine reaching the retinal vascularization. Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in
which intracellular cystine accumulates due to impaired transport out of
lysosomes. The clinical manifestations include renal tubular Fanconi syndrome in
the 1st year of life, with hypophosphatemic rickets, hypokalemia, polyuria,
dehydration and acidosis, growth retardation, hypothyroidism, photophobia, renal
glomerular deterioration by 10 years of age, and late complications such as
myopathy, pancreatic insufficiency, and retinal blindnesss. The cystinosis gene,
CTNS, codes for cystinosin, a 367 amino acid protein with seven transmembrane
domains. More than 50 CTNSmutations have been identified, but approximately 50%
of Northern European patients have a 57257-bp deletion which removes the first
nine exons of CTNS. The mainstay of cystinosis therapy is oral cysteamine
(Cystagon). This aminothiol can lower intracellular cystine content by 95%, and
has proven efficacy in delaying renal glomerular deterioration, enhancing
growth, preventing hypothyroidism, and lowering muscle cystine content. Its
early and diligent use is critical; in one study, for every month of treatment
prior to 3 years of age, 14 months' worth of later renal function were
preserved. Several examples of individual patients treated early and having
preserved renal function and normal growth are available. Newborn screening
using a chip containing cDNA to detect common CTNSmutations may allow diagnosis
and treatment in the first weeks of life.
CONCLUSIONS: Early diagnosis and treatment of nephropathic cystinosis can change
the course of this disease. Nephropathic cystinosis is characterized clinically by generalized proximal
renal tubular dysfunction, renal Fanconi Syndrome and progressive renal failure.
Glomerular-proximal tubule disconnection has been noted in renal biopsies from
patients with nephropathic cystinosis. In vitro studies performed in cystinotic
fibroblasts and renal proximal tubular cells support a role for apoptosis of the
glomerulotubular junction, and we have further extended these studies to human
native cystinotic kidney specimens. We performed semi-quantitative analysis of
tubular density in kidney biopsies from patients with nephropathic cystinosis
and demonstrated a significant reduction (p=0.0003) in the number of proximal
tubules in the kidney tissue of patients with cystinosis compared to normal
kidneys and kidneys with other causes of renal injury; this reduction appears to
be associated with the over-expression of caspase-4. This study provides the
first quantitative evidence of a loss of proximal tubules in nephropathic
cystinosis and suggests a possible role of caspase-4 in the apoptotic loss of
proximal tubular cells. Further work is needed to elucidate if this injury
mechanism may be causative for the progression of renal functional decline in
nephropathic cystinosis. Nephropathic cystinosis is a rare, inherited metabolic disease caused by
functional defects of cystinosin associated with mutations in the CTNS gene. The
mechanisms underlying the phenotypic alterations associated with this disease
are not well known. In this study, gene expression profiles in peripheral blood
of nephropathic cystinosis patients (N = 7) were compared with controls (N = 7)
using microarray technology. In unsupervised hierarchical clustering analysis,
cystinosis samples co-clustered, and 1,604 genes were significantly
differentially expressed between both groups. Gene ontology analysis revealed
that differentially expressed genes in cystinosis were enriched in cell
organelles such as mitochondria, lysosomes, and endoplasmic reticulum (p ≤
0.030). The majority of the differentially regulated genes were involved in
oxidative phosphorylation, apoptosis, mitochondrial dysfunction, endoplasmic
reticulum stress, antigen processing and presentation, B-cell-receptor
signaling, and oxidative stress (p ≤ 0.003). Validation of selected genes
involved in apoptosis and oxidative phosphorylation was performed by
quantitative real-time polymerase chain reaction (PCR). Electron microscopy and
confocal imaging of cystinotic renal proximal tubular epithelial cells further
confirmed anomalies in the cellular organelles and pathways identified by
microarray analysis. Further analysis of these genes and pathways may offer
critical insights into the clinical spectrum of cystinosis patients and
ultimately lead to novel links for targeted therapy. Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in
which intracellular cystine accumulates. It is caused by mutations in the CTNS
gene. Clinical manifestations include renal tubular Fanconi syndrome in the
first year of life, rickets, hypokalaemia, polyuria, dehydration and acidosis,
growth retardation, hypothyroidism, photophobia and renal glomerular
deterioration. Late complications include myopathy, pancreatic insufficiency and
retinal blindness. Skeletal manifestations described in these patients include
failure to thrive, osteomalacia, rickets and short stature. This paper describes
progressive bony abnormalities in three unrelated patients with nephropathic
cystinosis that have not been reported previously. Nephropathic cystinosis, characterized by accumulation of cystine in the
lysosomes, is caused by mutations in CTNS. The molecular and cellular mechanisms
underlying proximal tubular dysfunction and progressive renal failure in
nephropathic cystinosis are largely unclear, and increasing evidence supports
the notion that cystine accumulation alone is not responsible for the end organ
injury in cystinosis. We previously identified clusterin as potentially involved
in nephropathic cystinosis. Here, we studied the expression of clusterin in
renal proximal tubular epithelial cells obtained from patients with nephropathic
cystinosis. The cytoprotective secretory form of clusterin, as evaluated by
Western blot analysis, was low or absent in cystinosis cells compared with
normal primary cells. Confocal microscopy revealed elevated levels of
intracellular clusterin in cystinosis cells. Clusterin in cystinosis cells
localized to the nucleus and cytoplasm and showed a filamentous and punctate
aggresome-like pattern compared with diffuse cytoplasmic staining in normal
cells. In kidney biopsy samples from patients with nephropathic cystinosis,
clusterin protein expression was mainly limited to the proximal tubular cells.
Furthermore, expression of clusterin overlapped with the expression of apoptotic
proteins (apoptosis-inducing factor and cleaved caspase-3) and autophagy
proteins (LC3 II and p62). Silencing of the clusterin gene resulted in a
significant increase in cell viability and attenuation of apoptosis in
cystinosis cells. Results of this study identify clusterin as a pivotal factor
in the cell injury mechanism of nephropathic cystinosis and provide evidence
linking cellular stress and injury to Fanconi syndrome and progressive renal
injury in nephropathic cystinosis. Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations
in the CTNS gene ncoding the lysosomal cystine transporter cystinosin.
Cystinosin deficiency leads to accumulation of cystine in the lysosomes of cells
throughout the body and deregulation of endocytosis, trafficking of
intracellular vesicles and related cell signalling processes. One of the early
features of the disease is renal Fanconi syndrome characterized by polyuria,
proteinuria and urinary loss of various solutes. Later in life, extrarenal
complications become apparent, and decline of kidney function leads to the
development of end-stage renal disease. Modern therapy of the disease is based
on treatment with cystine-lowering drug cysteamine, which helps to postpone the
disease progression and development of extra-renal pathologies, but offers no
cure for the Fanconi syndrome. Besides the improvement of cystine-lowering
therapy based on new formulations of cysteamine, further development of therapy
is necessary. Some steps forward were done in the recent years, including
studies of cell signalling abnormalities in cystinosis and development of stem
cell and gene therapy approaches. OBJECTIVE: Nephropathic cystinosis is an autosomal recessive lysosomal storage
disorder that is characterised by the accumulation of the amino acid cystine in
several body tissues due to a mutation in the CTNS gene, which encodes the
cystinosin protein. The aim of this study was to sequence the coding exons of
the CTNS gene in five different Jordanian families and one family from Sudan
with nephropathic cystinosis.
METHODS: Probands initially presented with Fanconi syndrome symptoms. An eye
examination showed the accumulation of cystine crystals in the cornea by the age
of 2 years, suggesting cystinosis. All of the coding exons and flanking intronic
sequences and the promoter region of the CTNS gene were amplified using
polymerase chain reaction and subjected to sequencing.
RESULTS: None of the probands in this study carried the European 57-kb deletion
in the CTNS gene. Seven variants in the coding and promoter sequence of the CTNS
gene were identified in the probands of this study. Two of these variants were a
CTNS mutation that was previously identified in a heterozygous genotype in two
different patients of European descendant. The two mutations were c.829dupA in
exon 10 and c.890G>A in exon 11. The proband of family 2 was
compound-heterozygous for the two mutations.
CONCLUSION: This study is the first molecular study of infantile nephropathic
cystinosis in Jordan. We successfully identified the causative CTNS mutations in
Jordanian families. The results provide a basis for the early detection of the
disease using molecular tools in a highly consanguineous Jordanian population. Author information:
(1)Department of Pediatrics, Feinberg School of Medicine, Northwestern
University, Chicago, Illinois, USA; Division of Kidney Diseases, Department of
Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago,
Illinois, USA. Electronic address: [email protected].
(2)Department of Pediatrics, University of California, San Diego, La Jolla,
California, USA.
(3)Department of Pediatrics, Division of Pediatric Nephrology, Robert Debré
University Hospital, Paris, France.
(4)Department of Nephrology and Urology, Istituto di Ricovero e Cura a Carattere
Scientifico Bambino Gesù Children's Hospital, Rome, Italy.
(5)Department of Pediatrics, McGill University, Montreal Children's Hospital,
Montreal, Québec, Canada.
(6)Department of Nephrology, Queen Elizabeth Hospital, Birmingham, UK.
(7)Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta,
Canada.
(8)University Paris Descartes, Paris, France; Department of Biochemistry B,
Necker-Enfants Malades Hospital, Paris, France.
(9)Department of Nephrology-Transplantation, Necker Hospital, Assistance
Publique Hôpitaux de Paris, Paris Descartes University, Paris, France.
(10)Department of Pediatrics, Center of Pediatric Nephrology and
Transplantation, Cairo University, Cairo, Egypt.
(11)Department of Pediatric Genetics, University of Michigan, Ann Arbor,
Michigan, USA.
(12)Department of Pediatric Nephrology, University Hospitals Leuven, Belgium;
Department of Development and Regeneration, Katholieke Universiteit Leuven,
Belgium. Electronic address: [email protected]. Nephropathic cystinosis is an autosomal recessive lysosomal disease in which
cystine cannot exit the lysosome to complete its degradation in the cytoplasm,
thus accumulating in tissues. Some patients develop a distal myopathy involving
mainly hand muscles. Myopathology descriptions from only 5 patients are
available in the literature. We present a comprehensive clinical, pathological
and genetic description of 3 patients from 2 families with nephropathic
cystinosis. Intrafamiliar variability was detected in one family in which one
sibling developed a severe distal myopathy while the other sibling did not show
any signs of skeletal muscle involvement. One of the patients was on treatment
with Cysteamine for over 12 years but still developed the usual complications of
nephropathic cystinosis in his twenties. Novel pathological findings consisting
in sarcoplasmic deposits reactive for slow myosin were identified. Three
previously known and one novel mutation are reported. Nephropathic cystinosis
should be included in the differential diagnosis of distal myopathies in those
with early renal failure. Novel clinical and pathological features are reported
here contributing to the characterization of the muscle involvement in
nephropathic cystinosis. BACKGROUND AND OBJECTIVES: Infantile nephropathic cystinosis is a severe disease
that occurs due to mutations in the cystinosis gene, and it is characterized by
progressive dysfunction of multiple organs; >100 cystinosis gene mutations have
been identified in multiple populations. Our study aimed to identify the
clinical characteristics and spectrum of cystinosis gene mutations in Turkish
pediatric patients with cystinosis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified the clinical
characteristics and spectrum of cystinosis gene mutations in Turkish patients
with cystinosis in a multicenter registry that was established for data
collection. The data were extracted from this registry and analyzed.
RESULTS: In total, 136 patients (75 men and 61 women) were enrolled in the
study. The most common clinical findings were growth retardation, polyuria, and
loss of appetite. None of the patients had the 57-kb deletion, but seven novel
mutations were identified. The most common mutations identified were c.681G>A
(p.Glu227Glu; 31%), c.1015G>A (p.Gly339Arg; 22%), and c.18_21 del
(p.Thr7Phefs*7; 14%). These mutations were associated with earlier age of
disease onset than the other mutations. To understand the effects of these
allelic variants on clinical progression, the mutations were categorized into
two major groups (missense versus deletion/duplication/splice site). Although
patients with missense mutations had a better eGFR at the last follow-up visit,
the difference was not significant. Patients in whom treatment began at age <2
years old had later onset of ESRD (P=0.02). Time to ESRD did not differ between
the patients with group 1 and group 2 mutations.
CONCLUSIONS: The most common cystinosis gene mutations identified in Turkey were
c.681G>A (p.Glu227Glu), c.1015G>A (p.Gly339Arg), and c.18_21 del
(p.Thr7Phefs*7). Patients with less severe cystinosis gene mutations tend to
have better kidney outcome. Nephropatic cystinosis (NC) is a rare disease associated with pathogenic
variants in the CTNS gene, with a common variant that consists of a
57kb-deletion involving CTNS. Patients with NC that are treated with cysteamine
improve their life quality and expectancy. We report a 12-month-old girl with a
poor growth rate since the 4th month of life. She was admitted to the Hospital
with acute kidney injury, severe dehydration and metabolic acidosis. She was
treated with volume restorative and bicarbonate. Proximal tubulopathy and
Fanconi's syndrome was diagnosed. Medical treatment improved renal function that
was stabilized in stage 4 chronic kidney disease (CKD). Since infantile NC was
suspected, CTNS genetic analysis was considered. Genomic DNA was isolated from
peripheral blood to perform PCR for exons 3-12 in CTNS gene and for the specific
57kb-deletion PCR. Afterwards, variant segregation analysis was performed in the
familiar trio. The genetic analysis showed that the patient was homozygous for
the common 57kb-deletion encompassing CTNS that had been inherited from her
asymptomatic heterozygous parents. The molecular confirmation allowed genetic
counselling for parents and facilitated the access to cysteamine. Oral treatment
with cysteamine resulted in improvement of renal function to CKD stage 3. After
16 months of treatment the patient shows metabolic stability and mild recovery
of height. Ophthalmologic follow-up detected ocular cystine crystals 12 months
after diagnosis, starting cysteamine drops. Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present
in the first year of life with renal Fanconi syndrome that evolves to
progressive chronic kidney disease (CKD). Despite the multiple risk factors for
bone disease, the frequency and severity of skeletal disorders in nephropathic
cystinosis have not been described. We performed systematic bone and mineral
evaluations of subjects with cystinosis seen at the NIH (n = 30), including
history and physical examination, serum and urine biochemistries, DXA, vertebral
fracture assessment, skeletal radiographs, and renal ultrasound. Additionally,
histomorphometric analyses are reported on six subjects seen at the UCLA Bone
and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5
to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean
bone mineral density (BMD) Z-scores were decreased in the femoral neck, total
hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present
in 46% of subjects. Twenty-seven percent of subjects reported one or more long
bone fractures. Thirty-two percent of subjects had incidental vertebral
fractures, which were unrelated to transplant status. Long-bone deformity/bowing
was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21%
of evaluated subjects. Risk factors included CKD, phosphate wasting,
hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male
hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy.
Sixty-one percent of the non-transplanted subjects had ultrasonographic evidence
of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed
impaired mineralization in four of six studied subjects. We conclude that
skeletal deformities, decreased bone mass, and vertebral fractures are common
and relevant complications of nephropathic cystinosis, even before renal
transplantation. Efforts to minimize risk factors for skeletal disease include
optimizing mineral metabolism and hormonal status, combined with monitoring for
nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work
and is in the public domain in the USA. Nephropathic cystinosis is a rare autosomal recessive lysosomal disease
characterized by accumulation of pathognomonic cystine crystals in renal and
other tissues of the body. Cystinosis is caused by mutant cystinosin, the
cystine transport protein located in lysosomal membranes, leading to systemic
deposits of cystine and resultant end organ damage. Cystinosis is rarer in
Asians than Caucasians with only a handful of cases reported from India to date.
Due to its extreme rarity and clinically insidious presentation in contrast to
the infantile form, the diagnosis of juvenile nephropathic cystinosis is
frequently delayed or overlooked. Moreover, routine processing and sectioning of
paraffin embedded tissues dissolves cystine crystals, making it difficult to
diagnose this condition on light microscopic examination alone, mandating
electron microscopic (EM) analysis of renal biopsies for an accurate diagnosis
of this condition. We describe a case of juvenile nephropathic cystinosis
presenting with uveitis and photophobia in a 17-year-old Indian male, diagnosed
after EM examination of the patient's renal biopsy for evaluation of nephrotic
syndrome. While highlighting the diagnostic utility of EM, we describe a few
histopathologic clues which can prompt inclusion of EM analysis of renal
biopsies in this setting. BACKGROUND: Deletions or inactivating mutations of the cystinosin gene CTNS lead
to cystine accumulation and crystals at acidic pH in patients with nephropathic
cystinosis, a rare lysosomal storage disease and the main cause of hereditary
renal Fanconi syndrome. Early use of oral cysteamine to prevent cystine
accumulation slows progression of nephropathic cystinosis but it is a demanding
treatment and not a cure. The source of cystine accumulating in kidney proximal
tubular cells and cystine's role in disease progression are unknown.
METHODS: To investigate whether receptor-mediated endocytosis by the
megalin/LRP2 pathway of ultrafiltrated, disulfide-rich plasma proteins could be
a source of cystine in proximal tubular cells, we used a mouse model of
cystinosis in which conditional excision of floxed megalin/LRP2 alleles in
proximal tubular cells of cystinotic mice was achieved by a Cre-LoxP strategy
using Wnt4-CRE. We evaluated mice aged 6-9 months for kidney cystine levels and
crystals; histopathology, with emphasis on swan-neck lesions and
proximal-tubular-cell apoptosis and proliferation (turnover); and
proximal-tubular-cell expression of the major apical transporters
sodium-phosphate cotransporter 2A (NaPi-IIa) and sodium-glucose cotransporter-2
(SGLT-2).
RESULTS: Wnt4-CRE-driven megalin/LRP2 ablation in cystinotic mice efficiently
blocked kidney cystine accumulation, thereby preventing lysosomal deformations
and crystal deposition in proximal tubular cells. Swan-neck lesions were largely
prevented and proximal-tubular-cell turnover was normalized. Apical expression
of the two cotransporters was also preserved.
CONCLUSIONS: These observations support a key role of the megalin/LRP2 pathway
in the progression of nephropathic cystinosis and provide a proof of concept for
the pathway as a therapeutic target. Cystinosis is an autosomal recessive lysosomal storage disorder caused by CTNS
gene mutations. The CTNS gene encodes the protein cystinosin, which transports
free cystine from lysosomes to cytoplasm. In cases of cystinosin deficiency,
free cystine accumulates in lysosomes and forms toxic crystals that lead to
tissue and organ damage. Since CTNS gene mutations were first described, many
variations have been identified that vary according to geographic region,
although the phenotype remains the same. Cystinosis is a hereditary disease that
can be treated with the cystine-depleting agent cysteamine. Cysteamine slows
organ deterioration, but cannot treat renal Fanconi syndrome or prevent eventual
kidney failure; therefore, novel treatment modalities for cystinosis are of
great interest to researchers. The present review aims to highlight the
geographic differences in cystinosis-specifically in terms of its genetic
aspects, clinical features, management, and long-term complications. Cystinosis is a rare autosomal recessive lysosomal storage disorder
characterized by abnormal accumulation of intracellular cystine in various
tissues including the brain, kidneys, bones, and eyes. Infantile nephropathic
cystinosis is the most severe phenotype of cystinosis that has been associated
with a wide spectrum of ocular features. In this report, the author describes a
posterior segment spectral-domain optical coherence tomography (SD-OCT) finding
that has not been previously reported in a case of nephropathic cystinosis. Nephropathic cystinosis is a severe, monogenic systemic disorder that presents
early in life and leads to progressive organ damage, particularly affecting the
kidneys. It is caused by mutations in the CTNS gene, which encodes the lysosomal
transporter cystinosin, resulting in intralysosomal accumulation of cystine.
Recent studies demonstrated that the loss of cystinosin is associated with
disrupted autophagy dynamics, accumulation of distorted mitochondria, and
increased oxidative stress, leading to abnormal proliferation and dysfunction of
kidney cells. We discuss these molecular mechanisms driving nephropathic
cystinosis. Further, we consider how unravelling molecular mechanisms supports
the identification and development of new strategies for cystinosis by the use
of small molecules, biologicals, and genetic rescue of the disease in vitro and
in vivo. Author information:
(1)Department of Pediatric Subspecialties, Division of Nephrology, Bambino Gesù
Children's Hospital-IRCCS, Rome, Italy. Electronic address:
[email protected].
(2)Renal Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust,
London, UK.
(3)Department of Pediatric Nephrology, Children's Hospital RoMed Clinics
Rosenheim, Rosenheim, Germany.
(4)Department of Pediatric Nephrology, Hacettepe University School of Medicine,
Ankara, Turkey.
(5)Department of Pediatric Subspecialties, Division of Nephrology, Bambino Gesù
Children's Hospital-IRCCS, Rome, Italy.
(6)Division of Pediatric Nephrology, Hospital Universitari Vall d' Hebron,
Barcelona, Spain.
(7)Renal Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust,
London, UK; Department of Renal Medicine, University College London, London, UK.
(8)Department of Pediatric Nephrology and Development and Regeneration,
University Hospitals Leuven, Leuven, Belgium.
(9)Department of Pediatrics II, University Hospital Essen, University of
Duisburg-Essen, Essen, Germany.
(10)Department of Paediatric Nephrology, Birmingham Women's and Children's
Hospital NHS Trust, Birmingham, UK.
(11)Department of Pediatric Nephrology, Hacettepe University School of Medicine,
Ankara, Turkey; Nephrogenetic Laboratory, Hacettepe University School of
Medicine, Ankara, Turkey.
(12)Paris Descartes University, Imagine Institute, Inserm U1163, Paris, France;
Adult Nephrology and Transplantation, Centre de Référence des Maladies Rénales
Héréditaires de l'Enfant et de l'Adulte, Necker Hospital, Paris, France.
(13)Department of Pediatric Nephrology, Robert Debré Hospital, University of
Paris, Paris, France.
(14)Department of Paediatric Nephrology, University Hospital of Lille, Lille,
France.
(15)Hospices Civils de Lyon, Centre de Référence Maladies Rénales Rares, Lyon,
France.
(16)Department of Pediatric Nephrology, Pediatric Hepatology and Pediatric
Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
(17)Department of Pediatric Nephrology, Radboud University Medical Center,
Amalia Children's Hospital, Nijmegen, the Netherlands.
(18)Department of Internal Medicine, Radboud University Medical Center,
Nijmegen, the Netherlands.
(19)Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover
Medical School, Hannover, Germany.
(20)Clinical Pathways and Epidemiology Unit, Medical Direction, Bambino Gesù
Children's Hospital-IRCCS, Rome, Italy.
(21)Paris Descartes University, Imagine Institute, Laboratory of Hereditary
Kidney Diseases, INSERM UMR 1163, Paris, France; Department of Genetics, AP-HP,
Hôpital Necker-Enfants Malades, Paris, France.
(22)Division of Nephrology, Cliniques Universitaires Saint-Luc, UCLouvain,
Brussels, Belgium; Mechanisms of Inherited Kidney Disorders Group, University of
Zurich, Zurich, Switzerland.
(23)Pediatric Nephrology, Hôpital Necker-Enfants Malades, Paris University,
Paris, France. |
Which drugs are included in the Contrave pill? | Contrave® is an adjunct pharmacotherapy for obesity that contains bupropion (BUP) and naltrexone (NTX). | In March 2010, Orexigen(R) Therapeutics submitted a new drug application (NDA)
for approval of naltrexone sustained release (SR)/bupropion SR (Contrave(R)) for
the treatment of obesity in the US. The tablet contains naltrexone SR 32 mg and
bupropion SR 360 mg. The drug has been tested in four randomized, double-blind,
placebo-controlled, phase III trials and the co-primary endpoints were met in
each case. This review discusses the key development milestones and clinical
trial program to date. Contrave is an investigational fixed-dose combination drug of naltrexone and
bupropion currently in Phase III clinical trials for the treatment of obesity.
Orexigen Therapeutics, Inc. has demonstrated efficacy of their product and is
currently addressing FDA safety concerns and deciding future actions. Oral naltrexone extended-release/bupropion extended-release (naltrexone
ER/bupropion ER; Contrave(®), Mysimba(™)) is available as an adjunct to a
reduced-calorie diet and increased physical activity in adults with an initial
body mass index (BMI) of ≥ 30 kg/m(2) (i.e. obese) or a BMI of ≥ 27 kg/m(2)
(i.e. overweight) in the presence of at least one bodyweight-related
comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. In
56-week phase III trials in these patient populations, oral naltrexone
ER/bupropion ER 32/360 mg/day was significantly more effective than placebo with
regard to percentage bodyweight reductions from baseline and the proportion of
patients who achieved bodyweight reductions of ≥ 5 and ≥ 10%. Significantly
greater improvements in several cardiometabolic risk factors were also observed
with naltrexone ER/bupropion ER versus placebo, as well as greater improvements
in glycated haemoglobin levels in obese or overweight adults with type 2
diabetes. Naltrexone ER/bupropion ER was generally well tolerated in phase III
trials, with nausea being the most common adverse event. Thus, naltrexone
ER/bupropion ER 32/360 mg/day as an adjunct to a reduced-calorie diet and
increased physical activity, is an effective and well tolerated option for
chronic bodyweight management in obese adults or overweight adults with at least
one bodyweight-related comorbidity. Contrave(®) is a combination of naltrexone hydrochloride extended release and
bupropion hydrochloride extended release for the treatment of obesity, and is
used with lifestyle modification. Its safety and efficacy were assessed in four
randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials
in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies
demonstrated statistically significant and clinically meaningful weight loss
following up to 52 weeks of treatment with naltrexone/bupropion compared with
placebo. The average weight loss from baseline across the four studies was
approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for
weight loss, as well as significant improvements in cardiometabolic markers.
This review focuses on the four studies, their outcomes and the mechanism of
action of Contrave. Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic
Weight Management in Obese Adults. BACKGROUND: We report a case of erythrodermic pustular psoriasis associated with
initiation of bupropion/naltrexone (Contrave®; Orexigen Therapeutics, La Jolla,
CA) in a patient with no history of psoriasis.
CASE REPORT: A 55-year-old woman was transferred to our tertiary medical center
from a community hospital for possible Stevens-Johnson syndrome 3 weeks after
initiation of bupropion/naltrexone. The patient was admitted to the burn unit
for wound treatment and hydration. She received intravenous cyclosporine during
the admission that resulted in acute kidney injury and the therapy was
discontinued. The skin biopsy ruled out Stevens-Johnson syndrome and was more
consistent with generalized pustular psoriasis. After discharge, the patient
followed up with her dermatologist. She was diagnosed with acute generalized and
erythrodermic psoriasis and the patient was restarted on cyclosporine 100 mg
twice a day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Few case
reports of bupropion-induced generalized pustular psoriasis and erythrodermic
psoriasis in patients with a history of psoriasis have been reported. To our
knowledge, acute generalized erythrodermic pustular psoriasis associated with
bupropion/naltrexone has not been reported in a patient without history of
psoriasis. Due to increases in obesity and increases in prescribing of
bupropion/naltrexone SR, health care providers should be aware of this possible
severe adverse reaction. OBJECTIVE: Obesity is now the most prevalent chronic disease in the United
States, which amounts to an estimated $147 billion in health care spending
annually. The Affordable Care Act (ACA) enacted in 2010 included provisions for
private and public health insurance plans that expanded coverage for
lifestyle/behavior modification and bariatric surgery for the treatment of
obesity. Pharmacotherapy, however, has not been included despite their
evidence-based efficacy. We set out to investigate the coverage of Food and Drug
Administration-approved medications for obesity within Medicare, Medicaid and
ACA-established marketplace health insurance plans.
METHODS: We examined coverage for phentermine, diethylpropion, phendimetrazine,
Benzphentamine, Lorcaserin, Phentermine/Topiramate (Qysmia), Liraglutide
(Saxenda) and Buproprion/Naltrexone (Contrave) among Medicare, Medicaid and
marketplace insurance plans in 34 states.
RESULTS: Among 136 marketplace health insurance plans, 11% had some coverage for
the specified drugs in only nine states. Medicare policy strictly excludes drug
therapy for obesity. Only seven state Medicaid programs have drug coverage.
CONCLUSIONS: Obesity requires an integrated approach to combat its public health
threat. Broader coverage of pharmacotherapy can make a significant contribution
to fighting this complex and chronic disease. Contrave® is an adjunct pharmacotherapy for obesity that contains bupropion
(BUP) and naltrexone (NTX). To further explore the psychopharmacology of this
drug combination, male Sprague-Dawley rats were implanted with subcutaneous
osmotic mini-pumps releasing: 40 mg/kg/day BUP, 4 mg/kg/day NTX, or
40 + 4 mg/kg/day BUP and NTX (BN). During 12 days of exposure, the animals were
tested on operant intraoral self-administration (IOSA) of high fructose corn
syrup (HFCS) on continuous (FR1) and progressive ratio (PR) schedules, on home
cage drinking of HFCS, and on HFCS taste reactivity. Locomotion activity was
also assessed. At the conclusion of the study, mRNA expression of genes involved
in reward processing, appetite and mood were quantified. It was found that BN
produced effects that could largely be ascribed to either BUP or NTX
independently. More specifically, BN-induced reductions of HFCS IOSA on a FR1
schedule and home cage drinking, as well as alterations of MOR and POMC mRNA in
the nucleus accumbens core and hypothalamus respectively, were attributable to
NTX; while alterations of hippocampal BDNF mRNA was attributable to BUP. But,
there was also some evidence of drug synergy: only BN caused persistent
reductions of HFCS IOSA and drinking; BN produced the least gain of body weight;
and only BN-treated rats displayed altered D2R mRNA in the caudate-putamen.
Taken together, these observations support the use of BUP + NTX as a mean to
alter consumption of sugars and reducing their impact on brain systems involved
in reward, appetite and mood. A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is
an FDA approved pharmacotherapy for the treatment of obesity. A recent study
found that combining BPP with low-dose NTX reduced alcohol drinking in
alcohol-preferring male rats. To explore potential pharmacological effects of
the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J
mice were tested on one-week drinking-in-the dark (DID) and three-week
intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer
knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its
bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used
as a genetic control for the effects of the BPP + NTX. A single administration
of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J
males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the
caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In
contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment
with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the
anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the
3-week chronic IA model, single or repeated administrations for four days of
BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The
behavioral measures observed in C57Bl/6J mice provide clear evidence that
BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested
were not effective in females. Furthermore, our results suggest a hypothalamic
POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol
drinking in male mice. Erythroderma is a rare, potentially life-threatening presentation of psoriasis
that can be triggered by medication reactions. Bupropion is indicated for major
depressive disorder (Wellbutrin®, GlaxoSmithKline, Research Triangle Park, NC),
smoking cessation (Zyban®, GlaxoSmithKline, Research Triangle Park, NC), and
weight loss (when in formulation with naltrexone ER; Contrave®, Orixegen
Therapeutics, La Jolla, CA). Bupropion can exacerbate psoriasis, however, this
is an under-recognized side effect of the medication, particularly in the United
States. We report a case of bupropion-induced erythrodermic psoriasis in a
62-year-old female who was prescribed the medication for depression. Due to the
common comorbidities of depression, obesity, and tobacco abuse in psoriatic
patients, all for which treatment with bupropion is indicated, it is important
for physicians to be aware of the potential for a life-threatening medication
reaction in this patient population. |
When is lorlatinib used? | Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. | Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small
cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been
shown to be superior to standard platinum-based chemotherapy. However, secondary
progress of disease frequently occurs under ALK inhibitor treatment. The
clinical impact of re-biopsies for treatment decisions beyond secondary progress
is, however, still under debate. Here, we report on two novel subsequent
polyclonal on- and off-target resistance mutations in a patient with ALK-fused
NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced
stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated
with the second-generation ALK inhibitor alectinib and upon progressions
subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress
to alectinib was associated with a so far undescribed ALK mutation
(p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An
off-target KRAS-mutation (p.Q61K) occurred in association with subsequent
progression under second-line TKI treatment. Third-line lorlatinib showed
limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS
mutant clone and clinical tumor control for another eight months. In conclusion,
we suggest molecular profiling of progressive tumor disease also for
ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive
patients. |
Ladybird homeobox (Lbx) transcription factors regulate the development of what body systems/organs? | Ladybird homeobox (Lbx) transcription factors have crucial functions in muscle and nervous system development in many animals | The embryonic heart precursors of Drosophila are arranged in a repeated pattern
of segmental units. There is growing evidence that the development of individual
elements of this pattern depends on both mesoderm intrinsic patterning
information and inductive signals from the ectoderm. In this study, we
demonstrate that two homeobox genes, ladybird early and ladybird late, are
involved in the cardiogenic pathway in Drosophila. Their expression is specific
to a subset of cardioblast and pericardial cell precursors and is critically
dependent on mesodermal tinman function, epidermal Wingless signaling and the
coordinate action of neurogenic genes. Negative regulation by hedgehog is
required to restrict ladybird expression to two out of six cardioblasts in each
hemisegment. Overexpression of ladybird causes a hyperplasia of heart precursors
and alters the identity of even-skipped-positive pericardial cells. Loss of
ladybird function leads to the opposite transformation, suggesting that ladybird
participates in the determination of heart lineages and is required to specify
the identities of subpopulations of heart cells. We find that both early
Wingless signaling and ladybird-dependent late Wingless signaling are required
for proper heart formation. Thus, we propose that ladybird plays a dual role in
cardiogenesis: (i) during the early phase, it is involved in specification of a
segmental subset of heart precursors as a component of the cardiogenic
tinman-cascade and (ii) during the late phase, it is needed for maintaining
wingless activity and thereby sustaining the heart pattern process. These events
result in a diversification of heart cell identities within each segment. In the mesoderm of Drosophila embryos, a defined number of cells segregate as
progenitors of individual body wall muscles. Progenitors and their progeny
founder cells display lineage-specific expression of transcription factors but
the mechanisms that regulate their unique identities are poorly understood. Here
we show that the homeobox genes ladybird early and ladybird late are expressed
in only one muscle progenitor and its progeny: the segmental border muscle
founder cell and two precursors of adult muscles. The segregation of the
ladybird-positive progenitor requires coordinate action of neurogenic genes and
an interplay of inductive Hedgehog and Wingless signals from the overlying
ectoderm. Unlike so far described progenitors but similar to the neuroblasts,
the ladybird-positive progenitor undergoes morphologically asymmetric division.
We demonstrate that the ectopic ladybird expression is sufficient to change the
identity of a subset of progenitor/founder cells and to generate an altered
pattern of muscle precursors. When ectopically expressed, ladybird transforms
the identity of neighbouring, Krüppel-positive progenitors leading to the
formation of giant segmental border muscles and supernumerary precursors of
lateral adult muscles. In embryos lacking ladybird gene function, specification
of two ladybird-expressing myoblast lineages is affected. The segmental border
muscles do not form or have abnormal shapes and insertion sites while the number
of lateral precursors of adult muscles is dramatically reduced. Altogether our
results provide new insights into the genetic control of diversification of
muscle precursors and indicate a further similarity between the myogenic and
neurogenic pathways. Homeobox-containing (Hox) genes play important roles in development,
particularly in the development of neurons and sensory organs, and in
specification of body plan. The Hmx gene family is a new class of
homeobox-containing genes defined by a conserved homeobox region and a
characteristic pattern of expression in the central nervous system that is more
rostral than that of the Hox genes. To date, three closely related members of
the Hmx family, Hmx1, Hmx2, and Hmx3, have been described. All three Hmx genes
are expressed in the craniofacial region of developing embryos. Here we show,
for the first time, the expression of the transcription factor Hmx3 in
postnatally developing salivary glands. Hmx3 protein is expressed in a cell
type-specific manner in rat salivary glands. Hmx3 is present in both the nuclei
and cytoplasm of specific groups of duct cells of the submandibular, parotid,
and sublingual glands. Hmx3 expression increases during postnatal development of
the submandibular gland. The duct cells show increasing concentrations of Hmx3
protein with progressive development of the submandibular gland. In contrast,
the acinar cells of the three salivary glands do not exhibit detectable levels
of Hmx3 protein. In Drosophila, neurons and glial cells are produced by neural precursor cells
called neuroblasts (NBs), which can be individually identified. Each NB
generates a characteristic cell lineage specified by a precise spatiotemporal
control of gene expression within the NB and its progeny. Here we show that the
homeobox genes ladybird early and ladybird late are expressed in subsets of
cells deriving from neuroblasts NB 5-3 and NB 5-6 and are essential for their
correct development. Our analysis revealed that ladybird in Drosophila, like
their vertebrate orthologous Lbx1 genes, play an important role in cell fate
specification processes. Among those cells that express ladybird are NB
5-6-derived glial cells. In ladybird loss-of-function mutants, the NB
5-6-derived exit glial cells are absent while overexpression of these genes
leads to supernumerary glial cells of this type. Furthermore, aberrant glial
cell positioning and aberrant spacing of axonal fascicles in the nerve roots
observed in embryos with altered ladybird function suggest that the ladybird
genes might also control directed cell movements and cell-cell interactions
within the developing Drosophila ventral nerve cord. BACKGROUND: Lbx/ladybird genes originated as part of the metazoan cluster of Nk
homeobox genes. In all animals investigated so far, both the protostome genes
and the vertebrate Lbx1 genes were found to play crucial roles in neural and
muscle development. Recently however, additional Lbx genes with divergent
expression patterns were discovered in amniotes. Early in the evolution of
vertebrates, two rounds of whole genome duplication are thought to have
occurred, during which 4 Lbx genes were generated. Which of these genes were
maintained in extant vertebrates, and how these genes and their functions
evolved, is not known.
RESULTS: Here we searched vertebrate genomes for Lbx genes and discovered novel
members of this gene family. We also identified signature genes linked to
particular Lbx loci and traced the remts of 4 Lbx paralogons (two of which
retain Lbx genes) in amniotes. In teleosts, that have undergone an additional
genome duplication, 8 Lbx paralogons (three of which retain Lbx genes) were
found. Phylogenetic analyses of Lbx and Lbx-associated genes show that in
extant, bony vertebrates only Lbx1- and Lbx2-type genes are maintained. Of
these, some Lbx2 sequences evolved faster and were probably subject to
neofunctionalisation, while Lbx1 genes may have retained more features of the
ancestral Lbx gene. Genes at Lbx1 and former Lbx4 loci are more closely related,
as are genes at Lbx2 and former Lbx3 loci. This suggests that during the second
vertebrate genome duplication, Lbx1/4 and Lbx2/3 paralogons were generated from
the duplicated Lbx loci created during the first duplication event.
CONCLUSION: Our study establishes for the first time the evolutionary history of
Lbx genes in bony vertebrates, including the order of gene duplication events,
gene loss and phylogenetic relationships. Moreover, we identified genetic
hallmarks for each of the Lbx paralogons that can be used to trace Lbx genes as
other vertebrate genomes become available. Significantly, we show that bony
vertebrates only retained copies of Lbx1 and Lbx2 genes, with some Lbx2 genes
being highly divergent. Thus, we have established a base on which the evolution
of Lbx gene function in vertebrate development can be evaluated. BACKGROUND: Skeletal muscle differentiation requires assembly of contractile
proteins into organized myofibrils. The Drosophila ladybird homeobox gene (lad)
functions in founder cells of the segmental border muscle to promote myoblast
fusion and muscle shaping. Tetrapods have two homologous genes (Lbx). Lbx1
functions in migration and/or proliferation of hypaxial myoblasts, whereas the
function of Lbx2 is poorly understood.
RESULTS: To elucidate the role of Lbx in vertebrate myogenesis, we examined Lbx
function in zebrafish. Zebrafish lbx2 transcripts appear in newly formed
paraxial mesoderm and become restricted to adaxial cells, precursors of slow
muscle. Slow muscles lose lbx2 expression as they differentiate, while a subset
of differentiating fast muscle cells transiently expresses lbx2. Fin and hyoid
muscle express lbx2 later. In contrast, lbx1b expression first appears lateral
to the somites at late segmentation stages and is later restricted to fin
muscle. Morpholino knockdown of Lbx1b and Lbx2 suppresses hypaxial muscle
development. Moreover, knockdown of Lbx2 results in malformation of muscle
fibers and reduced fusion of fast precursors, although no obvious effects on
induction or specification are observed. Expression of myofilament genes,
including actin and myosin, requires the engrailed repressor domain of Lbx2.
CONCLUSION: Our results elucidate a new function of Lbx2 as a regulator of
myofibril formation. Ladybird (Lbx) homeodomain transcription factors function in neural and muscle
development--roles conserved from Drosophila to vertebrates. Lbx expression in
mice specifies neural cell types, including dorsally located interneurons and
association neurons, within the neural tube. Little, however, is known about the
regulation of vertebrate lbx family genes. Here we describe the expression
pattern of three zebrafish ladybird genes via mRNA in situ hybridization.
Zebrafish lbx genes are expressed in distinct but overlapping regions within the
developing neural tube, with strong expression within the hindbrain and spinal
cord. The Hox family of transcription factors, in cooperation with cofactors
such as Pbx and Meis, regulate hindbrain segmentation during embryogenesis. We
have identified a novel regulatory interaction in which lbx1 genes are strongly
downregulated in Pbx-depleted embryos. Further, we have produced a transgenic
zebrafish line expressing dTomato and EGFP under the control of an lbx1b
enhancer--a useful tool to acertain neuron location, migration, and morphology.
Using this transgenic strain, we have identified a minimal neural lbx1b enhancer
that contains key regulatory elements for expression of this transcription
factor. Author information:
(1)Department of Genetics, Rutgers, The State University of New Jersey,
Piscataway, USA.
(2)Laboratory for Bone and Joint Diseases, Center for Integrative Medical
Sciences, RIKEN, Tokyo, Japan.
(3)Laboratory for Medical Science Mathematics, Center for Integrative Medical
Sciences, RIKEN, Yokohama, Japan.
(4)Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for
Children, Dallas, USA School of Biotechnology, SMVDU, Katra, India.
(5)Laboratory for Bone and Joint Diseases, Center for Integrative Medical
Sciences, RIKEN, Tokyo, Japan Department of Orthopaedic Surgery, School of
Medicine, Keio University, Tokyo, Japan.
(6)Laboratory for Statistical Analysis, Center for Integrative Medical Sciences,
Riken, Yokohama, Japan.
(7)Department of Orthopaedic Surgery, School of Medicine, Keio University,
Tokyo, Japan.
(8)Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children,
Dallas, USA Department of Orthopaedics, University of Texas Southwestern Medical
Center at Dallas, Dallas, USA.
(9)Department of Orthopaedics and Traumatology, The Chinese University of Hong
Kong, Hong Kong, China Joint Scoliosis Research Center, The Chinese University
of Hong Kong and Nanjing University, Hong Kong, China.
(10)Functional Genomics and Biostatistical Computing Laboratory, Shenzhen
Research Institute of the Chinese University of Hong Kong, Hong Kong, China
Department of Chemical Pathology, the Chinese University of Hong Kong, Shatin,
Hong Kong SAR, China.
(11)Department of Biochemistry, University of Hong Kong, Hong Kong, China.
(12)Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, Nanjing, China.
(13)Department of Orthopedics, The Memorial Hospital of Sun Yat-Sen University,
Guangzhou, China.
(14)Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-Sen
University, Guangzhou, China.
(15)Department of Psychiatry, University of Hong Kong, Hong Kong, China.
(16)Department of Orthopaedics and Traumatology, University of Hong Kong, Hong
Kong, China.
(17)Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for
Children, Dallas, USA Department of Orthopaedics, University of Texas
Southwestern Medical Center at Dallas, Dallas, USA Department of Pediatrics,
University of Texas Southwestern Medical Center at Dallas, Dallas, USA McDermott
Center for Human Growth and Development, University of Texas Southwestern
Medical Center at Dallas, Dallas, USA. Homeobox genes are an evolutionarily conserved class of transcription factors
that are critical for development of many organ systems, including the brain and
eye. During retinogenesis, homeodomain-containing transcription factors, which
are encoded by homeobox genes, play essential roles in the regionalization and
patterning of the optic neuroepithelium, specification of retinal progenitors
and differentiation of all seven of the retinal cell classes that derive from a
common progenitor. Homeodomain transcription factors control retinal cell fate
by regulating the expression of target genes required for retinal progenitor
cell fate decisions and for terminal differentiation of specific retinal cell
types. The essential role of homeobox genes during retinal development is
demonstrated by the number of human eye diseases, including colobomas and
anophthalmia, which are attributed to homeobox gene mutations. In the following
review, we highlight the role of homeodomain transcription factors during
retinogenesis and regulation of their gene targets. Understanding the
complexities of vertebrate retina development will enhance our ability to drive
differentiation of specific retinal cell types towards novel cell-based
replacement therapies for retinal degenerative diseases. The migration of limb myogenic precursors from limb level somites to their
ultimate site of differentiation in the limb is a paradigmatic example of a set
of dynamic and orchestrated migratory cell behaviours. The homeobox containing
transcription factor ladybird homeobox 1 (Lbx1) is a central regulator of limb
myoblast migration, null mutations of Lbx1 result in severe disruptions to limb
muscle formation, particularly in the distal region of the limb in mice (Gross
et al., 2000). As such Lbx1 has been hypothesized to control lateral migration
of myoblasts into the distal limb anlage. It acts as a core regulator of the
limb myoblast migration machinery, controlled by Pax3. A secondary role for Lbx1
in the differentiation and commitment of limb musculature has also been proposed
(Brohmann et al., 2000; Uchiyama et al., 2000). Here we show that lateral
migration, but not differentiation or commitment of limb myoblasts, is
controlled by the phosphorylation of three adjacent serine residues of LBX1.
Electroporation of limb level somites in the chick embryo with a
dephosphomimetic form of Lbx1 results in a specific defect in the lateral
migration of limb myoblasts. Although the initial delamination and migration of
myoblasts is unaffected, migration into the distal limb bud is severely
disrupted. Interestingly, myoblasts undergo normal differentiation independent
of their migratory status, suggesting that the differentiation potential of
hypaxial muscle is not regulated by the phosphorylation state of LBX1.
Furthermore, we show that FGF8 and ERK mediated signal transduction, both
critical regulators of the developing limb bud, have the capacity to induce the
phosphorylation of LBX1 at these residues. Overall, this suggests a mechanism
whereby the phosphorylation of LBX1, potentially through FGF8 and ERK
signalling, controls the lateral migration of myoblasts into the distal limb
bud. Ladybird homeobox (Lbx) transcription factors have crucial functions in muscle
and nervous system development in many animals. Amniotes have two Lbx genes, but
only Lbx1 is expressed in spinal cord. In contrast, teleosts have three lbx
genes and we show here that zebrafish lbx1a, lbx1b, and lbx2 are expressed by
distinct spinal cell types, and that lbx1a is expressed in dI4, dI5, and dI6
interneurons, as in amniotes. Our data examining lbx expression in Scyliorhinus
canicula and Xenopus tropicalis suggest that the spinal interneuron expression
of zebrafish lbx1a is ancestral, whereas lbx1b has acquired a new expression
pattern in spinal cord progenitor cells. lbx2 spinal expression was probably
acquired in the ray-finned lineage, as this gene is not expressed in the spinal
cords of either amniotes or S. canicula. We also show that the spinal function
of zebrafish lbx1a is conserved with mouse Lbx1. In zebrafish lbx1a mutants,
there is a reduction in the number of inhibitory spinal interneurons and an
increase in the number of excitatory spinal interneurons, similar to mouse Lbx1
mutants. Interestingly, the number of inhibitory spinal interneurons is also
reduced in lbx1b mutants, although in this case the number of excitatory
interneurons is not increased. lbx1a;lbx1b double mutants have a similar spinal
interneuron phenotype to lbx1a single mutants. Taken together these data suggest
that lbx1b and lbx1a may be required in succession for correct specification of
dI4 and dI6 spinal interneurons, although only lbx1a is required for suppression
of excitatory fates in these cells. |
Should istiratumab be used for Pancreatic Cancer? | No. In a clinical trial Istiratumab failed to improve the efficacy of standard of care chemotherapy in metastatic pancreatic cancer patients. | BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like
growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to
IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested
whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the
efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC
selected for high IGF-1 serum levels.
PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind,
placebo-controlled phase II study for patients with previously untreated
metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and
safety. In part 2, patients with high free serum IGF-1 levels were randomized 1
: 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or
placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The
co-primary endpoints were progression-free survival (PFS) in patients with high
IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin
(HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective
response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate.
RESULTS: A total of 317 patients were screened, with 88 patients randomized in
part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort,
median PFS was 3.6 and 7.3 months in the experimental versus control arms,
respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+
subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39,
P = 0.42). Median OS and ORR for the overall population were similar between two
arms. No significant difference in serious or grade ≥3 AEs was observed,
although low-grade AEs leading to early discontinuation were higher in the
experimental (39.5%) versus control arm (24.4%).
CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in
this patient setting. High serum IGF-1 levels did not appear to be an adverse
prognostic factor when compared with non-biomarker-selected historic controls.
CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT:
2014-004572-34. |
When is the protein OAS1 activated? | OAS1 is a IFN-stimulated gene. Antiviral response. | Collaborators: Millar J, Nichol A, Walsh T, Shankar-Hari M, Ponting C, Meikle J,
Finer P, Mcmaster E, Law A, Baillie JK, Paterson T, Wackett T, Armstrong R,
Clark R, Coutts A, Donnelly L, Gilchrist T, Hafezi K, Macgillivray L, Maclean A,
McCafferty S, Morrice K, Weaver J, Boz C, Golightly A, Ward M, Mal H,
Szoor-McElhinney H, Brown A, Hendry R, Stenhouse A, Cullum L, Law D, Law S, Law
R, Swets M, Day N, Taneski F, Duncan E, Parkinson N, Collier D, Wood S, Zak A,
Borra C, Matharu M, May P, Alldis Z, Mitchelmore O, Bowles R, Easthope A, Bibi
F, Lancoma-Malcolm I, Gurasashvili J, Pheby J, Shiel J, Bolton M, Patel M,
Taylor M, Zongo O, Ebano P, Harding P, Astin-Chamberlain R, Choudhury Y, Cox A,
Kallon D, Burton M, Hall R, Blowes S, Prime Z, Biddle J, Prysyazhna O, Newman T,
Tierney C, Kassam J, Shankar-Hari M, Ostermann M, Campos S, Bociek A, Lim R,
Grau N, Jones TO, Whitton C, Marotti M, Arbane G, Bonner S, Hugill K, Reid J,
Welters I, Waugh V, Williams K, Shaw D, Roman JF, Martinez ML, Johnson E, Waite
A, Johnston B, Hamilton D, Mulla S, McPhail M, Smith J, Baillie JK, Barclay L,
Hope D, McCulloch C, McQuillan L, Clark S, Singleton J, Priestley K, Rea N,
Callaghan M, Campbell R, Andrew G, Marshall L, McKechnie S, Hutton P, Bashyal A,
Davidson N, Summers C, Polgarova P, Stroud K, Pathan N, Elston K, Agrawal S,
Battle C, Newey L, Rees T, Harford R, Brinkworth E, Williams M, Murphy C, White
I, Croft M, Bandla N, Gellamucho M, Tomlinson J, Turner H, Davies M, Quinn A,
Hussain I, Thompson C, Parker H, Bradley R, Griffiths R, Scriven J, Nilsson A,
Bates M, Dasgin J, Gill J, Puxty A, Cathcart S, Salutous D, Turner L, Duffy K,
Puxty K, Joseph A, Herdman-Grant R, Simms R, Swain A, Naranjo A, Crowe R,
Sollesta K, Loveridge A, Baptista D, Morino E, Davey M, Golden D, Jones J,
Moreno Cuesta J, Haldeos A, Bakthavatsalam D, Vincent R, Elhassan M, Xavier K,
Ganesan A, Purohit D, Abdelrazik M, Morgan J, Akeroyd L, Bano S, Lawton T,
Warren D, Bromley M, Sellick K, Gurr L, Wilkinson B, Nagarajan V, Szedlak P,
Cupitt J, Stoddard E, Benham L, Preston S, Laha S, Slawson N, Bradshaw Z, Brown
J, Caswell M, Melling S, Bamford P, Faulkner M, Cawley K, Jeffrey H, London E,
Sainsbury H, Nagra I, Nasir F, Dunmore C, Jones R, Abraheem A, Al-Moasseb M,
Girach R, Padden G, Egan J, Brantwood C, Alexander P, Bradley-Potts J, Allen S,
Felton T, Manna S, Farnell-Ward S, Leaver S, Queiroz J, Maccacari E, Dawson D,
Delgado CC, Saluzzio RP, Ezeobu O, Ding L, Sicat C, Kanu R, Durrant G, Texeira
J, Harrison A, Samakomva T, Scriven J, Willis H, Hopkins B, Thrasyvoulou L,
Jackson M, Zaki A, Tibke C, Bennett S, Woodyatt W, Kent A, Goodwin E, Brandwood
C, Clark R, Smith L, Rooney K, Thomson N, Rodden N, Hughes E, McGlynn D, Clark
C, Clark P, Abel L, Sundaram R, Gemmell L, Brett M, Hornsby J, MacGoey P, Price
R, Digby B, O'Neil P, McConnell P, Henderson P, Henderson S, Sim M, Kennedy-Hay
S, McParland C, Rooney L, Baxter N, Pogson D, Rose S, Daly Z, Brimfield L, Phull
MK, Hussain M, Pogreban T, Rosaroso L, Salciute E, Grauslyte L, Brealey D, Raith
E, MacCallum N, Bercades G, Hass I, Smyth D, Reyes A, Martir G, Clement ID,
Webster K, Hays C, Gulati A, Hodgson L, Margarson M, Gomez R, Baird Y, Thirlwall
Y, Folkes L, Butler A, Meadows E, Moore S, Raynard D, Fox H, Riddles L, King K,
Kimber S, Hobden G, McCarthy A, Cannons V, Balagosa I, Chadbourn I, Gardner A,
Horner D, McLaughlanv D, Charles B, Proudfoot N, Marsden T, McMorrow L,
Blackledge B, Pendlebury J, Harvey A, Apetri E, Basikolo C, Catlow L, Doo R,
Knowles K, Lee S, Lomas D, Lyons C, Perez J, Poulaka M, Slaughter M, Slevin K,
Taylor M, Thomas V, Walker D, Harris J, Drummond A, Tully R, Dearden J, Philbin
J, Munt S, Rishton C, O'Connor G, Mulcahy M, Dobson E, Cuttler J, Edward M,
Norris J, Hanson K, Poole A, Rose A, Sloan B, Buckley S, Brooke H, Smithson E,
Charlesworth R, Sandhu R, Thirumaran M, Wagstaff V, Suarez JC, Kaliappan A,
Vertue M, Nicholson A, Riches J, Solesbury A, Kittridge L, Forsey M, Maloney G,
Cole J, Davies M, Davies R, Hill H, Thomas E, Williams A, Duffin D, Player B,
Radhakrish J, Gibson S, Lyle A, McNeela F, Patel B, Gummadi M, Sloane G,
Dormand N, Salmi S, Farzad Z, Cristiano D, Liyanage K, Thwaites V, Varghese M,
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Whittle H, Prady H, Chan R, Ahmed A, Morris A, Gibson C, Gordon E, Kee S,
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Kee N, Young M, Garrioch S, Dawson J, Tolson M, Scholefield B, Bi R,
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Allen L, Crisp N, Hazleton T, Knight A, Deery J, Price C, Turney S, Tilbey S,
Beranova E, Wright D, George L, Twiss S, Cowton A, Wadd S, Postlethwaite K,
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Donnison P, Trim F, Leadbitter I, Butcher D, O'Sullivan S, Purewal B, Bell S,
Rivers V, O'Leary R, Birch J, Collins E, Anderson S, Hammerton K, Andrews E,
Higham A, Burns K, Edmond I, Salutous D, Todd A, Donnachie J, Turner P, Prentice
L, Symon L, Runciman N, Auld F, Halkes M, Mercer P, Thornton L, Debreceni G,
Wilkins J, Brown A, Crickmore V, Subramanian G, Marshall R, Jennings C, Latif M,
Bunni L, Spivey M, Bean S, Burt K, Linnett V, Ritzema J, Sanderson A, McCormick
W, Bokhari M, Kapoor R, Loader D, Ayers A, Harrison W, North J, Belagodu Z,
Paramsothy R, Olufuwa O, Gherman A, Fuller B, Stuart C, Kelsall O, Davis C, Wild
L, Wood H, Thrush J, Durie A, Austin K, Archer K, Anderson P, Vigurs C, Thorpe
C, Thomas A, Knights E, Boyle N, Price A, Kubisz-Pudelko A, Wood D, Lewis A,
Board S, Pippard L, Perry J, Beesley K, Rattray A, Taylor M, Lee E, Lennon L,
Douglas K, Bell D, Boyle R, Glass L, Nauman Akhtar M, Dent K, Potoczna D,
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Ortiz-Ruiz de Gordoa L, Barber R, Hewitt C, Hilldrith A, Shepardson S, Wills M,
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Mallinson J, Chandler B, Turnbull A, Quinn A, Finch C, Holl C, Cooper J, Evans
A, Khaliq W, Collins A, Gude ET, Love N, van Koutrik L, Hunt J, Kaye D, Fisher
E, Brayne A, Tuckey V, Jackson P, Parkin J, Brealey D, Raith E, Tariq A, Houlden
H, Tucci A, Hardy J, Moncur E, Highgate J, Cowley A, Mitra A, Stead R, Behan T,
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AYW, Horby PW, Ijaz S, Khoo S, Klenerman P, Lim WS, Mentzer AJ, Merson L,
Meynert AM, Noursadeghi M, Moore SC, Palmarini M, Paxton WA, Pollakis G, Price
N, Rambaut A, Robertson DL, Sancho-Shimizu V, Scott JT, de Silva T, Sigfrid L,
Solomon T, Sriskandan S, Stuart D, Tedder RS, Thomson EC, Thompson AAR, Thwaites
RS, Turtle LCW, Zambon M, Hardwick H, Donohue C, Lyons R, Norman L, Pius R,
Drake TM, Fairfield CJ, Knight SR, Mclean KA, Murphy D, Shaw CA, Dalton J,
Girvan M, Saviciute E, Roberts S, Harrison J, Marsh L, Connor M, Halpin S,
Jackson C, Gamble C, Leeming G, Wham M, Greenhalf W, Shaw V, McDonald S, Keating
S, Ganna A, Sulem P, van Heel DA, Cordioli M, Sveinbjornsson G, Niemi MEK,
Shelton JF, Shastri AJ, Ye C, Weldon CH, Filshtein-Sonmez T, Coker D, Symons A,
Esparza-Gordillo J, Aslibekyan S, Auton A, Krieger JE, Marques E, Jannes CE,
Mari F, Daga S, Baldassarri M, Benetti E, Furini S, Fallerini C, Fava F,
Valentino F, Doddato G, Giliberti A, Tita R, Amitrano S, Bruttini M, Croci S,
Meloni I, Pinto AM, Frullanti E, Mencarelli MA, Rizzo CL, Montagi F, Di Sarno
L, Tommasi A, Palmieri M, Emiliozzi A, Fabbiani M, Rossetti B, Zanelli G,
Bargagli E, Bergantini L, D'Alessandro M, Cameli P, Bennet D, Anedda F,
Marcantonio S, Scolletta S, Franchi F, Mazzei MA, Guerrini S, Conticini E,
Cantarini L, Frediani B, Tacconi D, Spertilli C, Feri M, Donati A, Scala R,
Guidelli L, Spargi G, Corridi M, Nencioni C, Croci L, Caldarelli GP, Spagnesi M,
Piacentini P, Bandini M, Desanctis E, Cappelli S, Canaccini A, Verzuri A,
Anemoli V, Ognibene A, Vaghi M, D'Arminio Monforte A, Merlini E, Mondelli MU,
Mantovani S, Ludovisi S, Girardis M, Venturelli S, Sita M, Cossarizza A,
Antinori A, Vergori A, Rusconi S, Siano M, Gabrieli A, Riva A, Francisci D,
Schiaroli E, Scotton PG, Andretta F, Panese S, Scaggiante R, Gatti F, Parisi SG,
Castelli F, Quiros-Roldan ME, Magro P, Zanella I, Della Monica M, Piscopo C,
Capasso M, Russo R, Andolfo I, Iolascon A, Fiorentino G, Carella M, Castori M,
Merla G, Aucella F, Raggi P, Marciano C, Perna R, Bassetti M, Di Biagio A,
Sanguinetti M, Masucci L, Valente S, Mandalà M, Giorli A, Salerni L, Zucchi P,
Parravicini P, Menatti E, Baratti S, Trotta T, Giannattasio F, Coiro G, Lena F,
Coviello DA, Mussini C, Bosio G, Martinelli E, Mancarella S, Tavecchia L, Crotti
L, Picchiotti N, Gori M, Gabbi C, Sanarico M, Ceri S, Pinoli P, Raimondi F,
Biscarini F, Stella A. The female reproductive tract (FRT) is a major site of HIV sexual transmission.
As the outermost layer of cells in the FRT, the human cervical epithelial cells
(HCEs) have direct contact with HIV or infected cells. Our early work showed
that supernatant (SN) from TLR3-activated HCEs contain the antiviral factors
that could potently inhibit HIV replication in macrophages. However, it remains
to be determined how HCEs transport the anti-HIV factors to macrophages. This
follow-up study examined the role of exosomes in HCE-mediated anti-HIV activity.
We found that TLR3 activation of HCEs resulted in the release of exosomes that
contained multiple IFN-stimulated genes (ISGs: ISG56, OAS1, MxA, and Mx2) and
the HIV restriction microRNAs (miR-28, miR-29 family members, miR-125b, miR-150,
miR-382, miR-223, miR-20a, and miR-198). The depletion of exosomes from SN of
TLR3-activated HCEs diminished HCE-mediated anti-HIV activity in macrophages,
indicating that HCE-derived exosomes are responsible for transporting the
antiviral molecules to macrophages. These in vitro findings suggest a novel
antiviral mechanism by which HCEs participate in the FRT innate immunity against
HIV infection. Further in vivo studies are necessary in order to develop an
exosome-based delivery system for prevention and treatment of HIV infection
through sexual transmission. BACKGROUND: Transposable elements (TEs) are repetitive sequences of viral origin
that compose almost half of the human genome. These elements are tightly
controlled within cells, and if activated, they can cause changes in both gene
regulation and immune viral responses that have been associated with several
chronic inflammatory diseases in humans. As oxidants are potent activators of
TEs, and because oxidative injury is a major risk factor in relation to
idiopathic pulmonary fibrosis (IPF), we hypothesized that TEs might be involved
in the regulation of gene expression and so contribute to inflammation in cases
of IPF. IPF is a fatal lung disease that involves the gradual replacement of the
alveolar tissue with fibrotic scars as well as the accumulation of inflammatory
cells in the lower respiratory tract. Although IPF is known to occur as a result
of the complex interaction between age, environmental risk factors (i.e.,
oxidative stress) and genetics, the relative contributions of these factors to
the disease remain unclear. To determine whether TEs are associated with IPF, we
compared the transcriptional profiles of the genes and TEs of lung cells
obtained from both healthy donors and IPF patients.
RESULTS: We quantified TE and gene expression levels using a published bulk
RNA-seq dataset containing 24 subjects (16 donors and eight IPF patients),
including three lung-cell types per subject, as well as an scRNA-seq dataset
concerning 16 subjects (eight donors and eight IPF patients). We found evidence
of TE dysregulation in the alveolar type II lung cells and alveolar macrophages
of the IPF patients. In addition, the activation of the LINE1 family of elements
in IPF is associated with the increased expression of TE cellular regulators
(MOV10, IFI16, SAMHD1, and APOBECG3), interferon-stimulating genes (ISG15, IFI6,
IFI27, IFI44, and OAS1), chemokines (CX3CL1 and CXCL9), and interleukins
(IL15RA). We also propose that TE derepression might be involved in the
regulation of previously reported IPF candidate genes (MUC5B, CHL1, SPP1, and
MMP7).
CONCLUSION: Based on our findings, we propose that TE derepression plays an
important role in the regulation of gene expression and can also prompt both the
recruitment of inflammatory processes and the disruption of the immunological
balance, which can lead to chronic inflammation in IPF. The innate immune system has an important role in developing the initial
resistance to virus infection, and the ability of oligoadenylate synthetase to
overcome viral evasion and enhance innate immunity is already established in
humans. In the present study, we have tried to explore the molecular and
structural variations present in Sahiwal (indigenous) and crossbred (Frieswal)
cattle to identify the molecular mechanism of action of OAS1 gene in activation
of innate immune response. The significant changes in structural alignment in
terms of orientation of loops, shortening of β-sheets and formation of 3-10
α-helix was noticed in Sahiwal and Frieswal cattle. Further, it has been
observed that OAS1 from Sahiwal had better binding with APC and DTP ligand than
Frieswal OAS1. A remarkable change was seen in orientation at the nucleoside
base region of both the ligands, which are bound with OAS1 protein from Frieswal
and Sahiwal cattle. The Molecular Dynamic study of apo and ligand complex
structures was provided more insight towards the stability of OAS1 from both
cattle. This analysis displayed that the Sahiwal cattle protein has more steady
nature throughout the simulation and has better binding towards Frieswal in
terms of APC and DTP binding. Thus, OAS1 protein is the potential target for
explaining the innate immune response in Sahiwal than Frieswal.Communicated by
Ramaswamy H. Sarma. |
Does Amblyopia affect the eye? | Amblyopia, also called lazy eye, is a disorder of sight in which the brain fails to process inputs from one eye and over time favors the other eye. It results in decreased vision in an eye that otherwise typically appears normal | The contrast sensitivity function of both eyes of subjects with functional
amblyopia has been measured. A clinically significant difference was found
between the amblyopic and the normal eye. It appears that the functionally
amblyopic eye takes more information from the peripheral parts of the stimulus
than does the normal eye. The sensitivity of the normal eye increases linearly
with increasing width of the stimulus to show a knee at a certain number of
grating lines, whereafter the sensitivity remains constant. The sensitivity of
the amblyopic eye initially rises much faster than that of the normal eye with
increasing stimulus width. In the amblyopic eye, there is no definite linear
relationship between width of stimulus and the contrast sensitivity and no
definite knee in the curve at which maximum sensitivity is reached. Amblyopia, commonly known as "lazy eye," is a frequent but preventable cause of
decreased vision. An anatomically normal eye, free from organic disease, has
reduced vision compared with the other eye. Ptosis of the eyelids, strabismus,
certain refractive disorders and other abnormalities may precede amblyopia. If
discovered early enough, usually before the age of five, amblyopia can often be
reversed. Experimental amblyopia in animal models causes a reduction of cell sizes in
lateral geniculate nucleus (LGN) laminae connected with the amblyopic eye.
However, direct evidence that the human amblyopic visual system is affected in a
similar manner has been lacking. Histologic study of the LGNs from a patient
with ophthalmologically confirmed anisometropic amblyopia shows a decrease of
cell sizes in the parvocellular layers innervated by the amblyopic eye. This
decrease was more pronounced in laminae receiving crossed fibers. To our
knowledge this is the first report about structural alterations in the afferent
visual pathway of a human amblyope and the data reaffirm the validity of the
monkey model for further study of the basic mechanisms in amblyopia. 1. Sometimes called "lazy eye," amblyopia is poor vision in an eye that did not
develop normal sight during early childhood. Amblyopia is common, affecting
approximately 2 or 3 out of every 100 people. The best time to correct amblyopia
is during infancy or early childhood. 2. Amblyopia has three major causes:
strabismus (misaligned eyes), unequal focus (refractive error), and cloudiness
in the normally clear eye tissues. 3. To correct amblyopia, a child must be made
to use the weak eye. This is usually done by patching or covering the strong
eye. Amblyopia cannot be cured by treating the cause alone; the weaker eye must
be made stronger in order to see normally. Although postmortem morphological changes in the lateral geniculate nucleus
(LGN) have been reported in human amblyopia, LGN function during monocular
viewing by amblyopic eyes has not been documented in humans. We used functional
magnetic resoce imaging (fMRI) to study monocular visual activation of the
LGN in a patient with anisometropic amblyopia. Four normal subjects, a patient
with optic neuritis and a patient with anisometropic amblyopia were studied with
fMRI at 1.5 T during monocular checkerboard stimulation. Activated areas in the
LGN and visual cortex were identified after data processing (motion correction
and spatial normalization) with SPM99. In the 4 normal subjects, comparable
activation of the LGN and visual cortex was obtained by stimulation of either
the right or left eye. In the patient with unilateral optic neuritis, activation
of the LGN and visual cortex was markedly decreased when the affected eye was
stimulated. Similarly, decreased activation of the LGN as well as the visual
cortex by the affected eye was demonstrated in the patient with anisometropic
amblyopia. Our preliminary results suggest that activation of the LGN is
diminished during monocular viewing by affected eyes in anisometropic amblyopia.
fMRI appears to be a feasible method to study LGN activity in human amblyopia. Visual processing is thought to involve initial local analyses that are
subsequently integrated globally to derive functional representations of
structure that extends over large areas of visual space. Amblyopia is a common
deficit in spatial vision that could be based on either unreliable local
estimates of image structure, irregularities in global image integration or a
combination of errors at both these stages. The purpose of this study was to
quantify the integration of local spatial information in amblyopia with global
orientation discrimination and inter-ocular matching tasks. Stimuli were
composed of pseudo-random arrays of highly visible and resolvable features
(Gabor patches) whose local orientation and position were drawn from global
distributions whose mean and variance statistics were systemically varied.
Global orientation discrimination thresholds in both the amblyopic and fellow
eye were elevated. The orientational and positional variances perceived by the
amblyopic eye were matched by stimuli with higher variances perceived in the
fellow eye. It would appear that amblyopes are able to integrate orientation
information across visual space but the global representation of local structure
shows greater variability compared to normal. It is this increased spatial
uncertainty that underlies the spatial deficit in amblyopia. We compared the optic nerve head topography and retinal nerve fiber layer (RNFL)
thickness of the strabismic and anisometropic amblyopic eyes with the normal
fellow eyes and age-matched controls and concluded that, although amblyopia is a
functional visual loss, RNFL thickness and optic nerve head topographic changes
in strabismic and anisometropic amblyopic eyes may be affected by amblyopia.
Further histopathological and clinic confirmations are needed. Amblyopia is a disorder of visual acuity in one eye, thought to arise from
suppression by the other eye during development of the visual cortex. In the
attentional blink, the second of two targets (T2) in a Rapid Serial Visual
Presentation (RSVP) stream is difficult to detect and identify when it appears
shortly but not immediately after the first target (T1). We investigated the
attentional blink seen through amblyopic eyes and found that it was less finely
tuned in time than when the 12 amblyopic observers viewed the stimuli with their
preferred eyes. T2 performance was slightly better through amblyopic eyes two
frames after T1 but worse one frame after T1. Previously (A. V. Popple & D. M.
Levi, 2007), we showed that when the targets were red letters in a stream of
gray letters (or vice versa), normal observers frequently confused T2 with the
letters before and after it (neighbor errors). Observers viewing through their
amblyopic eyes made significantly fewer neighbor errors and more T2 responses
consisting of letters that were never presented. In normal observers, T1 (on the
rare occasions when it was reported incorrectly) was often confused with the
letter immediately after it. Viewing through their amblyopic eyes, observers
with amblyopia made more responses to the letter immediately before T1. These
results suggest that childhood suppression of the input from amblyopic eyes
disrupts attentive processing. We hypothesize reduced connectivity between
monocularly tuned lower visual areas, subcortical structures that drive foveal
attention, and more frontal regions of the brain responsible for letter
recognition and working memory. Perhaps when viewing through their amblyopic
eyes, the observers were still processing the letter identity of a prior
distractor when the color flash associated with the target was detected. After
T1, unfocused temporal attention may have bound together erroneously the
features of succeeding letters, resulting in the appearance of letters that were
not actually presented. These findings highlight the role of early (monocular)
visual processes in modulating the attentional blink, as well as the role of
attention in amblyopic visual deficits. PURPOSE: To learn whether electrophysiological changes indicating amblyopia
occur even in the absence of clinically recognizable amblyopia.
DESIGN: Prospective study.
METHODS: Four consecutive infants between 7 and 19 months of age with unilateral
periocular vascular lesions that intermittently obstructed vision in the
affected eye and no clinical evidence of amblyopia were evaluated. No child had
anisometropia greater than 0.50 diopter in the greatest meridian or strabismus.
Sweep visual evoked potential vernier acuity was measured under monocular
viewing conditions with the fellow eye tested as the control.
RESULTS: Response amplitudes and acuity thresholds were significantly diminished
in the affected eyes. A phase analysis showed slowing of the response in the
affected eyes compared with the control eyes.
CONCLUSIONS: An amblyopia-like effect on vernier acuity occurred in infants with
unilateral periocular vascular birthmarks when the lesion caused intermittent
occlusion of the eye. Whether long-term effects will occur is unknown, but
children with no clinically apparent amblyopia in the setting of a vascular mark
or other cause of intermittent occlusion of the visual axis should be followed,
since these electrophysiology findings suggest amblyopia may be present. PURPOSE: To investigate, using optical coherence tomography (OCT), whether
retinal nerve fiber layer thickness (RNFLT) is affected in amblyopic eyes.
METHODS: Using OCT (Stratus OCT™ [Carl Zeiss, Dublin, CA]), the RNFLT was
measured in 26 patients with persistent unilateral amblyopia and in 25 patients
with recovered unilateral amblyopia. The RNFLT was compared between the affected
and fellow eyes in patients with persistent amblyopia and in those with
recovered amblyopia, and between the amblyopic eyes of patients with persistent
amblyopia and the previously amblyopic eyes of patients with recovered
amblyopia.
RESULTS: In patients with persistent amblyopia and in those with recovered
amblyopia, the affected eyes were significantly more hyperopic than the fellow
eyes. The average (±standard deviation) RNFLT measured 105.5 ± 14.0 μm for the
persistently amblyopic eyes; this value did not significantly differ from that
of the fellow eyes (105.2 ± 13.0 μm) or the previously amblyopic eyes of
recovered amblyopia (107.1 ± 11.7 μm). Also, logistic regression analysis
adjusting for refraction showed no significant difference in the RNFLT between
the persistently amblyopic eyes and the previously amblyopic eyes.
CONCLUSIONS: Our results indicate that there is no significant change in the
RNFLT in amblyopic eyes. Amblyopia is defined as reduced and uncorrectable vision in a structurally
normal eye. Early detection of amblyopia is very important. This can be
accomplished through screening programs designed to identify amblyopia risk
factors. Testing can be performed by trained teachers, technicians, school
nurses and pediatricians as well as by eye care professionals. Once a child is
identified as having an amblyopia risk factor it is crucial that the parents
follow up with a pediatric ophthalmologist for a comprehensive examination.
Amblyopia is the leading cause of monocular vision loss in the United States for
adults under the age of 40. Amblyopia is amenable to therapy and is cost
effective to treat. It is believed that earlier therapy for amblyopia provides
better outcomes, but treatment has been shown effective even in some older
children. In this paper, studies are cited regarding treatment of amblyopia. OBJECTIVE: To confirm if using a neutral density filter (NDF) affects eyes with
strabismic amblyopia differently compared to fellow non-amblyopic eyes, and to
determine if a similar effect could be observed when using a NDF during
peripheral visual field testing.
DESIGN: Prospective controlled case series.
PARTICIPANTS: 19 subjects with strabismic amblyopia with visual acuities between
20/400 and 20/40 in their affected eyes were recruited to the study. Fellow
non-amblyopic eyes served as the control group.
METHODS: Visual acuity in both eyes was assessed using a projected Snellen eye
chart with two NDFs (0.4 and 3.0 densities). Visual fields were assessed using a
Humphrey perimeter using one NDF (0.4 density). Best corrected visual acuity and
visual fields were also recorded.
RESULTS: When using a 3.0 NDF, visual acuity was reduced in all eyes (p <
0.0001). When using a 0.4 NDF, visual acuity was significantly improved in eyes
with strabismic amblyopia compared to unfiltered conditions (p = 0.0011). There
was no significant effect by NDFs on visual field testing in eyes with
strabismic amblyopia or fellow non-amblyopic eyes.
CONCLUSIONS: Neutral density filters affect eyes with strabismic amblyopia
differently than they do non-amblyopic eyes. A significant improvement in visual
acuity of eyes with strabismic amblyopia was observed when using a 0.4 NDF
compared to non-amblyopic eyes. Visual acuity was reduced in amblyopic as well
as non-amblyopic eyes when viewing through a 3.0 NDF. No significant change in
visual fields was observed when using a 0.4 NDF in amblyopic or non-amblyopic
eyes. Amblyopia is characterised by decrease in vision in one or both eyes as a result
of processing defect in the visual pathways of the brain. It is considered an
irreversible process if detected in the adult age group. This study was
conducted from July 1 to December 31, 2010, at Shifa Foundation Community Health
Centre, Islamabad, to determine if anisometropic amblyopia detected in adults
can be reversed. A total of 15 adults, 11 (73.33%) males and 4 (26.66%) females,
were managed for anisometropic amblyopia. All the patients were prescribed full
cycloplegic correction in the anisometropic eye simultaneously with part-time
occlusion therapy. Success was defined as visual acuity of 6/18 or better at the
end of the therapy. All patients were required to complete a structured
questionnaire regarding their experiences with the therapy. Reversal of
amblyopia was observed in 11 (73.33%) patients who felt more confident about
performing tasks for which they had earlier considered themselves unsuitable.
Poor compliance was responsible for not producing the desired outcome in 4
(26.66%) patients. Anisometropic amblyopia in adults is reversible with
dedicated efforts on behalf of both the ophthalmologist and the patient. Amblyopia or "lazy eye" represents a disorder of the visual system characterized
by poor vision in an eye that is otherwise physically normal. Anisometropia, the
condition in which the two eyes have an unequal refractive error, is considered
the second most common cause of amblyopia. The purpose of this study is to
determine the efficiency of HTS Amblyopia iNet Software by studying the progress
of visual acuity, contrast sensitivity and stereopsis vision in anisometropic
amblyopic children. 5 patients (age: 5-13 years), treated with HTS Amblyopia
iNet Software at OftaTotal Clinic from Sibiu, between 2010-2013, participated in
this clinical trial. Initially, visual acuity ranged from 0.25 to 0.8, contrast
sensitivity from 1.35 to 1.65 Log. Unit. and 1 patient presented stereoscopic
vision. After treatment, visual acuity ranged from 0.8 to 1, contrast
sensitivity from 1.35 to 1.95 Log. Unit., also all patients presented
stereoscopic vision. HTS Amblyopia iNet Software represents an effective modern
approach in the treatment of anisometropic amblyopia. Amblyopia is a developmental disorder resulting in poor vision in one eye. The
mechanism by which input to the affected eye is prevented from reaching the
level of awareness remains poorly understood. We recorded simultaneously from
large populations of neurons in the supragranular layers of areas V1 and V2 in 6
macaques that were made amblyopic by rearing with artificial strabismus or
anisometropia, and 1 normally reared control. In agreement with previous
reports, we found that cortical neuronal signals driven through the amblyopic
eyes were reduced, and that cortical neurons were on average more strongly
driven by the non-amblyopic than by the amblyopic eyes. We analyzed multiunit
recordings using standard population decoding methods, and found that visual
signals from the amblyopic eye, while weakened, were not degraded enough to
explain the behavioral deficits. Thus additional losses must arise in downstream
processing. We tested the idea that under monocular viewing conditions, only
signals from neurons dominated by - rather than driven by - the open eye might
be used. This reduces the proportion of neuronal signals available from the
amblyopic eye, and amplifies the interocular difference observed at the level of
single neurons. We conclude that amblyopia might arise in part from degradation
in the neuronal signals from the amblyopic eye, and in part from a reduction in
the number of signals processed by downstream areas. Amblyopia is defined as a loss of letter recognition visual acuity in the
affected eye; however, studies in both nonhuman primates and man have shown that
other important aspects of vision, including color, motion, and contour
perception, are also abnormal. The anatomical changes that occur in the lateral
geniculate nucleus and visual cortex following monocular visual deprivation
affect both eyes and follow very different patterns with deprivation that begins
at different ages and differ markedly in the magnocellular and parvocellular
pathways. The interactions between the eyes and the requirements for recovery
are very different following onset at different ages and differ for
magnocellular and parvocellular pathways. Electrophysiological and
psychophysical studies in man show different patterns of change in patients with
strabismic amblyopia of early and late onset and abnormalities of color and
motion processing that affect both amblyopic and fellow eyes and differ with age
of onset. Abnormal visual experience also has more general effects on
development, with amblyopic children showing abnormalities of eye-hand
coordination when using either their amblyopic or fellow eyes, and abnormalities
of reading. Differential effects of abnormal visual experience and treatment on
magnocellular and parvocellular pathways may account for some of the visual
deficits and treatment failures seen in amblyopia. Unilateral amblyopia is a visual disorder that arises after selective disruption
of visual input to one eye during critical periods of development. In the
clinic, amblyopia is understood as poor visual acuity in an eye that was
deprived of pattern vision early in life. By its nature, however, amblyopia has
an adverse effect on the development of a binocular visual system and the
interactions between signals from two eyes. Visual functions aside from visual
acuity are impacted, and many studies have indicated compromised sensitivity in
the fellow eye even though it demonstrates normal visual acuity. While these
fellow eye deficits have been noted, no overarching theory has been proposed to
describe why and under what conditions the fellow eye is impacted by amblyopia.
Here, we consider four explanations that may account for decreased fellow eye
sensitivity: the fellow eye is adversely impacted by treatment for amblyopia;
the maturation of the fellow eye is delayed by amblyopia; fellow eye sensitivity
is impacted for visual functions that rely on binocular cortex; and fellow eye
deficits reflect an adaptive mechanism that works to equalize the sensitivity of
the two eyes. To evaluate these ideas, we describe five visual functions that
are commonly reported to be deficient in the amblyopic eye (hyperacuity,
contrast sensitivity, spatial integration, global motion, and motion-defined
form), and unify the current evidence for fellow eye deficits. Further research
targeted at exploring fellow eye deficits in amblyopia will provide us with a
broader understanding of normal visual development and how amblyopia impacts the
developing visual system. OBJECTIVE: Amblyopia or lazy eye is a common visual problem affecting children
that cannot correct with lenses. Nitric oxide synthase (NOS) is a critical
enzyme that regulates the activity of nitric oxide (NO), a key signaling
molecule with multiple roles in many tissues. Among its many activities, NOS has
been proposed to be required for normal eye development and altered NOS
expression can lead to perturbations in eye development and vision.
MATERIALS AND METHODS: To examine the potential role of neuronal NOS (nNOS) in
vision loss, we generated a model of monocular deprivation amblyopia in rats.
After suturing one eye, we examined several parameters of neural activity and
nNOS expression in the retina 7, 14 and 28 days later.
RESULTS: We found the rapid and progressive loss of neural activity in the
retina of sutured eyes compared to non-treated and control eyes. The sutured
eyes also showed decreased expression of nNOS at the protein and mRNA levels,
indicating a strong correlation between nNOS expression and retina activity.
CONCLUSIONS: These data suggest a potential role for nNOS activity in vision
loss, opening potential avenues for therapeutic intervention. Amblyopia is a developmental disorder that affects the spatial vision of one or
both eyes in the absence of an obvious organic cause; it is associated with a
history of abnormal visual experience during childhood. Subtypes have been
defined based on the purported etiology, namely, strabismus (misaligned eyes)
and/or anisometropia (unequal refractive error). Here we consider the usefulness
of these subclassifications. Amblyopia is a neurodevelopmental visual disorder arising from decorrelated
binocular experience during the critical periods of development. The hallmark of
amblyopia is reduced visual acuity and impairment in binocular vision. The
consequences of amblyopia on various sensory and perceptual functions have been
studied extensively over the past 50 years. Historically, relatively fewer
studies examined the impact of amblyopia on visuomotor behaviours; however,
research in this area has flourished over the past 10 years. Therefore, the aim
of this review paper is to provide a comprehensive review of current knowledge
about the effects of amblyopia on eye movements, upper limb reaching and
grasping movements, as well as balance and gait. Accumulating evidence indicates
that amblyopia is associated with considerable deficits in visuomotor behaviour
during amblyopic eye viewing, as well as adaptations in behaviour during
binocular and fellow eye viewing in adults and children. Importantly, due to
amblyopia heterogeneity, visuomotor development in children and motor skill
performance in adults may be significantly influenced by the etiology and
clinical features, such as visual acuity and stereoacuity. Studies with larger
cohorts of children and adults are needed to disentangle the unique contribution
of these clinical characteristics to the development and performance of
visuomotor behaviours. BACKGROUND: The role of optometrists in paediatric visual assessment must
compliment the role of other eye-care practitioners at all levels of care. This
study was undertaken to determine if optometrists in Ghana screen, diagnose and
manage paediatric ocular conditions (for example, strabismus, amblyopia), and
further assessed if optometrists in Ghana have the requisite paediatric
instrumentation in their practices.
METHODS: This was a cross-sectional descriptive survey involving optometrists in
both public and private eye-care sectors in Ghana. A paediatric visual
assessment questionnaire was sent to all registered optometrists in Ghana. The
contents of the questionnaire evaluated areas of vision assessment, refraction,
and previous diagnosis and management, which were matched with practice
characteristics such as location, type of practice and type of employment.
Chi-squared statistic was used to test associations between variables.
RESULTS: Responses were obtained from 140 optometrists out of the 326 registered
optometrists, representing a response rate of 46 per cent. Overall, less than
half of respondents (64 which represents 46 per cent) assessed themselves as
practising full-scope paediatric eye care. These self-assessment views were more
common among optometrists at the regional level (111: 79.3 per cent), followed
by the district (20: 14.3 per cent) and sub-district levels (nine: 6.4 per cent)
(χ2 = 4.774, p < 0.05), but was not influenced by type of employment, type of
practice and level of training (p > 0.05). In addition, the study revealed that
many respondents were more likely to assess pre-schoolers' visual acuity (VA)
(121: 96.0 per cent), do refraction (109: 88.6 per cent) and perform binocular
vision (BV) assessment (93: 76.9 per cent) compared to the toddlers' VA (72:
55.4 per cent), refraction (57: 46 per cent) and BV assessment (68: 56.2 per
cent).
CONCLUSION: Full-scope paediatric eye care services among optometrists in Ghana
is limited. Amblyopia is the most common cause of monocular visual impairment in children,
with a prevalence of 2-3%. Not only is visual acuity reduced in one eye but
binocular vision is affected, fellow eye deficits may be present, eye-hand
coordination and reading can be affected, and self-perception may be diminished.
New technologies for preschool vision screening hold promise for accessible,
early, and accurate detection of amblyopia. Together with recent advances in our
theoretical understanding of amblyopia and technological advances in amblyopia
treatment, we anticipate improved visual outcomes for children affected by this
very common eye condition. This article is based on previously conducted studies
and does not contain any new studies with human participants or animals
performed by any of the authors. There is no consensus on whether amblyopia affects the retinal vascular plexus
and morphology. Previous studies focused on the differences between amblyopic
patients and normal controls without evaluating amblyopic eyes after patching.
To evaluate differences in the superficial vascular density of amblyopic eyes,
normal eyes, and amblyopic eyes reaching normal BCVA after patch therapy, OCTA
was used. All patients underwent a comprehensive ophthalmological examination,
including visual acuity, refraction, ocular motility tests, and anterior and
posterior segment examination. OCTA was performed by an expert physician using
the Zeiss Cirrus 5000-HD-OCT Angioplex (Carl Zeiss, Meditec, Inc., Dublin, OH,
USA). OCTA scans were performed using a 3 × 3 mm2 and 6 × 6 mm2 fovea-centered
image setting. The mean outer macular vessel density in the previously amblyopic
group was 19.15 ± 0.51%. This was statistically significantly higher than in
both the amblyopic group (18.70 ± 1.14%) and the normal controls (18.18 ± 1.40%)
(p = 0.014). The previously amblyopic group also significantly differed from
both normal controls and amblyopic eyes with regards to the inner (p = 0.011),
outer (p = 0.006), and full (p = 0.003) macular perfusion. Finally, linear
regression analysis revealed that BCVA was linearly correlated to outer
perfusion in amblyopic (p = 0.003) and ex amblyopic eyes (p < 0.001).
Considering the cross-sectional nature of our study, from our results, we can
only hypothesize a possible correlation between light stimulation and retinal
vasculature development. However, further longitudinal studies are needed to
support this hypothesis. Amblyopia is a reduced best-corrected visual acuity of one or both eyes that
cannot be attributed to a structural abnormality; it is a functional reduction
in the vision of an eye caused by disuse during a critical period of visual
development. It is considered the leading cause of visual defects in children.
With early diagnosis and treatment, children with amblyopia can significantly
improve their vision. However, if it is neglected and not treated during
childhood, unfortunately, it permanently decreases vision. Therefore,
prevention, detection, and treatment largely depend on parents. This article
explores parents' perspectives on amblyopia and routine examination of their
children's eyes. A cross-sectional study used an electronic questionnaire
consisting of five main sections to assess the level of awareness of amblyopia
among parents. As a result, a total of 325 participants were included in our
analysis. 209 (64.3%) were mothers, and 116 (35/7%) were fathers. The age groups
were 35-50 years of age (61.5%), 20-34 years (23.4%), and older than 50 years
(15%). Participants with a history of amblyopia numbered 23 (7.1%), and 39 had
an amblyopic child (12%). A good awareness level of amblyopia among parents was
found in only 10 (3%) participants, a fair awareness level in 202 (62%), and 113
(35%) participants were classified as having a poor awareness level of
amblyopia. Only 13.8% of the parents took their children for yearly routine eye
exams, while the majority (72%) took their children only if they had a
complaint, and 14.2% took them for eye checkups only before school entry. In
conclusion, parents' awareness of amblyopia in Tabuk City, KSA, was low. In
addition, a limited proportion of parents reported consistently taking their
children for routine eye exams. Therefore, raising awareness should be
considered in public education regarding the disease. |