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http://www.ncbi.nlm.nih.gov/pubmed/17327733 | 1. Curr Opin Crit Care. 2007 Apr;13(2):134-42. doi: 10.1097/MCC.0b013e3280895d5c.
Neuroprotection in traumatic brain injury: a complex struggle against the
biology of nature.
Schouten JW(1).
Author information:
(1)Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The
Netherlands. [email protected]
PURPOSE OF REVIEW: Translating the efficacy of neuroprotective agents in
experimental traumatic brain injury to clinical benefit has proven an extremely
complex and, to date, unsuccessful undertaking. The focus of this review is on
neuroprotective agents that have recently been evaluated in clinical trials and
are currently under clinical evaluation, as well as on those that appear
promising and are likely to undergo clinical evaluation in the near future.
RECENT FINDINGS: Excitatory neurotransmitter blockage and magnesium have
recently been evaluated in phase III clinical trials, but showed no
neuroprotective efficacy. Cyclosporin A, erythropoietin, progesterone and
bradykinin antagonists are currently under clinical investigation, and appear
promising.
SUMMARY: Traumatic brain injury is a complex disease, and development of
clinically effective neuroprotective agents is a difficult task. Experimental
traumatic brain injury has provided numerous promising compounds, but to date
these have not been translated into successful clinical trials. Continued
research efforts are required to identify and test new neuroprotective agents,
to develop a better understanding of the sequential activity of pathophysiologic
mechanisms, and to improve the design and analysis of clinical trials, thereby
optimizing chances for showing benefit in future clinical trials.
DOI: 10.1097/MCC.0b013e3280895d5c
PMID: 17327733 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23364988 | 1. Yonsei Med J. 2013 Mar 1;54(2):500-9. doi: 10.3349/ymj.2013.54.2.500.
Analysis of single nucleotide polymorphism in adolescent idiopathic scoliosis in
Korea: for personalized treatment.
Moon ES(1), Kim HS, Sharma V, Park JO, Lee HM, Moon SH, Chong HS.
Author information:
(1)Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei
University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-720, Korea.
PURPOSE: The incidence of adolescent idiopathic scoliosis (AIS) has rapidly
increased, and with it, physician consultations and expenditures (about one and
a half times) in the last 5 years. Recent etiological studies reveal that AIS is
a complex genetic disorder that results from the interaction of multiple gene
loci and the environment. For personalized treatment of AIS, a tool that can
accurately measure the progression of Cobb's angle would be of great use. Gene
analysis utilizing single nucleotide polymorphism (SNP) has been developed as a
diagnostic tool for use in Caucasians but not Koreans. Therefore, we attempted
to reveal AIS-related genes and their relevance in Koreans, exploring the
potential use of gene analysis as a diagnostic tool for personalized treatment
of AIS therein.
MATERIALS AND METHODS: A total of 68 Korean AIS and 35 age- and sex-matched,
healthy adolescents were enrolled in this study and were examined for 10
candidate scoliosis gene SNPs.
RESULTS: This study revealed that the SNPs of rs2449539 in lysosomal-associated
transmembrane protein 4 beta (LAPTM4B) and rs5742612 in upstream and
insulin-like growth factor 1 (IGF1) were associated with both susceptibility to
and curve severity in AIS. The results suggested that both LAPTM4B and IGF1
genes were important in AIS predisposition and progression.
CONCLUSION: Thus, on the basis of this study, if more SNPs or candidate genes
are studied in a larger population in Korea, personalized treatment of Korean
AIS patients might become a possibility.
DOI: 10.3349/ymj.2013.54.2.500
PMCID: PMC3575984
PMID: 23364988 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no financial conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18661102 | 1. J Neurooncol. 2008 Nov;90(2):229-35. doi: 10.1007/s11060-008-9655-9. Epub 2008
Jul 26.
A phase II study of thalidomide and irinotecan for treatment of glioblastoma
multiforme.
Fadul CE(1), Kingman LS, Meyer LP, Cole BF, Eskey CJ, Rhodes CH, Roberts DW,
Newton HB, Pipas JM.
Author information:
(1)Department of Medicine, Section of Hematology/Oncology, Norris Cotton Cancer
Center, Dartmouth Hitchcock Medical Center Drive, One Medical Center Drive,
Lebanon, NH 03756, USA. [email protected]
PURPOSE: Irinotecan is a cytotoxic agent with activity against gliomas.
Thalidomide, an antiangiogenic agent, may play a role in the treatment of
glioblastoma multiforme (GBM). To evaluate the combination of thalidomide and
irinotecan, we conducted a phase II trial in adults with newly-diagnosed or
recurrent GBM.
PATIENTS AND METHODS: Thalidomide was given at a dose of 100 mg/day, followed by
dose escalation every 2 weeks by 100 mg/day to a target of 400 mg/day.
Irinotecan was administered on day 1 of each 3 week cycle. Irinotecan dose was
700 mg/m(2) for patients taking enzyme-inducing anticonvulsants and 350 mg/m(2)
for all others. The primary endpoint was tumor response, assessed by MRI.
Secondary endpoints were toxicity, progression-free survival, and overall
survival.
RESULTS: Twenty-six patients with a median age of 55 years were enrolled, with
fourteen evaluable for the primary outcome, although all patients were included
for secondary endpoints. One patient (7%) exhibited a partial response after
twelve cycles, and eleven patients (79%) had stable disease. The intention to
treat group with recurrent disease included 16 patients who had a 6-month PFS of
19% (95% CI: 4-46%) and with newly-diagnosed disease included 10 patients who
had a 6-month PFS of 40% (95% CI: 12-74%). Gastrointestinal (GI) toxicity was
mild, but six patients (23%) experienced a venous thromboembolic complication.
Two patients had Grade 4 treatment-related serious adverse events that required
hospitalization. There were no treatment-related deaths.
CONCLUSION: The combination of irinotecan and thalidomide has limited activity
against GBM. Mild GI toxicity was observed, but venous thromboembolic
complications were common.
DOI: 10.1007/s11060-008-9655-9
PMCID: PMC3885231
PMID: 18661102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18571879 | 1. Gene. 2008 Aug 15;420(1):34-41. doi: 10.1016/j.gene.2008.05.008. Epub 2008 May
23.
Splicing and splice factor SRp55 participate in the response to DNA damage by
changing isoform ratios of target genes.
Filippov V(1), Schmidt EL, Filippova M, Duerksen-Hughes PJ.
Author information:
(1)Center for Health Disparities and Molecular Medicine, Department of
Biochemistry and Microbiology, Loma Linda University School of Medicine, Loma
Linda, CA 92354, USA.
Alternative splicing is an important source of protein diversity, and is an
established but not yet fully understood mechanism for gene regulation in higher
eukaryotes. Its regulation is governed by a variety of mechanisms, including
variation in the expression levels of splicing factors engaged in spliceosome
formation. SRp55 is one of the most ubiquitous splicing factors and one that can
be up-regulated by DNA damage in the absence of p53, and we had previously found
that depletion of its activity increased resistance to DNA damage in
p53-dependant manner. To assess its influence on the splicing patterns of genes
involved in apoptosis, we performed splice-specific microarray analysis of cells
treated with siRNA specific for this gene. This analysis, backed by RT-PCR
verification, identified three genes, KSR1, ZAK and mda7/IL24, which are
sensitive to SRp55 depletion. We also analyzed the splice patterns of
apoptosis-related genes in p53-deficient U2OS cells following treatment with the
genotoxic drug mitomycin C. This analysis revealed that DNA damage resulted in
changes in splicing activity that modified the splicing pattern of Fas, a key
pro-apoptotic, p53-inducible death receptor. Interestingly, this modification
led to an enrichment of the anti-apoptotic soluble Fas isoform, and this
secreted isoform was detected in the media surrounding cells subjected to DNA
damage. These findings show that modulation of splicing activity in
p53-deficient cells during the early response to sub-lethal DNA damage results
in a change in the splicing of target genes, thus modifying the cellular
response to genotoxic agents.
DOI: 10.1016/j.gene.2008.05.008
PMCID: PMC2562212
PMID: 18571879 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18360636 | 1. Ther Clin Risk Manag. 2007 Jun;3(2):277-89. doi: 10.2147/tcrm.2007.3.2.277.
Dapoxetine, a novel selective serotonin transport inhibitor for the treatment of
premature ejaculation.
Kendirci M, Salem E, Hellstrom WJ.
Premature ejaculation (PE) is the most common male sexual disorder, estimated to
affect up to 30% of men. Over the past one or two decades, clinical
investigators have participated in an increasing number of studies that are
helping in our understanding of PE, which will undoubtedly facilitate future
treatments. Apart from a number of behavioral approaches, the treatment of PE
consists of primarily off-label use of oral selective serotonin reuptake
inhibitors (SSRIs) via either on-demand or daily delivery. However, various
undesirable side-effects of these medications have led researchers to search for
and develop new therapeutic approaches for PE. Dapoxetine is a short-acting SSRI
developed specifically for the treatment of PE. Early trials with dapoxetine
have documented successful outcomes without serious short- or long-term
side-effects. This review addresses the definition, classification, diagnosis,
physiology, and neurobiopathology of PE, and evaluates therapeutic strategies
with novel treatments for PE.
DOI: 10.2147/tcrm.2007.3.2.277
PMCID: PMC1936309
PMID: 18360636 |
http://www.ncbi.nlm.nih.gov/pubmed/16053669 | 1. Cancer J. 2005 May-Jun;11(3):248-51. doi: 10.1097/00130404-200505000-00012.
Thalidomide is inactive in heavily pretreated patients with metastatic breast
cancer.
Morabito A(1), Carillio G, Longo R, Gasparini G.
Author information:
(1)Division of Medical Oncology, San Filippo Neri Hospital, Rome, Italy.
Experimental studies have demonstrated that thalidomide has anti-tumor activity
mediated by blockage of angiogenesis, with clinical efficacy in multiple
myeloma, glioblastoma multiforme, and renal cell cancer. We investigated the
therapeutic activity and toxicity of thalidomide in patients with progressive
metastatic breast cancer pretreated with chemotherapy. Inclusion criteria were
metastatic breast cancer in progression of disease after at least two lines of
chemotherapy, age > or = 18 years, performance status < or = 2, and adequate
hematologic, renal, and hepatic functions. Twelve patients entered the study,
eight of whom were pretreated with three or more lines of chemotherapy (66.7%).
Thalidomide was well tolerated: the most common side effects were constipation
and somnolence (58.3% of patients). No objective response or durable stable
disease was observed. Median time to progression and median overall survival
were 8 weeks (range, 4-10 weeks) and 16 weeks (range, 8-54 weeks), respectively.
In conclusion, thalidomide is an ineffective treatment in patients with
progressive metastatic breast cancer heavily pretreated with chemotherapy.
DOI: 10.1097/00130404-200505000-00012
PMID: 16053669 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18684638 | 1. Crit Rev Oncol Hematol. 2008 Dec;68(3):264-71. doi:
10.1016/j.critrevonc.2008.06.012. Epub 2008 Aug 6.
Angioimmunoblastic T-cell lymphoma.
Iannitto E(1), Ferreri AJ, Minardi V, Tripodo C, Kreipe HH.
Author information:
(1)Division of Hematology, High Dose Therapy Unit, Policlinico Paolo Giaccone,
Palermo, Italy.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive neoplasm
clinically characterized by sudden onset of constitutional symptoms,
lymphadenopathy, hepatosplenomegaly, frequent autoimmune phenomena, particularly
hemolytic anemia and thrombocytopenia, and polyclonal hypergammaglobulinemia.
The lymph node histological picture is also distinctive, constituted by a
polymorphic infiltrate, a marked proliferation of high endothelial venules, and
a dense meshwork of dentritic cells. The neoplastic CD4+ T-cells represent a
minority of the lymph node cell population; its detection is facilitated by the
aberrant expression of CD10. Almost all cases arbor an EBV infected B-cell
population. Patients with AITL have a poor prognosis with conventional
treatment, with a median overall survival of less than 3 years. Patients
achieving a good clinical response seem beneficiate from a consolidation with
high-dose therapy and autologous stem cell transplantation. Constitutional
symptoms and autoimmune phenomena, and some times also the neoplastic masses may
respond to immunosuppressive or immunomodulatory agents such as thalidomide.
DOI: 10.1016/j.critrevonc.2008.06.012
PMID: 18684638 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15175031 | 1. J Invest Dermatol. 2004 Jun;122(6):1406-12. doi:
10.1111/j.0022-202X.2004.22619.x.
Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin
deposition in allergen-challenged human atopic skin.
Phipps S(1), Flood-Page P, Menzies-Gow A, Ong YE, Kay AB.
Author information:
(1)Department of Allergy and Clinical Immunology, Imperial College London, NHLI
Division, London, UK.
Anti-IL-5 monoclonal antibody (mepolizumab) reduces baseline bronchial mucosal
eosinophils and deposition of extracellular matrix proteins in the reticular
basement membrane in mild asthma. Here we report the effect of anti-IL-5, in the
same patients, on allergen-induced eosinophil accumulation, tenascin deposition
(as a marker of repair and remodelling) and the magnitude of the late-phase
allergic cutaneous reaction. Skin biopsies were performed in 24 atopic subjects
at allergen- and diluent-injected sites before 6 and 48 h after, three infusions
of a humanized, monoclonal antibody against IL-5 (mepolizumab) using a
randomized double-blind, placebo-controlled design. Anti-IL-5 significantly
inhibited eosinophil infiltration in 6 h and 48 h skin biopsies as well as the
numbers of tenascin immunoreactive cells at 48 h. In contrast, anti-IL-5 had no
significant effect on the size of the 6 or 48 h late-phase cutaneous allergic
reaction. This study (a) suggests that eosinophils are unlikely to cause the
redness, swelling, and induration characteristic of the peak (6 h) late-phase
cutaneous allergic reaction and (b) shows that decreases in tenascin positive
cells at 48 h correlates with reduction of eosinophils, so providing further
evidence of involvement in remodelling processes associated with allergic
inflammation.
DOI: 10.1111/j.0022-202X.2004.22619.x
PMID: 15175031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21192222 | 1. Spine (Phila Pa 1976). 2011 Jan 1;36(1):37-40. doi:
10.1097/BRS.0b013e3181e8755b.
Genetic variants in melatonin synthesis and signaling pathway are not associated
with adolescent idiopathic scoliosis.
Nelson LM(1), Ward K, Ogilvie JW.
Author information:
(1)Axial Biotech, Inc, Salt Lake City, Utah, USA. [email protected]
STUDY DESIGN: Genetic association study investigating the association of genetic
markers of melatonin signaling and biosynthesis with adolescent idiopathic
scoliosis (AIS).
OBJECTIVE: To determine whether gene polymorphisms related to the melatonin
signaling or biosynthesis pathways are associated with AIS.
SUMMARY OF BACKGROUND DATA: Data have been published on the potential role of
gene polymorphisms for melatonin receptor (MTNR) 1B in predicting AIS. Other
genes in the melatonin pathways have been tested for association with AIS.
METHODS: The following genes involved in melatonin synthesis were evaluated
herein: tryptophan 5-hyroxylase 1 (TPH1), serotonin N-acetyltransferase (SNAT),
and hydroxyindoleo-methyltransferase (HIOMT). In addition, proteins involved in
melatonin signaling were also included in this study: MTNR1A, MTNR1B, and
protein kinase C delta (PKCd). High throughput microarray-based single
nucleotide polymorphism (SNP) genotyping was performed for these seven genes
using DNA samples from 589 AIS subjects and 1533 ethnically matched controls.
Chi-square analyses of allele frequency between AIS cases and controls were
performed and odds ratios were calculated for all SNP markers.
RESULTS: Three SNPs were tested for both MTNR1A and HIOMT, 4 for TPH1 and SNAT,
12 for PKCd, and 7 for MTNR1B. The minor allele frequencies were not
significantly different between AIS cases and controls. No association was thus
found between AIS and the investigated SNPs.
CONCLUSIONS: Genetic polymorphisms associated with either melatonin synthesis or
its signaling pathway are unlikely to be commonly associated with AIS.
DOI: 10.1097/BRS.0b013e3181e8755b
PMID: 21192222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15643101 | 1. J Clin Psychopharmacol. 2005 Feb;25(1):59-73. doi:
10.1097/01.jcp.0000150228.61501.e4.
The use of selective serotonin reuptake inhibitors during pregnancy and
breast-feeding: a review and clinical aspects.
Hallberg P(1), Sjöblom V.
Author information:
(1)Department of Clinical Pharmacology, Uppsala University Hospital, Uppsala,
Sweden. [email protected]
Mood and anxiety disorders are common in women during their childbearing years.
The prevalence of depression has been reported to be between 10% and 16% during
pregnancy. The use of selective serotonin reuptake inhibitors during pregnancy
or lactation is, to date, not promoted because of lack of safety documentation.
However, the off-label use of these drugs has been common for several years. In
the treatment of mood and anxiety disorders during pregnancy, the serotonin
reuptake inhibitors are often preferred over tricyclic antidepressants because
of their relatively few adverse effects and safety in overdose. This has created
concern among women planning pregnancies and pregnant women, as well as among
their families and physicians. Several studies and reports of the use of
serotonin reuptake inhibitors during both pregnancy and lactation have been
published and advanced our knowledge. We here review and discuss those studies
which have been published so far on this subject.
DOI: 10.1097/01.jcp.0000150228.61501.e4
PMID: 15643101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10951518 | 1. Eur J Hum Genet. 2000 Aug;8(8):571-7. doi: 10.1038/sj.ejhg.5200499.
A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to
craniosynostosis?
Johnson D(1), Wall SA, Mann S, Wilkie AO.
Author information:
(1)Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford,
UK.
Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3)
and TWIST genes have been identified in several syndromic forms of
craniosynostosis. There remains, however, a significant number of patients with
non-syndromic craniosynostosis in whom no genetic cause can be identified. We
describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino
acid substitution Ala315Ser) in a girl with non-syndromic unicoronal
craniosynostosis. The mutation is also present in her mother and her maternal
grandfather who have mild facial asymmetry but do not have craniosynostosis.
None of these individuals has the Crouzonoid appearance typically associated
with FGFR2 mutations. However, the obstetric history revealed that the proband
was in persistent breech presentation in utero and was delivered by Caesarean
section, at which time compression of the skull was apparent. We propose that
this particular FGFR2 mutation only confers a predisposition to craniosynostosis
and that an additional environmental insult (in this case foetal head constraint
associated with breech position) is necessary for craniosynostosis to occur. To
our knowledge, this is the first report of an interaction between a weakly
pathogenic mutation and intrauterine constraint, leading to craniosynostosis.
DOI: 10.1038/sj.ejhg.5200499
PMID: 10951518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17031561 | 1. J Neurooncol. 2007 Feb;81(3):271-7. doi: 10.1007/s11060-006-9225-y. Epub 2006
Sep 22.
A North American brain tumor consortium (NABTC 99-04) phase II trial of
temozolomide plus thalidomide for recurrent glioblastoma multiforme.
Groves MD(1), Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW,
Liu TJ, Peterson P, Schiff D, Cloughesy TF, Wen PY, Greenberg H, Abrey LE,
DeAngelis LM, Hess KR, Lamborn KR, Prados MD, Yung WK.
Author information:
(1)Department of Neuro-Oncology, The University of Texas MD Anderson Cancer
Center, 1400 Holcombe, 431, Houston, TX, 77030, USA. [email protected]
BACKGROUND: Laboratory and clinical data suggest that the anti-angiogenic agent,
thalidomide, if combined with cytotoxic agents, may be effective against
recurrent glioblastoma multiforme (GBM).
OBJECTIVES: To determine 6-month progression-free survival (6PFS) and toxicity
of temozolomide plus thalidomide in adults with recurrent GBM.
PATIENTS AND METHODS: Eligible patients had recurrent GBM after surgery,
radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200
mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at
400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients
were evaluated with magnetic resonance imaging scans every 56 days. The study
was designed to detect an increase of the historical 6PFS for GBM from 10 to
30%.
RESULTS: Forty-four patients were enrolled, 43 were evaluable for efficacy and
safety. The study population included 15 women, 29 men; median age was 53 years
(range 32-84); median Karnofsky performance status was 80% (range 60-100%).
Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of
toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in
15 patients (34%). The objective response rate was 7%. The estimated probability
of being progression-free at 6 months with this therapy is 24% [95% confidence
interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I.
10-20 weeks). There was no observed correlation between serum levels of vascular
endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS
outcome.
CONCLUSION: This drug combination was reasonably safe, but with little
indication of improvement compared to temozolomide alone.
DOI: 10.1007/s11060-006-9225-y
PMID: 17031561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19546072 | 1. Heart Surg Forum. 2009 Jun;12(3):E175-9. doi: 10.1532/HSF98.20081133.
Trimetazidine may protect the myocardium during cardiac surgery.
Iskesen I(1), Kurdal AT, Eserdag M, Cerrahoglu M, Sirin BH.
Author information:
(1)Department of Cardiovascular Surgery, Celal Bayar University, School of
Medicine, Manisa, Turkey. [email protected]
BACKGROUND: Trimetazidine is an anti-ischemic agent with cardioprotective
effects. The purpose of this double-blind, controlled, prospective randomized
study was to investigate the possible effects of the preoperative use of
trimetazidine on the biochemical markers of myocardial injury during open heart
surgery and to determine if it has any myocardial protective effects.
METHODS: Thirty patients undergoing coronary artery bypass grafting surgery,
received either trimetazidine (study group, n = 15) or not (control group, n =
15). Pretreatment began 2 weeks before the operation with trimetazidine (60
mg/day orally), and the control group received no medication. We measured the
levels of serum creatine kinase (CK), CK isoenzyme MB (CK-MB), myoglobin, and
troponin T in venous blood samples obtained before and after the operation to
evaluate the effect of this drug against myocardial damage. We also took serial
blood samples from the radial artery and the coronary sinus before the
institution of cardiopulmonary bypass (CPB) and at 2 and 15 minutes after the
removal of the cross-clamp to measure lactate levels and calculate the lactate
extraction of the myocardium.
RESULTS: Postoperative levels of myoglobin, troponin T, CK, and CK-MB were
significantly lower in the trimetazidine group than in the control group (P <
.05). There was also a significant difference in the values for the lactate
extraction calculation between the groups at minute 2 after the removal of the
cross-clamp (P < .05).
CONCLUSION: We conclude that pretreatment with trimetazidine has some beneficial
effects in protecting the myocardium and decreasing myocardial injury during the
cardioplegic arrest period in open heart surgery without affecting postoperative
hemodynamics.
DOI: 10.1532/HSF98.20081133
PMID: 19546072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9917362 | 1. Dev Biol. 1999 Jan 15;205(2):260-74. doi: 10.1006/dbio.1998.9114.
Msx2 gene dosage influences the number of proliferative osteogenic cells in
growth centers of the developing murine skull: a possible mechanism for
MSX2-mediated craniosynostosis in humans.
Liu YH(1), Tang Z, Kundu RK, Wu L, Luo W, Zhu D, Sangiorgi F, Snead ML, Maxson
RE.
Author information:
(1)Department of Biochemistry and Molecular Biology, Kenneth R. Norris Cancer
Hospital and Institute, 1441 Eastlake Avenue, Los Angeles, California, 90033,
USA.
Throughout its complex morphogenesis, the vertebrate skull must at once protect
the brain and expand to accommodate its growth. A key structural adaptation that
allows this dual role is the separation of the bony plates of the skull with
sutures, fibrous joints that serve as growth centers and allow the calvarial
bones to expand as the brain enlarges. Craniosynostosis, the premature fusion of
one or more calvarial bones with consequent abnormalities in skull shape, is a
common developmental anomaly that disrupts this process. We found previously
that a single amino acid substitution in the homeodomain of the human MSX2 gene
is associated with the autosomal dominant disorder craniosynostosis, Boston
type. This mutation enhances the affinity of Msx2 for its target sequence,
suggesting that the mutation acts by a dominant positive mechanism. Consistent
with this prediction, we showed that general overexpression of Msx2 under the
control of the broadly expressed CMV promoter causes the calvarial bones to
invade the sagittal suture. Here we use tissue-specific overexpression of Msx2
within the calvarial sutures to address the developmental mechanisms of
craniosynostosis and skull morphogenesis. We demonstrate that a segment of the
Msx2 promoter directs reporter gene expression to subsets of cells within the
sutures. In late embryonic and neonatal stages, this promoter is expressed in
undifferentiated mesenchymal cells medial to the growing bone. By P4, promoter
activity is reduced in the suture, exhibiting a punctate pattern in
undifferentiated osteoblastic cells in the outer margin of the osteogenic front.
Overexpression of Msx2 under the control of this promoter is sufficient to
enhance parietal bone growth into the sagittal suture by P6. This phenotype is
preceded by an increase in both the number and the BrdU labeling of osteoblastic
cells in the osteogenic fronts of the calvarial bones. These findings suggest
that an important early event in MSX2-mediated craniosynostosis in humans is a
transient retardation of osteogenic cell differentiation in the suture and a
consequent increase in the pool of osteogenic cells.
Copyright 1999 Academic Press.
DOI: 10.1006/dbio.1998.9114
PMID: 9917362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22615788 | 1. PLoS One. 2012;7(5):e36648. doi: 10.1371/journal.pone.0036648. Epub 2012 May
15.
Normal leptin expression, lower adipogenic ability, decreased leptin receptor
and hyposensitivity to Leptin in Adolescent Idiopathic Scoliosis.
Liang G(1), Gao W, Liang A, Ye W, Peng Y, Zhang L, Sharma S, Su P, Huang D.
Author information:
(1)Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen
University, Guangzhou, Guangdong, China.
Leptin has been suggested to play a role in the etiology of Adolescent
Idiopathic Scoliosis (AIS), however, the leptin levels in AIS girls are still a
discrepancy, and no in vitro study of leptin in AIS is reported. We took a
series of case-control studies, trying to understand whether Leptin gene
polymorphisms are involved in the etiology of the AIS or the change in leptin
level is a secondary event, to assess the level of leptin receptor, and to
evaluate the differences of response to leptin between AIS cases and controls.
We screened all exons of Leptin gene in 45 cases and 45 controls and selected
six tag SNPs to cover all the observed variations. Association analysis in 446
AIS patients and 550 healthy controls showed no association between the
polymorphisms of Leptin gene and susceptibility/severity to AIS. Moreover,
adipogenesis assay of bone mesenchymal stem cells (MSCs) suggested that the
adipogenic ability of MSCs from AIS girls was lower than controls. After
adjusting the differentiation rate, expressions of leptin and leptin receptor
were similar between two groups. Meanwhile, osteogenesis assay of MSC showed the
leptin level was similar after adjusting the differentiation rate, but the
leptin receptor level was decreased in induced AIS osteoblasts.
Immunocytochemistry and western blot analysis showed less leptin receptors
expressed in AIS group. Furthermore, factorial designed studies with
adipogenesis and osteogenesis revealed that the MSCs from patients have no
response to leptin treatment. Our results suggested that Leptin gene variations
are not associated with AIS and low serum leptin probably is a secondary outcome
which may be related to the low capability of adipogenesis in AIS. The decreased
leptin receptor levels may lead to the hyposensitivity to leptin. These findings
implied that abnormal peripheral leptin signaling plays an important role in the
pathological mechanism of AIS.
DOI: 10.1371/journal.pone.0036648
PMCID: PMC3352937
PMID: 22615788 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/20543391 | 1. Stud Health Technol Inform. 2010;158:3-7.
Recent advances in the study of candidate genes for adolescent idiopathic
scoliosis.
Fendri K(1), Patten S, Zaouter C, Parent S, Kaufman G, Labelle H, Edery P,
Moldovan F.
Author information:
(1)CHU Sainte Justine and Université de Montréal, Montreal, Canada.
We used a microarray approach to evaluate gene expression profiles in human AIS
osteoblasts, and to identify genes that are differentially expressed following
estrogen exposure in non-AIS and AIS human osteoblasts. We found that more than
one gene is likely responsible for AIS. Furthermore, some of these genes are
estrogen-regulated, suggesting a possible role of estrogens in the etiology of
scoliosis.
PMID: 20543391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17003465 | 1. Sci STKE. 2006 Sep 26;2006(354):pe35. doi: 10.1126/stke.3542006pe35.
Tumor suppression by p53 is mediated in part by the antiangiogenic activity of
endostatin and tumstatin.
Folkman J(1).
Author information:
(1)Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
[email protected]
Recent research shows that p53 suppresses tumor angiogenesis by
transcriptionally activating the alpha(II) collagen prolyl-4-hydroxylase gene.
This results in the extracellular release of the potent endogenous angiogenesis
inhibitors endostatin and tumstatin from collagens 18 and 4, respectively. The
involvement of these inhibitors elucidates a molecular mechanism. By
simultaneously repressing a multitude of proangiogenic pathways and by inducing
antiangiogenic pathways, a tumor suppressor protein can prevent an incipient
tumor from switching to the angiogenic phenotype. Thus, p53 guards the genome
from cancer by controlling the three fundamental processes that are critical for
growth of a primary tumor and its metastases-tumor cell proliferation,
apoptosis, and tumor angiogenesis.
DOI: 10.1126/stke.3542006pe35
PMID: 17003465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22324799 | 1. Anal Chem. 2012 Mar 20;84(6):2631-7. doi: 10.1021/ac300006b. Epub 2012 Mar 1.
Consecutive proteolytic digestion in an enzyme reactor increases depth of
proteomic and phosphoproteomic analysis.
Wiśniewski JR(1), Mann M.
Author information:
(1)Department of Proteomics and Signal Transduction, Max Planck Institute of
Biochemistry, Martinsried, Germany. [email protected]
Analytical advantages of using multiple enzymes for sample digestion (MED),
primarily an increase of sequence coverage, have been reported in several
studies. However, this approach is only rarely used, mainly because it requires
additional sample and mass spectrometric measurement time. We have previously
described Filter Aided Sample Preparation (FASP), a type of proteomic reactor,
in which samples dissolved in sodium dodecyl sulfate (SDS) are digested in an
ultrafiltration unit. In FASP, such as in any other preparation protocol, a
portion of sample remains after digestion and peptide elution. Making use of
this fact, we here develop a protocol enabling consecutive digestion of the
sample with two or three enzymes. By use of the FASP method, peptides are
liberated after each digestion step and remaining material is subsequently
cleaved with the next proteinase. We observed excellent performance of the
ultrafiltration devices in this mode, allowing efficient separation of
orthogonal populations of peptides, resulting in an increase in the numbers of
identified peptides and proteins. At the low microgram level, we found that the
consecutive use of endoproteinases LysC and trypsin enabled identification of up
to 40% more proteins and phosphorylation sites in comparison to the commonly
used one-step tryptic digestion. MED-FASP offers efficient exploration of
previously unused sample material, increasing depth of proteomic analyses and
sequence coverage.
DOI: 10.1021/ac300006b
PMID: 22324799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15770836 | 1. Pediatr Hematol Oncol. 2005 Jan-Feb;22(1):83-7. doi:
10.1080/08880010590896440.
No aberrant methylation of neurofibromatosis 1 gene (NF1) promoter in pilocytic
astrocytoma in childhood.
Ebinger M(1), Senf L, Wachowski O, Scheurlen W.
Author information:
(1)Institute of Pathology, Department of Molecular Pathology, University
Hospital, Tuebingen, Germany. [email protected]
Tumors of the central nervous system are the most frequent solid tumors in
childhood. With 30-40% of this heterogenous group, low-grade astrocytomas
represent the most common subtype. Neurofibromatosis type 1 (NF1) is strongly
associated with the development of pilocytic astrocytoma (PA), frequently
appearing as optic glioma. Neurofibromatosis 1 gene (NF1 ) fulfills the criteria
of a tumor suppressor gene and is deleted or mutated heterozygously in patients
with NF1. This suggests an involvement in the development of PA. To clarify
whether silencing of NF1 by promoter methylation plays a role in PA and
especially in optic glioma, the authors investigated the methylation status in
30 PA, 6 of which had optic glioma. However, no methylation was found at the NF1
promoter region in PA. To rule out that silencing of NF1 by promoter methylation
is restricted to higher-grade astrocytomas, 15 pediatric WHO II degree and IV
degree astrocytomas were analyzed: 12 astrocytomas II and 3 glioblastomas
displayed no NF1 promoter methylation. The authors conclude that NF1 silencing
by methylation plays no role in low-grade astrocytoma.
DOI: 10.1080/08880010590896440
PMID: 15770836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24353405 | 1. Drug Des Devel Ther. 2013 Dec 6;7:1471-8. doi: 10.2147/DDDT.S41431.
Disease-modifying drugs in Alzheimer's disease.
Ghezzi L(1), Scarpini E(1), Galimberti D(1).
Author information:
(1)Neurology Unit, Department of Pathophysiology and Transplantation, University
of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan,
Italy.
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the
most common cause of dementia. The early stages of AD are characterized by
short-term memory loss. Once the disease progresses, patients experience
difficulties in sense of direction, oral communication, calculation, ability to
learn, and cognitive thinking. The median duration of the disease is 10 years.
The pathology is characterized by deposition of amyloid beta peptide (so-called
senile plaques) and tau protein in the form of neurofibrillary tangles.
Currently, two classes of drugs are licensed by the European Medicines Agency
for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to
moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for
moderate and severe AD. Treatment with acetylcholinesterase inhibitors or
memantine aims at slowing progression and controlling symptoms, whereas drugs
under development are intended to modify the pathologic steps leading to AD.
Herein, we review the clinical features, pharmacologic properties, and
cost-effectiveness of the available acetylcholinesterase inhibitors and
memantine, and focus on disease-modifying drugs aiming to interfere with the
amyloid beta peptide, including vaccination, passive immunization, and tau
deposition.
DOI: 10.2147/DDDT.S41431
PMCID: PMC3862506
PMID: 24353405 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11745432 | 1. Int J Cancer. 2001 Nov;94(4):480-4. doi: 10.1002/ijc.1512.
C-MYC and IGF-II mRNA-binding protein (CRD-BP/IMP-1) in benign and malignant
mesenchymal tumors.
Ioannidis P(1), Trangas T, Dimitriadis E, Samiotaki M, Kyriazoglou I, Tsiapalis
CM, Kittas C, Agnantis N, Nielsen FC, Nielsen J, Christiansen J, Pandis N.
Author information:
(1)Department of Genetics, St. Savas Hospital, Athens, Greece.
Mouse coding region determinant-binding (mCRD-BP) and human IGF-II mRNA-binding
1 (hIMP-1) proteins are orthologous mRNA-binding proteins that recognize c-myc
and IGF-II mRNA, respectively, and regulate their expression
posttranscriptionally. Here, we confirm that human CRD-BP/IMP-1 binds to c-myc
mRNA and that it is predominantly expressed in fetal tissues. Moreover,
hCRD-BP/IMP-1 expression was detected in cell lines of neoplastic origin and in
selected primary tumors. In a series of 33 malignant and 10 benign mesenchymal
tumors, 73% and 40%, respectively, were found to express hCRD-BP/IMP-1. In
particular, expression was significant in 14 Ewing's sarcomas, all of which were
positive. The data suggest that hCRD-BP/IMP-1 plays a role in abnormal cell
proliferation in mesenchymal tumors.
Copyright 2001 Wiley-Liss, Inc.
DOI: 10.1002/ijc.1512
PMID: 11745432 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22848160 | 1. Int J Nanomedicine. 2012;7:3259-78. doi: 10.2147/IJN.S30919. Epub 2012 Jul 9.
Neurological disorders and therapeutics targeted to surmount the blood-brain
barrier.
Kanwar JR(1), Sriramoju B, Kanwar RK.
Author information:
(1)Nanomedicine Laboratory of Immunology and Molecular Biomedical Research,
Centre for Biotechnology and Interdisciplinary Biosciences, Institute for
Frontier Materials-IFM, Deakin University, Waurn Ponds, Victoria, Australia.
[email protected]
We are now in an aging population, so neurological disorders, particularly the
neurodegenerative diseases, are becoming more prevalent in society. As per the
epidemiological studies, Europe alone suffers 35% of the burden, indicating an
alarming rate of disease progression. Further, treatment for these disorders is
a challenging area due to the presence of the tightly regulated blood-brain
barrier and its unique ability to protect the brain from xenobiotics.
Conventional therapeutics, although effective, remain critically below levels of
optimum therapeutic efficacy. Hence, methods to overcome the blood-brain barrier
are currently a focus of research. Nanotechnological applications are gaining
paramount importance in addressing this question, and yielding some promising
results. This review addresses the pathophysiology of the more common
neurological disorders and novel drug candidates, along with targeted
nanoparticle applications for brain delivery.
DOI: 10.2147/IJN.S30919
PMCID: PMC3405884
PMID: 22848160 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19108833 | 1. Atherosclerosis. 2009 Jul;205(1):126-34. doi:
10.1016/j.atherosclerosis.2008.11.011. Epub 2008 Nov 24.
Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in
smooth muscle cells.
Brito PM(1), Devillard R, Nègre-Salvayre A, Almeida LM, Dinis TC, Salvayre R,
Augé N.
Author information:
(1)Laboratory of Biochemistry, Faculty of Pharmacy, and Center for Neurosciences
and Cell Biology, University of Coimbra, Coimbra, Portugal.
Erratum in
Atherosclerosis. 2019 Jun;285:178. doi:
10.1016/j.atherosclerosis.2019.03.018.
OBJECTIVES: Smooth muscle cell (SMC) proliferation is a major feature in
atherosclerosis, since it contributes to the formation of the fibrous cap, thus
to plaque stability, but also to arterial stenosis and post-angioplasty
restenosis. Among the various mitogenic signaling pathways involved in SMC
proliferation, the mTOR pathway regulates both the cell cycle and cell growth.
Resveratrol, a polyphenolic compound from grapes and red wine, has potential
anti-atherogenic and anti-cancer properties. This work was designed to
investigate the activation of the mTOR pathway by the proatherogenic oxidized
LDL (oxLDL) in SMC, and the potential inhibitory effect of resveratrol.
RESULTS: mTOR and its downstream target p70S6 kinase are phosphorylated and
activated by mitogenic concentrations of oxLDL (50 microg/ml), and are involved
in SMC proliferation, as assessed by the inhibitory effect of the mTOR inhibitor
rapamycin. The activation of mTOR signaling by oxLDL, requires the upstream
activation of PI3K and Akt, as assessed by the inhibitory effect of the PI3K
inhibitor Ly294002 on mTOR activation and DNA synthesis. Resveratrol blocked the
oxLDL-induced phosphorylation and activation of the PI3K/Akt/mTOR/p70S6K pathway
and strongly inhibited both the DNA synthesis and proliferation of SMC. This
activity is independent of the anti-oxidant effect and of AMPK activation by
resveratrol.
CONCLUSION: These data indicate that the mTOR pathway is activated by oxLDL via
PI3K/PDK1/Akt, and is required for SMC proliferation. Resveratrol blocks
specifically this pathway, thereby inhibiting oxLDL-induced SMC proliferation.
These data highlight a new property for resveratrol that could contribute to the
general anti-atherogenic properties of this polyphenol.
DOI: 10.1016/j.atherosclerosis.2008.11.011
PMID: 19108833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25713988 | 1. Immunotherapy. 2015;7(2):119-33. doi: 10.2217/imt.14.101.
Efficacy and safety of emerging immunotherapies in psoriasis.
Yiu ZZ(1), Warren RB.
Author information:
(1)The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester
Academic Health Science Centre, University of Manchester, Manchester, UK.
Erratum in
Immunotherapy. 2015;7(7):839-41. doi: 10.2217/imt.15.51.
Psoriasis is a common chronic inflammatory disease of the skin. Current biologic
therapies are highly effective in the treatment of psoriasis, transforming the
lives of patients with this significantly disabling disease. Advances in the
understanding of the immunological pathogenesis of psoriasis have led to the
development of new biologic therapies, targeting specific inflammatory cytokines
upregulated in psoriasis. These include the IL-17 antagonists, secukinumab,
brodalumab and ixekizumab; the IL-23 antagonists, guselkumab and tildrakizumab;
and the oral small molecule therapies, tofacitinib and apremilast. Here, we
review evidence for the efficacy and safety of these novel psoriasis therapies,
providing clinicians with an overview of the next era in immunotherapy for
psoriasis.
DOI: 10.2217/imt.14.101
PMID: 25713988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3886611 | 1. J Adolesc Health Care. 1985 May;6(3):224-32. doi:
10.1016/s0197-0070(85)80023-1.
The advisability of the prudent diet in adolescence.
Belmaker E, Cohen JD.
Risk factor status for cardiovascular disease is affected by life style.
Adolescence is a time during which long term life-style habits, including
dietary habits, are established. Physicians who treat adolescent patients have a
responsibility to be aware of the scientific evidence on the diet-heart question
so that they can provide their patients with sound dietary advice. The American
Heart Association has recommended that Americans consume a "prudent diet" in
which daily consumption of cholesterol is no more than 300 mg with up to 30-35%
of calories derived from fat, and less than 10% of calories derived from
saturated fat and less than 10% from polyunsaturated fat. This paper reviews
this recommendation with particular reference to studies of adolescents. This
review centers around four main issues: 1) the estimated effect on serum
cholesterol levels of a switch from the usual American diet to the prudent diet;
2) the effect of a predicted decrease in serum cholesterol on the risk of
developing cardiovascular disease; 3) evaluation of the evidence of possible
adverse effects of the prudent diet; 4) feasibility of the prudent diet. Based
on a review of these four issues, the authors feel that the American Heart
Association's prudent diet should be strongly recommended for all healthy
adolescents.
DOI: 10.1016/s0197-0070(85)80023-1
PMID: 3886611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24685200 | 1. Arch Bronconeumol. 2014 Aug;50(8):355-61. doi: 10.1016/j.arbres.2014.02.002.
Epub 2014 Mar 29.
Future biologic therapies in asthma.
[Article in English, Spanish]
Quirce S(1), Bobolea I(2), Domínguez-Ortega J(2), Barranco P(2).
Author information:
(1)Servicio de Alergología, Instituto de Investigación Hospital Universitario La
Paz (IdiPAZ), Madrid, España. Electronic address:
[email protected].
(2)Servicio de Alergología, Instituto de Investigación Hospital Universitario La
Paz (IdiPAZ), Madrid, España.
Despite the administration of appropriate treatment, a high number of patients
with asthma remain uncontrolled. This suggests the need for alternative
treatments that are effective, safe and selective for the established asthma
phenotypes, especially in patients with uncontrolled severe asthma. The most
promising options among the new asthma treatments in development are biological
therapies, particularly those monoclonal antibodies directed at selective
targets. It should be noted that the different drugs, and especially the new
biologics, act on very specific pathogenic pathways. Therefore, determination of
the individual profile of predominant pathophysiological alterations of each
patient will be increasingly important for prescribing the most appropriate
treatment in each case. The treatment of severe allergic asthma with anti-IgE
monoclonal antibody (omalizumab) has been shown to be effective in a large
number of patients, and new anti-IgE antibodies with improved pharmacodynamic
properties are being investigated. Among developing therapies, biologics
designed to block certain pro-inflammatory cytokines, such as IL-5 (mepolizumab)
and IL-13 (lebrikizumab), have a greater chance of being used in the clinic.
Perhaps blocking more than one cytokine pathway (such as IL-4 and IL-13 with
dulipumab) might confer increased efficacy of treatment, along with acceptable
safety. Stratification of asthma based on the predominant pathogenic mechanisms
of each patient (phenoendotypes) is slowly, but probably irreversibly, emerging
as a tailored medical approach to asthma, and is becoming a key factor in the
development of drugs for this complex respiratory syndrome.
Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.
DOI: 10.1016/j.arbres.2014.02.002
PMID: 24685200 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22266062 | 1. Eur J Paediatr Neurol. 2012 Sep;16(5):459-63. doi: 10.1016/j.ejpn.2011.12.012.
Epub 2012 Jan 21.
First long-term experience with the orphan drug rufinamide in children with
myoclonic-astatic epilepsy (Doose syndrome).
von Stülpnagel C(1), Coppola G, Striano P, Müller A, Staudt M, Kluger G.
Author information:
(1)Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy-Center
for Children and Adolescents, Vogtareuth, Germany.
INTRODUCTION: We evaluated the long-term efficacy and tolerability of the orphan
drug rufinamide (RUF) in children with pharmacoresistant myoclonic-astatic
epilepsy (MAE, Doose syndrome).
METHODS: This was a retrospective European multicenter study on eight patients
who had started an intention-to-treat trial of RUF between July 2007 and June
2010. Clinical information was collected via questionnaire. Responder rate was
defined as reduction of seizure frequency ≥50% in comparison to four weeks
before starting RUF. Maximum follow-up was eighteen months.
RESULTS: Responder rates were 7/8 patients after 3 months, 6/8 patients after 6
months and 5/8 patients after 12 months. RUF seemed particularly effective in
the prevention of myoclonic-astatic seizures (comparable with drop attacks in
Lennox-Gastaut-Syndrome, for which RUF is particularly effective). Some loss of
efficacy was noticed in the long-term observation. Side-effects occurred in two
patients. Seizure aggravation was not observed.
CONCLUSION: RUF seems to be a promising therapeutic option in children with MAE.
Further studies are warranted to confirm these first observations.
Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier
Ltd. All rights reserved.
DOI: 10.1016/j.ejpn.2011.12.012
PMID: 22266062 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15989562 | 1. Expert Opin Investig Drugs. 1997 Jan;6(1):65-78. doi: 10.1517/13543784.6.1.65.
Venlafaxine:a novel antidepressant compound.
Schweizer E(1), Thielen RJ, Frazer A.
Author information:
(1)Department of Pharmacology, The University of Texas Health Science Center at
San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA.
Venlafaxine is a new antidepressant that inhibits the reuptake of both
5-hydroxytryptamine (serotonin; 5-HT) and noradrenaline (NA). It is somewhat
more potent as an inhibitor of the reuptake of 5-HT than NA. Its potency to
inhibit the reuptake of 5-HT is comparable to that of tricyclic antidepressants
(TCAs) such as amitriptyline or imipramine, but it is less potent than these
drugs at inhibiting the reuptake of NA. Consequently, at low doses, venlafaxine
may be a more effective inhibitor of the reuptake of 5-HT than that of NA. The
major metabolite of venlafaxine in humans, O-desmethylvenlafaxine, has
comparable potency to the parent drug for inhibiting the reuptake of either NA
or 5-HT in vitro, but it is less potent in vivo. Both venlafaxine and
O-desmethylvenlafaxine are essentially devoid of activity at muscarinic
cholinergic, H1 histaminergic, and 1-adrenoceptors. This probably accounts for
venlafaxine having a side-effect profile similar to that of selective serotonin
reuptake inhibitors (SSRIs) rather than that of TCAs. Venlafaxine is subject to
extensive first-pass metabolism and is metabolised by the cytochrome P450
isoenzyme IID6 in the liver. The half-life of venlafaxine is 3-4 h and that of
its principal metabolite is about 10 h. The daily dose of venlafaxine can be
administered as either two or three divided doses without altering significantly
the pharmacokinetics of venlafaxine. The most common side-effects of venlafaxine
are nausea, sedation, dizziness, dry mouth and sweating, as well as sexual
dysfunctions, primarily problems with erection and delayed ejaculation. In some
patients, venlafaxine also causes sustained elevations in both systolic and
diastolic blood pressure; this effect is dose-dependent. Venlafaxine is much
safer in overdosage than the TCAs. Antidepressant efficacy of venlafaxine has
been found both in out-patients and in-patients. In general, its efficacy is
comparable to that of comparator drugs (primarily TCAs or SSRIs), and in some
cases even greater, and its efficacy is greater than that measured with placebo.
DOI: 10.1517/13543784.6.1.65
PMID: 15989562 |
http://www.ncbi.nlm.nih.gov/pubmed/23208322 | 1. Eur J Clin Pharmacol. 2013 May;69(5):1113-20. doi: 10.1007/s00228-012-1448-6.
Epub 2012 Dec 4.
Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage.
Wang LS(1), Shang JJ, Shi SY, Zhang YQ, Lin J, Guo ZH, Wang YC, Tang J, Liu J,
Liu YZ, Li Z, Tan ZR, Zhou HH, Jiang HH, Xie HT.
Author information:
(1)Pharmacogenetics Research Institute, Institute of Clinical Pharmacology of
Central South University, Changsha, China. [email protected]
PURPOSE: ORM1 is a plasma drug binding protein. Its polymorphism rs17650 (S>F)
has been reported to be an important factor affecting the binding ability and
effect of antiretroviral protease inhibitors. The aim of this study was to
determine whether the ORM1 rs17650 polymorphism also influences warfarin
therapy.
METHODS: A total of 191 Chinese patients with steady-dose warfarin therapy were
enrolled in this study. The patients were studied for warfarin maintenance dose,
the ORM1 rs17650 polymorphism, and two polymorphisms previously demonstrated to
affect warfarin response [CYP2C9 rs1057910 (3) and VKORC1 rs7294 (-1639 G>A)].
RESULTS: Warfarin dose was partially correlated with the VKORC1 rs7294, CYP2C9
rs1057910 and ORM1 rs17650 polymorphisms. Patients carrying the wild-type of
these three genes (n = 96) took a mean dose of 3.0 ± 1.1 mg warfarin, which was
significantly higher than that taken by the 52 S patients (2.7 ± 0.7) and 11 S S
patients (2.5 ± 0.6 mg) (p = 0.048).
CONCLUSION: We identified ORM1 as another polymorphic gene affecting warfarin
dose requirements. ORM1 S carriers require lower maintenance doses to achieve
and maintain an optimal level of anticoagulation.
DOI: 10.1007/s00228-012-1448-6
PMID: 23208322 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10490914 | 1. J Pharmacol Exp Ther. 1999 Oct;291(1):280-4.
Mechanism of sodium channel block by venlafaxine in guinea pig ventricular
myocytes.
Khalifa M(1), Daleau P, Turgeon aJ.
Author information:
(1)Quebec Heart Institute, Laval Hospital, Faculty of Pharmacy, Laval
University, Sainte-Foy, Canada.
Venlafaxine is a newly introduced antidepressant agent. The drug causes
selective inhibition of neuronal reuptake of serotonine and norepinephrine with
little effect on other neurotransmitter systems. Cases of seizures, tachycardia,
and QRS prolongation have been observed following drug overdose in humans. The
clinical manifestations of cardiac toxicity suggest that venlafaxine may exhibit
cardiac electrophysiological effects on fast conducting cells. Consequently,
studies were undertaken to characterize effects of venlafaxine on the fast
inward sodium current (I(Na)) of isolated guinea pig ventricular myocytes.
Currents were recorded with the whole-cell configuration of the patch-clamp
technique in the presence of Ca(2+) and K(+) channel blockers. Results obtained
demonstrated that venlafaxine inhibits peak I(Na) in a concentration-dependent
manner with an estimated IC(50) of 8. 10(-6) M. Inhibition was exclusively of a
tonic nature and rate-independent. Neither kinetics of inactivation (tau(inac)=
0.652 +/- 0.020 ms, under control conditions; tau(inac)= 0.636 +/- 0.050, in the
presence of 10(-5) M venlafaxine; n = 5 cells isolated from five animals) nor
kinetics of recovery from inactivation of the sodium channels (tau(re)= 58.7 +/-
1.6 ms, under control conditions; tau(re)= 54.4 +/- 1.8, in the presence of
10(-5) M venlafaxine; n = 10 cells isolated from six animals) were significantly
altered by 10(-5) M venlafaxine. These observations led us to conclude that
venlafaxine blocks I(Na) following its binding to the resting state of the
channel. Thus, the characteristics of block of I(Na) by venlafaxine are
different from those usually observed with most tricyclic antidepressants or
conventional class I antiarrhythmic drugs.
PMID: 10490914 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22815475 | 1. J Biol Chem. 2012 Sep 28;287(40):33756-65. doi: 10.1074/jbc.M112.390849. Epub
2012 Jul 19.
Methylation of lysine 9 in histone H3 directs alternative modes of highly
dynamic interaction of heterochromatin protein hHP1β with the nucleosome.
Munari F(1), Soeroes S, Zenn HM, Schomburg A, Kost N, Schröder S, Klingberg R,
Rezaei-Ghaleh N, Stützer A, Gelato KA, Walla PJ, Becker S, Schwarzer D,
Zimmermann B, Fischle W, Zweckstetter M.
Author information:
(1)Department of NMR-based Structural Biology, Max Planck Institute for
Biophysical Chemistry, Göttingen, Germany.
Binding of heterochromatin protein 1 (HP1) to the histone H3 lysine 9
trimethylation (H3K9me3) mark is a hallmark of establishment and maintenance of
heterochromatin. Although genetic and cell biological aspects have been
elucidated, the molecular details of HP1 binding to H3K9me3 nucleosomes are
unknown. Using a combination of NMR spectroscopy and biophysical measurements on
fully defined recombinant experimental systems, we demonstrate that H3K9me3
works as an on/off switch regulating distinct binding modes of hHP1β to the
nucleosome. The methyl-mark determines a highly flexible and very dynamic
interaction of the chromodomain of hHP1β with the H3-tail. There are no other
constraints of interaction or additional multimerization interfaces. In
contrast, in the absence of methylation, the hinge region and the N-terminal
tail form weak nucleosome contacts mainly with DNA. In agreement with the high
flexibility within the hHP1β-H3K9me3 nucleosome complex, the chromoshadow domain
does not provide a direct binding interface. Our results report the first
detailed structural analysis of a dynamic protein-nucleosome complex directed by
a histone modification and provide a conceptual framework for understanding
similar interactions in the context of chromatin.
DOI: 10.1074/jbc.M112.390849
PMCID: PMC3460472
PMID: 22815475 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22302819 | 1. J Neurosci. 2012 Feb 1;32(5):1803-10. doi: 10.1523/JNEUROSCI.0865-11.2012.
A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and
improves respiratory function in a mouse model of Rett syndrome.
Schmid DA(1), Yang T, Ogier M, Adams I, Mirakhur Y, Wang Q, Massa SM, Longo FM,
Katz DM.
Author information:
(1)Department of Neurosciences, Case Western Reserve University School of
Medicine, Cleveland, Ohio 44106, USA.
Erratum in
J Neurosci. 2014 Jan 29;34(5):2012.
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding
the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor,
respiratory and autonomic control, cognitive impairment, autistic-like behaviors
and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced
expression of brain-derived neurotrophic factor (BDNF), which has been linked in
mice to increased respiratory frequency, a hallmark of RTT. The present study
was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are
associated with reduced activation of the BDNF receptor, TrkB, and that
pharmacologic activation of TrkB would improve respiratory function. We
characterized BDNF protein expression, TrkB activation and respiration in
heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the
somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated
the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical
and functional abnormalities in these animals. We found that Het mice exhibit
(1) reduced BDNF expression and TrkB activation in the medulla and pons and (2)
breathing dysfunction, characterized by increased frequency due to periods of
tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with
LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the
medulla and pons and restored wild-type breathing frequency. These data provide
new insight into the role of BDNF signaling deficits in the pathophysiology of
RTT and highlight TrkB as a possible therapeutic target in this disease.
DOI: 10.1523/JNEUROSCI.0865-11.2012
PMCID: PMC3710112
PMID: 22302819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19488075 | 1. Nat Rev Endocrinol. 2009 Jul;5(7):401-8. doi: 10.1038/nrendo.2009.102. Epub
2009 Jun 2.
Epigenetic mechanisms that underpin metabolic and cardiovascular diseases.
Gluckman PD(1), Hanson MA, Buklijas T, Low FM, Beedle AS.
Author information:
(1)Centre for Human Evolution, Adaptation and Disease, Liggins Institute, The
University of Auckland, New Zealand. [email protected]
Cellular commitment to a specific lineage is controlled by differential
silencing of genes, which in turn depends on epigenetic processes such as DNA
methylation and histone modification. During early embryogenesis, the mammalian
genome is 'wiped clean' of most epigenetic modifications, which are
progressively re-established during embryonic development. Thus, the epigenome
of each mature cellular lineage carries the record of its developmental history.
The subsequent trajectory and pattern of development are also responsive to
environmental influences, and such plasticity is likely to have an epigenetic
basis. Epigenetic marks may be transmitted across generations, either directly
by persisting through meiosis or indirectly through replication in the next
generation of the conditions in which the epigenetic change occurred.
Developmental plasticity evolved to match an organism to its environment, and a
mismatch between the phenotypic outcome of adaptive plasticity and the current
environment increases the risk of metabolic and cardiovascular disease. These
considerations point to epigenetic processes as a key mechanism that underpins
the developmental origins of chronic noncommunicable disease. Here, we review
the evidence that environmental influences during mammalian development lead to
stable changes in the epigenome that alter the individual's susceptibility to
chronic metabolic and cardiovascular disease, and discuss the clinical
implications.
DOI: 10.1038/nrendo.2009.102
PMID: 19488075 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17105462 | 1. Epilepsia. 2006;47 Suppl 2:53-5. doi: 10.1111/j.1528-1167.2006.00690.x.
The natural history of myoclonic astatic epilepsy (Doose syndrome) and
Lennox-Gastaut syndrome.
Stephani U(1).
Author information:
(1)University Children's Hospital, Department of Neuropediatrics, Kiel, Germany.
[email protected]
The purpose of this article is to present a short review of the natural history
of myoclonic astatic epilepsy (MAE; Doose syndrome) and the Lennox-Gastaut
syndrome (LGS). In the 1989 classification of the International League Against
Epilepsy (ILAE, 1989), MAE and LGS were initially included in group 2.2:
"Cryptogenic or symptomatic generalized epilepsies and syndromes." The
subsequent classification of the Proposed Diagnostic Scheme for People with
Epileptic Seizures and with Epilepsy (see Ref. 8) placed MAE in axis 3 in the
"generalized epilepsy" group and LGS, severe myoclonic epilepsy of infancy (SMEI
or Dravet syndrome) and atypical benign partial epilepsy/pseudo-Lennox syndrome
(ABPE/PLS) in the "epileptic encephalopathy" group. The semiology of MAE and LGS
and their differential diagnosis from SMEI and ABPE/PLS are described. Before
the onset of SMEI, MAE, and ABPE/PLS, the development of the child is usually
normal. In contrast, in LGS, development is frequently retarded at the onset,
depending on the etiopathogenesis of the underlying brain disease. The course of
MAE is highly variable with regard to seizure outcome (complete remission in
some cases, persistent epilepsy in others) and cognitive development (normal or
delayed). The course of LGS and SMEI is generally poor, both with regard to the
epilepsy and to the cognitive development whereas the course and seizure outcome
of ABPE/PLS is favorable; the patients will be seizure-free at puberty. However,
the neuropsychological outcome is less favorable; most patients remain mentally
retarded.
DOI: 10.1111/j.1528-1167.2006.00690.x
PMID: 17105462 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22482074 | 1. Int J Alzheimers Dis. 2012;2012:630182. doi: 10.1155/2012/630182. Epub 2012
Mar 8.
Amyloid Beta and tau proteins as therapeutic targets for Alzheimer's disease
treatment: rethinking the current strategy.
Mondragón-Rodríguez S(1), Perry G, Zhu X, Boehm J.
Author information:
(1)Le Groupe de Recherche sur le Système Nerveux Central, Département de
Physiologie, Université de Montréal, Montréal, QC, Canada.
Alzheimer's disease (AD) is defined by the concurrence of accumulation of
abnormal aggregates composed of two proteins: Amyloid beta (Aβ) and tau, and of
cellular changes including neurite degeneration and loss of neurons and
cognitive functions. Based on their strong association with disease, genetically
and pathologically, it is not surprising that there has been a focus towards
developing therapies against the aggregated structures. Unfortunately, current
therapies have but mild benefit. With this in mind we will focus on the
relationship of synaptic plasticity with Aβ and tau protein and their role as
potential targets for the development of therapeutic drugs. Finally, we will
provide perspectives in developing a multifactorial strategy for AD treatment.
DOI: 10.1155/2012/630182
PMCID: PMC3310047
PMID: 22482074 |
http://www.ncbi.nlm.nih.gov/pubmed/16822461 | 1. Semin Hematol. 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004.
Severe congenital neutropenia.
Welte K(1), Zeidler C, Dale DC.
Author information:
(1)Department of Pediatric Hematology/Oncology, Medical School Hannover,
Hannover, Germany. [email protected]
Severe congenital neutropenia (CN) includes a variety of hematologic disorders
characterized by severe neutropenia, with absolute neutrophil counts (ANC) below
0.5 x 10(9)/L, and associated with severe systemic bacterial infections from
early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive
disorder, characterized histopathologically by early-stage maturation arrest of
myeloid differentiation. CN with similar clinical features occurs as an
autosomal dominant disorder and many sporadic cases also have been reported.
This genetic heterogeneity suggests that several pathophysiological mechanisms
may lead to this common clinical phenotype. Recent studies on the genetic bases
of CN have detected inherited or spontaneous point mutations in the neutrophil
elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly,
mutations in other genes. Acquisition of additional genetic defects during the
course of the disease, for example, granulocyte colony-stimulating factor
(G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an
underlying genetic instability as a common feature for all congenital
neutropenia subtypes. Data on more than 600 patients with CN collected by the
Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that,
regardless of the particular CN subtype, more than 95% of these patients respond
to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x
10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant
transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment
impacts on these adverse events is not fully understood. In recent analyses the
influence of the G-CSF dose required to achieve neutrophil response (ANC
>1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been
reported. Hematopoietic stem cell transplantation (HSCT) is still the only
treatment available for patients who are refractory to G-CSF treatment.
DOI: 10.1053/j.seminhematol.2006.04.004
PMID: 16822461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23787814 | 1. Hepatology. 2013 Dec;58(6):2001-11. doi: 10.1002/hep.26585. Epub 2013 Oct 25.
Hepatic myofibroblasts promote the progression of human cholangiocarcinoma
through activation of epidermal growth factor receptor.
Clapéron A(1), Mergey M, Aoudjehane L, Ho-Bouldoires TH, Wendum D, Prignon A,
Merabtene F, Firrincieli D, Desbois-Mouthon C, Scatton O, Conti F, Housset C,
Fouassier L.
Author information:
(1)Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France; UPMC,
Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France.
Erratum in
Hepatology. 2014 Aug;60(2):770.
Comment in
J Hepatol. 2014 Aug;61(2):432-4. doi: 10.1016/j.jhep.2014.04.014.
Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant
desmoplastic environment. Poor prognosis of CCA has been associated with the
presence of alpha-smooth muscle actin (α-SMA)-positive myofibroblasts (MFs) in
the stroma and with the sustained activation of the epidermal growth factor
receptor (EGFR) in tumor cells. Among EGFR ligands, heparin-binding epidermal
growth factor (HB-EGF) has emerged as a paracrine factor that contributes to
intercellular communications between MFs and tumor cells in several cancers.
This study was designed to test whether hepatic MFs contributed to CCA
progression through EGFR signaling. The interplay between CCA cells and hepatic
MFs was examined first in vivo, using subcutaneous xenografts into
immunocompromised mice. In these experiments, cotransplantation of CCA cells
with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and
metastatic dissemination of tumors. These effects were abolished by gefitinib,
an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA
tissues showed that stromal MFs expressed HB-EGF, whereas EGFR was detected in
cancer cells. In vitro, HLMFs produced HB-EGF and their conditioned media
induced EGFR activation and promoted disruption of adherens junctions, migratory
and invasive properties in CCA cells. These effects were abolished in the
presence of gefitinib or HB-EGF-neutralizing antibody. We also showed that CCA
cells produced transforming growth factor beta 1, which, in turn, induced HB-EGF
expression in HLMFs.
CONCLUSION: A reciprocal cross-talk between CCA cells and myofibroblasts through
the HB-EGF/EGFR axis contributes to CCA progression.
© 2013 by the American Association for the Study of Liver Diseases.
DOI: 10.1002/hep.26585
PMID: 23787814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7585697 | 1. Carbohydr Res. 1995 Apr 30;270(2):131-47. doi: 10.1016/0008-6215(94)00012-5.
Utility of non-covalent complexes in the matrix-assisted laser desorption
ionization mass spectrometry of heparin-derived oligosaccharides.
Juhasz P(1), Biemann K.
Author information:
(1)Department of Chemistry, Massachusetts Institute of Technology, Cambridge
02139, USA.
Molecular weights of heparin-derived oligosaccharides ranging from disaccharides
to hexadecasaccharides have been determined by matrix-assisted laser desorption
ionization time-of-flight mass spectrometry. While these compounds ionize poorly
or not at all when used as such, a strong signal can be obtained of their ionic
complexes formed with a basic peptide or protein. The molecular weight of the
sulfated oligosaccharide is determined by subtracting the mass of the basic
component from that of the complex. Optimization of the experimental conditions
resulted in sub-picomole sensitivity, in the elimination of sulfate loss and of
the interference from attachment of inorganic cations. Synthetic peptides
(Arg-Gly)10 and (Arg-Gly)15 were specifically designed as complexing agents for
synthetic and natural heparin fragments up to decasaccharides. Accurate
molecular weight determination on chemically homogeneous oligosaccharides (+/-
0.05%) unambiguously identified the number of saccharide units, and the number
of O,N-sulfate and N-acetyl groups. For oligosaccharides larger than
decasaccharides, a small basic protein, angiogenin (M(r) = 14,120), was used to
form the complex (an inhomogeneous hexadecasaccharide fraction was the largest
available for this study). For inhomogeneous samples larger than
decasaccharides, the mass accuracy is lower (+/- 0.2-0.3%) but still suffices to
determine the number of saccharide units present and to estimate the number of
sulfate groups, except it is no longer possible to differentiate one sulfate
from two N-acetyl groups (delta = 4 Da). However, taking into account known
regularities of sulfation and acetylation, the specificity of heparin lyases and
chemical degradation steps, the method promises to contribute significantly to
the determination of the primary structure of heparin and other sulfated
glycosaminoglycans.
DOI: 10.1016/0008-6215(94)00012-5
PMID: 7585697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1511475 | 1. Cardiology. 1992;80(3-4):283-93. doi: 10.1159/000175014.
Effects on serum lipids of adding fruits and vegetables to prudent diet in the
Indian Experiment of Infarct Survival (IEIS).
Singh RB(1), Ghosh S, Singh R.
Author information:
(1)Medical Hospital and Research Centre, Moradabad, India.
In a randomized, single-blind and controlled trial, the effects of the
administration of fruits and vegetables (mean 582 vs. 188 g/day) for 12 weeks
were compared as adjuncts to a prudent diet in the management of 202 group A and
204 group B patients with acute myocardial infarction (AMI). Fruits and
vegetables decreased total serum cholesterol level (26.4 vs. 13.8 mg/dl, p less
than 0.01) low-density lipoprotein cholesterol (20.0 vs. 9.8 mg/dl, p less than
0.01), triglycerides (20.6 vs. 10.6 mg/dl, p less than 0.01) and fasting blood
glucose (22.4 vs. 12.6 mg/dl, p less than 0.01) levels more significant in the
intervention group than changes in the control group. Adherence to dietary
advice was assessed by questionnaires. Total adherence score in group A was
significantly higher than in group B. Group A patients also had a significantly
smaller rise in lactate dehydrogenase cardiac enzyme which indicates that the
protective effects of such a diet may be observed within 1 week. There was a
significantly greater decrease in mean blood pressure in group A than changes in
group B. These data suggest that fruits and vegetables, because of their high
soluble dietary fibre and possibly high antioxidant contents, may be a useful
and safe adjunct to a prudent diet in the treatment of patients with AMI. The
use of fruits and vegetables may be preferred over oat bran, psyllium and guar
gum because of their high content of vitamins and minerals.
DOI: 10.1159/000175014
PMID: 1511475 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24163373 | 1. J Biol Chem. 2013 Nov 29;288(48):34719-28. doi: 10.1074/jbc.M113.506568. Epub
2013 Oct 25.
Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like
protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem
cells.
Liu L(1), Souto J, Liao W, Jiang Y, Li Y, Nishinakamura R, Huang S, Rosengart T,
Yang VW, Schuster M, Ma Y, Yang J.
Author information:
(1)From the Departments of Surgery.
The stem cell protein SALL4 plays a critical role in hematopoiesis by regulating
the cell fate. In primitive hematopoietic precursors, it activates or represses
important genes via recruitment of various epigenetic factors such as DNA
methyltransferases, and histone deacylases. Here, we demonstrate that LSD1, a
histone lysine demethylase, also participates in the trans-repressive effects of
SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important
in suppressing SALL4-mediated reporter transcription. In freshly isolated adult
mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in
undifferentiated progenitor cells and co-localize in the nuclei. Further
sequential chromatin immunoprecipitation assay confirmed that these two factors
share the same binding sites at the promoter regions of important hematopoietic
regulatory genes including EBF1, GATA1, and TNF. In addition, studies from both
gain- and loss-of-function models revealed that SALL4 dynamically controls the
binding levels of LSD1, which is accompanied by a reversely changed histone 3
dimethylated lysine 4 at the same promoter regions. Finally, shRNA-mediated
knockdown of LSD1 in hematopoietic precursor cells resulted in altered SALL4
downstream gene expression and increased cellular activity. Thus, our data
revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated
transcription, and the dynamic regulation of SALL4-associated epigenetic factors
cooperatively modulates early hematopoietic precursor proliferation.
DOI: 10.1074/jbc.M113.506568
PMCID: PMC3843083
PMID: 24163373 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15083883 | 1. Clin Exp Rheumatol. 2004 Mar-Apr;22(2):165-70.
Early rheumatoid arthritis: does gender influence disease expression?
Voulgari PV(1), Papadopoulos IA, Alamanos Y, Katsaraki A, Drosos AA.
Author information:
(1)Division of Rheumatology, Department of Internal Medicine, Medical School,
University of Ioannina, Ioannina, Greece.
OBJECTIVE: To investigate whether gender is an independent factor associated
with disease expression in early rheumatoid arthritis (RA) patients.
METHODS: 438 patients with early RA (disease duration less than one year) were
studied. They all were patients with early RA who presented at the Rheumatology
Clinic of the University Hospital of Ioannina during the period 1991-2000. All
patients fulfilled the American College of Rheumatology criteria for RA. The
demographic, clinical, laboratory, radiological and therapeutic characteristics
of the disease at diagnosis, and at the last follow-up were analyzed according
to gender.
RESULTS: We studied 312 women and 126 men with early RA. The female to male
ratio was 2.5:1 and the mean age at diagnosis was 49.4 +/- 14.9 years for women
and 55.3 +/-15.6 years for men (P < 0.0003). Women had a longer duration of
follow-up (P < 0.0003). There were no differences between genders in the general
symptoms or the simmetricity of joint involvement at at disease onset. However
at disease onset women had a higher erythrocyte sedimentation rate (ESR) (> 30
mm/1st hour), although there were no significant differences between the two
groups concerninig the rest of the clinical, laboratory and radiological
findings. At the last follow-up women still had a higher ESR (>30 min/1st hour),
but no significant differences were found between the two groups concerning the
rest of the parameters investigated independently of the follow-up duration.
Finally, women and men showed the same degree of radiological changes and
functional ability and were treated similarly except for the more frequent use
of hydroxychloroquine in women.
CONCLUSION: It seems that gender does not signficantly influence the expression
of RA.
PMID: 15083883 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19798443 | 1. PLoS Genet. 2009 Oct;5(10):e1000670. doi: 10.1371/journal.pgen.1000670. Epub
2009 Oct 2.
Heterochromatin protein 1 (HP1a) positively regulates euchromatic gene
expression through RNA transcript association and interaction with hnRNPs in
Drosophila.
Piacentini L(1), Fanti L, Negri R, Del Vescovo V, Fatica A, Altieri F,
Pimpinelli S.
Author information:
(1)Dipartimento di Genetica e Biologia Molecolare, Università La Sapienza,
Istituto Pasteur, Fondazione Cenci Bolognetti, Roma, Italy.
Heterochromatin Protein 1 (HP1a) is a well-known conserved protein involved in
heterochromatin formation and gene silencing in different species including
humans. A general model has been proposed for heterochromatin formation and
epigenetic gene silencing in different species that implies an essential role
for HP1a. According to the model, histone methyltransferase enzymes (HMTases)
methylate the histone H3 at lysine 9 (H3K9me), creating selective binding sites
for itself and the chromodomain of HP1a. This complex is thought to form a
higher order chromatin state that represses gene activity. It has also been
found that HP1a plays a role in telomere capping. Surprisingly, recent studies
have shown that HP1a is present at many euchromatic sites along polytene
chromosomes of Drosophila melanogaster, including the developmental and
heat-shock-induced puffs, and that this protein can be removed from these sites
by in vivo RNase treatment, thus suggesting an association of HP1a with the
transcripts of many active genes. To test this suggestion, we performed an
extensive screening by RIP-chip assay (RNA-immunoprecipitation on microarrays),
and we found that HP1a is associated with transcripts of more than one hundred
euchromatic genes. An expression analysis in HP1a mutants shows that HP1a is
required for positive regulation of these genes. Cytogenetic and molecular
assays show that HP1a also interacts with the well known proteins DDP1, HRB87F,
and PEP, which belong to different classes of heterogeneous nuclear
ribonucleoproteins (hnRNPs) involved in RNA processing. Surprisingly, we found
that all these hnRNP proteins also bind heterochromatin and are dominant
suppressors of position effect variegation. Together, our data show novel and
unexpected functions for HP1a and hnRNPs proteins. All these proteins are in
fact involved both in RNA transcript processing and in heterochromatin
formation. This suggests that, in general, similar epigenetic mechanisms have a
significant role on both RNA and heterochromatin metabolisms.
DOI: 10.1371/journal.pgen.1000670
PMCID: PMC2743825
PMID: 19798443 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22771625 | 1. Infect Genet Evol. 2012 Dec;12(8):1780-7. doi: 10.1016/j.meegid.2012.06.013.
Epub 2012 Jul 4.
Differential carbonylation of cytoskeletal proteins in blood group O
erythrocytes: potential role in protection against severe malaria.
Méndez D(1), Hernáez ML, Kamali AN, Diez A, Puyet A, Bautista JM.
Author information:
(1)Department of Biochemistry and Molecular Biology IV, Universidad Complutense
de Madrid, Ciudad Universitaria, Madrid, Spain.
The molecular basis for the prevalence of blood group O in regions where malaria
is endemic remains unclear. In some genetic backgrounds oxidative modifications
have been linked to a reduced susceptibility to severe malaria disease. Through
redox proteomics, we detected differences in carbonylated membrane proteins
among the different blood groups, both in Plasmodium-infected and uninfected
erythrocytes (RBC). Carbonylation profiles of RBC membrane proteins revealed
that group O blood shows a reduced protein oxidation pattern compared to groups
A, B and AB. Upon infection with Plasmodium falciparum Dd2, erythrocytes of all
blood groups showed increased oxidation of membrane proteins. By examining
4-hydroxy-2-nonenal (4-HNE) modified proteins by LC-MS/MS (liquid
chromatography/mass spectrometry) we observed that, upon malaria infection, the
protein components of lipid rafts and cytoskeleton were the main targets of
4-HNE carbonylation in all blood groups. Ankyrins and protein bands 4.2 and 4.1
were differentially carbonylated in group O as compared to A and B groups.
During trophozoite maturation in group O erythrocytes, a steady increase was
observed in the number of 4-HNE-modified proteins, suggesting a parasite-driven
4-HNE-carbonylation process. Our findings indicate a possible correlation
between the protection against severe malaria in blood group O individuals and a
specific pattern of 4-HNE-carbonylation of cytoskeleton proteins.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.meegid.2012.06.013
PMID: 22771625 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15853117 | 1. Nutr Metab Cardiovasc Dis. 2004 Dec;14(6):334-43. doi:
10.1016/s0939-4753(04)80023-1.
Prudent diet and the risk of insulin resistance.
Villegas R, Salim A, Flynn A, Perry IJ.
BACKGROUND AND AIM: Diet is a potentially modifiable risk factor for diabetes.
Dietary patterns may exert greater effects on health than individual foods,
nutrients or food groups. Data on associations between dietary patterns and the
risk of insulin resistance and type 2 diabetes are sparse. The aim of the study
was to examine associations between dietary patterns and the risk of insulin
resistance.
METHODS AND RESULTS: We performed a cross sectional study involving a group of
1018 men and women, sampled from 17 general practice lists in the South of
Ireland, with a response rate of 69%. Participants completed a detailed health
and lifestyle questionnaire and provided fasting blood samples for analysis of
glucose, insulin and lipids. Dietary intake was assessed using a food frequency
questionnaire. The food frequency questionnaire was a modification of the UK arm
of the European Prospective Investigation into cancer, EPIC study, which was
based on that used in the US Nurses' Health Study. Dietary patterns were
assessed by K cluster analysis. Insulin resistance was estimated on the basis of
fasting glucose and insulin, using the glucose homeostasis model (HOMA scores).
Insulin resistance was defined as the upper quartile of the HOMA scores. Three
dietary patterns were identified by cluster analysis (traditional Irish diet, a
prudent diet and an alcohol and convenience foods diet). Participants in
clusters 1 (traditional Irish diet) and 3 (high alcohol and convenience foods)
had a lower intake of more 'healthy' food groups (such as fruit, vegetables, low
fat dairy products, poultry, fish and whole grain products) and higher intake of
foods richer in total and SFA content (such as high fat dairy products, butter,
meat and meat products). Cluster 2 (prudent dietary pattern) was characterized
by a higher intake of food groups that are typically recommended in health
promotion programs and a lower intake of meat (read meat), meat products,
sweets, high fat dairy and white bread (white bread and unrefined cereal). The
prudent diet had the lowest HOMA scores in analysis of covariance. The
prevalence of insulin resistance in the prudent diet was lower than that in the
traditional diet (OR=0.53; 95%CI, 0.33-0.85 in fully adjusted analysis).
CONCLUSION: A prudent diet may be associated with enhanced insulin sensitivity
and a lower risk of type 2 diabetes.
DOI: 10.1016/s0939-4753(04)80023-1
PMID: 15853117 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15832907 | 1. J Spinal Cord Med. 2005;28(1):69-73. doi: 10.1080/10790268.2005.11753801.
Anterior spinal artery syndrome in two children with genetic thrombotic
disorders.
Hakimi KN(1), Massagli TL.
Author information:
(1)Department of Rehabilitation Medicine, Box 356490, University of Washington,
1959 NE Pacific Street, Seattle, WA 98195-6490, USA. [email protected]
BACKGROUND: Spinal cord infarction is a well-described, but rare, etiology of
myelopathy, especially in children. The most common syndrome, anterior spinal
artery syndrome (ASAS), is caused by interruption of blood flow to the anterior
spinal artery, producing ischemia in the anterior two-thirds of the cord, with
resulting neurologic deficits. Causes of ASAS include aortic disease,
thoracolumbar surgery, sepsis, hypotension, and thromboembolic disorders.
METHODS: Case reports of 2 patients.
RESULTS: Two children developed spinal cord infarctions consistent with ASAS,
mostly likely caused by previously undiagnosed thrombotic disorders. A child
with prothrombin variant experienced acute bilateral lower limb weakness without
any preceding event. Magnetic resonance imaging (MRI) revealed increased T2
signal in the anterior cord from midthoracic level to the conus medullaris. A
child with protein S deficiency developed lower limb weakness 1 day after a
posterior thoracolumbar fusion for idiopathic scoliosis. Computed tomography
(CT) myelogram revealed no spinal cord compression. The prothrombin variant
mutation is associated with a 2-fold risk of thrombotic events. Individuals with
protein S deficiency have an 8-fold increased risk of thrombosis.
CONCLUSION: As knowledge of the coagulation pathways grows, it is likely that
more patients with spinal cord infarctions will be diagnosed with genetic
thrombotic disorders as the etiology of their injury. We review these two
disorders, prothrombin variant and protein S deficiency, and the considerations
for long-term anticoagulation.
DOI: 10.1080/10790268.2005.11753801
PMID: 15832907 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23217568 | 1. Gend Med. 2012 Dec;9(6):490-510.e5. doi: 10.1016/j.genm.2012.10.005.
Gender differences in Latin-American patients with rheumatoid arthritis.
Barragán-Martínez C(1), Amaya-Amaya J, Pineda-Tamayo R, Mantilla RD,
Castellanos-de la Hoz J, Bernal-Macías S, Rojas-Villarraga A, Anaya JM.
Author information:
(1)Center for Autoimmune Diseases Research (CREA), School of Medicine and Health
Sciences, Universidad del Rosario, Bogotá, Colombia.
BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in
non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a
large population with unique characteristics, including high admixture.
OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in
LAC.
METHODS: This was a 2-phase study. First we conducted a cross-sectional and
analytical study in which 1128 consecutive Colombian patients with RA were
assessed. Second, a systematic review of the literature was done to evaluate the
effect of gender in LAC patients with RA.
RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of
5.2 women per man. Colombian women with RA are more at risk of having an early
age at onset and developing polyautoimmunity and abdominal obesity, and they
perform more household duties than their male counterparts. However, male gender
was associated with the presence of extra-articular manifestations. Of a total
of 641 potentially relevant articles, 38 were considered for final analysis, in
which several factors and outcomes related to gender were identified.
CONCLUSIONS: RA in LAC women is not only more common but presents with some
clinical characteristics that differ from RA presentation in men. Some of those
characteristics could explain the high rates of disability and worse prognosis
observed in women with RA in LAC.
Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.
DOI: 10.1016/j.genm.2012.10.005
PMID: 23217568 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17965425 | 1. Ann Rheum Dis. 2008 Aug;67(8):1127-31. doi: 10.1136/ard.2007.079913. Epub 2007
Oct 27.
Influence of age and gender on the 28-joint Disease Activity Score (DAS28) in
rheumatoid arthritis.
Radovits BJ(1), Fransen J, van Riel PL, Laan RF.
Author information:
(1)Radboud University Nijmegen Medical Centre, Department of Rheumatology, PO
Box 9101, HP 470, 6500 HB Nijmegen, The Netherlands. [email protected]
OBJECTIVES: To investigate the influence of age and gender on the components of
the 28-joint Disease Activity Score (DAS28) in patients with rheumatoid
arthritis (RA), and to clarify whether a high DAS28 can be equally interpreted
in all age groups, independent of gender.
METHODS: A prospective cohort of 553 patients with RA was studied for
approximately 20 years after diagnosis. The single measures of disease activity
and the share of different components of the DAS28 (eg, erythrocyte
sedimentation rate; ESR) were analysed and compared between three age groups
(<45, 45-65 and >65 years) and per gender, using analysis of variance (ANOVA).
The performance of the DAS28 and its components was explored in moderate to high
and low DAS28 categories. Linear mixed model analysis was used to design the
models best predicting ESR and the share of ESR.
RESULTS: ESR significantly increased with age, independent of other variables of
disease activity. This increase was more pronounced in male than in female
patients. Nevertheless, the share of ESR increased with age only in male
patients with a low DAS28 (<3.2). If the DAS28 score was >3.2, age and gender
did not have a significant effect on any components of the DAS28. C-reactive
protein (CRP) and DAS28(CRP) were not influenced by age.
CONCLUSIONS: A high DAS28 was found to perform equally in all age groups, in men
and women, despite the elevating effect of age on ESR. In elderly men with low
disease activity, remission rate could be underestimated by an elevated ESR.
DOI: 10.1136/ard.2007.079913
PMID: 17965425 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24161037 | 1. Semin Nephrol. 2013 Nov;33(6):508-30. doi: 10.1016/j.semnephrol.2013.08.003.
Atypical hemolytic uremic syndrome.
Kavanagh D(1), Goodship TH, Richards A.
Author information:
(1)The Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne,
UK. Electronic address: [email protected].
Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia,
thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease
characterized by complement overactivation. Inherited defects in complement
genes and acquired autoantibodies against complement regulatory proteins have
been described. Incomplete penetrance of mutations in all predisposing genes is
reported, suggesting that a precipitating event or trigger is required to unmask
the complement regulatory deficiency. The underlying genetic defect predicts the
prognosis both in native kidneys and after renal transplantation. The successful
trials of the complement inhibitor eculizumab in the treatment of atypical HUS
will revolutionize disease management.
© 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.semnephrol.2013.08.003
PMCID: PMC3863953
PMID: 24161037 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23425613 | 1. Z Kinder Jugendpsychiatr Psychother. 2013 Mar;41(2):109-19. doi:
10.1024/1422-4917/a000218.
[Depressive disorders in childhood and adolescence - an analysis of KinderAGATE
2010].
[Article in German]
Stegmann B(1), Wenzel-Seifert K, Haen E.
Author information:
(1)Klinische Pharmakologie am Lehrstuhl mit Poliklinik für Psychiatrie und
Psychotherapie der Universität Regensburg.
[email protected]
OBJECTIVE: The present analysis evaluates the prevalence and medication use in
inpatients with depression during childhood and adolescence at the KinderAGATE
hospitals in 2010. Also discussed are age and sex distribution.
METHOD: Since 2009 the following information has been recorded anonymously twice
a year from each patient at the participating hospitals of KinderAGATE: age,
sex, leading diagnosis, prescribed medication and dosage. The data obtained
provide an excellent epidemiological basis for the observation of the
prescription practice in child and adolescent psychiatry.
RESULTS: In 2010, 8.4 % of the patients included were treated for a depressive
disorder at the KinderAGATE hospitals. This is only a small portion compared to
the rates found in adult psychiatry (25.8 % of patients). In our sample male
patients diagnosed with depression (58 % DPat, mean age 13.8 years) were treated
more often and earlier than female patients (42 % DPat, mean age 15.3 years).
Fluoxetine and mirtazapine were the most frequently prescribed substances.
Sertraline, escitalopram, and citalopram were also prescribed.
CONCLUSION: A reserved medical treatment can be observed in child and
adolescence psychiatry. Off-label use seems to be nearly unavoidable due to the
lack of newly authorized medicine. Moreover, the numerous prescriptions for
fluoxetine, the only SSRI currently approved for this age group in Germany, lead
to the question of possible unauthorized alternatives.
DOI: 10.1024/1422-4917/a000218
PMID: 23425613 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17414906 | 1. Spine (Phila Pa 1976). 2007 Apr 1;32(7):735-41. doi:
10.1097/01.brs.0000259081.40354.e2.
The mutant guppy syndrome curveback as a model for human heritable spinal
curvature.
Gorman KF(1), Tredwell SJ, Breden F.
Author information:
(1)Department of Biological Sciences, Simon Fraser University, Burnaby, British
Columbia, Canada. [email protected]
STUDY DESIGN: This study investigated the morphology, pathogenesis, and
inheritance of idiopathic-like spinal curvature in the guppy syndrome,
curveback.
OBJECTIVE: To determine whether curveback could be applied as a model for the
primary factors that contribute to heritable spinal curvature in humans,
specifically, the etiopathogenesis of human familial idiopathic scoliosis.
SUMMARY OF BACKGROUND DATA: Although a genetic basis is accepted, phenotypic
complexity and the lack of an animal model with noninduced curvature have made
identification of idiopathic scoliosis etiology difficult. It is well
established that humans and fish share many genes with similar tissue and
temporal expression characteristics, and comparisons between human and fish
genomes have proven to be valuable for understanding the genetics of diseases
affecting humans.
METHODS: The curveback lineage of guppies was constructed from a single curved
male crossed to a normal female. Offspring (103) from the original cross were
scored from birth until death for the presence and magnitude of spinal
curvature. Genetic architecture was investigated through selective inbreeding,
analysis of the distribution of curve magnitude in the mature population, and
assessment of curve dynamics during development. Computed tomography assessed
vertebral detail.
RESULTS: Computed tomography reveals that vertebral breakage or fusion is not
associated with the curveback syndrome. Inbreeding demonstrates a strong genetic
influence on curveback, and the distribution of curve magnitude among adult fish
suggests polygenic inheritance. There is a female bias for curves of high
magnitude and curves that resolve before maturity. There is developmental
variability for the age of curve onset, curve progression, and final curve
magnitude.
CONCLUSIONS: Observed parallels between the curveback syndrome and human
idiopathic scoliosis suggest that the guppy model is an unexploited resource for
the identification of primary etiological factors involved in curvature. As
models for biomedical research, teleosts offer great potential regarding spinal
stability and deformity.
DOI: 10.1097/01.brs.0000259081.40354.e2
PMID: 17414906 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23194084 | 1. Diabetes Obes Metab. 2013 May;15(5):432-40. doi: 10.1111/dom.12047. Epub 2013
Jan 25.
Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes
mellitus in Japanese patients with inadequate glycaemic control: a phase II
multicentre, randomized, double-blind, placebo-controlled trial.
Kaku K(1), Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, Tokudome T,
Langkilde AM, Parikh S.
Author information:
(1)Department of Internal Medicine, Division of Diabetes, Endocrinology and
Metabolism, Kawasaki Medical School, Okayama, Japan. [email protected]
AIM: Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2)
inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM).
This study assessed the efficacy and safety of dapagliflozin monotherapy in
Japanese T2DM patients with inadequate glycaemic control.
METHODS: Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5
or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was
change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints
included change from baseline in fasting plasma glucose (FPG) and proportion of
patients achieving HbA1c <7.0% at week 12.
RESULTS: Significant reductions in HbA1c were seen with all dapagliflozin doses
(-0.11 to -0.44%) versus placebo (+0.37%). Reductions were also observed in FPG
with dapagliflozin (-0.87 to -1.77 mmol/l [-15.61 to -31.94 mg/dl]) versus
placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the
proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin
versus placebo. Adverse events (AEs) were more frequent with dapagliflozin
(40.7-53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity.
Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5
mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract
or genital infections was 0-3.8 and 0-1.8% respectively with dapagliflozin and
1.9 and 0% with placebo. No AEs of pyelonephritis were observed.
CONCLUSIONS: Compared with placebo, dapagliflozin significantly reduced
hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM
patients with inadequate glycaemic control.
© 2012 Blackwell Publishing Ltd.
DOI: 10.1111/dom.12047
PMID: 23194084 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23278769 | 1. Alcohol Clin Exp Res. 2013 May;37(5):885-9. doi: 10.1111/acer.12028. Epub 2012
Dec 20.
A novel scoring system to guide risk assessment of Wernicke's encephalopathy.
Green A(1), Parker R, Williams TM.
Author information:
(1)Bristol Specialist Drugs and Alcohol Service, Colston Fort, Bristol, United
Kingdom. [email protected]
BACKGROUND: Thiamine deficiency in patients who abuse alcohol can cause
Wernicke's encephalopathy (WE). Thiamine supplements are given to prevent this
complication. Guidelines exist for giving thiamine supplementation in the
inpatient population. However, similar guidelines are not available for
clinicians detoxifying patients in the community, and consequently, assessment
of risk of WE and prophylaxis can be inconsistent.
METHODS: A scoring system to assess risk of WE was developed and evaluated by
comparing practice before and after introduction of the system. One hundred and
twenty-six cases requiring alcohol detoxification were examined: 94 before
introduction of the scoring system and 32 afterward.
RESULTS: Before introduction of the scoring system, a risk assessment for
developing WE was performed in 30% of patients and parenteral thiamine
prescribed in 32%. After introduction of the scoring system, risk assessment and
administration of parenteral thiamine increased to 100 and 75%, respectively.
There was 1 probable case of WE before introduction of the scoring system and
none afterward.
CONCLUSIONS: We conclude that assessment of WE is often inadequate, leading to
inadequate thiamine administration. The new scoring system allows simple,
structured risk assessment for WE and thus guides appropriate thiamine
administration. This is of most value to clinicians treating the consequences of
alcohol dependence in the community.
Copyright © 2012 by the Research Society on Alcoholism.
DOI: 10.1111/acer.12028
PMID: 23278769 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23292032 | 1. Eur J Pediatr. 2013 Oct;172(10):1287-92. doi: 10.1007/s00431-012-1920-4. Epub
2013 Jan 5.
Stem cells in pediatric cardiology.
Patel P(1), Mital S.
Author information:
(1)Division of Pediatric Cardiology, Hospital for Sick Children, University of
Toronto, Toronto, ON, Canada.
The ability to reprogram virtually any cell of human origin to behave like
embryonic or pluripotent stem cells is a major breakthrough in stem cell
biology. Human induced pluripotent stem cells (iPSC) provide a unique
opportunity to study "disease in a dish" within a defined genetic and
environmental background. Patient-derived iPSCs have been successfully used to
model cardiomyopathies, rhythm disorders and vascular disorders. They also
provide an exciting opportunity for drug discovery and drug repurposing for
disorders with a known molecular basis including childhood onset heart disease,
particularly cardiac genetic disorders. The review will discuss their use in
drug discovery, efficacy and toxicity studies with emphasis on challenges in
pediatric-focused drug discovery. Issues that will need to be addressed in the
coming years include development of maturation protocols for iPSC-derived
cardiac lineages, use of iPSCs to study not just cardiac but extra-cardiac
phenotypes in the same patient, scaling up of stem cell platforms for
high-throughput drug screens, translating drug testing results to clinical
applications in the paradigm of personalized medicine, and improving both the
efficiency and the safety of iPSC-derived lineages for future stem cell
therapies.
DOI: 10.1007/s00431-012-1920-4
PMID: 23292032 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19278965 | 1. Haematologica. 2009 Apr;94(4):487-95. doi: 10.3324/haematol.13592. Epub 2009
Mar 10.
Diagnosis of Fanconi anemia in patients with bone marrow failure.
Pinto FO(1), Leblanc T, Chamousset D, Le Roux G, Brethon B, Cassinat B, Larghero
J, de Villartay JP, Stoppa-Lyonnet D, Baruchel A, Socié G, Gluckman E, Soulier
J.
Author information:
(1)Hematology Laboratory APHP, INSERM U944, Université Denis Diderot, Hôpital
Saint-Louis, 1, Av Claude Vellefaux, 75010 Paris, France.
BACKGROUND: Patients with bone marrow failure and undiagnosed underlying Fanconi
anemia may experience major toxicity if given standard-dose conditioning
regimens for hematopoietic stem cell transplant. Due to clinical variability
and/or potential emergence of genetic reversion with hematopoietic somatic
mosaicism, a straightforward Fanconi anemia diagnosis can be difficult to make,
and diagnostic strategies combining different assays in addition to classical
breakage tests in blood may be needed.
DESIGN AND METHODS: We evaluated Fanconi anemia diagnosis on blood lymphocytes
and skin fibroblasts from a cohort of 87 bone marrow failure patients (55
children and 32 adults) with no obvious full clinical picture of Fanconi anemia,
by performing a combination of chromosomal breakage tests,
FANCD2-monoubiquitination assays, a new flow cytometry-based mitomycin C
sensitivity test in fibroblasts, and, when Fanconi anemia was diagnosed,
complementation group and mutation analyses. The mitomycin C sensitivity test in
fibroblasts was validated on control Fanconi anemia and non-Fanconi anemia
samples, including other chromosomal instability disorders.
RESULTS: When this diagnosis strategy was applied to the cohort of bone marrow
failure patients, 7 Fanconi anemia patients were found (3 children and 4
adults). Classical chromosomal breakage tests in blood detected 4, but analyses
on fibroblasts were necessary to diagnose 3 more patients with hematopoietic
somatic mosaicism. Importantly, Fanconi anemia was excluded in all the other
patients who were fully evaluated.
CONCLUSIONS: In this large cohort of patients with bone marrow failure our
results confirmed that when any clinical/biological suspicion of Fanconi anemia
remains after chromosome breakage tests in blood, based on physical examination,
history or inconclusive results, then further evaluation including fibroblast
analysis should be made. For that purpose, the flow-based mitomycin C
sensitivity test here described proved to be a reliable alternative method to
evaluate Fanconi anemia phenotype in fibroblasts. This global strategy allowed
early and accurate confirmation or rejection of Fanconi anemia diagnosis with
immediate clinical impact for those who underwent hematopoietic stem cell
transplant.
DOI: 10.3324/haematol.13592
PMCID: PMC2663612
PMID: 19278965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25276464 | 1. RETRACTED ARTICLE
Case Rep Surg. 2014;2014:281210. doi: 10.1155/2014/281210. Epub 2014 Sep 7.
A Fatal Case of Wernicke's Encephalopathy after Sleeve Gastrectomy for Morbid
Obesity.
Manatakis DK(1), Georgopoulos N(1).
Author information:
(1)2nd Surgical Department, Athens Naval and Veterans Hospital, 70 Deinokratous
Street, Athens, Greece.
Retraction in
Case Rep Surg. 2017;2017:6764073. doi: 10.1155/2017/6764073.
For legal reasons, the publisher has withdrawn this article from public view.
For additional information, please contact the publisher.
DOI: 10.1155/2014/281210
PMCID: PMC4170760
PMID: 25276464 |
http://www.ncbi.nlm.nih.gov/pubmed/1618284 | 1. Exp Neurol. 1992 Jul;117(1):17-27. doi: 10.1016/0014-4886(92)90106-z.
Quantitative light microscopic demonstration of increased pallidal and striatal
met5-enkephalin-like immunoreactivity in rats following chronic treatment with
haloperidol but not with clozapine: implications for the pathogenesis of
neuroleptic-induced movement disorders.
Auchus AP(1), Pickel VM.
Author information:
(1)Department of Neurology and Neuroscience, Cornell University Medical College,
New York, New York 10021.
Acute and late onset movement disorders frequently complicate the treatment of
psychosis with typical neuroleptic drugs like haloperidol, but not with atypical
neuroleptic drugs like clozapine. Although the neural mechanisms underlying
neuroleptic-induced movement disorders remain unknown, alterations in basal
ganglia function are likely involved. A potential role for the endogenous opiate
peptides in neuroleptic-induced movement disorders is suggested by the
immunocytochemical localization of met5-enkephalin (ME) in the striatopallidal
projection pathway, and by the increased levels of ME measured by
radioimmunoassay in the rat caudate-putamen nuclei (CPN) following haloperidol
treatment. We sought to determine whether met5-enkephalin-like immunoreactivity
(MELI) in terminal fields within globus pallidus and in perikarya in CPN was
differentially altered in rats chronically treated with haloperidol or
clozapine. Acrolein-fixed forebrain sections were collected from cohorts of
adult rats receiving 21-day oral administration of haloperidol, clozapine, or
water. Sections from the three treatment groups were collectively processed for
immunocytochemical labeling using varying dilutions of ME antiserum and the
avidin-biotin peroxidase method. In globus pallidus, densitometry measures
revealed significantly increased levels of immunoperoxidase labeling for ME in
haloperidol-treated, but not in clozapine-treated animals. In CPN, optical
densitometry as well as cell counting measurements also showed a significant
increase in MELI only in the haloperidol-treated group. These results support
the concept that alterations in endogenous opiate peptides in basal ganglia may
contribute to movement disorders seen in patients receiving typical neuroleptic
drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
DOI: 10.1016/0014-4886(92)90106-z
PMID: 1618284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8976819 | 1. Eur J Cancer. 1996;32A Suppl 4:S26-30. doi: 10.1016/s0959-8049(96)00332-2.
Amifostine (Ethyol): pharmacokinetic and pharmacodynamic effects in vivo.
van der Vijgh WJ(1), Korst AE.
Author information:
(1)Department of Medical Oncology, University Hospital Vrije Universiteit,
Amsterdam, The Netherlands.
Amifostine (Ethyol) administered to cancer patients is rapidly cleared from
plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and
a T1/2 beta of 8.8 min. The result is that more than 90% of the drug has
disappeared from the plasma compartment 6 min after intravenous (i.v.)
administration. Only approximately 1% of the dose appears in the ascites. Animal
studies indicate that amifostine is primarily excreted in urine-approximately 6%
of the dose is excreted in the urine as amifostine and its metabolites WR-1065
and disulphides-which means that a large percentage of the dose is taken up by
the tissues. Maximal tissue concentrations of WR-1065 and the disulphides were
obtained between 10 and 30 min after an intraperitoneal injection of amifostine
in mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives
protection to normal tissues rather than rescue, the pharmacokinetic data
indicate that amifostine must be given shortly before administration of the
cytostatic drug or radiation from which protection is required. For these
reasons, amifostine is given to patients as a 15-min i.v. infusion before
cisplatin and carboplatin to protect against their dose-limiting toxicities. In
some regimens carboplatin is combined with three doses of amifostine because of
the high concentration of the active carboplatin species during the first 4 h
after administration. When carboplatin was administered as a 15-min i.v.
infusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just
before and 2 and 4 h after carboplatin, the area under the plasma
concentration-time curve for ultrafilterable platinum increased from 253 +/- 45
microM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for
carboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3
xenografts showed that amifostine, given once before cisplatin or three times in
combination with carboplatin, did not affect the antitumour effect of these
drugs. When amifostine was only given just before carboplatin, it even
stimulated the antitumour effect of carboplatin significantly.
DOI: 10.1016/s0959-8049(96)00332-2
PMID: 8976819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19202000 | 1. Am J Physiol Heart Circ Physiol. 2009 Apr;296(4):H1133-40. doi:
10.1152/ajpheart.00929.2008. Epub 2009 Feb 6.
Differential involvement of COX1 and COX2 in the vasculopathy associated with
the alpha-galactosidase A-knockout mouse.
Park JL(1), Shu L, Shayman JA.
Author information:
(1)Univ. of Michigan, 1560 MSRB2, 1150 W. Medical Center Dr., Ann Arbor, MI
48109-5676, USA. [email protected]
The lysosomal storage disorder Fabry disease is characterized by excessive
globotriaosylceramide (Gb3) accumulation in major organs such as the heart and
kidney. Defective lysosomal alpha-galactosidase A (Gla) is responsible for
excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3
accumulation is vascular endothelium. Endothelial dysfunction is associated with
Fabry disease and excessive cellular Gb3. We previously demonstrated that
excessive vascular Gb3 in a mouse model of Fabry disease, the Gla-knockout
(Gla(-/0)) mouse, results in abnormal vascular function, which includes abnormal
endothelium-dependent contractions, a vascular phenomenon known to involve
cyclooxygenase (COX). Therefore, we hypothesized that the vasculopathy in the
Gla knockout mouse may be due to a vasoactive COX-derived product. To test this
hypothesis, vascular reactivity experiments were performed in aortic rings from
wild-type (Gla(+/0)) and Gla(-/0) mice in the presence and absence of specific
and nonspecific COX inhibitors. Specific inhibition of COX1 or COX2 in
endothelium-intact rings from Gla(-/0) mice decreased overall phenylephrine
contractility compared with untreated Gla(-/0) rings, whereas COX inhibitors had
no effect on contractility in endothelium-denuded rings. Nonspecific inhibition
of COX with indomethacin (10 micromol/l) or COX1 inhibition with valeryl
salicylate (3 mmol/l) improved endothelial function in rings from Gla(-/0) mice,
but COX2 inhibition with NS-398 (1 micromol/l) further increased endothelial
dysfunction in rings from Gla(-/0) mice. These results suggest that, in the
Gla(-/0) mice, COX1 and COX2 activity are increased and localized in the
endothelium, producing vasopressor and vasorelaxant products, which contribute
to the Fabry-related vasculopathy.
DOI: 10.1152/ajpheart.00929.2008
PMCID: PMC2670691
PMID: 19202000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9329962 | 1. J Clin Invest. 1997 Oct 15;100(8):1991-9. doi: 10.1172/JCI119730.
Overexpression of insulin-like growth factor-1 in mice protects from myocyte
death after infarction, attenuating ventricular dilation, wall stress, and
cardiac hypertrophy.
Li Q(1), Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P.
Author information:
(1)Department of Medicine, New York Medical College, Valhalla, New York 10595,
USA.
To determine whether IGF-1 opposes the stimulation of myocyte death in the
surviving myocardium after infarction, transgenic mice overexpressing human
IGF-1B in myocytes (FVB.Igf+/-) and wild-type littermates at 1.5 and 2.5 mo of
age were subjected to coronary ligation and killed 7 d later. Myocardial
infarction involved an average 50% of the left ventricle, and produced cardiac
failure. In the region proximate to infarction, myocyte apoptosis increased 4.
2-fold and 2.1-fold in nontransgenics at 1.5 and 2.5 mo, respectively.
Corresponding increases in myocyte necrosis were 1. 8-fold and 1.6-fold. In
contrast, apoptotic and necrotic myocyte death did not increase in FVB.Igf+/-
mice at either age after infarction. In 2.5-mo-old infarcted nontransgenics,
functional impairment was associated with a 29% decrease in wall thickness, 43%
increase in chamber diameter, and a 131% expansion in chamber volume.
Conversely, the changes in wall thickness, chamber diameter, and cavitary volume
were 41, 58, and 48% smaller in infarcted FVB.Igf+/- than in nontransgenics. The
differential response to infarction of FVB.Igf+/- mice resulted in an attenuated
increase in diastolic wall stress, cardiac weight, and left and right
ventricular weight-to-body wt ratios. In conclusion, constitutive overexpression
of IGF-1 prevented activation of cell death in the viable myocardium after
infarction, limiting ventricular dilation, myocardial loading, and cardiac
hypertrophy.
DOI: 10.1172/JCI119730
PMCID: PMC508388
PMID: 9329962 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25314060 | 1. Br J Cancer. 2014 Nov 11;111(10):2024-32. doi: 10.1038/bjc.2014.538. Epub 2014
Oct 14.
TERT promoter mutations in gliomas, genetic associations and
clinico-pathological correlations.
Labussière M(1), Di Stefano AL(2), Gleize V(1), Boisselier B(3), Giry M(1),
Mangesius S(1), Bruno A(1), Paterra R(4), Marie Y(5), Rahimian A(6), Finocchiaro
G(4), Houlston RS(7), Hoang-Xuan K(8), Idbaih A(8), Delattre JY(9), Mokhtari
K(10), Sanson M(9).
Author information:
(1)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
(2)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] National
Neurological Institute C. Mondino, University of Pavia, 27100 Pavia, Italy.
(3)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Institut
du Cerveau et de la Moelle épinière (ICM), Plateforme de Génotypage Séquençage,
Paris 75013, France.
(4)Dipartimento di Neuro Oncologia Molecolare Fondazione I.R.C.C.S. Istituto
Neurologico C. Besta, Milano 20134, Italy.
(5)1] Institut du Cerveau et de la Moelle épinière (ICM), Plateforme de
Génotypage Séquençage, Paris 75013, France [2] Onconeurothèque, Paris 75013,
France.
(6)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4]
Onconeurothèque, Paris 75013, France.
(7)Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey
SM2 5NG, UK.
(8)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] AP-HP,
Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013,
France.
(9)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4]
Onconeurothèque, Paris 75013, France [5] AP-HP, Groupe Hospitalier
Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France.
(10)1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de
l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U
1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4]
Onconeurothèque, Paris 75013, France [5] AP-HP, Groupe Hospitalier
Pitié-Salpêtrière, Laboratoire de Neuropathologie R. Escourolle, Paris 75013,
France.
BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis
has been recently further strengthened by the frequent occurrence of TERT
promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic
rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF
transcription factors, whereas the common rs2853669 polymorphism disrupts
another Ets/TCF site on TERT promoter.
METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and
analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp
polymorphism rs2853669 were correlated with histology, genomic profile, TERT
mRNA expression, clinical outcome and rs2736100 genotype.
RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally
associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on
TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and
IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2)
TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3)
TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut
and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was
associated with higher TERT mRNA expression, whereas the rs2853669 variant was
associated with lower TERT mRNA expression. The mutation of CIC (a repressor of
ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA
upregulation.
CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status
of glial tumours should afford enhanced prognostic stratification of patients
with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation
influence Tert expression. This effect could be mediated by Ets/TCF
transcription factors.
DOI: 10.1038/bjc.2014.538
PMCID: PMC4229642
PMID: 25314060 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24094458 | 1. Eur J Obstet Gynecol Reprod Biol. 2013 Dec;171(2):197-204. doi:
10.1016/j.ejogrb.2013.09.005. Epub 2013 Sep 11.
Non-invasive prenatal testing for fetal sex determination: is ultrasound still
relevant?
Colmant C(1), Morin-Surroca M, Fuchs F, Fernandez H, Senat MV.
Author information:
(1)AP-HP, Hôpital Bicêtre, Service Gynécologie Obstétrique, 78 rue du Général
Leclerc, 94270 Le Kremlin Bicêtre, France. Electronic address:
[email protected].
Early prenatal diagnosis of fetal sex is necessary to optimize pregnancy
management in families known to be at risk of some heritable disorders. The
demonstration of cell-free fetal DNA (cffDNA) in the mother's blood has made it
possible to identify Y chromosome sequences in maternal blood and to determine
fetal sex noninvasively, during the first trimester. This procedure can
significantly reduce the number of invasive procedures for women with fetuses at
risk of sex-linked diseases and optimize the management of these pregnancies.
Fetal sex can be diagnosed by ultrasound with the same sensitivity and
specificity, but later in pregnancy. We performed a review of the published
literature evaluating the use of cffDNA and ultrasound for prenatal
determination of fetal sex during the first trimester of pregnancy. We present
the feasibility of the two methods and their impact on clinical practice. We
applied a sensitive search of multiple bibliographic databases including Pubmed
(MEDLINE), EMBASE, the Cochrane Library and Web of science between 1998 and
2013. Sixteen reports of the determination of fetal sex in maternal blood and 13
reports of the determination by ultrasound met our inclusion criteria. We found
a sensitivity and specificity of nearly 100% from 8 weeks of gestation for
cffDNA and from 13 weeks of gestation for ultrasound respectively. Based on this
review, we conclude that fetal sex can be determined with a high level of
accuracy by analyzing cffDNA and at an earlier gestation than ultrasound. Ten
years after the first feasibility study, the French National Authority for
Health (HAS) released a technological assessment report on the determination of
fetal sex in maternal blood, which has resulted in validating this test for
reimbursement by the national health insurance fund for the following
indications: X-linked recessive disease and congenital adrenal hyperplasia.
Copyright © 2013. Published by Elsevier Ireland Ltd.
DOI: 10.1016/j.ejogrb.2013.09.005
PMID: 24094458 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24315007 | 1. Transplant Proc. 2013;45(10):3719-23. doi: 10.1016/j.transproceed.2013.08.079.
Urinary exosomes as a source of kidney dysfunction biomarker in renal
transplantation.
Alvarez S(1), Suazo C, Boltansky A, Ursu M, Carvajal D, Innocenti G, Vukusich A,
Hurtado M, Villanueva S, Carreño JE, Rogelio A, Irarrazabal CE.
Author information:
(1)Transplantation Unit, Davila Clinic, Santiago, Chile.
End-stage renal disease (ESRD) requires for its treatment permanent dialysis or
kidney transplantation (KT). KT is the best clinical treatment, however, the
early function of the allograft varies depending on multiple factors associated
with cold ischemia time (CIT) and the allograft rejection process. It is known
that serum creatinine is an insensitive and late marker for predicting graft
recovery after KT, mainly in patients with delayed graft function (DGF).
Neutrophil gelatinase-associated lipocalin (NGAL) is produced in the distal
nephron and it is one of the most promising novel biomarkers for acute kidney
injury (AKI) and chronic kidney disease (CKD). NGAL has been proposed to be a
predictor of organ recovery from DGF after KT from donors after cardiac death.
Because nonrenal diseases can also induce NGAL, more information is necessary to
validate the sensitivity and specificity of urine and plasma NGAL in clinical
samples. The exosomes are vesicles released into the urine from the kidney
epithelium and they have been proposed as better source to explore as biomarker
of renal dysfunction. The molecular composition of the urinary exosomes could be
representative of the physiological or physiopathologic condition of the urinary
system. We propose that determination of NGAL in urinary exosomes is a better
predictor of kidney dysfunction after KT than other urinary fractions. We
analyzed 15 kidney allograft recipients, with a mean age of 36 years (range,
16-60 years) and 75% were male: 11 living donors (LD) and 4 deceased donors
(DD). The average length of CIT was 14 hours in DD and less than 1 hour in LD.
Three patient developed DGF. Using Western blot analysis, NGAL was detectable in
the cellular and exosomal fraction of the urine. The exosomes expressed higher
levels of NGAL than the cellular fraction. The expression of NGAL was observed
from the first day after transplantation. In the cellular fraction of the urine,
no significant differences of NGAL were observed between the patients. However,
the median of NGAL expression in the exosomes fraction was significantly higher
in DD patient, from the first day after KT (P < .05). Moreover, we noticed that
NGAL expression in exosomes remained elevated in the patients with DGF compared
with non-DGF patients (P < .05). Considering the highest abundance of NGAL in
the urinary exosomes and its correlation with DGF patients, we suggest the
exosomal fraction as a more sensitive substrate to evaluate early biomarkers of
DGF after KT.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.transproceed.2013.08.079
PMID: 24315007 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23738048 | 1. Oxid Med Cell Longev. 2013;2013:984546. doi: 10.1155/2013/984546. Epub 2013
May 7.
Activation of the Nrf2 pathway by inorganic arsenic in human hepatocytes and the
role of transcriptional repressor Bach1.
Liu D(1), Duan X, Dong D, Bai C, Li X, Sun G, Li B.
Author information:
(1)Department of Occupational and Environmental Health, Liaoning Provincial Key
Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health,
China Medical University, 92 North 2nd Road, Heping District, Shenyang 110001,
China.
Previous studies have proved that the environmental toxicant, inorganic arsenic,
activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in many
different cell types. This study tried to explore the hepatic Nrf2 pathway upon
arsenic treatment comprehensively, since liver is one of the major target organs
of arsenical toxicity. Our results showed that inorganic arsenic significantly
induced Nrf2 protein and mRNA expression in Chang human hepatocytes. We also
observed a dose-dependent increase of antioxidant response element- (ARE-)
luciferase activity. Both the mRNA and protein levels of NAD(P)H:quinone
oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were all upregulated
dramatically. On the other hand, entry and accumulation of Nrf2 protein in the
nucleus, while exportting the transcriptional repressor BTB and CNC homology 1
(Bach1) from nucleus to cytoplasm, were also confirmed by western blot and
immunofluorescence assay. Our results therefore confirmed the arsenic-induced
Nrf2 pathway activation in hepatocytes and also suggested that the translocation
of Bach1 was associated with the regulation of Nrf2 pathway by arsenic. Hepatic
Nrf2 pathway plays indispensable roles for cellular defenses against arsenic
hepatotoxicity, and the interplay of Bach1 and Nrf2 may be helpful to understand
the self-defensive responses and the diverse biological effects of arsenicals.
DOI: 10.1155/2013/984546
PMCID: PMC3664501
PMID: 23738048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17128093 | 1. Rev Neurol (Paris). 2006 Jun;162 Spec No 2:4S81-4S90.
[Differential diagnosis and atypical subsets of amyotrophic lateral sclerosis].
[Article in French]
Pradat PF(1), Bruneteau G.
Author information:
(1)Fédération des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière,
Paris. [email protected]
Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and
lower motor neurons. In the absence of any validated biological marker, the
diagnosis of ALS depends upon recognition of characteristic symptoms and signs
together with supportive electrophysiological findings. The diagnosis of ALS is
easy to recognize in its fully developed form but during the early stages both
false positive and false negative diagnoses are common. In clinical practice,
diagnostic difficulties mostly arise with patients who present either with only
upper motor neuron, or with only lower motor neuron signs. It may be difficult
to distinguish ALS with clinically predominant lower motor neuron involvement
from alternative diagnoses including spinal atrophies of adult onset, Kennedy's
disease, inclusion body myositis and motor neuropathies with conduction blocks.
The diagnosis of ALS related syndromes (progressive muscular atrophy, primary
lateral sclerosis and progressive bulbar palsy) requires the elimination of
alternate diagnoses. This paper reviews the main characteristics of diseases
mimicking ALS and the atypical subsets of ALS.
PMID: 17128093 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15520695 | 1. Am J Orthod Dentofacial Orthop. 2004 Nov;126(5):615-9. doi:
10.1016/j.ajodo.2004.02.007.
Relationships among nocturnal jaw muscle activities, decreased esophageal pH,
and sleep positions.
Miyawaki S(1), Tanimoto Y, Araki Y, Katayama A, Imai M, Takano-Yamamoto T.
Author information:
(1)Department of Orthodontics and Dentofacial Orthopedics, Okayama University
Graduate School of Medicine and Dentistry, Okayama, Japan.
The purpose of this study was to examine the relationships among nocturnal jaw
muscle activities, decreased esophageal pH, and sleep positions. Twelve adult
volunteers, including 4 bruxism patients, participated in this study. Portable
pH monitoring, electromyography of the temporal muscle, and audio-video
recordings were conducted during the night in the subjects' homes. Rhythmic
masticatory muscle activity (RMMA) episodes were observed most frequently, with
single short-burst episodes the second most frequent. The frequencies of RMMA,
single short-burst, and clenching episodes were significantly higher during
decreased esophageal pH episodes than those during other times. Both the
electromyography and the decreased esophageal pH episodes were most frequently
observed in the supine position. These results suggest that most jaw muscle
activities, ie, RMMA, single short-burst, and clenching episodes, occur in
relation to gastroesophageal reflux mainly in the supine position.
DOI: 10.1016/j.ajodo.2004.02.007
PMID: 15520695 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9323559 | 1. J Inherit Metab Dis. 1997 Sep;20(5):643-57. doi: 10.1023/a:1005366224351.
Human alpha-galactosidase A: high plasma activity expressed by the -30G-->A
allele.
Fitzmaurice TF(1), Desnick RJ, Bishop DF.
Author information:
(1)Department of Human Genetics, Mount Sinai School of Medicine, New York, NY
10029, USA.
Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal
exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl
residues from glycoconjugates and is the defective enzyme causing Fabry disease
(McKusick 301500). An unusally elevated level of plasma alpha-Gal A activity (>
2.5 times the normal mean) was detected in two unrelated normal males and the
elevated activities were inherited as X-linked traits in their families.
Sequencing of the alpha-Gal A coding region, intron/exon boundaries and
5'-flanking region from the proband identified a single mutation, a G-->A
transition 30 nt upstream from the initiation of translation codon in exon 1.
The -30G-->A mutation occurred in a putative NF kappa B/Ets consensus binding
site that was recently shown to inhibit protein binding to the 5'-untranslated
region of the gene, providing a possible explanation for its high activity. To
further characterize the mutation, the mRNA and protein expressed by this
variant allele were studied. Purified plasma and lymphoblast alpha-Gal A
activity from individuals with the -30G-->A mutation had normal physical and
kinetic properties. In vitro translation of mRNAs from the cloned normal and
high plasma activity alleles resulted in similar levels of alpha-Gal A protein,
indicating that this mutation did not enhance translation. These findings
suggest that the -30G-->A mutation in the 5'-untranslated region of the
alpha-Gal A gene enhances transcription, presumably by interfering with the
binding of negatively-acting transcription factors which normally decrease
alpha-Gal A expression in various cells. Preliminary studies of the frequency of
the -30G-->A mutation in 395 unrelated normal males of mixed ancestry revealed
two additional unrelated individuals who had high plasma enzymatic activity and
the mutation, confirming the effect of this mutation on enzyme expression and
suggesting that about 0.5% of normal individuals have high plasma alpha-Gal A
activity due to this variant allele.
DOI: 10.1023/a:1005366224351
PMID: 9323559 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23212593 | 1. Mod Rheumatol. 2013 May;23(3):415-24. doi: 10.1007/s10165-012-0799-2. Epub
2012 Dec 5.
JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to
clinical.
Tanaka Y(1), Yamaoka K.
Author information:
(1)The First Department of Internal Medicine, School of Medicine, University of
Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Kitakyushu
807-8555, Japan. [email protected]
Rheumatoid arthritis (RA) is a representative autoimmune disease characterized
by chronic and destructive inflammatory synovitis. The multiple cytokines play
pivotal roles in RA pathogenesis by inducing intracellular signaling, and
members of the Janus kinase (JAK) family are essential for such signal
transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied
for RA, with satisfactory effects and acceptable safety in multiple clinical
examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg
twice a day appear suitable for further evaluation. Subsequently, multiple phase
3 studies were carried out, and tofacitinib with or without methotrexate (MTX)
is efficacious and has a manageable safety profile in active RA patients who are
MTX naïve or show inadequate response to methotrexate (MTX-IR),
disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor
(TNF)-inhibitor-IR. The common adverse events were infections, such as
nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and
decreases in neutrophil counts. Although the mode of action of tofacitinib
remains unclear, we clarified that the inhibitory effects of tofacitinib could
be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ
production and proliferation of CD4(+) T cells in the inflamed synovium. Taken
together, an orally available kinase inhibitor tofacitinib targeting
JAK-mediated signals would be expected to be a new option for RA treatment.
DOI: 10.1007/s10165-012-0799-2
PMID: 23212593 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10694306 | 1. Eur J Dermatol. 2000 Mar;10(2):98-102.
Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis,
seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP
syndrome?
Boente MC(1), Bibas-Bonet H, Coronel AM, Asial RA.
Author information:
(1)Department of Dermatology. Universidad Nacional de Tucumán, Tucumán, 4000,
Argentina. [email protected]
A boy with congenital atrichia, ichthyosis follicular, keratitis, cutaneous
infections and a huge inguinal hernia, but without deafness is reported. We
believe it represents a new case of a rare X-linked recessive syndrome known as
ichthyosis follicularis, alopecia, photophobia syndrome (IFAP). The differential
diagnosis from keratitis ichthyosis deafness is discussed. The cutaneous
infections seen in our case suggest the possibility of considering a genetic
link between these syndromes.
PMID: 10694306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22385148 | 1. Br J Pharmacol. 2013 May;169(2):318-27. doi: 10.1111/j.1476-5381.2012.01928.x.
Chemical genetics and its potential in cardiac stem cell therapy.
Vieira JM(1), Riley PR.
Author information:
(1)Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford,
UK.
Over the last decade or so, intensive research in cardiac stem cell biology has
led to significant discoveries towards a potential therapy for cardiovascular
disease; the main cause of morbidity and mortality in humans. The major goal
within the field of cardiovascular regenerative medicine is to replace lost or
damaged cardiac muscle and coronaries following ischaemic disease. At present,
de novo cardiomyocytes can be generated either in vitro, for cell
transplantation or disease modelling using directed differentiation of embryonic
stem cells or induced pluripotent stem cells, or in vivo via direct
reprogramming of resident adult cardiac fibroblast or ectopic stimulation of
resident cardiac stem or progenitor cells. A major bottleneck with all of these
approaches is the low efficiency of cardiomyocyte differentiation alongside
their relative functional immaturity. Chemical genetics, and the application of
phenotypic screening with small molecule libraries, represent a means to enhance
understanding of the molecular pathways controlling cardiovascular cell
differentiation and, moreover, offer the potential for discovery of new drugs to
invoke heart repair and regeneration. Here, we review the potential of chemical
genetics in cardiac stem cell therapy, highlighting not only the major
contributions to the field so far, but also the future challenges.
© 2012 The Authors. British Journal of Pharmacology © 2012 The British
Pharmacological Society.
DOI: 10.1111/j.1476-5381.2012.01928.x
PMCID: PMC3651658
PMID: 22385148 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15951423 | 1. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71. doi:
10.1073/pnas.0502678102. Epub 2005 Jun 10.
Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and
regenerate infarcted myocardium, improving cardiac function.
Linke A(1), Müller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo
C, Cascapera S, Böhm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J,
Anversa P.
Author information:
(1)Cardiovascular Research Institute, Department of Medicine, New York Medical
College, Valhalla, NY 10595, USA.
The purpose of this study was to determine whether the heart in large mammals
contains cardiac progenitor cells that regulate organ homeostasis and regenerate
dead myocardium after infarction. We report that the dog heart possesses a
cardiac stem cell pool characterized by undifferentiated cells that are
self-renewing, clonogenic, and multipotent. These clonogenic cells and early
committed progeny possess a hepatocyte growth factor (HGF)-c-Met and an
insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated
to induce their migration, proliferation, and survival. Therefore, myocardial
infarction was induced in chronically instrumented dogs implanted with
sonomicrometric crystals in the region of the left ventricular wall supplied by
the occluded left anterior descending coronary artery. After infarction, HGF and
IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor
cells. This intervention led to the formation of myocytes and coronary vessels
within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic
proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas
alpha-sarcomeric actin, cardiac myosin heavy chain, troponin I, and
alpha-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were
also present. Myocardial reconstitution resulted in a marked recovery of
contractile performance of the infarcted heart. In conclusion, the activation of
resident primitive cells in the damaged dog heart can promote a significant
restoration of dead tissue, which is paralleled by a progressive improvement in
cardiac function. These results suggest that strategies capable of activating
the growth reserve of the myocardium may be important in cardiac repair after
ischemic injury.
DOI: 10.1073/pnas.0502678102
PMCID: PMC1157041
PMID: 15951423 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24260207 | 1. PLoS One. 2013 Nov 18;8(11):e79363. doi: 10.1371/journal.pone.0079363.
eCollection 2013.
Familial hypertrophic cardiomyopathy related cardiac troponin C L29Q mutation
alters length-dependent activation and functional effects of phosphomimetic
troponin I*.
Li AY(1), Stevens CM, Liang B, Rayani K, Little S, Davis J, Tibbits GF.
Author information:
(1)Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby,
British Columbia, Canada.
The Ca(2+) binding properties of the FHC-associated cardiac troponin C (cTnC)
mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted
thin filament preparations, and skinned cardiomyocytes. While higher Ca(2+)
binding affinity was apparent for the L29Q mutant in isolated cTnC, this
phenomenon was not observed in the cTn complex. At the level of the thin
filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the
Ca(2+) affinity by 27% in the steady-state measurement and increased the Ca(2+)
dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations
suggest that L29Q destabilizes the conformation of cNTnC in the presence of
phosphomimetic cTnI and potentially modulates the Ca(2+) sensitivity due to the
changes of the opening/closing equilibrium of cNTnC. In the skinned
cardiomyocyte preparation, L29Q cTnC increased Ca(2+) sensitivity in a highly
sarcomere length (SL)-dependent manner. The well-established reduction of Ca(2+)
sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the
mutation and it also depressed the SL-dependent increase in myofilament Ca(2+)
sensitivity. This might result from its modified interaction with cTnI which
altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex.
This study demonstrates that the L29Q mutation alters the contractility and the
functional effects of the phosphomimetic cTnI in both thin filament and single
skinned cardiomyocytes and importantly that this effect is highly sarcomere
length dependent.
DOI: 10.1371/journal.pone.0079363
PMCID: PMC3832503
PMID: 24260207 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/24218053 | 1. Drugs. 2013 Nov;73(17):1967-75. doi: 10.1007/s40265-013-0149-5.
Riociguat: first global approval.
Conole D(1), Scott LJ.
Author information:
(1)Adis R&D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North
Shore, 0754, Auckland, New Zealand, [email protected].
Riociguat (Adempas(®)), an oral first-in-class soluble guanylate cyclase (sGC)
stimulator, is under global development by Bayer Healthcare Pharmaceuticals Inc.
for the treatment of adult patients with inoperable or chronic/persistent
chronic thromboembolic pulmonary hypertension (CTEPH) and for the treatment of
adult patients with pulmonary arterial hypertension (PAH). The drug directly
stimulates sGC in a nitric oxide independent manner, thereby increasing the
sensitivity of sGC to nitric oxide, leading to increased cyclic guanosine
monophosphate generation (a key signalling molecule involved in regulating
vascular tone, proliferation, fibrosis and inflammation). Riociguat is the
world's first approved pharmacotherapy for CTEPH, with its first global approval
in this indication occurring in Canada. It has subsequently been approved in the
USA for the treatment of patients with CTEPH and also received its first global
approval in patients with PAH in the USA. It is undergoing regulatory review for
these indications in Europe and for use in patients with CTEPH in Japan. This
article summarizes the milestones in the development of riociguat, leading to
its first global approvals in patients with CTEPH and PAH.
DOI: 10.1007/s40265-013-0149-5
PMID: 24218053 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21862473 | 1. J Antimicrob Chemother. 2011 Nov;66(11):2647-50. doi: 10.1093/jac/dkr351. Epub
2011 Aug 22.
Variation in gentamicin and vancomycin dosage and monitoring in UK neonatal
units.
Kadambari S(1), Heath PT, Sharland M, Lewis S, Nichols A, Turner MA.
Author information:
(1)Paediatric Infectious Disease Unit, St George's University of London, Cranmer
Terrace, London SW17 0RE, UK. [email protected]
BACKGROUND: Gentamicin and vancomycin are commonly used in neonatal units for
the treatment of life-threatening infections. This study aimed to describe the
dosage regimen and the approach to therapeutic drug monitoring (TDM) for both
antibiotics in units that participate in a UK neonatal network.
METHODS: Questionnaires were sent to all units across the Extended Neonatal
Network, requesting details of each unit's dosing regimen and TDM practice.
RESULTS: A total of 43 (of 114) units replied to the gentamicin questionnaire
and 29 to the vancomycin questionnaire. Ten different gentamicin dosing regimens
were used, depending on gestational age and weight. Most units (79%) followed
British National Formulary for Children dosing guidance regarding vancomycin,
but there were nine variations in TDM practice.
CONCLUSIONS: There is significant variation in gentamicin and vancomycin dosing
regimens and TDM guidance across a UK network of neonatal units. The development
of standardized, evidence-based protocols should be prioritized.
DOI: 10.1093/jac/dkr351
PMID: 21862473 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21400356 | 1. SAR QSAR Environ Res. 2011 Jun;22(3):239-63. doi:
10.1080/1062936X.2010.548830.
Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER
1) tyrosine kinase inhibitors.
Gupta AK(1), Bhunia SS, Balaramnavar VM, Saxena AK.
Author information:
(1)Medicinal and Process Chemistry Division, Central Drug Research Institute,
CSIR, Lucknow, India.
A pharmacophore model has been developed using diverse classes of epidermal
growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the
treatment of human tumours. Among the top 10 generated hypotheses, the second
hypothesis, with one hydrogen bond acceptor, one ring aromatic and three
hydrophobic features, was found to be the best on the basis of Cat Scramble
validation as well as test set prediction (r(training) = 0.89, r(test) = 0.82).
The model also maps well to the external test set molecules as well as
clinically active molecules and corroborates the docking studies. Finally, 10
hits were identified as potential leads after virtual screening of ZINC database
for EGFR TK inhibition. The study may facilitate the designing and discovery of
novel EGFR TK inhibitors.
DOI: 10.1080/1062936X.2010.548830
PMID: 21400356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24937153 | 1. PLoS One. 2014 Jun 17;9(6):e100297. doi: 10.1371/journal.pone.0100297.
eCollection 2014.
TERT promoter mutations lead to high transcriptional activity under hypoxia and
temozolomide treatment and predict poor prognosis in gliomas.
Chen C(1), Han S(2), Meng L(2), Li Z(2), Zhang X(3), Wu A(4).
Author information:
(1)Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology,
Ministry of Education, College of Basic Medical Science, China Medical
University, Shenyang, Liaoning, China.
(2)Department of Neurosurgery, the First Affiliated Hospital of China Medical
University, Shenyang, Liaoning, China.
(3)Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology,
Ministry of Education, College of Basic Medical Science, China Medical
University, Shenyang, Liaoning, China; Department of Medical Genetics, Peking
Union Medical University, Peking, China.
(4)Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology,
Ministry of Education, College of Basic Medical Science, China Medical
University, Shenyang, Liaoning, China; Department of Neurosurgery, the First
Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
OBJECTIVE: This study explored the effects of telomerase reverse transcriptase
(TERT) promoter mutations on transcriptional activity of the TERT gene under
hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status
and prognostic value of these mutations in gliomas.
METHODS: The effect of TERT promoter mutations on the transcriptional activity
of the TERT gene under hypoxic and TMZ treatment conditions was investigated in
glioma cells using the luciferase assay. TERT promoter mutations were detected
in 101 glioma samples (grades I-IV) and 49 other brain tumors by sequencing.
TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios
from survival analysis of glioma patients were determined relative to the
presence of TERT promoter mutations.
RESULTS: Mutations in the TERT promoter enhanced gene transcription even under
hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA
expression. Mutations were detected in gliomas, but not in meningiomas,
pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues,
or peripheral blood of glioma patients. Patients with TERT promoter mutations
had lower survival rates, even after adjusting for other known or potential risk
factors, and the incidence of mutation was correlated with patient age.
CONCLUSION: TERT promoter mutations were specific to gliomas. TERT promoter
mutations maintained its ability of inducing high transcriptional activity even
under hypoxic and TMZ treatment conditions, and the presence of mutations was
associated with poor prognosis in glioma patients. These findings demonstrate
that TERT promoter mutations are novel prognostic markers for gliomas that can
inform prospective therapeutic strategies.
DOI: 10.1371/journal.pone.0100297
PMCID: PMC4061075
PMID: 24937153 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/10837071 | 1. Annu Rev Immunol. 2000;18:621-63. doi: 10.1146/annurev.immunol.18.1.621.
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
Karin M(1), Ben-Neriah Y.
Author information:
(1)Department of Pharmacology, Laboratory of Gene Regulation and Signal
Transduction University of California, San Diego, La Jolla, California
92093-0636, USA. [email protected]
NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric
transcription factors composed of members of the Rel family of DNA-binding
proteins that recognize a common sequence motif. NF-kappaB is found in
essentially all cell types and is involved in activation of an exceptionally
large number of genes in response to infections, inflammation, and other
stressful situations requiring rapid reprogramming of gene expression. NF-kappaB
is normally sequestered in the cytoplasm of nonstimulated cells and consequently
must be translocated into the nucleus to function. The subcellular location of
NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind
NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear
uptake. Exposure of cells to a variety of extracellular stimuli leads to the
rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of
IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates
gene transcription. NF-kappaB activation represents a paradigm for controlling
the function of a regulatory protein via ubiquitination-dependent proteolysis,
as an integral part of a phosphorylationbased signaling cascade. Recently,
considerable progress has been made in understanding the details of the
signaling pathways that regulate NF-kappaB activity, particularly those
responding to the proinflammatory cytokines tumor necrosis factor-alpha and
interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible
IkappaB phosphorylation is the point of convergence for most
NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and
IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene
knockout studies have shed light on the very different physiological functions
of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on
IkappaB serve as an essential part of a specific recognition site for
E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how
IKK controls IkappaB ubiquitination and degradation. A variety of other
signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation
of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB
precursors, provide additional mechanisms that modulate the level and duration
of NF-kappaB activity.
DOI: 10.1146/annurev.immunol.18.1.621
PMID: 10837071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23524842 | 1. Autophagy. 2013 Jun 1;9(6):928-30. doi: 10.4161/auto.24371. Epub 2013 Mar 22.
RRAG GTPases link nutrient availability to gene expression, autophagy and
lysosomal biogenesis.
Martina JA(1), Puertollano R.
Author information:
(1)Laboratory of Cell Biology, National Heart, Lung and Blood Institute,
National Institutes of Health, Bethesda, MD, USA.
Comment on
Martina JA, Puertollano R. Rag GTPases mediate amino acid-dependent
recruitment of TFEB and MITF to lysosomes. J Cell Biol. 2013;200:475–91. doi:
10.1083/jcb.201209135.
When the levels of intracellular amino acids are high, RRAG GTPases recruit
MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit
specific MTORC1 substrates to the lysosomal surface, thus facilitating
MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs
interact with the transcription factor EB (TFEB), the master regulator of a gene
network that promotes lysosomal biogenesis and autophagy. Redistribution to
lysosomes is critical for MTORC1-dependent inactivation of TFEB under
nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating
nutrient availability and cellular clearance.
DOI: 10.4161/auto.24371
PMCID: PMC3672304
PMID: 23524842 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10320209 | 1. Psychiatry Res. 1999 Feb 22;90(1):31-9. doi: 10.1016/s0925-4927(98)00054-7.
Positive correlation between reduction of handwriting area and D2 dopamine
receptor occupancy during treatment with neuroleptic drugs.
Kuenstler U(1), Juhnhold U, Knapp WH, Gertz HJ.
Author information:
(1)Department of Psychiatry, University of Leipzig, Germany.
[email protected]
We investigated the relationship between fine extrapyramidal-motor symptoms
(reduction of handwriting area) and D2 dopamine receptor occupancy under
neuroleptic treatment. The handwriting of 18 schizophrenic patients before and
during treatment with typical (haloperidol, haloperidol decanoate) and atypical
(clozapine, risperidone) neuroleptic drugs was examined. Data analysis of the
handwriting's examination was carried out with a planimetric computer programme.
At the time of the second test of handwriting, D2 receptor occupancy was
determined with single photon emission tomography (SPET) using
[(123)I]iodobenzamide ((123)I-IBZM). In all patients, a reduction of handwriting
area and a D2 receptor occupancy were found. The correlation between reduction
of handwriting area and D2 receptor occupancy for typical and atypical
neuroleptic drugs was linear and statistically significant (r=0.9; P > 0.001).
Our findings point to the possibility that the reduction of handwriting area may
be used as a clinical indicator of D2 receptor occupancy under treatment with
neuroleptic drugs.
DOI: 10.1016/s0925-4927(98)00054-7
PMID: 10320209 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22628388 | 1. Brain. 2012 Jun;135(Pt 6):1714-23. doi: 10.1093/brain/aws108.
Autosomal dominant congenital spinal muscular atrophy: a true form of spinal
muscular atrophy caused by early loss of anterior horn cells.
Oates EC(1), Reddel S, Rodriguez ML, Gandolfo LC, Bahlo M, Hawke SH, Lamandé SR,
Clarke NF, North KN.
Author information:
(1)Institute for Neuroscience and Muscle Research, Children's Hospital at
Westmead, Locked Bag 4001, Westmead, New South Wales, 2145, Australia.
Autosomal dominant congenital spinal muscular atrophy is characterized by
predominantly lower limb weakness and wasting, and congenital or early-onset
contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation
channel, have recently been identified in one large dominant congenital spinal
muscular atrophy kindred, but the genetic basis of dominant congenital spinal
muscular atrophy in many families remains unknown. It has been hypothesized that
differences in the timing and site of anterior horn cell loss in the central
nervous system account for the variations in clinical phenotype between
different forms of spinal muscular atrophy, but there has been a lack of
neuropathological data to support this concept in dominant congenital spinal
muscular atrophy. We report clinical, electrophysiology, muscle magnetic
resonance imaging and histopathology findings in a four generation family with
typical dominant congenital spinal muscular atrophy features, without mutations
in TRPV4, and in whom linkage to other known dominant neuropathy and spinal
muscular atrophy genes has been excluded. The autopsy findings in the proband,
who died at 14 months of age from an unrelated illness, provided a rare
opportunity to study the neuropathological basis of dominant congenital spinal
muscular atrophy. There was a reduction in anterior horn cell number in the
lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the
ventral nerve roots at these levels, in the absence of additional peripheral
nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young
age of the child at the time of autopsy, there was no pathological evidence of
ongoing loss or degeneration of anterior horn cells suggesting that anterior
horn cell loss in dominant congenital spinal muscular atrophy occurs in early
life, and is largely complete by the end of infancy. These findings confirm that
dominant congenital spinal muscular atrophy is a true form of spinal muscular
atrophy caused by a loss of anterior horn cells localized to lumbar and cervical
regions early in development.
DOI: 10.1093/brain/aws108
PMID: 22628388 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25774734 | 1. Dtsch Med Wochenschr. 2015 Mar;140(6):426-7. doi: 10.1055/s-0041-100947. Epub
2015 Mar 16.
[Pulmonary infection in neutropenia].
[Article in German]
Haap M(1), Neumayer B(2), Kopp HG(1), Peter S(3), Haen S(2), Riessen R(1),
Artunc F(1), Fend F(2), Kanz L(1), Müller MR(1).
Author information:
(1)Abteilung für Endokrinologie, Diabetologie, Angiologie, Nephrologie und
Klinische Chemie, Medizinische Klinik und Poliklinik, Universitätsklinikum
Tübingen.
(2)Institut für Pathologie, Universitätsklinikum Tübingen.
(3)Abteilung für Onkologie, Hämatologie, Klinische Immunologie, Rheumatologie
und Pulmonologie, Medizinische Klinik und Poliklinik, Universitätsklinikum
Tübingen.
MEDICAL HISTORY AND CLINICAL COURSE: A 42-year-old patient with hairy cell
leukemia had been treated for 3 years by a hematologist in private practice.
Initially the patient received 1 course of cladribine upon which the disease
went into complete remission. 6 weeks ago a relapse was diagnosed and
combination therapy with cladibrin and rituximab was initiated. Now the patient
presented to the emergency room with shortness of breath and pain when
breathing.
INVESTIGATIONS, TREATMENT AND COURSE: In the chest x-ray, patchy infiltrates and
pleural effusions were found on both sides. The subsequently performed computed
tomography showed bilateral compactions with an Halo suspicious for fungal
infiltrates. Upon admission to the hospital, an empirical antibiotic therapy
with clarithromycin and piperacillin/tazobactam was initiated, which was later
escalated to meropenem and linezolid. Additionally, an antifungal therapy with
voriconazole was started and later switched to liposomal amphotericin B. At his
admission, a positive aspergillus antigen could be detected in the
microbiological laboratory. Under antimycotic treatment the aspergillus antigen
was repeatedly negative. The patient presented with pronounced cytopenias and
after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could
only be stimulated insufficiently. The patient was transferred to the intensive
care unit three days after admission with severe respiratory failure. He died on
day 8 after admission. AUTOPSY AND DIAGNOSIS: Diagnosis was consistent with
relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow
infiltration > 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack
of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae
were found in both lungs and an infarction of the spleen with evidence of fungal
hyphae was detected. The cultural findings post mortem on yeast or mold were
negative.
CONCLUSION: Patients with refractory hairy cell leukemia and prolonged
neutropenia are at increased risk for systemic fungal infections. Therefore,
prohylactic antimycotic therapy should be considered early in this group of
patients. The therapeutic approach of vemurafenib in treatment-refractory hairy
cell leukemia is promising and offers an additional treatment option. In the
present case, the patient could unfortunately not be stabilized due to the
septic complications.
© Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0041-100947
PMID: 25774734 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24137951 | 1. Ter Arkh. 2013;85(7):76-8.
[Successful use of vemurafenib in a patient with resistant hairy cell leukemia].
[Article in Russian]
Urnova ES, Al'-Radi LS, Kuz'mina LA, Kariakina AA, Kovrigina AM, Dvirnyk VN,
Iakutik IA, Sudarikov AB, Parovichnikova EN, Savchenko VG.
The paper describes a case of a patient with refractory hairy cell leukemia. In
spite of the absence of CD25 expression, the disease was classified as a
classical form according to the WHO classification (2008), as also confirmed by
the detection of BRAFV600E mutation. The disease was characterized by resistance
to all lines of therapy (interferon-a, splenectomy, cladribin). Clinical and
hematological remission was achieved within 2 months of administration of the
BRAF kinase inhibitor vemurafenib.
PMID: 24137951 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9600226 | 1. J Neuropathol Exp Neurol. 1998 Apr;57(4):334-7. doi:
10.1097/00005072-199804000-00005.
Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's
disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity.
Irizarry MC(1), Growdon W, Gomez-Isla T, Newell K, George JM, Clayton DF, Hyman
BT.
Author information:
(1)Alzheimer's Disease Research Unit, Massachusetts General Hospital-East,
Charlestown 02129, USA.
A mutation in the alpha-synuclein gene has recently been linked to some cases of
familial Parkinson's disease (PD). We characterized the expression of this
presynaptic protein in the midbrain, striatum, and temporal cortex of control,
PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate
pericellular immunostaining. PD brain demonstrated alpha-synuclein
immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare
neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases
demonstrated these findings as well as alpha-synuclein immunoreactivity in
cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in
sporadic cases, there is an early and direct role for alpha-synuclein in the
pathogenesis of PD and the neuropathologically related disorder DLB.
DOI: 10.1097/00005072-199804000-00005
PMID: 9600226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21215270 | 1. J Mol Cell Cardiol. 2011 Oct;51(4):506-11. doi: 10.1016/j.yjmcc.2010.12.012.
Epub 2011 Jan 5.
Translational potential of thyroid hormone and its analogs.
Arsanjani R(1), McCarren M, Bahl JJ, Goldman S.
Author information:
(1)Southern Arizona VA Health Care System, Section of Cardiology, Department of
Medicine, 1-111C, 3601 S. 6th Avenue, Tucson, AZ 85723, USA.
Thyroid hormone has unique properties affecting the heart, and the vasculature
and cholesterol metabolism. There is interest in using thyromimetic agents as
possible treatment options for heart failure based on data demonstrating the
ability of these agents to improve systolic and diastolic left ventricular
function as well as their vasodilatory action. The inverse relationship between
heart failure severity and serum triiodothyronine (T3) levels has also been
interpreted by some as an indication that thyroid hormone therapy might be
useful. In the 1950s, investigators began developing thyroid hormone analogs
that could lower cholesterol, that selectively bind to β1-type nuclear thyroid
hormone receptors (TR), which are responsible for cholesterol-lowering activity,
without activating α1-type receptors in the heart. The identification of
3,5-diiodothyropropionic acid (DITPA) that binds to both α- and β-type TRs with
relatively low affinity was unique in that this analog improves left ventricular
function in heart failure as well as lowers cholesterol. The aim of this review
is to summarize information known about the interactions between thyroid
hormones and the cardiovascular system, and the potential therapeutic effects of
thyroid analogs in chronic heart disease. This article is part of a special
issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
Published by Elsevier Ltd.
DOI: 10.1016/j.yjmcc.2010.12.012
PMID: 21215270 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22661385 | 1. Protein Eng Des Sel. 2012 Oct;25(10):507-21. doi: 10.1093/protein/gzs024. Epub
2012 Jun 2.
Computer-aided antibody design.
Kuroda D(1), Shirai H, Jacobson MP, Nakamura H.
Author information:
(1)Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita,
Osaka, Japan. [email protected]
Recent clinical trials using antibodies with low toxicity and high efficiency
have raised expectations for the development of next-generation protein
therapeutics. However, the process of obtaining therapeutic antibodies remains
time consuming and empirical. This review summarizes recent progresses in the
field of computer-aided antibody development mainly focusing on antibody
modeling, which is divided essentially into two parts: (i) modeling the
antigen-binding site, also called the complementarity determining regions
(CDRs), and (ii) predicting the relative orientations of the variable heavy
(V(H)) and light (V(L)) chains. Among the six CDR loops, the greatest challenge
is predicting the conformation of CDR-H3, which is the most important in antigen
recognition. Further computational methods could be used in drug development
based on crystal structures or homology models, including antibody-antigen
dockings and energy calculations with approximate potential functions. These
methods should guide experimental studies to improve the affinities and
physicochemical properties of antibodies. Finally, several successful examples
of in silico structure-based antibody designs are reviewed. We also briefly
review structure-based antigen or immunogen design, with application to rational
vaccine development.
DOI: 10.1093/protein/gzs024
PMCID: PMC3449398
PMID: 22661385 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22330137 | 1. Oncogene. 2013 Jan 3;32(1):15-26. doi: 10.1038/onc.2012.29. Epub 2012 Feb 13.
Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and
serves as a biomarker of invasive cervical cancer.
Su PH(1), Lin YW, Huang RL, Liao YP, Lee HY, Wang HC, Chao TK, Chen CK, Chan MW,
Chu TY, Yu MH, Lai HC.
Author information:
(1)Graduate Institute of Medical Sciences, National Defense Medical Center,
Taipei, Taiwan.
Epigenetic modifications are a driving force in carcinogenesis. However, their
role in cancer metastasis remains poorly understood. The present study
investigated the role of DNA methylation in the cervical cancer metastasis.
Here, we report evidence of the overexpression of DNA methyltransferases 3B
(DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by
DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with
microarray analysis, we found that the protein tyrosine phosphatase receptor
type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical
cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the
transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs.
The methylation status of PTPRR increased in cervical scrapings (n=358) in
accordance with disease severity, especially in invasive cancer. Methylation of
the PTPRR promoter has an important role in the metastasis and may be a
biomarker of invasive cervical cancer.
DOI: 10.1038/onc.2012.29
PMID: 22330137 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15936275 | 1. Curr Biol. 2005 Jun 7;15(11):1039-44. doi: 10.1016/j.cub.2005.04.062.
Subcellular localization and signaling properties of dishevelled in developing
vertebrate embryos.
Park TJ(1), Gray RS, Sato A, Habas R, Wallingford JB.
Author information:
(1)Section of Molecular Cell and Developmental Biology, and Institute for
Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, USA.
The Dishevelled protein mediates several diverse biological processes.
Intriguingly, within the same tissues where Xenopus Dishevelled (Xdsh) controls
cell fate via canonical Wnt signaling, it also controls cell polarity via the
vertebrate planar cell polarity (PCP) cascade [1, 2, 3, 4, 5, 6, 7, 8 and 9].
The relationship between subcellular localization of Dishevelled and its
signaling activities remains unclear; conflicting results have been reported
depending upon the organism and cell types examined [8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19 and 20]. We have approached this issue by developing new
reagents to sequester wild-type Dishevelled protein either at the cell membrane
or away from the cell membrane. Removal of Dishevelled from the cell membrane
disrupts convergent extension by preventing Rho/Rac activation and mediolateral
cell polarization. By manipulating the subcellular localization of K-->M (dsh1),
we show that this mutation inhibits Dishevelled activation of Rac, regardless of
its subcellular localization. These data demonstrate that membrane localization
of Dishevelled is a prerequisite for vertebrate PCP signaling. However, both
membrane-targeted and cytoplasm-targeted Dishevelled can potently activate
canonical Wnt signaling, suggesting that local concentration of Dishevelled
protein, but not its spatial localization, is central to canonical Wnt
signaling. These results suggest that in vertebrate embryos, subcellular
localization is insufficient to account for the pathway specificity of
Dishevelled in the canonical Wnt versus PCP signaling cascades.
DOI: 10.1016/j.cub.2005.04.062
PMID: 15936275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15842668 | 1. Br J Haematol. 2005 May;129(3):432-4. doi: 10.1111/j.1365-2141.2005.05473.x.
Identification of DKC1 gene mutations in Japanese patients with X-linked
dyskeratosis congenita.
Kanegane H(1), Kasahara Y, Okamura J, Hongo T, Tanaka R, Nomura K, Kojima S,
Miyawaki T.
Author information:
(1)Department of Paediatrics, Faculty of Medicine, Toyama Medical and
Pharmaceutical University, Toyama 930-0194, Japan. [email protected]
Dyskeratosis congenita (DC) is a rare inherited multisystem disorder
characterized by the triad of abnormal skin pigmentation, nail dystrophy and
mucosal leucoplakia. X-linked recessive inheritances are recognized in
approximately 40% of the patients. DKC1 has been identified as the gene
responsible for X-linked DC, and genetic analyses have been performed in a
worldwide study. Here, we performed genetic analysis of five Japanese patients
with presumed X-linked DC, and identified four mutations in the DKC1 gene,
including two novel missense mutations (Q31K and T357A). Such genetic analysis
is useful for the definite diagnosis and genetic counselling of patients.
DOI: 10.1111/j.1365-2141.2005.05473.x
PMID: 15842668 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20687509 | 1. Adv Exp Med Biol. 2010;685:215-9. doi: 10.1007/978-1-4419-6448-9_20.
Dyskeratosis congenita.
Gupta V(1), Kumar A.
Author information:
(1)Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu
University, Varanasi-221005, India. [email protected]
Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome
characterized by reticulated hyperpigmentation, dystrophic nails and oral
leukoplakia. Another name for the condition is Zinsser-Cole-Engman syndrome.
Hematologic manifestations usually do not appear in childhood but later in early
adulthood. Patients are also prone to carcinomas, particularly of the head and
neck. The disease has X-linked or autosomal dominant/recessive inheritance.
Early childhood variants (Hoyeraal-Hreidarsson syndrome) are associated with
immunological abnormalities in the form of low T- and B-cell numbers. Four
genes, namely DKC1 (codes for dyskerin), TERC and TERT (code for telomerase) and
NOP10, have been implicated in the pathogenesis; the short telomeres provide a
marker for genetic linkage studies. Androgens, with or without granulocyte
colony stimulating factor, have been tried in the treatment of the conditions
with variable results. Stem cell transplantation from matched sibling donor is
currently the treatment of choice. It requires modified nonmyeloablative
conditioning protocols, since the patients with DC are prone to pulmonary and
hepatic complications.
DOI: 10.1007/978-1-4419-6448-9_20
PMID: 20687509 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23642624 | 1. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):285-91. doi:
10.1016/j.ijrobp.2013.02.013.
Health-related quality of life in elderly patients with newly diagnosed
glioblastoma treated with short-course radiation therapy plus concomitant and
adjuvant temozolomide.
Minniti G(1), Scaringi C, Baldoni A, Lanzetta G, De Sanctis V, Esposito V,
Enrici RM.
Author information:
(1)Department of Radiation Oncology, Sant' Andrea Hospital, University Sapienza,
Rome, Italy. [email protected]
PURPOSE: To describe the quality of life (QOL) in elderly patients with
glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT;
40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ).
METHODS AND MATERIALS: Health-related QOL (HRQOL) was assessed by European
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life
Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score
of 9 preselected domains (global QLQ, social functioning, cognitive functioning,
emotional functioning, physical functioning, motor dysfunction, communication
deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter
every 8 weeks during the treatment until disease progression. The proportion of
patients with improved HRQOL scores, defined as a change of 10 points or more,
and duration of changes were recorded.
RESULTS: Sixty-five patients completed the questionnaires at baseline. The
treatment was consistently associated with improvement or stability in most of
the preselected HRQOL domains. Global health improved over time; mean score
differed by 9.6 points between baseline and 6-month follow-up (P=.03). For
social functioning and cognitive functioning, mean scores improved over time,
with a maximum difference of 10.4 points and 9.5 points between baseline and
6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened
over time, with a difference in mean score of 5.6 points between baseline and
4-month follow-up (P=.02).
CONCLUSIONS: A short course of RT in combination with TMZ in elderly patients
with GBM was associated with survival benefit without a negative effect on HRQOL
until the time of disease progression.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ijrobp.2013.02.013
PMID: 23642624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9272155 | 1. Hum Genet. 1997 Sep;100(3-4):356-61. doi: 10.1007/s004390050516.
The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1
gene.
van den Berg MH(1), Wilde AA, Robles de Medina EO, Meyer H, Geelen JL, Jongbloed
RJ, Wellens HJ, Geraedts JP.
Author information:
(1)Division of Genetics, University Maastricht, The Netherlands.
The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of
inheritance. Patients suffer from syncopal attacks often resulting in sudden
cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as
judged by electro-cardiographic investigation. LQTS is a genetically
heterogeneous disease with four loci having been identified to date: chromosome
11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3) and 4q25-26 (LQT4). The
corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2)
and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized by six
transmembrane domains (S1-S6), a pore region situated between the S5 and S6
domains and a C-terminal domain accounting for approximately 60% of the channel.
This domain is thought to be co-associated with another protein, viz. minK
(minimal potassium channel). We have studied a Romano Ward family with several
affected individuals showing a severe LQTS phenotype (syncopes and occurrence of
sudden death). Most affected individuals had considerable prolongations of
QT(c). By using haplotyping with a set of markers covering the four LQT loci,
strong linkage was established to the LQT1 locus, whereas the other loci (LQT2,
LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism
analysis and direct sequencing were used to screen the KVLQT1 gene for mutations
in the S1-S6 region, including the pore domain. We identified a Gly-216-Arg
substitution in the S6 transmembrane domain of KVLQT1. The mutation was present
in all affected family members but absent in normal control individuals,
providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in
this family. The mutated KVLQT1-gene product thus probably results in a dominant
negative suppression of channel activity.
DOI: 10.1007/s004390050516
PMID: 9272155 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12584728 | 1. J Neurosci Res. 2003 Mar 1;71(5):701-9. doi: 10.1002/jnr.10521.
Organic cation transporter capable of transporting serotonin is up-regulated in
serotonin transporter-deficient mice.
Schmitt A(1), Mössner R, Gossmann A, Fischer IG, Gorboulev V, Murphy DL,
Koepsell H, Lesch KP.
Author information:
(1)Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg,
Germany.
The serotonin (5HT) transporter (5HTT) regulates serotonergic neurotransmission
by mediating the reuptake of 5HT from the synaptic cleft. Although lacking the
high affinity and selectivity of the 5HTT, the brain expresses a large number of
other transporters, including the polyspecific organic cation transporters
(OCTs). OCT1 and OCT3, members of the potential-sensitive organic cation
transporter gene family, physiologically transport a wide spectrum of organic
cations. In addition, both transporters mediate low-affinity 5HT transport and,
therefore, may participate in the clearance of excessive 5HT. Because
concentrations of extracellular 5HT are increased in the brain of 5HTT-deficient
mice, they are a model for investigating the role of OCTs in 5HT system
homeostasis. Here, we analyzed OCT1 and OCT3 gene expression in the brain of
5HTT knockout mice by semiquantitative competitive polymerase chain reaction and
in situ hybridization. We demonstrate that, in 5HTT-deficient mice, OCT3 mRNA
concentrations were significantly increased in the hippocampus, but not in other
brain regions, including cortex, striatum, cerebellum, and brainstem. In
contrast, no difference in OCT1 expression was detected between 5HTT knockout
and control mice. Up-regulation of OCT3 expression and enhanced low-affinity 5HT
uptake may limit the adverse effects of elevated extracellular 5HT and may play
a critical role in maintaining 5HT-dependent functions of the hippocampus in the
absence of 5HTT.
Copyright 2002 Wiley-Liss, Inc.
DOI: 10.1002/jnr.10521
PMID: 12584728 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23390563 | 1. Am J Transl Res. 2013;5(1):21-35. Epub 2013 Jan 21.
Human induced pluripotent stem cell-derived endothelial cells exhibit functional
heterogeneity.
Rufaihah AJ(1), Huang NF, Kim J, Herold J, Volz KS, Park TS, Lee JC, Zambidis
ET, Reijo-Pera R, Cooke JP.
Author information:
(1)Division of Cardiovascular Medicine, Stanford University School of Medicine
300 Pasteur Drive, Stanford, CA 94305, USA.
Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) are
promising for treatment of vascular diseases. However, hiPSC-ECs purified based
on CD31 expression are comprised of arterial, venous, and lymphatic subtypes. It
is unclear whether hiPSC-ECs are heterogeneous in nature, and whether there may
be functional benefits of enriching for specific subtypes. Therefore, we sought
to characterize the hiPSC-ECs and enrich for each subtype, and demonstrate
whether such enrichment would have functional significance. The hiPSC-ECs were
generated from differentiation of hiPSCs using vascular endothelial growth
factor (VEGF)-A and bone morphogenetic protein-4. The hiPSC-ECs were purified
based on positive expression of CD31. Subsequently, we sought to enrich for each
subtype. Arterial hiPSC-ECs were induced using higher concentrations of VEGF-A
and 8-bromoadenosine-3':5'-cyclic monophosphate in the media, whereas lower
concentrations of VEGF-A favored venous subtype. VEGF-C and angiopoietin-1
promoted the expression of lymphatic phenotype. Upon FACS purification based on
CD31+ expression, the hiPSC-EC population was observed to display typical
endothelial surface markers and functions. However, the hiPSC-EC population was
heterogeneous in that they displayed arterial, venous, and to a lesser degree,
lymphatic lineage markers. Upon comparing vascular formation in matrigel plugs
in vivo, we observed that arterial enriched hiPSC-ECs formed a more extensive
capillary network in this model, by comparison to a heterogeneous population of
hiPSC-ECs. This study demonstrates that FACS purification of CD31+ hiPSC-ECs
produces a diverse population of ECs. Refining the differentiation methods can
enrich for subtype-specific hiPSC-ECs with functional benefits of enhancing
neovascularization.
PMCID: PMC3560482
PMID: 23390563 |
http://www.ncbi.nlm.nih.gov/pubmed/16454041 | 1. Biotechniques. 2006 Jan;40(1):61-6. doi: 10.2144/000112036.
Identification of new fluorescent protein fragments for bimolecular fluorescence
complementation analysis under physiological conditions.
Shyu YJ(1), Liu H, Deng X, Hu CD.
Author information:
(1)Purdue University, West Lafayette IN 47907, USA.
Protein-protein interactions play a pivotal role in coordinating many cellular
processes. Determination of subcellular localization of interacting proteins and
visualization of dynamic interactions in living cells are crucial to elucidate
cellular functions of proteins. Using fluorescent proteins, we previously
developed a bimolecular fluorescence complementation (BiFC) assay and a
multicolor BiFC assay to visualize protein-protein interactions in living cells.
However, the sensitivity of chromophore maturation of enhanced yellow
fluorescent protein (YFP) to higher temperatures requires preincubation at lower
temperatures prior to visualizing the BiFC signal. This could potentially limit
their applications for the study of many signaling molecules. Here we report the
identification of new fluorescent protein fragments derived from Venus and
Cerulean for BiFC and multicolor BiFC assays under physiological culture
conditions. More importantly, the newly identified combinations exhibit a
13-fold higher BiFC efficiency than originally identified fragments derived from
YFP. Furthermore, the use of new combinations reduces the amount of plasmid
required for transfection and shortens the incubation time, leading to a 2-fold
increase in specific BiFC signals. These newly identified fluorescent protein
fragments will facilitate the study of protein-protein interactions in living
cells and whole animals under physiological conditions.
DOI: 10.2144/000112036
PMID: 16454041 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24860588 | 1. Front Plant Sci. 2014 May 14;5:201. doi: 10.3389/fpls.2014.00201. eCollection
2014.
Composition and function of P bodies in Arabidopsis thaliana.
Maldonado-Bonilla LD(1).
Author information:
(1)Laboratory of Plant Molecular Biology, Instituto Potosino de Investigación
Científica y Tecnológica, San Luis Potosí Mexico.
mRNA accumulation is tightly regulated by diverse molecular pathways. The
identification and characterization of enzymes and regulatory proteins involved
in controlling the fate of mRNA offers the possibility to broaden our
understanding of posttranscriptional gene regulation. Processing bodies (P
bodies, PB) are cytoplasmic protein complexes involved in degradation and
translational arrest of mRNA. Composition and dynamics of these subcellular
structures have been studied in animal systems, yeasts and in the model plant
Arabidopsis. Their assembly implies the aggregation of specific factors related
to decapping, deadenylation, and exoribonucleases that operate synchronously to
regulate certain mRNA targets during development and adaptation to stress.
Although the general function of PB along with the flow of genetic information
is understood, several questions still remain open. This review summarizes data
on the composition, potential molecular roles, and biological significance of PB
and potentially related proteins in Arabidopsis.
DOI: 10.3389/fpls.2014.00201
PMCID: PMC4030149
PMID: 24860588 |
http://www.ncbi.nlm.nih.gov/pubmed/19419704 | 1. Biochim Biophys Acta. 2009 Apr;1792(4):371-9. doi:
10.1016/j.bbadis.2009.01.010. Epub 2009 Feb 7.
Dyskeratosis congenita, stem cells and telomeres.
Kirwan M(1), Dokal I.
Author information:
(1)Barts and the London School of Medicine and Dentistry, Queen Mary University
of London, UK. [email protected]
Dyskeratosis congenita (DC) is a multi-system disorder which in its classical
form is characterised by abnormalities of the skin, nails and mucous membranes.
In approximately 80% of cases, it is associated with bone marrow dysfunction. A
variety of other abnormalities (including bone, brain, cancer, dental, eye,
gastrointestinal, immunological and lung) have also been reported. Although
first described almost a century ago it is the last 10 years, following the
identification of the first DC gene (DKC1) in 1998, in which there has been
rapid progress in its understanding. Six genes have been identified, defects in
which cause different genetic subtypes (X-linked recessive, autosomal dominant,
autosomal recessive) of DC. The products of these genes encode components that
are critical for telomere maintenance; either because they are core constituents
of telomerase (dyskerin, TERC, TERT, NOP10 and NHP2) or are part of the
shelterin complex that protects the telomeric end (TIN2). These advances have
also highlighted the connection between the more "cryptic/atypical" forms of the
disease including aplastic anaemia and idiopathic pulmonary fibrosis. Equally,
studies on this disease have demonstrated the critical importance of telomeres
in human cells (including stem cells) and the severe consequences of their
dysfunction. In this context DC and related diseases can now be regarded as
disorders of "telomere and stem cell dysfunction".
DOI: 10.1016/j.bbadis.2009.01.010
PMCID: PMC2686081
PMID: 19419704 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21199492 | 1. Clin Genet. 2012 Jan;81(1):76-81. doi: 10.1111/j.1399-0004.2010.01605.x. Epub
2011 Jan 4.
Telomere length measurement can distinguish pathogenic from non-pathogenic
variants in the shelterin component, TIN2.
Vulliamy T(1), Beswick R, Kirwan MJ, Hossain U, Walne AJ, Dokal I.
Author information:
(1)Centre for Paediatrics, Blizard Institute of Cell and Molecular Science,
Barts and The London School of Medicine and Dentistry, Queen Mary University of
London, London, UK. [email protected]
Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure syndrome with
seven disease-causing genes identified to date, six of which are linked to
telomere maintenance. Mutations in one of these genes (TINF2), which encodes a
component of the shelterin complex, are associated with particularly short
telomeres. Among the 224 consecutive patients with different forms of bone
marrow failure (46 with DC, 122 with aplastic anaemia and 57 with some features
of DC), we have identified 16 new families with variants in exon 6 of the TINF2
gene, eight of which are novel. We observe that the phenotype associated with
these mutations extends to a severe early presentation, not always classified as
DC. In addition, we see that some of the variants identified are not associated
with short telomeres and are also found in asymptomatic individuals. In the
absence of any direct functional assay, the data indicates that the telomere
length measurement can inform us as to which variants in TINF2 are pathogenic
and which may be non-pathogenic.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1399-0004.2010.01605.x
PMCID: PMC3654171
PMID: 21199492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24352520 | 1. Circulation. 2014 Mar 11;129(10):1092-103. doi:
10.1161/CIRCULATIONAHA.113.003077. Epub 2013 Dec 18.
Missense mutations in plakophilin-2 cause sodium current deficit and associate
with a Brugada syndrome phenotype.
Cerrone M(1), Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H,
Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano
C, Priori SG, Delmar M.
Author information:
(1)Leon H. Charney Division of Cardiology (M.C., X.L., M.Z., E.A.-P., A.P.,
H.C.G., S.P., M.D.), and Cardiovascular Genetics Program (M.C., S.P.), NYU
School of Medicine, New York, NY; Molecular Cardiology, Maugeri Foundation,
Pavia, Italy (V.N., C.N., S.P.); Del E. Webb Center for Neuroscience, Aging &
Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA
(C.K., T.T., H.-S.V.C.); Department of Bioscience and Biotechnology, Sejong
University, Seoul, Korea (C.K.); Division of Cardiology, Johns Hopkins
University School of Medicine, Baltimore, MD (D.P.J.); and Department of
Pharmacology, NYU School of Medicine, New York, NY (E.R.).
BACKGROUND: Brugada syndrome (BrS) primarily associates with the loss of sodium
channel function. Previous studies showed features consistent with sodium
current (INa) deficit in patients carrying desmosomal mutations, diagnosed with
arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular
cardiomyopathy). Experimental models showed correlation between the loss of
expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We
hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype,
even without overt structural features characteristic of arrhythmogenic right
ventricular cardiomyopathy.
METHODS AND RESULTS: We searched for PKP2 variants in the genomic DNA of 200
patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no
mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5
cases of single amino acid substitutions. Mutations were tested in HL-1-derived
cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss
of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These
deficits were restored by the transfection of wild-type PKP2, but not of
BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes
from a patient with a PKP2 deficit showed drastically reduced INa. The deficit
was restored by transfection of wild type, but not BrS-related PKP2.
Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa
deficiency to the reduced number of channels at the intercalated disc and
increased separation of microtubules from the cell end.
CONCLUSIONS: This is the first systematic retrospective analysis of a patient
group to define the coexistence of sodium channelopathy and genetic PKP2
variations. PKP2 mutations may be a molecular substrate leading to the diagnosis
of BrS.
DOI: 10.1161/CIRCULATIONAHA.113.003077
PMCID: PMC3954430
PMID: 24352520 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: None. |
http://www.ncbi.nlm.nih.gov/pubmed/21105711 | 1. J Med Chem. 2010 Dec 23;53(24):8468-84. doi: 10.1021/jm1004286. Epub 2010 Nov
24.
Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for
the treatment of autoimmune diseases and organ transplant rejection.
Flanagan ME(1), Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C,
Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson
KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C,
Sun J, Whipple DA, Changelian PS.
Author information:
(1)Groton Laboratories, Pfizer Global Research & Development, Groton,
Connecticut 06340, USA. [email protected]
There is a critical need for safer and more convenient treatments for organ
transplant rejection and autoimmune disorders such as rheumatoid arthritis.
Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are
involved in the signaling of multiple cytokines important for various T cell
functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was
anticipated to provide therapeutic immunosuppression/immunomodulation. The
Pfizer compound library was screened against the catalytic domain of JAK3
resulting in the identification of a pyrrolopyrimidine-based series of
inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were
screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast
proliferation assay. Select compounds were evaluated in rodent efficacy models
of allograft rejection and destructive inflammatory arthritis. Optimization
within this chemical series led to identification of CP-690,550 1, a potential
first-in-class JAK inhibitor for treatment of autoimmune diseases and organ
transplant rejection.
DOI: 10.1021/jm1004286
PMID: 21105711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15524173 | 1. Mol Cell Biochem. 2004 Aug;263(1-2):131-6.
Phosphorylation of phospholamban in ischemia-reperfusion injury: functional role
of Thr17 residue.
Mattiazzi A(1), Mundiña-Weilenmann C, Vittone L, Said M.
Author information:
(1)Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, La
Plata, Argentina. [email protected]
Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that when
phosphorylated at Ser16 by PKA and/or at Thr17 by CaMKII increases the affinity
of the SR Ca2+ pump for Ca2+. PLB is therefore, a critical regulator of SR
function, myocardial relaxation and myocardial contractility. The present study
was undertaken to examine the status of PLB phosphorylation after ischemia and
reperfusion and to provide evidence about the possible role of the
phosphorylation of Thr17 PLB residue on the recovery of contractility and
relaxation after a period of ischemia. Experiments were performed in Langendorff
perfused hearts from Wistar rats. Hearts were submitted to a protocol of global
normothermic ischemia and reperfusion. The results showed that (1) the
phosphorylation of Ser16 and Thr17 residues of PLB increased at the end of the
ischemia and the onset of reperfusion, respectively. The increase in Thr17
phosphorylation was associated with a recovery of relaxation to preischemic
values. This recovery occurred in spite of the fact that contractility was
depressed. (2) The reperfusion-induced increase in Thr17 phosphorylation was
dependent on Ca2+ entry to the cardiac cell. This Ca2+ influx would mainly occur
by the coupled activation of the Na+ / H+ exchanger and the Na+ / Ca2+ exchanger
working in the reverse mode, since phosphorylation of Thr17 was decreased by
inhibition of these exchangers and not affected by blockade of the L-type Ca2+
channels. (3) Specific inhibition of CaMKII by KN93 significantly decreased
Thr17 phosphorylation. This decrease was associated with an impairment of
myocardial relaxation. The present study suggests that the phosphorylation of
Thr17 of PLB upon reflow, may favor the full recovery of relaxation after
ischemia.
PMID: 15524173 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22072384 | 1. Bioinformatics. 2012 Jan 1;28(1):63-8. doi: 10.1093/bioinformatics/btr616.
Epub 2011 Nov 8.
Using Poisson mixed-effects model to quantify transcript-level gene expression
in RNA-Seq.
Hu M(1), Zhu Y, Taylor JM, Liu JS, Qin ZS.
Author information:
(1)Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
MOTIVATION: RNA sequencing (RNA-Seq) is a powerful new technology for mapping
and quantifying transcriptomes using ultra high-throughput next-generation
sequencing technologies. Using deep sequencing, gene expression levels of all
transcripts including novel ones can be quantified digitally. Although extremely
promising, the massive amounts of data generated by RNA-Seq, substantial biases
and uncertainty in short read alignment pose challenges for data analysis. In
particular, large base-specific variation and between-base dependence make
simple approaches, such as those that use averaging to normalize RNA-Seq data
and quantify gene expressions, ineffective.
RESULTS: In this study, we propose a Poisson mixed-effects (POME) model to
characterize base-level read coverage within each transcript. The underlying
expression level is included as a key parameter in this model. Since the
proposed model is capable of incorporating base-specific variation as well as
between-base dependence that affect read coverage profile throughout the
transcript, it can lead to improved quantification of the true underlying
expression level.
AVAILABILITY AND IMPLEMENTATION: POME can be freely downloaded at
http://www.stat.purdue.edu/~yuzhu/pome.html.
CONTACT: [email protected]; [email protected]
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
DOI: 10.1093/bioinformatics/btr616
PMCID: PMC3244770
PMID: 22072384 [Indexed for MEDLINE] |