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http://www.ncbi.nlm.nih.gov/pubmed/20668034 | 1. J Clin Endocrinol Metab. 2010 Oct;95(10):4526-34. doi: 10.1210/jc.2010-1052.
Epub 2010 Jul 28.
Clinical review: Thyroid hormone therapy for postoperative nonthyroidal
illnesses: a systematic review and synthesis.
Kaptein EM(1), Sanchez A, Beale E, Chan LS.
Author information:
(1)Department of Medicine, University of Southern California, Los Angeles,
California 90033, USA. [email protected]
CONTEXT: Effects of thyroid hormone therapy on postoperative morbidity and
mortality in adults remain controversial.
OBJECTIVE: The aim was to conduct a systematic review evaluating effects and
risks of postoperative T(3) therapy in adults.
DATA SOURCES: Electronic databases and reference lists through March 2010 were
searched.
STUDY SELECTION: Studies with comparable control groups comparing T(3) to
placebo therapy in randomized controlled trials were selected.
DATA EXTRACTION: Two reviewers independently screened and reviewed titles,
abstracts, and articles. Data were abstracted from 14 randomized controlled
trials (13 cardiac surgery and one renal transplantation). In seven studies, iv
T(3) was given in high doses (0.175-0.333 μg/kg · h) for 6 to 9 h, in four
studies iv T(3) was given in low doses (0.0275-0.0333 μg/kg · h for 14 to 24 h),
and in three studies T(3) was given orally in variable doses and durations.
DATA SYNTHESIS: Both high- and low-dose iv T(3) therapy increased cardiac index
after coronary artery bypass surgery. Mortality was not significantly altered by
high-dose iv T(3) therapy and could not be assessed for low-dose iv or oral
T(3). Effects on systemic vascular resistance, heart rate, pulmonary capillary
wedge pressure, new onset atrial fibrillation, inotrope use, serum TSH and T(4)
were inconclusive.
LIMITATIONS: Numbers of usable unique studies and group sizes were small.
Duration of T(3) therapy was short, and dosages and routes of administration
varied.
CONCLUSIONS: Short duration postoperative iv T(3) therapy increases cardiac
index and does not alter mortality. Effects on other parameters are
inconclusive.
DOI: 10.1210/jc.2010-1052
PMID: 20668034 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26273687 | 1. Ann Clin Transl Neurol. 2015 Jul;2(7):748-55. doi: 10.1002/acn3.212. Epub 2015
May 25.
CSF neurofilament light chain reflects corticospinal tract degeneration in ALS.
Menke RA(1), Gray E(1), Lu CH(2), Kuhle J(3), Talbot K(1), Malaspina A(2),
Turner MR(1).
Author information:
(1)Nuffield Department of Clinical Neurosciences, University of Oxford Oxford,
United Kingdom.
(2)Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London
School of Medicine and Dentistry, Queen Mary University of London London, United
Kingdom.
(3)Department of Neurology, University Hospital Basel Basel, Switzerland.
OBJECTIVE: Diffusion tensor imaging (DTI) is sensitive to white matter tract
pathology. A core signature involving the corticospinal tracts (CSTs) has been
identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light
chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal
damage in a range of neurological disorders. The relationship between these two
measures was explored.
METHODS: CSF and serum NfL concentrations and DTI acquired at 3 Tesla on the
same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy,
age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between
NfL and DTI measures of microstructural integrity in major white matter tracts
(CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were
performed using tract-based spatial statistics.
RESULTS: NfL levels were higher in patients compared to controls. CSF levels
correlated with clinical upper motor neuron burden and rate of disease
progression. Higher NfL levels were significantly associated with lower DTI
fractional anisotropy and increased radial diffusivity in the CSTs of ALS
patients, but not in controls.
INTERPRETATION: Elevated CSF and serum NfL is, in part, a result of CST
degeneration in ALS. This highlights the wider potential for combining
neurochemical and neuroimaging-based biomarkers in neurological disease.
DOI: 10.1002/acn3.212
PMCID: PMC4531057
PMID: 26273687 |
http://www.ncbi.nlm.nih.gov/pubmed/16778717 | 1. Ther Drug Monit. 2006 Jun;28(3):339-44. doi:
10.1097/01.ftd.0000211808.74192.86.
Population pharmacokinetics of allopurinol in full-term neonates with perinatal
asphyxia.
van Kesteren C(1), Benders MJ, Groenendaal F, van Bel F, Ververs FF, Rademaker
CM.
Author information:
(1)Department of Pharmacy, University Medical Center, Wilhelmina Children's
Hospital, University Medical Center, Utrecht, The Netherlands.
[email protected]
In newborn infants, allopurinol is being tested as a free radical scavenger to
prevent brain damage caused by reperfusion and oxygenation after perinatal
hypoxia and ischemia (birth asphyxia). To develop rational dosing schemes for
future studies, knowledge of the pharmacokinetics in this patient group is
essential. In the present study, a population pharmacokinetic model was designed
and validated for allopurinol in this specific patient group. One-compartment
and 2-compartment models were fitted to plasma concentration time data of 24
newborns entered in 2 clinical trials using nonlinear mixed effects modeling. A
bootstrap procedure was performed to check the robustness of the model. The data
were best described using a 1-compartment model with linear elimination.
Estimated pharmacokinetic parameters were volume of the central compartment (V,
0.79 L/kg) and total body clearance (CL, 0.078 L/h/kg), with 42% and 60%
interindividual variability, respectively. The median values for these
parameters of 1000 bootstrap replicates were very similar (95% confidence
intervals were 0.67 to 0.96 and 0.054 to 0.10 for V and CL, respectively),
indicating the robustness of the model. A population pharmacokinetic model has
been designed and validated which adequately describes the data of 2 clinical
studies in critically ill newborn infants. The model will be used to design
dosing strategies for future evaluation of the benefits of allopurinol in these
patients.
DOI: 10.1097/01.ftd.0000211808.74192.86
PMID: 16778717 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21197541 | 1. J Neurol. 2011 May;258(5):882-8. doi: 10.1007/s00415-010-5863-2. Epub 2011 Jan
1.
Glial fibrillary acidic protein: a potential biomarker for progression in
multiple sclerosis.
Axelsson M(1), Malmeström C, Nilsson S, Haghighi S, Rosengren L, Lycke J.
Author information:
(1)Department of Neurosciences, Sahlgrenska Academy, Institute of Neuroscience
and Physiology, Gothenburg University, Gothenburg, Sweden.
[email protected]
The major intermediate cytoskeletal protein of astrocytes, glial fibrillary
acidic protein (GFAP), and that of axons, neurofilament light protein (NFL), may
both be released into the cerebrospinal fluid (CSF) during pathological
processes in the central nervous system (CNS). We investigated GFAP and NFL
levels in CSF as possible biomarkers for progression in multiple sclerosis (MS).
Patients with relapsing-remitting MS (RRMS, n = 15) or secondary progressive MS
(SPMS, n = 10) and healthy control subjects (n = 28) were examined twice with an
interval of 8-10 years apart. Neurological deficits were scored with the
Expanded Disability Status Scale (EDSS). GFAP and NFL levels were determined in
CSF by enzyme-linked immunosorbent assay (ELISA). GFAP levels and NFL levels
correlated with age (r and r (s) = 0.50, p = 0.006). Adjusting for age, MS
patients had increased GFAP levels compared with controls (p = 0.03) and GFAP
levels correlated with neurological disability (EDSS, r = 0.51, p < 0.05) and
disease progression [Multiple Sclerosis Severity Score (MSSS), r = 0.47, p <
0.05]. The mean annual increase of GFAP was 6.5 ng/L for controls, 8.1 ng/L for
RRMS patients, and 18.9 ng/L for SPMS patients. GFAP level at the first
examination had predictive value for neurological disability 8-10 years later
(EDSS, r = 0.45, p < 0.05) but not for EDSS increase between the examinations.
NFL levels were not significantly increased in MS patients compared with
controls and had no relationship to disability or progression and no prognostic
value for disability development. GFAP, a marker for astrogliosis, is a
potential biomarker for MS progression and may have a role in clinical trials
for assessing the impact of therapies on MS progression.
DOI: 10.1007/s00415-010-5863-2
PMID: 21197541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20232113 | 1. Mol Cell Biochem. 2010 Jul;340(1-2):291-300. doi: 10.1007/s11010-010-0430-9.
Epub 2010 Mar 16.
Non-genomic effects of thyroid hormone in adult cardiac myocytes: relevance to
gene expression and cell growth.
Iordanidou A(1), Hadzopoulou-Cladaras M, Lazou A.
Author information:
(1)Laboratory of Developmental Biology, School of Biology, Aristotle University
of Thessaloniki, 54124 Thessaloniki, Greece.
Besides the well-characterized genomic action of thyroid hormone (TH), mediated
by thyroid hormone receptors (TRs), accumulating data support the so-called
non-genomic action of TH, which is often related to activation of signalling
pathways. In this study, we sought to determine whether TH activates
intracellular signalling pathways in the adult cardiac myocytes and whether such
activation modulates cell growth and the expression of target proteins important
in cardiac function. We demonstrate that TH promotes a rapid increase in the
phosphorylation of several kinases, ERK1/2, PKCdelta, p38-MAPK and Akt. This
activation is inhibited by triiodothyroacetic acid (triac), which is a TH
analogue known to displace the hormone from membrane bound receptors, indicating
that this TH effect is mediated through a cell membrane-initiated mechanism.
Furthermore, using specific inhibitors of the TH-activated kinases, we show that
the long-term effects of TH on the expression of sarcoplasmic reticulum
Ca(2+)-ATPase (SERCA), alpha- and beta-myosin heavy chain (MHC) and cell growth
are reverted, implying that what is initiated as a non-genomic action of the
hormone interfaces with genomic effects. These data provide further insights
into the underlying mechanisms of TH action in the heart with potentially
important implications in the management of cardiac pathology.
DOI: 10.1007/s11010-010-0430-9
PMID: 20232113 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24120896 | 1. Gene. 2014 Jan 1;533(1):451-5. doi: 10.1016/j.gene.2013.09.075. Epub 2013 Oct
8.
Transgene expression from CpG-reduced lentiviral gene delivery vectors in vitro.
Low PT(1), Lai MI, Ngai SC, Abdullah S.
Author information:
(1)Medical Genetics Laboratory, Clinical Genetics Unit, Faculty of Medicine and
Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor,
Malaysia. Electronic address: [email protected].
Current viral gene delivery vectors for gene therapy are inefficient due to
short-lived transgene expression attributed to the cytosine-phosphate-guanine
(CpG) motifs in the transgene. Here we assessed the effects of CpG motif
reduction in lentiviral (LV) gene delivery context on the level and duration of
reporter gene expression in Chinese Hamster Ovary (CHO) cells, Human
Immortalized Myelogenous Leukemia (K562) cells and hematopoietic stem cells
(HSCs). The cells were transduced with LV carrying Zero-CpG green fluorescent
protein (ZGFP) reporter gene, LV/CMV/ZGFP. The GFP expression was compared to
its non CpG-depleted GFP reporter gene LV (LV/CMV/GFP) counterpart. The
LV/CMV/ZGFP exhibited prolonged transgene expression in CHO cells and HSCs up to
10 days and 14 days, in the respective cells. This effect was not seen in the
transduced K562 cells, which may be due to the DNA hypomethylation status of the
cancer cell line. Transgene copy number analysis verified that the GFP
expression was not from pseudo-transduction and the transgene remained in the
genome of the cells throughout the period of the study. The modest positive
effects from the LV/CMV/ZGFP suggest that the reduction of CpG in the LV
construct was not substantial to generate higher and more prolonged transgene
expression.
© 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2013.09.075
PMID: 24120896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17621527 | 1. J Child Neurol. 2007 Apr;22(4):447-51. doi: 10.1177/0883073807301930.
X-linked myotubular myopathy: report of a case with novel mutation.
Hortobágyi T(1), Szabó H, Kovács KS, Bódi I, Bereg E, Katona M, Biancalana V,
Túri S, Sztriha L.
Author information:
(1)Department of Histopathology University of Szeged, Szeged, Hungary.
[email protected]
Myotubular myopathy is a well-defined entity within the centronuclear myopathy
subgroup of congenital myopathies. The authors present a patient with the most
severe X-linked recessive type (XLMTM). A baby boy presented at birth with
severe hypotonia, weak spontaneous movements, arthrogryposis, and respiratory
insufficiency. Muscle biopsy showed features of myotubular myopathy. The
diagnosis was confirmed and further specified by genetic analysis, revealing a
novel frameshift mutation (1314-1315insT) of the myotubularin-coding MTM1 gene.
This case underlines the importance of interdisciplinary analysis of congenital
muscle diseases, including histomorphological and genetic investigations.
DOI: 10.1177/0883073807301930
PMID: 17621527 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8633935 | 1. Ann Thorac Surg. 1996 May;61(5):1323-7; discussion 1328-9. doi:
10.1016/0003-4975(96)00102-6.
Triiodothyronine therapy lowers the incidence of atrial fibrillation after
cardiac operations.
Klemperer JD(1), Klein IL, Ojamaa K, Helm RE, Gomez M, Isom OW, Krieger KH.
Author information:
(1)Department of Cardiothoracic Surgery, New York Hospital-Cornell University
Medical College, NY 10021, USA.
BACKGROUND: Cardiopulmonary bypass results in a euthyroid sick state, and recent
evidence suggests that perioperative triiodothyronine (T3) supplementation may
have hemodynamic benefits. In light of the known effects of thyroid hormone on
atrial electrophysiology, we investigated the effects of perioperative T3
supplementation on the incidence of postoperative arrhythmias.
METHODS: One hundred forty-two patients with depressed left ventricular function
(ejection fraction < 0.40) undergoing coronary artery bypass grafting were
randomized to either T3 or placebo treatment groups in a prospective,
double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg
intravenous bolus at the time of aortic cross-clamp removal followed by an
infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for
the development of arrhythmias during the first 5 postoperative days.
RESULTS: The incidence of sinus tachycardia and ventricular arrhythmias were
similar between groups. Triiodothyronine-treated patients had a lower incidence
of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required
cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p =
0.013) during hospitalization. Six patients in the T3 group versus 16 in the
placebo group required antiarrhythmic therapy at discharge (p = 0.019).
CONCLUSIONS: Perioperative T3 administration decreased the incidence and need
for treatment of postoperative atrial fibrillation.
DOI: 10.1016/0003-4975(96)00102-6
PMID: 8633935 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23529999 | 1. Mult Scler. 2013 Oct;19(12):1597-603. doi: 10.1177/1352458513482374. Epub 2013
Mar 25.
A comparative study of CSF neurofilament light and heavy chain protein in MS.
Kuhle J(1), Plattner K, Bestwick JP, Lindberg RL, Ramagopalan SV, Norgren N,
Nissim A, Malaspina A, Leppert D, Giovannoni G, Kappos L.
Author information:
(1)Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, UK.
BACKGROUND: There is a lack of reliable biomarkers of axonal degeneration.
Neurofilaments are promising candidates to fulfil this task. We compared two
highly sensitive assays to measure two subunits of the neurofilament protein
(neurofilament light (NfL) and neurofilament heavy chain (NfH)).
METHODS: We evaluated the analytical and clinical performance of the
UmanDiagnostics NF-light(®) enzyme-linked immunosorbent assay (ELISA) in the
cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated
syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our
results with referring levels of our previously-developed CSF NfH(SMI35) assay.
RESULTS: Exposure to room temperature (up to 8 days) or repetitive thawing (up
to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL
were higher in all disease stages of CIS/MS, in comparison to controls (p ≤
0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS)
score in patients with relapsing disease (r(s) = 0.31; p = 0.002), spinal cord
relapses and with CSF markers of acute inflammation. The ability of NfL to
distinguish patients from controls was greater than that of NfH(SMI35) in both
CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035).
CONCLUSIONS: NfL proved to be a stable protein, an important prerequisite for a
reliable biomarker, and the NF-light(®) ELISA performed better in discriminating
patients from controls, compared with the ECL-NfH(SMI35) immunoassay. We
confirmed and expanded upon previous findings regarding neurofilaments as
quantitative markers of neurodegeneration. Our results further support the role
of neurofilaments as a potential surrogate measure for neuroprotective treatment
in MS studies.
DOI: 10.1177/1352458513482374
PMID: 23529999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23718879 | 1. BMC Neurol. 2013 May 29;13:54. doi: 10.1186/1471-2377-13-54.
Cerebrospinal fluid neurofilament light chain protein levels in subtypes of
frontotemporal dementia.
Landqvist Waldö M(1), Frizell Santillo A, Passant U, Zetterberg H, Rosengren L,
Nilsson C, Englund E.
Author information:
(1)Section of Geriatric Psychiatry, Department of Clinical Sciences, Lund
University Hospital, Klinikgatan 22, Lund SE-221 85, Sweden.
[email protected]
BACKGROUND: Frontotemporal dementia (FTD) is recognised as a clinically and
morphologically heterogeneous group of interrelated neurodegenerative
conditions. One of the subtypes within this disease spectrum is the behavioural
variant FTD (bvFTD). This is known to be a varied disorder with a mixture of
tau-positive and tau-negative underlying pathologies. The other subtypes include
semantic dementia (SD), which generally exhibits tau-negative pathology, and
progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the
clinical presentation of these subtypes may overlap, a specific diagnosis can be
difficult to attain and today no specific biomarker can predict the underlying
pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent
of intermediate filaments, is thought to reflect neuronal and axonal death when
appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in
CSF in patients with FTD compared with AD and controls. Our hypothesis was that
the levels of NFL also differ between the subtypes of FTD and may indicate the
underlying pathological subtype.
METHODS: We retrospectively analysed data from previous CSF analyses in 34 FTD
cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A
separate group of 10 neuropathologically verified and subtyped FTD cases (seven
tau-negative, three tau-positive) were also analysed.
RESULT: NFL levels were significantly higher in FTD compared with both AD
(p<0.001) and controls (p<0.001). The NFL levels of SD and bvFTD were
significantly higher (p<0.001) compared with AD. The biomarker profiles of PNFA
and AD were similar. In the neuropathologically verified FTD cases, NFL was
higher in the tau-negative than in the tau-positive cases (exact p=0.017).
CONCLUSIONS: The marked NFL elevation in some but not all FTD cases is likely to
reflect the different underlying pathologies. The highest NFL values found in
the SD group as well as in the neuropathologically verified tau-negative cases
may be of subtype diagnostic value, if corroborated in larger patient cohorts.
In bvFTD, a mixture of tau-positive and tau-negative underlying pathologies
could possibly explain the intermediate NFL values.
DOI: 10.1186/1471-2377-13-54
PMCID: PMC3671150
PMID: 23718879 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20061818 | 1. Cancer Biol Ther. 2010 Mar 15;9(6):423-9. doi: 10.4161/cbt.9.6.10996. Epub
2010 Mar 20.
Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel
node melanoma metastasis are correlated to clinical outcome.
Franco R(1), Cantile M, Scala S, Catalano E, Cerrone M, Scognamiglio G, Pinto A,
Chiofalo MG, Caracò C, Anniciello AM, Abbruzzese A, Caraglia M, Botti G.
Author information:
(1)Pathology Unit, Istituto dei Tumori, Fondazione Pascale, Naples, Italy.
INTRODUCTION: Sentinel lymph node (SLN) biopsy is an important independent
prognostic factor for invasive cutaneuos melanoma, although its role is strongly
debated. In clinical practice SLN leads to complete lymph node dissection of
basin draining melanoma site. However only 7-30% of positive sentinel node
patients present additional non SLN metastasis. Melanoma cells diffusion through
SLN and extranodal spreading depends upon biological features, such as cell
chemokine receptors and adhesion molecules. CXCR4 has been proposed in melanoma
patients as prognostic marker. Therefore we have analyzed both histopathological
parameters and CXCR4 expression in melanoma infiltrate of SLN, in order to
evaluate its potential prognostic role.
RESULTS: Micrometastases were detected in 23 cases (48.93%); metastases >2 mm in
23 cases (48.93%) and isolated metastatic cells in one case (2.01%). High CXCR4
expression was observed in 21 nodal metastases. Node metastases in complete
dissection were associated to >10% relative tumor area (RTA) in all lymph nodes
(p = 0.006). Extranodal invasion (p = 0.006) and >2 mm centripetal metastasis
thickness (p = 0.01), while shorter Disease Free Survival (DFS) was
significantly associated to high CXCR4 expression (p = 0.02).
MATERIALS AND METHODS: Forty-seven positive lymph node metastases were collected
and analysed for both histopathological parameters and CXCR4 expression.
CONCLUSION: More than 10% RTA in SLN, extranodal invasion and centripetal
metastasis thickness all predict additional lymph node metastases in melanoma
site draining basins. Moreover, high CXCR4 expression is correlated to shorter
DFS and could be used as a prognostic marker in order to stratify melanoma
patients at higher progression risk.
DOI: 10.4161/cbt.9.6.10996
PMID: 20061818 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15383454 | 1. Blood. 2005 Feb 1;105(3):1329-36. doi: 10.1182/blood-2004-05-1852. Epub 2004
Sep 21.
Detection of somatic mosaicism and classification of Fanconi anemia patients by
analysis of the FA/BRCA pathway.
Soulier J(1), Leblanc T, Larghero J, Dastot H, Shimamura A, Guardiola P, Esperou
H, Ferry C, Jubert C, Feugeas JP, Henri A, Toubert A, Socié G, Baruchel A,
Sigaux F, D'Andrea AD, Gluckman E.
Author information:
(1)Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central
d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, 1
Ave Claude Vellefaux, 75010 Paris, France. [email protected]
Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow
failure, chromosome fragility, and cancer susceptibility. Eight FA-associated
genes have been identified so far, the products of which function in the FA/BRCA
pathway. A key event in the pathway is the monoubiquitination of the FANCD2
protein, which depends on a multiprotein FA core complex. In a number of
patients, spontaneous genetic reversion can correct FA mutations, leading to
somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2
immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination
was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA
reversion was further shown in these patients by comparison of primary
fibro-blasts and PBLs. Reversion was associated with higher blood counts and
clinical stability or improvement. Once constitutional FANCD2 patterns were
determined, patients could be classified based on the level of FA/BRCA pathway
disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4,
8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified
group patients were therefore relatively common, and they had more severe
congenital phenotypes. These results show that specific analysis of the FA/BRCA
pathway, combined with clinical and chromosome breakage data, allows a
comprehensive characterization of FA patients.
DOI: 10.1182/blood-2004-05-1852
PMID: 15383454 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22496755 | 1. PLoS One. 2012;7(4):e33606. doi: 10.1371/journal.pone.0033606. Epub 2012 Apr
4.
CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head
trauma.
Neselius S(1), Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J.
Author information:
(1)Department. of Orthopaedics, Sahlgrenska University Hospital, Gothenburg,
Sweden. [email protected]
BACKGROUND: Sports-related head trauma is common but still there is no
established laboratory test used in the diagnostics of minimal or mild traumatic
brain injuries. Further the effects of recurrent head trauma on brain injury
markers are unknown. The purpose of this study was to investigate the
relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF)
brain injury biomarkers.
METHODS: The study was designed as a prospective cohort study. Thirty Olympic
boxers with a minimum of 45 bouts and 25 non-boxing matched controls were
included in the study. CSF samples were collected by lumbar puncture 1-6 days
after a bout and after a rest period for at least 14 days. The controls were
tested once. Biomarkers for acute and chronic brain injury were analysed.
RESULTS: NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs
247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29
vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after
boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L
p = 0.001) concentrations remained elevated after the rest period.
CONCLUSION: Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the
boxers demonstrate that both the acute and the cumulative effect of head trauma
in Olympic boxing may induce CSF biomarker changes that suggest minor central
nervous injuries. The lack of normalization of NFL and GFAP after the rest
period in a subgroup of boxers may indicate ongoing degeneration. The recurrent
head trauma in boxing may be associated with increased risk of chronic traumatic
brain injury.
DOI: 10.1371/journal.pone.0033606
PMCID: PMC3319096
PMID: 22496755 [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/23650783 | 1. Acta Gastroenterol Belg. 2013 Mar;76(1):49-56.
Towards a tailored therapy in pancreatic cancer.
Maréchal R(1), Van Laethem JL.
Author information:
(1)Department of Gastroenterology and Gastrointestinal cancer Unit, Erasme
Hospital, Université Libre de Bruxelles, Brussels, Belgium.
[email protected]
Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem.
As conventional treatments have shown only a modest impact on disease course,
development of new therapeutic strategies based on the molecular biology of PDAC
must be a high priority. The identification of relevant predictive and
prognostic biomarkers which can be used to select patient subgroups that may
benefit from conventional treatments and new targeted agents will be of
considerable interest. We have demonstrated the ability of the metabolizing
gemcitabine protein (the human Equilibrative nucleoside transporter 1 and the
deoxycytidine kinase) in predicting the benefit of adjuvant gemcitabine-based
therapy in resected PDAC patients. Beside these predictive biomarkers, we have
evaluated different molecular factors that may impact on the likely course of
this cancer. The chemokine receptor CXCR4 that has been shown to be implicated
in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for
survival after a curative-intent surgery and was associated with the pattern of
tumour recurrence (distant versus local relapse). Our findings were validated in
an independent cohort of patients. Overall our results suggested that (i) the
benefit of an adjuvant gemcitabine-based therapy can be predicted based on the
tumour expression of hENT1 and dCK, (ii) CXCR4 is an independent negative
prognostic factor and an independent predictor of distant relapse suggesting
that anti-CXCR4 targeting therapies can be a promising treatment in combination
with cytotoxic chemotherapy in the adjuvant setting. These data open new
perspectives for designing trials based on a molecular driven strategy.
PMID: 23650783 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17596713 | 1. Neurodegener Dis. 2007;4(2-3):185-94. doi: 10.1159/000101843.
A systematic review and meta-analysis of CSF neurofilament protein levels as
biomarkers in dementia.
Petzold A(1), Keir G, Warren J, Fox N, Rossor MN.
Author information:
(1)Department of Neuroimmunology, Institute of Neurology, UCL, London, UK.
[email protected]
BACKGROUND: Loss of cortical neurons is a key pathological feature in
neurodegenerative dementias. Cerebrospinal fluid (CSF) neurofilaments (Nf) are a
biomarker for neuronal death and axonal loss.
OBJECTIVE: To perform a meta-analysis to investigate the value of CSF Nf levels
for the laboratory-supported differential diagnosis of neurodegenerative
dementias.
METHODS: A systematic review and meta-analysis of studies on CSF Nf heavy (NfH)
and light (NfL) levels in patients with dementia. The dementia subgroups
analysed were Alzheimer (AD), frontotemporal lobe dementia (FTLD), vascular
dementia (SVD), minimal cognitive deficit (MCI).
RESULTS: We identified 12 studies on CSF NfH and NfL levels which met the
inclusion criteria and 11 were of a quality good enough to be used in this
meta-analysis. CSF data was available on 818 patients (306 AD, 106 SVD, 98 FTLD,
25 MCI, 283 controls). Overall CSF NfH and NfL levels were higher in patients
with AD, FTLD and SVD when compared to controls. The size of the effect ranged
from 0.71 to 1.38. The strongest effect was observed for the comparison of FTLD
patients with controls, both for NfL (1.38) and NfH (0.74). CSF NfL were also
able to separate patients with FTLD from those with AD.
CONCLUSION: At present we cannot recommend CSF NfH and NfL levels for use as a
screening test in the diagnosis of dementia because of the rather small effect
size. However, both neurofilament proteins may be of value for targeted
investigation of some patients with FTLD, SVD and AD.
2007 S. Karger AG, Basel
DOI: 10.1159/000101843
PMID: 17596713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20200812 | 1. Exp Clin Endocrinol Diabetes. 2010 Jul;118(7):449-52. doi:
10.1055/s-0030-1248289. Epub 2010 Mar 3.
Weight reducing and metabolic effects of topiramate in patients with
migraine--an observational study.
Schütt M(1), Brinkhoff J, Drenckhan M, Lehnert H, Sommer C.
Author information:
(1)Department of Internal Medicine I, University of Lübeck, Lübeck, Germany.
[email protected]
Topiramate is an anticonvulsant agent effective in the prophylaxis of migraine,
which also induces weight reduction by an unknown mechanism. We investigated the
effect of topiramate on metabolic and endocrine parameters in patients with
migraine independently of any intention to lose body weight. Six patients (26-61
years old, body mass indices [BMI] 20.9-32.1 kg/m(2)) with migraine were treated
with an average dose of 100 mg topiramate/day over a period of 20 weeks. The
following parameters were measured every 4-8 weeks: BMI, body fat proportion,
waist and hip circumference, HOMA insulin resistance, fasting serum-/plasma
concentrations of adiponectin, leptin, ghrelin, vascular endothelial growth
factor (VEGF), cortisol, interleukin-6 and tumor necrosis factor (TNF)-alpha.
Profound metabolic changes were observed for the whole treatment period.
Compared with the baseline value, 20 weeks of treatment reduced the BMI by
7.2+/-1.4%, body fat proportion by 11.6+/-3.6%, waist circumference by
4.2+/-1.2%, leptin by 39.2+/-6.5% and HOMA insulin resistance by 37.3+/-5%,
while adiponectin was increased by 69.9+/-17.3% (P<0.05, respectively). VEGF
concentrations increased during the week 2-4 by 177.4+/-39.4% (P<0.05) followed
by a continuous decrease. There were trends for a reduction in ghrelin
concentration, whereas cortisol, interleukin-6 and TNF-alpha values were
unchanged. In summary, in this small sample of migraine patients topiramate
treatment was associated with increased insulin sensitivity, increased
adiponectin concentration and a reduction of body fat in all treated patients.
The role of increased VEGF concentrations prior to these metabolic changes is
not clear and might, hypothetically, involve a centrally mediated effect of
topiramate on body weight regulation.
J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart, New York.
DOI: 10.1055/s-0030-1248289
PMID: 20200812 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12498419 | 1. Hum Reprod Update. 2002 Nov-Dec;8(6):493-500. doi: 10.1093/humupd/8.6.493.
Cell-free fetal DNA and intact fetal cells in maternal blood circulation:
implications for first and second trimester non-invasive prenatal diagnosis.
Bischoff FZ(1), Sinacori MK, Dang DD, Marquez-Do D, Horne C, Lewis DE, Simpson
JL.
Author information:
(1)Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston,
Texas 77030, USA. [email protected]
Both intact fetal cells as well as cell-free fetal DNA are present in the
maternal circulation and can be recovered for non-invasive prenatal genetic
diagnosis. Although methods for enrichment and isolation of rare intact fetal
cells have been challenging, diagnosis of fetal chromosomal aneuploidy including
trisomy 21 in first- and second-trimester pregnancies has been achieved with a
50-75% detection rate. Similarly, cell-free fetal DNA can be reliably recovered
from maternal plasma and assessed by quantitative PCR to detect fetal trisomy 21
and paternally derived single gene mutations. Real-time PCR assays are robust in
detecting low-level fetal DNA concentrations, with sensitivity of approximately
95-100% and specificity near 100%. Comparing intact fetal cell versus cell-free
fetal DNA methods for non-invasive prenatal screening for fetal chromosomal
aneuploidy reveals that the latter is at least four times more sensitive. These
preliminary results do not support a relationship between frequency of intact
fetal cells and concentration of cell-free fetal DNA. The above results imply
that the concentration of fetal DNA in maternal plasma may not be dependent on
circulating intact fetal cells but rather be a product of growth and cellular
turnover during embryonic or fetal development.
DOI: 10.1093/humupd/8.6.493
PMID: 12498419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23371439 | 1. Prenat Diagn. 2013 Mar;33(3):223-31. doi: 10.1002/pd.4047. Epub 2013 Feb 1.
Maternal serum protein profile and immune response protein subunits as markers
for non-invasive prenatal diagnosis of trisomy 21, 18, and 13.
Narasimhan K(1), Lin SL, Tong T, Baig S, Ho S, Sukumar P, Biswas A, Hahn S,
Bajic VB, Choolani M.
Author information:
(1)Diagnostic Biomarker Discovery Laboratory, Department of Obstetrics and
Gynaecology, Yong Loo Lin School of Medicine, National University Health System,
Singapore.
OBJECTIVES: To use proteomics to identify and characterize proteins in maternal
serum from patients at high-risk for fetal trisomy 21, trisomy 18, and trisomy
13 on the basis of ultrasound and maternal serum triple tests.
METHODS: We performed a comprehensive proteomic analysis on 23 trisomy cases and
85 normal cases during the early second trimester of pregnancy. Protein
profiling along with conventional sodium dodecyl sulfate polyacrylamide gel
electrophoresis/Tandem mass spectrometry analysis was carried out to
characterize proteins associated with each trisomy condition and later validated
using Western blot.
RESULTS: Protein profiling approach using surface enhanced laser
desorption/ionization time-of-flight mass (SELDI-TOF/MS) spectrometry resulted
in the identification of 37 unique hydrophobic proteomic features for three
trisomy conditions. Using sodium dodecyl sulfate polyacrylamide gel
electrophoresis followed by Matrix Assisted Laser Desorption Ionization - Time
of Flight/Time of Flight (MALDI-TOF/TOF) and western blot, glyco proteins such
as alpha-1-antitrypsin, apolipoprotein E, apolipoprotein H, and serum carrier
protein transthyretin were identified as potential maternal serum markers for
fetal trisomy condition. The identified proteins showed differential expression
at the subunit level.
CONCLUSIONS: Maternal serum protein profiling using proteomics may allow
non-invasive diagnostic testing for the most common trisomies and may complement
ultrasound-based methods to more accurately determine pregnancies with fetal
aneuploidies.
© 2013 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.4047
PMID: 23371439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18753244 | 1. J Gen Virol. 2008 Sep;89(Pt 9):2339-2348. doi: 10.1099/vir.0.2008/002139-0.
Arabidopsis thaliana class II poly(A)-binding proteins are required for
efficient multiplication of turnip mosaic virus.
Dufresne PJ(1), Ubalijoro E(1), Fortin MG(1), Laliberté JF(2).
Author information:
(1)Department of Plant Science, McGill University, Ste-Anne-de-Bellevue, Québec
H9X 3V9, Canada.
(2)Institut national de la recherche scientifique, Institut Armand-Frappier,
Laval, Québec H7V 1B7, Canada.
The poly(A)-binding protein (PABP) is an important translation initiation factor
that binds to the polyadenylated 3' end of mRNA. We have previously shown that
PABP2 interacts with the RNA-dependent RNA polymerase (RdRp) and VPg-Pro of
turnip mosaic virus (TuMV) within virus-induced vesicles. At least eight PABP
isoforms are produced in Arabidopsis thaliana, three of which (PABP2, PABP4 and
PABP8) are highly and broadly expressed and probably constitute the bulk of PABP
required for cellular functions. Upon TuMV infection, an increase in protein and
mRNA expression from PAB2, PAB4 and PAB8 genes was recorded. In vitro binding
assays revealed that RdRp and the viral genome-linked protein (VPg-Pro) interact
preferentially with PABP2 but are also capable of interaction with one or both
of the other class II PABPs (i.e. PABP4 and PABP8). To assess whether PABP is
required for potyvirus replication, A. thaliana single and double pab knockouts
were isolated and inoculated with TuMV. All lines showed susceptibility to TuMV.
However, when precise monitoring of viral RNA accumulation was performed, it was
found to be reduced by 2.2- and 3.5-fold in pab2 pab4 and pab2 pab8 mutants,
respectively, when compared with wild-type plants. PABP levels were most
significantly reduced in the membrane-associated fraction in both of these
mutants. TuMV mRNA levels thus correlated with cellular PABP concentrations in
these A. thaliana knockout lines. These data provide further support for a role
of PABP in potyvirus replication.
DOI: 10.1099/vir.0.2008/002139-0
PMID: 18753244 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18523546 | 1. PLoS One. 2008 Jun 4;3(6):e2327. doi: 10.1371/journal.pone.0002327.
The intermediate filament network in cultured human keratinocytes is remarkably
extensible and resilient.
Fudge D(1), Russell D, Beriault D, Moore W, Lane EB, Vogl AW.
Author information:
(1)Department of Cellular & Physiological Sciences, University of British
Columbia, Vancouver, Canada. [email protected]
The prevailing model of the mechanical function of intermediate filaments in
cells assumes that these 10 nm diameter filaments make up networks that behave
as entropic gels, with individual intermediate filaments never experiencing
direct loading in tension. However, recent work has shown that single
intermediate filaments and bundles are remarkably extensible and elastic in
vitro, and therefore well-suited to bearing tensional loads. Here we tested the
hypothesis that the intermediate filament network in keratinocytes is extensible
and elastic as predicted by the available in vitro data. To do this, we
monitored the morphology of fluorescently-tagged intermediate filament networks
in cultured human keratinocytes as they were subjected to uniaxial cell strains
as high as 133%. We found that keratinocytes not only survived these high
strains, but their intermediate filament networks sustained only minor damage at
cell strains as high as 100%. Electron microscopy of stretched cells suggests
that intermediate filaments are straightened at high cell strains, and therefore
likely to be loaded in tension. Furthermore, the buckling behavior of
intermediate filament bundles in cells after stretching is consistent with the
emerging view that intermediate filaments are far less stiff than the two other
major cytoskeletal components F-actin and microtubules. These insights into the
mechanical behavior of keratinocytes and the cytokeratin network provide
important baseline information for current attempts to understand the
biophysical basis of genetic diseases caused by mutations in intermediate
filament genes.
DOI: 10.1371/journal.pone.0002327
PMCID: PMC2390850
PMID: 18523546 [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/23015735 | 1. mBio. 2012 Sep 25;3(5):e00196-12. doi: 10.1128/mBio.00196-12. Print 2012.
Cryptococcal genotype influences immunologic response and human clinical outcome
after meningitis.
Wiesner DL(1), Moskalenko O, Corcoran JM, McDonald T, Rolfes MA, Meya DB,
Kajumbula H, Kambugu A, Bohjanen PR, Knight JF, Boulware DR, Nielsen K.
Author information:
(1)Department of Microbiology, Medical School, University of Minnesota,
Minneapolis, Minnesota, USA.
In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a
predominant cause of AIDS-related mortality. Understanding virulence and
improving clinical treatments remain important. To characterize the role of the
fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus
isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107
nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans
var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was
used to characterize genotypes, yielding 15 sequence types and 4 clonal
clusters. The largest clonal cluster consisted of 74 isolates. The results of
Burst and phylogenetic analysis suggested that the C. neoformans var. grubii
strains could be separated into three nonredundant evolutionary groups (Burst
group 1 to group 3). Patient mortality was differentially associated with the
different evolutionary groups (P = 0.04), with the highest mortality observed
among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group
3 strains, Burst group 1 strains were associated with higher mortality (P =
0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more
pronounced Th(2) response during ex vivo cytokine release assays with
strain-specific capsule stimulation (P = 0.02). The results of these analyses
suggest that cryptococcal strain variation can be an important determinant of
human immune responses and mortality.
IMPORTANCE: Cryptococcus neoformans is a common life-threatening human fungal
pathogen that is responsible for an estimated 1 million cases of meningitis in
HIV-infected patients annually. Virulence factors that are important in human
disease have been identified, yet the impacts of the fungal strain genotype on
virulence and outcomes of human infection remain poorly understood. Using an
analysis of strain variation based on in vitro assays and clinical data from
Ugandans living with AIDS and cryptococcal infection, we report that strain
genotype predicts the type of immune response and mortality risk. These studies
suggest that knowledge of the strain genotype during human infections could be
used to predict disease outcomes and lead to improved treatment approaches aimed
at targeting the specific combination of pathogen virulence and host response.
DOI: 10.1128/mBio.00196-12
PMCID: PMC3448160
PMID: 23015735 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22473623 | 1. J Surg Oncol. 2012 Sep 15;106(4):393-8. doi: 10.1002/jso.23113. Epub 2012 Apr
3.
The chemokine receptor CXCR4 as a novel independent prognostic marker for
node-positive breast cancer patients.
Parker CC(1), Kim RH, Li BD, Chu QD.
Author information:
(1)Department of Surgery and Division of Surgical Oncology, Louisiana State
University Health Sciences Center, Shreveport, Louisiana 71130, USA.
BACKGROUND: Node-positive breast cancer patients are a high-risk group. However,
not all such patients will succumb to the disease. The molecular basis for this
biologic heterogeneity is poorly understood. The chemokine receptor CXCR4 is a
marker of metastatic disease. Its prognostic role in node-positive patients is
unknown. We postulate that high CXCR4 overexpression in node-positive breast
cancer specimens predicts a poor outcome.
METHODS: 185 node-positive breast cancer patients were evaluated. All had
standardized treatment and surveillance protocols. CXCR4 levels were detected
with Western blots. Results were quantified against 1 µg of HeLa cells. CXCR4
expression was defined as high (≥ 7.5-fold) or low (<7.5-fold). Primary
endpoints were cancer recurrence and death. Statistical analyses were
Kaplan-Meier curves, log-rank test, and Cox proportional hazard model, with a
P-value of ≤ 0.05 as significant.
RESULTS: The mean follow-up time was 54 months; 148 patients (80%) had low CXCR4
and 37 patients (20%) had high CXCR4 level. The 5-year overall survival (OS) for
the low and high CXCR4 group was 69% and 57%, respectively (P=0.02). The 5-year
disease-free survival (DFS) for the low and high CXCR4 group was 62% and 53%,
respectively (P=0.08). On multivariate analysis, T stage (P=0.001) and grade
(P=0.04) were independent predictors of DFS, while T stage (P=0.005), grade
(P=0.024), and CXCR4 level (P=0.01) were independent predictors of OS.
CONCLUSION: High CXCR4 level in cancer specimens independently predicts a poor
outcome for patients with node-positive breast cancer.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/jso.23113
PMID: 22473623 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18682226 | 1. Structure. 2008 Aug 6;16(8):1245-56. doi: 10.1016/j.str.2008.04.015.
Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit
TAF3.
van Ingen H(1), van Schaik FM, Wienk H, Ballering J, Rehmann H, Dechesne AC,
Kruijzer JA, Liskamp RM, Timmers HT, Boelens R.
Author information:
(1)Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH
Utrecht, The Netherlands.
Trimethylation of lysine residue K4 of histone H3 (H3K4me3) strongly correlates
with active promoters for RNA polymerase II-transcribed genes. Several reader
proteins, including the basal transcription factor TFIID, for this nucleosomal
mark have been identified. Its TAF3 subunit specifically binds the H3K4me3 mark
via its conserved plant homeodomain (PHD) finger. Here, we report the solution
structure of the TAF3-PHD finger and its complex with an H3K4me3 peptide. Using
a combination of NMR, mutagenesis, and affinity measurements, we reveal the
structural basis of binding affinity, methylation-state specificity, and
crosstalk with asymmetric dimethylation of R2. A unique local structure
rearrangement in the K4me3-binding pocket of TAF3 due to a conserved sequence
insertion underscores the requirement for cation-pi interactions by two aromatic
residues. Interference by asymmetric dimethylation of arginine 2 suggests that a
H3R2/K4 "methyl-methyl" switch in the histone code dynamically regulates
TFIID-promoter association.
DOI: 10.1016/j.str.2008.04.015
PMID: 18682226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24820828 | 1. Indian J Med Res. 2014 Mar;139(3):343-8.
Migraine & paediatric obesity: a plausible link?
Ravid S(1).
Author information:
(1)Pediatric Neurology Unit, Meyer Children's Hospital, Rambam Health Care
Campus, Haifa, Israel.
Obesity and migraine are both highly prevalent disorders in the general
population, influenced by genetic and environmental risk factors. In recent
studies, obesity was found to be a strong risk factor for transformed migraine
and, among migraineurs, obesity was associated with frequent headaches and
higher disability scores. Suggested mechanisms included: (i) obesity as a
pro-inflammatory state may be associated with neurovascular inflammation in
patients with migraine; (ii) elevated levels of plasma calcitonin gene-related
peptide (CGRP) in obese individuals may play a role as an important
post-synaptic mediator of trigeminovascular inflammation in migraine; (iii)
dismodulation in the hypothalamic neuropeptide, orexin, in obese persons may be
associated with increased susceptibility to neurogenic inflammation causing
migraine attacks; and (iv) leptin and adiponectin can activate proinflammatory
cytokine release that is involved in the pathogenesis of migraine. In addition,
both conditions are associated with psychiatric co-morbidities, such as
depression and anxiety, that can further increase headache frequency and
disability. Therefore, the effect of obesity on migraine outcome is important.
Weight and BMI should be measured and calculated in all children presenting with
migraine, and weight control should be a part of the treatment.
PMCID: PMC4069728
PMID: 24820828 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21435340 | 1. Dev Biol. 2011 Sep 15;357(2):450-62. doi: 10.1016/j.ydbio.2011.03.007. Epub
2011 Mar 22.
Identification of cis regulatory features in the embryonic zebrafish genome
through large-scale profiling of H3K4me1 and H3K4me3 binding sites.
Aday AW(1), Zhu LJ, Lakshmanan A, Wang J, Lawson ND.
Author information:
(1)Program in Gene Function and Expression, University of Massachusetts Medical
School, Worcester, MA 01602, USA.
An organism's genome sequence serves as a blueprint for the proteins and
regulatory RNAs essential for cellular function. The genome also harbors
cis-acting non-coding sequences that control gene expression and are essential
to coordinate regulatory programs during embryonic development. However, the
genome sequence is largely identical between cell types within a multi-cellular
organism indicating that factors such as DNA accessibility and chromatin
structure play a crucial role in governing cell-specific gene expression. Recent
studies have identified particular chromatin modifications that define
functionally distinct cis regulatory elements. Among these are forms of histone
3 that are mono- or tri-methylated at lysine 4 (H3K4me1 or H3K4me3,
respectively), which bind preferentially to promoter and enhancer elements in
the mammalian genome. In this work, we investigated whether these modified
histones could similarly identify cis regulatory elements within the zebrafish
genome. By applying chromatin immunoprecipitation followed by deep sequencing,
we find that H3K4me1 and H3K4me3 are enriched at transcriptional start sites in
the genome of the developing zebrafish embryo and that this association
correlates with gene expression. We further find that these modifications
associate with distal non-coding conserved elements, including known active
enhancers. Finally, we demonstrate that it is possible to utilize H3K4me1 and
H3K4me3 binding profiles in combination with available expression data to
computationally identify relevant cis regulatory sequences flanking
syn-expressed genes in the developing embryo. Taken together, our results
indicate that H3K4me1 and H3K4me3 generally mark cis regulatory elements within
the zebrafish genome and indicate that further characterization of the zebrafish
using this approach will prove valuable in defining transcriptional networks in
this model system.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ydbio.2011.03.007
PMCID: PMC3273848
PMID: 21435340 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22038362 | 1. J Huazhong Univ Sci Technolog Med Sci. 2011 Oct;31(5):687. doi:
10.1007/s11596-011-0583-0. Epub 2011 Oct 25.
Non-invasive prenatal diagnosis of trisomy 21 by dosage ratio of fetal
chromosome-specific epigenetic markers in maternal plasma.
Zhang M(1), Li T(2), Chen J(1), Li L(1), Zhou C(1), Wang Y(1), Liu W(1), Zhang
Y(3).
Author information:
(1)Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan,
430071, China.
(2)Department of Ophthalmology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, 430030, China.
(3)Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan,
430071, China. [email protected].
This study examined the methylation difference in AIRE and RASSF1A between
maternal and placental DNA, and the implication of this difference in the
identification of free fetal DNA in maternal plasma and in prenatal diagnosis of
trisomy 21. Maternal plasma samples were collected from 388 singleton
pregnancies, and placental or chorionic villus tissues from 112 of them.
Methylation-specific PCR (MSP) and methylation-sensitive restriction enzyme
digestion followed by fluorescent quantitative PCR (MSRE + PCR) were employed to
detect the maternal-fetal methylation difference in AIRE and RASSF1A. Diagnosis
of trisomy 21 was established according to the ratio of fetal-specific AIRE to
RASSF1A in maternal plasma. Both methods confirmed that AIRE and RASSF1A were
hypomethylated in maternal blood cells but hypermethylated in placental or
chorionic villus tissues. Moreover, the differential methylation for each locus
could be seen during the whole pregnant period. The positive rates of fetal AIRE
and RASSF1A in maternal plasma were found to be 78.1% and 82.1% by MSP and 94.8%
and 96.9% by MSRE + PCR. MSRE + PCR was superior to MSP in the identification of
fetal-specific hypermethylated sequences (P<0.05). Based on the data from 266
euploidy pregnancies, the 95% reference interval of the fetal AIRE/RASSF1A ratio
in maternal plasma was 0.33-1.77, which was taken as the reference value for
determining the numbers of fetal chromosome 21 in 102 pregnancies. The accuracy
rate in 98 euploidy pregnancies was 96.9% (95/98). Three of the four trisomy 21
pregnancies were confirmed with this method. It was concluded that
hypermethylated AIRE and RASSF1A may serve as fetal-specific markers for the
identification of fetal DNA in maternal plasma and may be used for noninvasive
prenatal diagnosis of trisomy 21.
DOI: 10.1007/s11596-011-0583-0
PMID: 22038362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19833968 | 1. Science. 2009 Oct 16;326(5951):437-40. doi: 10.1126/science.1172156.
AMPK regulates the circadian clock by cryptochrome phosphorylation and
degradation.
Lamia KA(1), Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez
DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM.
Author information:
(1)Gene Expression Laboratory, the Salk Institute, La Jolla, CA 92037, USA.
Comment in
Science. 2009 Oct 16;326(5951):378-9. doi: 10.1126/science.1181278.
Circadian clocks coordinate behavioral and physiological processes with daily
light-dark cycles by driving rhythmic transcription of thousands of genes.
Whereas the master clock in the brain is set by light, pacemakers in peripheral
organs, such as the liver, are reset by food availability, although the setting,
or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we
demonstrated that the nutrient-responsive adenosine monophosphate-activated
protein kinase (AMPK) phosphorylates and destabilizes the clock component
cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization
were rhythmic and inversely correlated with CRY1 nuclear protein abundance.
Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms,
and mice in which the AMPK pathway was genetically disrupted showed alterations
in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to
transduce nutrient signals to circadian clocks in mammalian peripheral organs.
DOI: 10.1126/science.1172156
PMCID: PMC2819106
PMID: 19833968 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21217880 | 1. Interdiscip Toxicol. 2010 Sep;3(3):89-93. doi: 10.2478/v10102-010-0018-y.
Importance of molecular cell biology investigations in human medicine in the
story of the Hutchinson-Gilford progeria syndrome.
Raška I(1).
Author information:
(1)Charles University in Prague, First Faculty of Medicine, Institute of
Cellular Biology and Pathology, and Institute of Physiology, Academy of Sciences
of the Czech Republic, v.v.i., Department of Cell Biology, Albertov 4, 128 01,
Prague, Czech Republic.
Ranged among laminopathies, Hutchinson-Gilford progeria syndrome is a syndrome
that involves premature aging, leading usually to death at the age between 10 to
14 years predominatly due to a myocardial infarction or a stroke. In the lecture
I shall overview the importance of molecular cell biology investigations that
led to the discovery of the basic mechanism standing behind this rare syndrome.
The genetic basis in most cases is a mutation at the nucleotide position 1824 of
the lamin A gene. At this position, cytosine is substituted for thymine so that
a cryptic splice site within the precursor mRNA for lamin A is generated. This
results in a production of abnormal lamin A, termed progerin, its presence in
cells having a deleterious dominant effect. Depending on the cell type and
tissue, progerin induces a pleiotropy of defects that vary in different tissues.
The present endeavour how to challenge this terrible disease will be also
mentioned.
DOI: 10.2478/v10102-010-0018-y
PMCID: PMC2984137
PMID: 21217880 |
http://www.ncbi.nlm.nih.gov/pubmed/22896784 | 1. Commun Integr Biol. 2012 May 1;5(3):243-7. doi: 10.4161/cib.19347.
An integrated model for the nucleo-cytoplasmic transport of cytoplasmic
poly(A)-binding proteins.
Burgess HM, Gray NK.
Cytoplasmic poly(A)-binding proteins (PABPs) regulate mRNA stability and
translation. Although predominantly localized in the cytoplasm, PABP proteins
also cycle through the nucleus. Recent work has established that their
steady-state localization can be altered by cellular stresses such as
ultraviolet (UV) radiation, and infection by several viruses, resulting in
nuclear accumulation of PABPs. Here, we present further evidence that their
interaction with and release from mRNA and translation complexes are important
in determining their sub-cellular distribution and propose an integrated model
for regulated nucleo-cytoplasmic transport of PABPs.
DOI: 10.4161/cib.19347
PMCID: PMC3419106
PMID: 22896784 |
http://www.ncbi.nlm.nih.gov/pubmed/20223299 | 1. Ageing Res Rev. 2010 Jul;9(3):265-8. doi: 10.1016/j.arr.2010.02.005. Epub 2010
Mar 17.
Mechanistic contribution of carnitine deficiency to geriatric frailty.
Crentsil V(1).
Author information:
(1)Division of General Internal Medicine, Johns Hopkins University, School of
Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA. [email protected]
Frailty is a geriatric syndrome characterized by muscle weakness, sarcopenia,
and fatigue, and is associated with several adverse health outcomes, including
disability. Design of therapeutic interventions for geriatric frailty has been
challenging and may be because of inadequate understanding of its biological
underpinnings. Carnitine is important for energy production in skeletal muscles
and there seems to be a negative correlation between advancing age and muscle
carnitine levels. Carnitine deficiency may therefore contribute to geriatric
frailty. Age-associated carnitine deficiency from a variety of etiologies,
including organic cation transporter (OCTN2) mutation and carnitine
palmitoyltransferase II (CPT) deficiency, may potentially explain the
relationship between carnitine-associated mitochondrial dysfunction and
geriatric frailty. Development of therapeutic agents capable of prevention or
reversal of carnitine deficiency in older adults may minimize the occurrence of
frailty in geriatric populations.
2010 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.arr.2010.02.005
PMID: 20223299 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22848616 | 1. PLoS One. 2012;7(7):e41814. doi: 10.1371/journal.pone.0041814. Epub 2012 Jul
25.
Nanoscale strain-hardening of keratin fibres.
Fortier P(1), Suei S, Kreplak L.
Author information:
(1)Department of Physics and Atmospheric Science, Dalhousie University, Halifax,
Canada.
Mammalian appendages such as hair, quill and wool have a unique structure
composed of a cuticle, a cortex and a medulla. The cortex, responsible for the
mechanical properties of the fibers, is an assemblage of spindle-shaped
keratinized cells bound together by a lipid/protein sandwich called the cell
membrane complex. Each cell is itself an assembly of macrofibrils around 300 nm
in diameter that are paracrystalline arrays of keratin intermediate filaments
embedded in a sulfur-rich protein matrix. Each macrofibril is also attached to
its neighbors by a cell membrane complex. In this study, we combined atomic
force microscopy based nano-indentation with peak-force imaging to study the
nanomechanical properties of macrofibrils perpendicular to their axis. For
indentation depths in the 200 to 500 nm range we observed a decrease of the
dynamic elastic modulus at 1 Hz with increasing depth. This yielded an estimate
of 1.6GPa for the lateral modulus at 1 Hz of porcupine quill's macrofibrils.
Using the same data we also estimated the dynamic elastic modulus at 1 Hz of the
cell membrane complex surrounding each macrofibril, i.e., 13GPa. A similar
estimate was obtained independently through elastic maps of the macrofibrils
surface obtained in peak-force mode at 1 kHz. Furthermore, the macrofibrillar
texture of the cortical cells was clearly identified on the elasticity maps,
with the boundaries between macrofibrils being 40-50% stiffer than the
macrofibrils themselves. Elasticity maps after indentation also revealed a local
increase in dynamic elastic modulus over time indicative of a relaxation induced
strain hardening that could be explained in term of a α-helix to β-sheet
transition within the macrofibrils.
DOI: 10.1371/journal.pone.0041814
PMCID: PMC3404990
PMID: 22848616 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have read the
journal’s policy and have the following conflicts: LK is an academic Editor of
PLoS One. This does not alter the authors’ adherence to all the PLoS ONE
policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/19559031 | 1. J Mol Biol. 2009 Aug 21;391(3):648-60. doi: 10.1016/j.jmb.2009.06.045. Epub
2009 Jun 24.
Structural properties of neurofilament sidearms: sequence-based modeling of
neurofilament architecture.
Chang R(1), Kwak Y, Gebremichael Y.
Author information:
(1)Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of
Korea. [email protected]
Neurofilaments (NFs) are essential cytoskeletal filaments that impart mechanical
integrity to nerve cells. They are assembled from three distinct molecular mass
proteins that bind to each other to form a 10-nm-diameter filamentous rod with
sidearm extensions. The sidearms are considered to play a critical role in
modulating interfilament spacing and axonal caliber. However, the precise
mechanism by which NF protrusions regulate axonal diameter remains to be well
understood. In particular, the role played by individual NF protrusions in
specifying interfilament distances is yet to be established. To gain insight
into the role of individual proteins, we investigated the structural
organization of NF architecture under different phosphorylation conditions. To
this end, a physically motivated sequence-based coarse-grain model of NF brush
has been developed based on the three-dimensional architecture of NFs. The model
incorporates the charge distribution of sidearms, including charges from the
phosphorylation sites corresponding to Lys-Ser-Pro repeat motifs. The model also
incorporates the proper grafting of the real NF sidearms based on the
stoichiometry of the three subunits. The equilibrium structure of the NF brush
is then investigated under different phosphorylation conditions. The
phosphorylation of NF modifies the structural organization of sidearms. Upon
phosphorylation, a dramatic change involving a transformation from a compact
conformation to an extended conformation is found in the heavy NF (NF-H)
protein. However, in spite of extensive phosphorylation sites present in the
NF-H subunit, the tails of the medium NF subunit are found to be more extended
than the NF-H sidearms. This supports the notion that medium NF protrusions are
critical in regulating NF spacings and, hence, axonal caliber.
DOI: 10.1016/j.jmb.2009.06.045
PMID: 19559031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18693275 | 1. Genesis. 2008 Aug;46(8):418-23. doi: 10.1002/dvg.20412.
Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development.
Fujii T, Tamura M, Tanaka S, Kato Y, Yamamoto H, Mizushina Y, Shiroishi T.
Members of the novel gene family Gasdermin (Gsdm) are exclusively expressed in a
highly tissue-specific manner in the epithelium of skin and the gastrointestinal
tract. Based on their expression patterns and the phenotype of the Gsdma3
spontaneous mutations, it is inferred that the Gsdm family genes are involved in
epithelial cell growth and/or differentiations in different tissues. To
investigate possible roles of the Gsdm gene family in the development of
intestinal tracts, we generated a Gsdmd mutant mouse, which is a solitary member
of the Gsdmd subfamily and which is predominantly expressed in the intestinal
tract by means of targeted disruption. In the mutant homozygotes, we found no
abnormality of intestinal tract morphology. Moreover, in mutant mice, there was
normal differentiation of all constituent cell types of the intestinal
epithelium. Thus, this study clearly shows that Gsdmd is not essential for
development of mouse intestinal tract or epithelial cell differentiation.
DOI: 10.1002/dvg.20412
PMID: 18693275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19051310 | 1. Genes Chromosomes Cancer. 2009 Mar;48(3):261-71. doi: 10.1002/gcc.20636.
Distinctive expression and function of four GSDM family genes (GSDMA-D) in
normal and malignant upper gastrointestinal epithelium.
Saeki N(1), Usui T, Aoyagi K, Kim DH, Sato M, Mabuchi T, Yanagihara K, Ogawa K,
Sakamoto H, Yoshida T, Sasaki H.
Author information:
(1)Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Gasdermin (GSDM or GSDMA), expressed in the upper gastrointestinal tract but
frequently silenced in gastric cancers (GCs), regulates apoptosis of the gastric
epithelium. It has three human homologs, GSDMB, GSDMC, and GSDMD (GSDM family)
and they are considered to be involved in the regulation of epithelial apoptosis
but not yet known. We investigated the expression pattern of the family genes in
the upper gastrointestinal epithelium and cancers. Reverse
transcriptase-polymerase chain reaction revealed that, unlike GSDMA expressed in
differentiated cells, GSDMB is expressed in proliferating cells and GSDMD in
differentiating cells. GSDMC, meanwhile, is expressed in both differentiating
and differentiated cells. Colony formation assay showed that GSDMB, closely
related to GSDMA, has no cell-growth inhibition activity in gastric cancer
cells, and that GSDMC and GSDMD, respectively, exhibit the activity with
different strengths from that of GSDMA. Expression analyses of the four family
genes in esophageal and GCs suggested that GSDMC and GSDMD as well as GSDMA are
tumor suppressors and that GSDMB, which was amplified and overexpressed in some
GCs, could be an oncogene. The results of the expression analysis and colony
formation assay suggest that each family gene may have a distinct function in
the upper gastrointestinal epithelium.
Copyright 2008 Wiley-Liss, Inc.
DOI: 10.1002/gcc.20636
PMID: 19051310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22126386 | 1. Pathol Int. 2011 Dec;61(12):762-7. doi: 10.1111/j.1440-1827.2011.02733.x. Epub
2011 Sep 26.
Sinonasal teratocarcinosarcoma with rhabdoid features.
Kim JH(1), Maeng YH, Lee JS, Jung S, Lim SC, Lee MC.
Author information:
(1)Department of Pathology, Jeju National University Medical School, Jeju,
Korea.
Sinonasal teratocarcinosarcoma (SNTCS) is a very rare tumor developed in the
nasal cavity and paranasal sinuses. The rhabdoid phenotype represents an
aggressive biological behavior, but the rhabdoid feature has hitherto not been
reported in cases of SNTCS. A 46-year-old man complained of a 1-month history of
left-sided nasal obstruction. Computed tomography scan and magnetic resonance
imaging showed a tumor mass involving the left nasal cavity, ethmoid sinus, and
ethmoid bone with extension to the left frontal lobe of the brain. A gross total
resection of the mass was performed and postoperative radiation therapy
administered. Seven weeks later, several recurring masses were detected in the
left frontotemporal lobe of the brain. A gross total resection of the mass was
performed and postoperative chemotherapy administered. Histopathologically, the
tumor showed benign and malignant epithelial, mesenchymal, neural, and immature
elements. In addition, diffuse sheets of rhabdoid cells were immunopositive for
vimentin, nestin, neuron-specific enolase, and INI1. Ultrastructurally, rhabdoid
cells showed paranuclear aggregates and whorls of intermediate filaments with a
9-10 nm diameter. In conclusion, we report first case of rhabdoid features in
SNTCS. The present case showed an advanced stage and early recurrence; the
rhabdoid component was probably responsible for this aggressive behavior.
© 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology
and Blackwell Publishing Asia Pty Ltd.
DOI: 10.1111/j.1440-1827.2011.02733.x
PMID: 22126386 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17387144 | 1. Genome Res. 2007 May;17(5):545-55. doi: 10.1101/gr.6086307. Epub 2007 Mar 26.
Genomic regulatory blocks encompass multiple neighboring genes and maintain
conserved synteny in vertebrates.
Kikuta H(1), Laplante M, Navratilova P, Komisarczuk AZ, Engström PG, Fredman D,
Akalin A, Caccamo M, Sealy I, Howe K, Ghislain J, Pezeron G, Mourrain P,
Ellingsen S, Oates AC, Thisse C, Thisse B, Foucher I, Adolf B, Geling A, Lenhard
B, Becker TS.
Author information:
(1)Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen,
Norway.
We report evidence for a mechanism for the maintenance of long-range conserved
synteny across vertebrate genomes. We found the largest mammal-teleost conserved
chromosomal segments to be spanned by highly conserved noncoding elements
(HCNEs), their developmental regulatory target genes, and phylogenetically and
functionally unrelated "bystander" genes. Bystander genes are not specifically
under the control of the regulatory elements that drive the target genes and are
expressed in patterns that are different from those of the target genes.
Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2,
rx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the
expression patterns of these genes even if located inside or beyond bystander
genes, suggesting that the regulatory domain of a developmental regulatory gene
can extend into and beyond adjacent transcriptional units. We termed these
chromosomal segments genomic regulatory blocks (GRBs). After whole genome
duplication in teleosts, GRBs, including HCNEs and target genes, were often
maintained in both copies, while bystander genes were typically lost from one
GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy
GRBs of higher vertebrates intact. We show that loss of bystander genes and
other mutational events suffered by duplicated GRBs in teleost genomes permits
target gene identification and HCNE/target gene assignment. These findings
explain the absence of evolutionary breakpoints from large vertebrate
chromosomal segments and will aid in the recognition of position effect
mutations within human GRBs.
DOI: 10.1101/gr.6086307
PMCID: PMC1855176
PMID: 17387144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14717712 | 1. Eur J Biochem. 2004 Jan;271(2):450-7. doi: 10.1046/j.1432-1033.2003.03945.x.
Human PABP binds AU-rich RNA via RNA-binding domains 3 and 4.
Sladic RT(1), Lagnado CA, Bagley CJ, Goodall GJ.
Author information:
(1)Division of Human Immunology and Hanson Institute, Institute of Medical and
Veterinary Science, Adelaide, Australia.
Poly(A) binding protein (PABP) binds mRNA poly(A) tails and affects mRNA
stability and translation. We show here that there is little free PABP in NIH3T3
cells, with the vast majority complexed with RNA. We found that PABP in NIH3T3
cytoplasmic lysates and recombinant human PABP can bind to AU-rich RNA with high
affinity. Human PABP bound an AU-rich RNA with Kd in the nm range, which was
only sixfold weaker than the affinity for oligo(A) RNA. Truncated PABP
containing RNA recognition motif domains 3 and 4 retained binding to both
AU-rich and oligo(A) RNA, whereas a truncated PABP containing RNA recognition
motif domains 1 and 2 was highly selective for oligo(A) RNA. The inducible PABP,
iPABP, was found to be even less discriminating than PABP in RNA binding, with
affinities for AU-rich and oligo(A) RNAs differing by only twofold. These data
suggest that iPABP and PABP may in some situations interact with other RNA
regions in addition to the poly(A) tail.
DOI: 10.1046/j.1432-1033.2003.03945.x
PMID: 14717712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18678825 | 1. Neurology. 2008 Aug 5;71(6):426-9. doi: 10.1212/01.wnl.0000324266.95814.74.
Acute ophthalmoplegia (without ataxia) associated with anti-GQ1b antibody.
Lee SH(1), Lim GH, Kim JS, Oh SY, Kim JK, Cha JK, Yun CH, Kang JK, Lee H, Song
HK, Chung KC.
Author information:
(1)Department of Neurology, College of Medicine, Chonnam National University,
Korea.
BACKGROUND: Anti-GQ1b antibody has been found in Miller Fisher syndrome (MFS),
Guillain-Barré syndrome (GBS) with ophthalmoplegia, Bickerstaff brainstem
encephalitis (BBE), and acute ophthalmoplegia without ataxia (AO). The aim of
this study was to determine the clinical features of AO associated with
anti-GQ1b antibody.
METHODS: We retrospectively collected 34 patients with anti-GQ1b antibody
syndrome. Of these patients, 31 patients had ophthalmoplegia. The patients with
ophthalmoplegia were classified into MFS (n = 13), AO (n = 11), GBS with
ophthalmoplegia (n = 6), and BBE (n = 1). We analyzed clinical features and
patterns of external and internal ophthalmoplegia of AO, and
neuro-ophthalmologic findings were compared with those of other anti-GQ1b
syndromes with ophthalmoplegia.
RESULTS: AO was observed in 11 (32.4%) of the 34 patients with anti-GQ1b
antibody. External ophthalmoparesis was present in all the patients and included
mixed horizontal-vertical (n = 7), pure horizontal (n = 3), and pure vertical
gaze palsy (n = 1). Binocular involvement was common, but unilateral
ophthalmoparesis was also observed in 27.3%. Other findings included ptosis (n =
5, 45.5%) and internal ophthalmoplegia (n = 6, 54.5%). Other anti-GQ1b antibody
syndromes had prominent neurologic signs including ataxia, weakness, and facial
palsy in addition to ophthalmoplegia. The patterns of neuro-ophthalmologic
findings did not differ between AO and other anti-GQ1b antibody syndromes with
ophthalmoplegia.
CONCLUSIONS: Acute ophthalmoplegia (AO) commonly occurs in anti-GQ1b antibody
syndrome and manifests as various combinations of external and internal
ophthalmoplegia. Internal ophthalmoplegia is fairly common and unilateral
involvement may occur in AO.
DOI: 10.1212/01.wnl.0000324266.95814.74
PMID: 18678825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16647786 | 1. Eur J Cell Biol. 2006 Jun;85(6):551-65. doi: 10.1016/j.ejcb.2006.01.015. Epub
2006 May 2.
Human bone marrow stroma cells display certain neural characteristics and
integrate in the subventricular compartment after injection into the liquor
system.
Arnhold S(1), Klein H, Klinz FJ, Absenger Y, Schmidt A, Schinköthe T, Brixius K,
Kozlowski J, Desai B, Bloch W, Addicks K.
Author information:
(1)Department of Anatomy I, University of Cologne, Josef-Stelzmannstr. 9,
D-50931 Köln, Germany. [email protected]
Because the neural differentiation capacity of bone marrow stromal cells (BMSCs)
is still a matter of controversial debate, we performed a thorough investigation
into the differentiation capacity of human BMSCs and examined their therapeutic
potency. BMSCs were isolated from the femur and kept in cell cultures with
various cultivation protocols being applied. In standard culture conditions
using a fetal calf serum-enriched medium, while not exhibiting a neural
phenotype, the majority of cells expressed a variety of neuronal marker proteins
as well as the astrocyte marker GFAP. Only a minority of stem cells expressed
nestin, a marker for neural precursor cells. Cultivation in serum-free medium
supplemented with specific growth factors resulted in a markedly higher
percentage of nestin-positive cells. To establish the therapeutic potency of
bone marrow-derived cells, the synthesis of neurotrophic factors such as NGF,
BDNF and GDNF was analyzed under non-stimulating standard culture conditions as
well as after a neural selection procedure. The therapeutic potency of BMSCs was
further examined with regard to their migratory potential in vitro and after
transplantation in vivo. After stereotactic engraftment into the lateral
ventricle of adult rats, mesenchymal stem cells were seen to adhere to the
ependymocytes and cells of the choroids plexus. Afterwards grafted cells passed
through the ependymal barrier, locating in the subventricular space. Their BMSCs
took up a close host graft interaction without any degenerative influence on the
host cells. Furthermore, there was morphological as well as immunohistochemical
evidence for a transdifferentiation within the host tissue. In addition, BMSCs
could be efficiently transduced using a third-generation adenoviral vector,
indicating their potential feasibility for a gene-therapeutic option.
DOI: 10.1016/j.ejcb.2006.01.015
PMID: 16647786 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20100521 | 1. Biochim Biophys Acta. 2010 Apr;1803(4):492-8. doi:
10.1016/j.bbamcr.2010.01.012. Epub 2010 Jan 25.
Conserved amino acid residues in C-terminus of PERIOD 2 are involved in
interaction with CRYPTOCHROME 1.
Tomita T(1), Miyazaki K, Onishi Y, Honda S, Ishida N, Oishi K.
Author information:
(1)Institute for Biological Resources and Functions, National Institute of
Advanced Industrial Science and Technology, Tsukuba Central 6, 1-1-1 Higashi,
Tsukuba, Ibaraki 305-8566, Japan. [email protected]
We investigated the amino acid sequences of rat PERIOD2 (rPER2) that are
required for interaction with CRYPTOCHROME1 (CRY1) to understand the molecular
mechanism of the circadian clock. Co-immunoprecipitation assays using various
C-terminal fragments of rPER2 with internal deletions revealed that amino acid
residues 1179-1198 are necessary for interaction with CRY1. To identify
precisely which amino acid residues are responsible for the interaction, we
substituted alanine for residues conserved among PER isoforms and species. We
found that more than three mutations of conserved PER2 residues impaired not
only binding to CRY1 but also subsequent nuclear translocation, although
mutations of non-conserved residues did not affect interaction with CRY1. Thus,
the conserved amino acid residues of 1179-1198 in PER2 are apparently
responsible for binding to CRY1.
2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2010.01.012
PMID: 20100521 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1128606 | 1. N Engl J Med. 1975 Jun 19;292(25):1305-9. doi: 10.1056/NEJM197506192922501.
Heat-labile enzymes in skin fibroblasts from subjects with progeria.
Goldstein S, Moerman E.
To characterize further the genetic basis of progeria, thermolability studies
were performed on three genetically distinct enzymes in crude extracts of
cultured skin fibroblasts derived from two subjects with that syndrome. At early
passage the progeric fibroblasts, as compared to controls, contained a
significantly higher percentage of heat-labile glucose-6-phosphate dehydrogenase
(12.83 plus or minus 1.72 vs 1.11 plus or minus 0.44 [mean plus or minus
S.E.M.], p smaller than 0.001), 6-phosphogluconate dehydrogenase (9.71 plus or
minus 0.68 vs. 0.67 plus or minus 0.22, p smaller than 0.001), and
hypoxanthine-guanine phosphoribosyltransferase (31.41 plus or minus 1.89 vs 7.67
plus or minus 1.71, p smaller than 0.001), and the differences were maintained
throughout the in vitro life-span. These data, in conjunction with previous
reports of defective HL-A antigens, indicate a widespread defect in genetic
expression. The most likely cause appears to be an aberration in protein
synthesis or degradation, or both, although multiple somatic mutations cannot be
ruled out. Increased thermolability of enzymes in cultured cells may provide a
screening test for persons predisposed to progeria and other disorders of
premature aging.
DOI: 10.1056/NEJM197506192922501
PMID: 1128606 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23355544 | 1. Mol Plant. 2013 Sep;6(5):1463-72. doi: 10.1093/mp/sst018. Epub 2013 Jan 25.
Genome-wide analysis of histone modifications: H3K4me2, H3K4me3, H3K9ac, and
H3K27ac in Oryza sativa L. Japonica.
Du Z(1), Li H, Wei Q, Zhao X, Wang C, Zhu Q, Yi X, Xu W, Liu XS, Jin W, Su Z.
Author information:
(1)State Key Laboratory of Plant Physiology and Biochemistry, College of
Biological Sciences, China Agricultural University, Beijing 100193, China.
While previous studies have shown that histone modifications could influence
plant growth and development by regulating gene transcription, knowledge about
the relationships between these modifications and gene expression is still
limited. This study used chromatin immunoprecipitation followed by
high-throughput sequencing (ChIP-Seq), to investigate the genome-wide
distribution of four histone modifications: di and trimethylation of H3K4
(H3K4me2 and H3K4me3) and acylation of H3K9 and H3K27 (H3K9ac and H3K27ac) in
Oryza sativa L. japonica. By analyzing published DNase-Seq data, this study
explored DNase-Hypersensitive (DH) sites along the rice genome. The histone
marks appeared mainly in generic regions and were enriched around the
transcription start sites (TSSs) of genes. This analysis demonstrated that the
four histone modifications and the DH sites were all associated with active
transcription. Furthermore, the four histone modifications were highly
concurrent with transcript regions-a promising feature that was used to predict
missing genes in the rice gene annotation. The predictions were further
validated by experimentally confirming the transcription of two predicted
missing genes. Moreover, a sequence motif analysis was constructed in order to
identify the DH sites and many putative transcription factor binding sites.
DOI: 10.1093/mp/sst018
PMCID: PMC3842134
PMID: 23355544 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17989259 | 1. Genome Res. 2007 Dec;17(12):1898-908. doi: 10.1101/gr.6669607. Epub 2007 Nov
7.
Genomic regulatory blocks underlie extensive microsynteny conservation in
insects.
Engström PG(1), Ho Sui SJ, Drivenes O, Becker TS, Lenhard B.
Author information:
(1)Computational Biology Unit, Bergen Center for Computational Science,
University of Bergen, Bergen 5008, Norway.
Insect genomes contain larger blocks of conserved gene order (microsynteny) than
would be expected under a random breakage model of chromosome evolution. We
present evidence that microsynteny has been retained to keep large arrays of
highly conserved noncoding elements (HCNEs) intact. These arrays span key
developmental regulatory genes, forming genomic regulatory blocks (GRBs). We
recently described GRBs in vertebrates, where most HCNEs function as enhancers
and HCNE arrays specify complex expression programs of their target genes. Here
we present a comparison of five Drosophila genomes showing that HCNE density
peaks centrally in large synteny blocks containing multiple genes. Besides
developmental regulators that are likely targets of HCNE enhancers, HCNE arrays
often span unrelated neighboring genes. We describe differences in core
promoters between the target genes and the unrelated genes that offer an
explanation for the differences in their responsiveness to enhancers. We show
examples of a striking correspondence between boundaries of synteny blocks, HCNE
arrays, and Polycomb binding regions, confirming that the synteny blocks
correspond to regulatory domains. Although few noncoding elements are highly
conserved between Drosophila and the malaria mosquito Anopheles gambiae, we find
that A. gambiae regions orthologous to Drosophila GRBs contain an equivalent
distribution of noncoding elements highly conserved in the yellow fever mosquito
Aëdes aegypti and coincide with regions of ancient microsynteny between
Drosophila and mosquitoes. The structural and functional equivalence between
insect and vertebrate GRBs marks them as an ancient feature of metazoan genomes
and as a key to future studies of development and gene regulation.
DOI: 10.1101/gr.6669607
PMCID: PMC2099597
PMID: 17989259 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12381662 | 1. Genes Dev. 2002 Oct 15;16(20):2633-8. doi: 10.1101/gad.233702.
Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice.
Oster H(1), Yasui A, van der Horst GT, Albrecht U.
Author information:
(1)Max Planck Institute for Experimental Endocrinology, 30625 Hannover, Germany.
Many biochemical, physiological, and behavioral processes display daily rhythms
generated by an internal timekeeping mechanism referred to as the circadian
clock. The core oscillator driving this clock is located in the ventral part of
the hypothalamus, the so called suprachiasmatic nuclei (SCN). At the molecular
level, this oscillator is thought to be composed of interlocking autoregulatory
feedback loops involving a set of clock genes. Among the components driving the
mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and
Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPer2 gene leads
to a gradual loss of circadian rhythmicity in mice kept in constant darkness
(DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice
restores circadian rhythmicity and normal clock gene expression patterns. Thus,
mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or
indirect interactions of PER2 and CRY2 proteins. In marked contrast,
inactivation of mCry1 in mPer2 mutant mice does not restore circadian
rhythmicity but instead results in complete behavioral arrhythmicity in DD,
indicating different effects of mCry1 and mCry2 in the clock mechanism
DOI: 10.1101/gad.233702
PMCID: PMC187457
PMID: 12381662 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16567040 | 1. Neurosci Lett. 2006 Jun 19;401(1-2):71-6. doi: 10.1016/j.neulet.2006.03.010.
Epub 2006 Mar 29.
Antioxidant Cu/Zn SOD: expression in postnatal brain progenitor cells.
Faiz M(1), Acarin L, Peluffo H, Villapol S, Castellano B, González B.
Author information:
(1)Department of Cell Biology, Physiology and Immunology, Unit of Medical
Histology, and Institute of Neurosciences, Universitat Autònoma de Barcelona,
Spain. [email protected]
Precursor cells have been shown to be affected by oxidative stress, in vivo and
vitro, but little is known about the expression of antioxidant mechanisms in
neuronal/glial differentiation. We have characterized the expression of Cu/Zn
superoxide dismutase (Cu/Zn SOD), one of the main antioxidant proteins involved
in the breakdown of superoxide, in the immature rat dorsolateral subventricular
zone (SVZ), rostral migratory stream (RMS) and hippocampal subgranular zone
(SGZ). Progenitor cells were identified immunohistochemically on cryostat
sections by 5'Bromodeoxyuridine (BrdU) incorporation and expressing cells were
further characterized using double labeling for progenitor markers. In the SVZ,
only a subpopulation of BrdU+ cells, mostly found in the medial SVZ, expressed
Cu/Zn SOD. These cells were mostly nestin+ and some were also vimentin+. In
contrast, in the lateral SVZ few Cu/Zn SOD+/BrdU+ cells were found. These were
primarily nestin+, vimentin-, showed some PSA-NCAM expression, but only a few
were NG2+. In the RMS and SGZ virtually all BrdU+ progenitors were Cu/Zn SOD+
and expressed nestin and vimentin. Some RMS cells were also PSA-NCAM+. These
findings show a heterogeneous expression of Cu/Zn SOD in restricted cell types
in the germinative zones and suggest a role for antioxidant Cu/Zn SOD in
progenitor cells of the immature rat brain.
DOI: 10.1016/j.neulet.2006.03.010
PMID: 16567040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18726512 | 1. Sci China C Life Sci. 1999 Oct;42(5):485-93. doi: 10.1007/BF02881772.
Assembly characteristics of plant keratin intermediate filamentsin vitro.
Min G(1), Yang C, Tong X, Zhai Z.
Author information:
(1)College of Life Sciences, Peking University, 100871, Beijing, China.
After selective extraction and purification, plant keratin intermediate
filaments were reassembledin vitro. Scanning tunneling microscope (STM) and
transmission electron microscope (TEM) micrographs showed that acidic keratins
and basic keratins can assemble into dimers and further into 10 nm filamentsin
vitro. In higher mcation images, it can be seen that fully assembled plant
keratin intermediate filaments consist of several thinner filaments of 3 nm in
diameter, which indicates the formation of protofilaments in the assembly
processes. One of the explicit features of plant keratin intermediate filaments
is a 24-25 nm periodic structural repeat alone the axis of both the 10 nm
filaments and protofilarnents. The periodic repeat is one of the fundamental
characteristic of all intermediate filaments, and demonstrates the half
staggered arrangement of keratin molecules within the filaments.
DOI: 10.1007/BF02881772
PMID: 18726512 |
http://www.ncbi.nlm.nih.gov/pubmed/24079768 | 1. Curr Pharm Des. 2014;20(18):3068-82. doi: 10.2174/13816128113196660705.
Pharmaceutical interventions for frailty and sarcopenia.
Laosa O, Alonso C, Castro M, Rodriguez-Manas L(1).
Author information:
(1)Sº de Geriatria, Hospital Universitario de Getafe, Ctra. de Toledo, Km. 12,5,
28905-GETAFE, Spain. [email protected].
Frailty has emerged as one of the most relevant clinical syndromes in older
patients. This term relates to the loss of functional reserve that can occur in
some older people following exposure to one or more low-intensity stressors
placing them at high risk for developing a number of adverse outcomes such as
disability, falls, hospitalization and death. Frailty is the outcome of two
combined effects: the ageing process and other superimposed injuries like
chronic disease or, indeed, psychological and social stressors. The mechanisms
leading to frailty typically involve several systems: mainly hormones, oxidative
stress, inflammation, immunity, and vascular system. One of the most outstanding
pillars of the frailty syndrome is the loss of muscle quantity and function,
referred to as sarcopenia. The main bulk of experimental pharmacological
interventions addressing the clinical problem of frailty have been focused on
the use of hormones, as replacement therapy in subjects with low or normal
circulating basal levels of the hormone. Results have been disappointing, except
for the case of testosterone that have shown some benefits. The effectiveness of
other potential therapeutic interventions (antioxidants, anti-inflammatory
agents, nutritional supplements) appears to be limited or has not been explored
in detail until now. In conclusion, there is an available path to prevent the
development of disability in older people through the treatment of frailty, its
main risk factor. Aditional research and further experimental testing will help
to identify new targets and help to make this journey successful.
DOI: 10.2174/13816128113196660705
PMID: 24079768 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19858287 | 1. Mol Cell Biol. 2010 Jan;30(1):197-205. doi: 10.1128/MCB.01154-09.
Circadian amplitude of cryptochrome 1 is modulated by mRNA stability regulation
via cytoplasmic hnRNP D oscillation.
Woo KC(1), Ha DC, Lee KH, Kim DY, Kim TD, Kim KT.
Author information:
(1)Department of Life Science, Division of Molecular and Life Science, Pohang
University of Science and Technology, Pohang 790784, South Korea.
The mammalian circadian rhythm is observed not only at the suprachiasmatic
nucleus, a master pacemaker, but also throughout the peripheral tissues. Its
conserved molecular basis has been thought to consist of intracellular
transcriptional feedback loops of key clock genes. However, little is known
about posttranscriptional regulation of these genes. In the present study, we
investigated the role of the 3'-untranslated region (3'UTR) of the mouse
cryptochrome 1 (mcry1) gene at the posttranscriptional level. Mature mcry1 mRNA
has a 610-nucleotide 3'UTR and mediates its own degradation. The middle part of
the 3'UTR contains a destabilizing cis-acting element. The deletion of this
element led to a dramatic increase in mRNA stability, and heterogeneous nuclear
ribonucleoprotein D (hnRNP D) was identified as an RNA binding protein
responsible for this effect. Cytoplasmic hnRNP D levels displayed a pattern that
was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1
mRNA and resulted in enhancement of the oscillation amplitude and a slight delay
of the phase. Our results suggest that hnRNP D plays a role as a fine regulator
contributing to the mcry1 mRNA turnover rate and the modulation of circadian
rhythm.
DOI: 10.1128/MCB.01154-09
PMCID: PMC2798294
PMID: 19858287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21553025 | 1. Chromosoma. 2011 Aug;120(4):377-85. doi: 10.1007/s00412-011-0318-9. Epub 2011
May 7.
Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L,
SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo.
Roberts AR(1), Blewitt ME, Youngson NA, Whitelaw E, Chong S.
Author information:
(1)Epigenetics Laboratory, Queensland Institute of Medical Research, Herston,
QLD, Australia.
Studies carried out in cultured cells have implicated modifiers of epigenetic
reprogramming in the regulation of telomere length, reporting elongation in
cells that were null for DNA methyltransferase DNA methyltransferase 1 (Dnmt1),
both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone
methyltransferases. To investigate this further, we assayed telomere length in
whole embryos or adult tissue from mice carrying mutations in four different
modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like,
structural maintenance of chromosomes hinge domain containing 1, and forkhead
box O3a. Terminal restriction fragment analysis was used to compare telomere
length in homozygous mutants, heterozygous mutants and wild-type littermates.
Contrary to expectation, we did not detect overall lengthening in the mutants,
raising questions about the role of epigenetic processes in telomere length in
vivo.
DOI: 10.1007/s00412-011-0318-9
PMCID: PMC3140923
PMID: 21553025 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22538524 | 1. Plant Cell Rep. 2012 Sep;31(9):1549-61. doi: 10.1007/s00299-012-1269-1. Epub
2012 Apr 27.
ddm1 plants are sensitive to methyl methane sulfonate and NaCl stresses and are
deficient in DNA repair.
Yao Y(1), Bilichak A, Golubov A, Kovalchuk I.
Author information:
(1)Department of Biological Sciences, University of Lethbridge, University Drive
4401, Lethbridge, AB, T1K 3M4, Canada. [email protected]
Plant response to stress includes changes in gene expression and chromatin
structure. Our previous work showed that Arabidopsis thaliana Dicer-like (DCL)
mutants were impaired in transgenerational response to stress that included an
increase in recombination frequency, cytosine methylation and stress tolerance.
It can be hypothesized that changes in chromatin structure are important for an
efficient stress response. To test this hypothesis, we analyzed the stress
response of ddm1, a mutant impaired in DDM1, a member of the SWI/SNF family of
adenosine triphosphate-dependent chromatin remodeling genes. We exposed
Arabidopsis thaliana ddm1 mutants to methyl methane sulfonate (MMS) and NaCl and
found that these plants were more sensitive. At the same time, ddm1 plants were
similar to wild-type plants in sensitivity to temperature and bleomycin
stresses. Direct comparison to met1 plants, deficient in maintenance
methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl. The
level of DNA strand breaks upon exposure to MMS increased in wild-type plants
but decreased in ddm1 plants. DNA methylation analysis showed that heterozygous
ddm1/DDM1 plants had lower methylation as compared to fourth generation of
homozygous ddm1/ddm1 plants. Exposure to MMS resulted in a decrease in
methylation in wild-type plants and an increase in ddm1 plants. Finally, in
vitro DNA excision repair assay showed lower capacity for ddm1 mutant. Our
results provided a new example of a link between genetic genome stability and
epigenetic genome stability.
KEY MESSAGE: We demonstrate that heterozygous ddm1/DDM1 plants are more
sensitive to stress and have more severe changes in methylation than homozygous
ddm1/ddm1 plants.
DOI: 10.1007/s00299-012-1269-1
PMID: 22538524 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11966554 | 1. Anaesthesia. 2002 May;57(5):446-50. doi: 10.1046/j.0003-2409.2002.02569.x.
Comparison of sevoflurane and nitrous oxide mixture with nitrous oxide alone for
inhalation conscious sedation in children having dental treatment: a randomised
controlled trial.
Lahoud GY(1), Averley PA.
Author information:
(1)Scarborough Hospital, Scarborough YO12 6QL, UK. [email protected]
Comment in
Anaesthesia. 2002 Apr;57(4):412-3. doi: 10.1046/j.1365-2044.2002.2575_14.x.
We studied 411 children aged 3-10 years who were referred for dental treatment.
They were randomly allocated to have inhalation conscious sedation with either
sevoflurane/nitrous oxide mixture or nitrous oxide alone. Dental treatment was
satisfactorily completed in 215/241 children who were given sevoflurane/nitrous
oxide mixture (89%) compared with 89/170 who were given nitrous oxide alone
(52%) (Chi square 70.3, p < 0.0001). All children remained conscious and
responsive to verbal contact throughout the treatment and in the recovery room.
No adverse side-effects were recorded in either group and there were no
significant differences in oxygen saturation, heart rate, recovery profile, or
time to discharge home between the groups. The study concluded that, for every
100 children treated with sevoflurane/nitrous oxide mixture, 37 children would
be saved a general anaesthetic if given combined sevoflurane and nitrous oxide
mixture rather than nitrous oxide alone. The use of sevoflurane in low
concentrations 0.1-0.3% to supplement nitrous oxide and oxygen for inhalation
conscious sedation is safe, practical, and significantly more effective than
nitrous oxide alone in children having dental treatment.
DOI: 10.1046/j.0003-2409.2002.02569.x
PMID: 11966554 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16731656 | 1. J Biol Rhythms. 2006 Jun;21(3):169-76. doi: 10.1177/0748730406288040.
Restoration of circadian rhythmicity in circadian clock-deficient mice in
constant light.
Abraham D(1), Dallmann R, Steinlechner S, Albrecht U, Eichele G, Oster H.
Author information:
(1)Max-Planck Institute of Experimental Endocrinology, Hannover, Germany.
In mammals, circadian rhythms in behavior and physiology are controlled by a
central pacemaker, the SCN, and subordinated clocks throughout the body. On the
molecular level, these clocks are based on transcriptional/translational
feedback loops involving a set of clock genes that regulate their own
transcription. Among the components driving the mammalian circadian clock are
the Period 1 and 2 (Per1 and Per2) and Cryptochrome 1 and 2 (Cry1 and Cry2)
genes. In the present study, the authors characterize the behavioral and
molecular rhythms of Per2/Cry1 double mutant mice under 3 different lighting
conditions. In an LD cycle, the activity of these animals is masked by light,
while in DD, the mutants lose circadian rhythmicity but exhibit strong ultradian
rhythms. In LL of higher intensity, circadian rhythms are restored on the
behavioral level with a drastically shortened endogenous period. Furthermore,
both in the SCN and in the periphery, clock gene rhythms are restored. Based on
these observations and also on the fact that light-mediated induction of Per
gene expression is preserved in these mutants, the authors propose a mechanism
by which endogenous ultradian rhythms may relay timed light exposure to the SCN,
leading to a reinitiation of self-sustained circadian rhythms in LL.
DOI: 10.1177/0748730406288040
PMID: 16731656 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19450230 | 1. Biochem J. 2009 Jul 15;421(3):449-61. doi: 10.1042/BJ20090142.
SUMOylation enhances DNA methyltransferase 1 activity.
Lee B(1), Muller MT.
Author information:
(1)Department of Molecular Biology and Microbiology, Burnett School of
Biomedical Sciences, College of Medicine, University of Central Florida,
Orlando, FL 32826-3227, USA.
DNA methylation regulates gene expression through a complex network of
protein-protein and protein-DNA interactions in chromatin. The maintenance
methylase, DNMT1 (DNA methyltransferase 1), is a prominent enzyme in the process
that is linked to DNA replication and drives the heritable nature of epigenetic
modifications. The mechanistic details that explain how DNMT1 catalytic action
is directed and regulated in chromatin are important in our overall
understanding of gene control. In this work, we show that DNMT1 is modified by
SUMOylation and we have mapped these SUMOylation sites by defined mutations.
SUMOylated DNMT1 is catalytically active on genomic DNA in vivo and we find that
SUMOylation significantly enhances the methylase activity of DNMT1 both in vitro
and in chromatin. These data suggest that SUMOylation modulates the endogenous
activity of a prominent epigenetic maintenance pathway in somatic cells.
DOI: 10.1042/BJ20090142
PMID: 19450230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22027098 | 1. J Pharmacol Sci. 2011;117(3):208-12. doi: 10.1254/jphs.11120sc. Epub 2011 Oct
25.
Expression of the ubiquitin ligase HRD1 in neural stem/progenitor cells of the
adult mouse brain.
Kawada K(1), Kaneko M, Nomura Y, Mimori S, Hamana H, Ogita K, Murayama T, Fujino
H, Okuma Y.
Author information:
(1)Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba
Institute of Science, Choshi, Chiba 288-0025, Japan.
Neural stem/progenitor cells (NSCs) reside in the subventricular zone (SVZ) and
subgranular zone of the hippocampal dentate gyrus in adult mammals. The
ubiquitin ligase HRD1 is associated with degradation of amyloid precursor
protein and believed to be specifically expressed in neurons and not in
astrocytes. We investigated expression of HRD1 using immunohistochemistry and
found colocalization of HRD1 with the NSC marker protein nestin and glial
fibrillary acidic protein in the NSCs of the SVZ (the SVZ astrocytes) but not in
the hippocampus. In the hippocampal dentate gyrus, HRD1 is localized in the
nucleus of nestin-positive cells.
DOI: 10.1254/jphs.11120sc
PMID: 22027098 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23979942 | 1. G3 (Bethesda). 2013 Oct 3;3(10):1843-50. doi: 10.1534/g3.113.007393.
Functional conservation of Gsdma cluster genes specifically duplicated in the
mouse genome.
Tanaka S(1), Mizushina Y, Kato Y, Tamura M, Shiroishi T.
Author information:
(1)Mammalian Genetics Laboratory, Genetic Strains Research Center, National
Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8450, Japan.
Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations
exhibiting alopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2,
whereas human and rat have only one related gene. To date, no skin mutation has
been reported for human GSDMA and rat Gsdma as well as mouse Gsdma and Gsdma2.
Therefore, it is possible that only Gsdma3 has gain-of-function type mutations
to cause dominant skin phenotype. To elucidate functional divergence among the
Gsdma-related genes in mice, and to infer the function of the human and rat
orthologs, we examined in vivo function of mouse Gsdma by generating Gsdma
knockout mice and transgenic mice that overexpress wild-type Gsdma or Gsdma
harboring a point mutation (Alanine339Threonine). The Gsdma knockout mice shows
no visible phenotype, indicating that Gsdma is not essential for differentiation
of epidermal cells and maintenance of the hair cycle, and that Gsdma is
expressed specifically both in the inner root sheath of hair follicles and in
suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers.
By contrast, both types of the transgenic mice exhibited epidermal hyperplasia
resembling the Gsdma3 mutations, although the phenotype depended on the genetic
background. These results indicate that the mouse Gsdma and Gsdma3 genes share
common function to regulate epithelial maintenance and/or homeostasis, and
suggest that the function of human GSDMA and rat Gsdma, which are orthologs of
mouse Gsdma, is conserved as well.
DOI: 10.1534/g3.113.007393
PMCID: PMC3789809
PMID: 23979942 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25860519 | 1. J Neurosurg Spine. 2015 Jul;23(1):128-34. doi: 10.3171/2014.10.SPINE14559.
Epub 2015 Apr 10.
Postoperative infection in spine surgery: does the month matter?
Durkin MJ(1)(2), Dicks KV(1)(2), Baker AW(1)(2), Moehring RW(1)(2)(3), Chen
LF(1)(2), Sexton DJ(1)(2), Lewis SS(1)(2), Anderson DJ(1)(2).
Author information:
(1)Department of Medicine, Division of Infectious Diseases, Duke University
Medical Center;
(2)Duke Infection Control Outreach Network; and.
(3)Durham VA Medical Center, Durham, North Carolina.
Comment in
Infect Control Hosp Epidemiol. 2016 Jan;37(1):121-3. doi:
10.1017/ice.2015.279.
OBJECT: The relationship between time of year and surgical site infection (SSI)
following neurosurgical procedures is poorly understood. Authors of previous
reports have demonstrated that rates of SSI following neurosurgical procedures
performed during the summer months were higher compared with rates during other
seasons. It is unclear, however, if this difference was related to
climatological changes or inexperienced medical trainees (the July effect). The
aim of this study was to evaluate for seasonal variation of SSI following spine
surgery in a network of nonteaching community hospitals.
METHODS: The authors analyzed 6 years of prospectively collected surveillance
data (January 1, 2007, to December 31, 2012) from all laminectomies and spinal
fusions from 20 hospitals in the Duke Infection Control Outreach Network of
community hospitals. Surgical site infections were defined using National
Healthcare Safety Network criteria and identified using standardized methods
across study hospitals. Regression models were then constructed using Poisson
distribution to evaluate for seasonal trends by month. Each analysis was first
performed for all SSIs and then for SSIs caused by specific organisms or classes
of organisms. Categorical analysis was performed using two separate definitions
of summer: June through September (definition 1), and July through September
(definition 2). The prevalence rate of SSIs during the summer was compared with
the prevalence rate during the remainder of the year by calculating prevalence
rate ratios and 95% confidence intervals.
RESULTS: The authors identified 642 SSIs following 57,559 neurosurgical
procedures (overall prevalence rate = 1.11/100 procedures); 215 occurred
following 24,466 laminectomies (prevalence rate = 0.88/100 procedures), and 427
following 33,093 spinal fusions (prevalence rate = 1.29/100 procedures). Common
causes of SSI were Staphylococcus aureus (n = 380; 59%), coagulase-negative
staphylococci (n = 90; 14%), and Escherichia coli (n = 41; 6.4%). Poisson
regression models demonstrated increases in the rates of SSI during each of the
summer months for all SSIs and SSIs due to gram-positive cocci, S. aureus, and
methicillin-sensitive S. aureus. Categorical analysis confirmed that the rate of
SSI during the 4-month summer period was higher than the rate during the
remainder of the year, regardless of which definition for summer was used
(definition 1, p = 0.008; definition 2, p = 0.003). Similarly, the rates of SSI
due to grampositive cocci and S. aureus were higher during the summer months
than the remainder of the year regardless of which definition of summer was
used. However, the rate of SSI due to gram-negative bacilli was not.
CONCLUSIONS: The rate of SSI following fusion or spinal laminectomy/laminoplasty
was higher during the summer in this network of community hospitals. The
increase appears to be related to increases in SSIs caused by gram-positive
cocci and, more specifically, S. aureus. Given the nonteaching nature of these
hospitals, the findings demonstrate that increases in the rate of SSI during the
summer are more likely related to ecological and/or environmental factors than
the July effect.
DOI: 10.3171/2014.10.SPINE14559
PMCID: PMC4490093
PMID: 25860519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14715941 | 1. J Neurosci. 2004 Jan 7;24(1):85-95. doi: 10.1523/JNEUROSCI.1574-03.2004.
Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse
subventricular zone and olfactory bulb.
Moreno-López B(1), Romero-Grimaldi C, Noval JA, Murillo-Carretero M, Matarredona
ER, Estrada C.
Author information:
(1)Area de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11003 Cádiz,
Spain.
The subventricular zone of the rodent brain retains the capacity of generating
new neurons in adulthood. The newly formed neuroblasts migrate rostrally toward
the olfactory bulb, where they differentiate as granular and periglomerular
interneurons. The reported presence of differentiated neurons expressing the
neuronal isoform of nitric oxide synthase (NOS) in the periphery of the
neurogenic region and the organization of their varicose axons as a network in
which the precursors are immersed raised the hypothesis that endogenous nitric
oxide (NO) may participate in the control of neurogenesis in the subventricular
zone. Systemic administration of the NOS inhibitors N(omega)-nitro-L-arginine
methyl ester or 7-nitroindazole to adult mice produced a dose- and
time-dependent increase in the number of mitotic cells in the subventricular
zone, rostral migratory stream, and olfactory bulb, but not in the dentate gyrus
of the hippocampus, without affecting apoptosis. In the subventricular zone,
this effect was exerted selectively on a precursor subpopulation expressing
nestin but not neuronal or glial cell-specific proteins. In addition, in the
olfactory bulb, analysis of maturation markers in the newly generated neurons
indicated that chronic NOS inhibition caused a delay in neuronal
differentiation. Postmitotic cell survival and migration were not affected when
NO production was impaired. Our results suggest that NO, produced by nitrergic
neurons in the adult mouse subventricular zone and olfactory bulb, exerts a
negative control on the size of the undifferentiated precursor pool and promotes
neuronal differentiation.
DOI: 10.1523/JNEUROSCI.1574-03.2004
PMCID: PMC6729566
PMID: 14715941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11294470 | 1. Cell Transplant. 2001 Jan-Feb;10(1):31-40.
Adult bone marrow transplantation after stroke in adult rats.
Li Y(1), Chen J, Chopp M.
Author information:
(1)Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI
48202, USA.
We transplanted adult whole bone marrow prelabeled with bromodeoxyuridine (BrdU)
into the ischemic boundary zone of the adult rat brain at 1 day after 2 h of
middle cerebral artery occlusion (MCAo). Approximately 3.3% of 10(6)
transplanted bone marrow cells were BrdU reactive at 14 days after MCAo.
BrdU-reactive cells expressed neuronal and astrocytic proteins, neuronal nuclei
protein (NeuN, 1%), and glial fibrillary acidic protein (GFAP, 5%)
immunoreactivities, respectively. In addition, bone marrow transplantation
promoted proliferation of ependymal and subependymal cells, identified by nestin
(a neuroepithelial stem cell marker), within the ventricular zone and
subventricular zone (VZ/SVZ). These data suggest that intracerebral
transplantation of bone marrow could potentially be used to induce plasticity in
ischemic brain.
PMID: 11294470 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17387144 | 1. Genome Res. 2007 May;17(5):545-55. doi: 10.1101/gr.6086307. Epub 2007 Mar 26.
Genomic regulatory blocks encompass multiple neighboring genes and maintain
conserved synteny in vertebrates.
Kikuta H(1), Laplante M, Navratilova P, Komisarczuk AZ, Engström PG, Fredman D,
Akalin A, Caccamo M, Sealy I, Howe K, Ghislain J, Pezeron G, Mourrain P,
Ellingsen S, Oates AC, Thisse C, Thisse B, Foucher I, Adolf B, Geling A, Lenhard
B, Becker TS.
Author information:
(1)Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen,
Norway.
We report evidence for a mechanism for the maintenance of long-range conserved
synteny across vertebrate genomes. We found the largest mammal-teleost conserved
chromosomal segments to be spanned by highly conserved noncoding elements
(HCNEs), their developmental regulatory target genes, and phylogenetically and
functionally unrelated "bystander" genes. Bystander genes are not specifically
under the control of the regulatory elements that drive the target genes and are
expressed in patterns that are different from those of the target genes.
Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2,
rx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the
expression patterns of these genes even if located inside or beyond bystander
genes, suggesting that the regulatory domain of a developmental regulatory gene
can extend into and beyond adjacent transcriptional units. We termed these
chromosomal segments genomic regulatory blocks (GRBs). After whole genome
duplication in teleosts, GRBs, including HCNEs and target genes, were often
maintained in both copies, while bystander genes were typically lost from one
GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy
GRBs of higher vertebrates intact. We show that loss of bystander genes and
other mutational events suffered by duplicated GRBs in teleost genomes permits
target gene identification and HCNE/target gene assignment. These findings
explain the absence of evolutionary breakpoints from large vertebrate
chromosomal segments and will aid in the recognition of position effect
mutations within human GRBs.
DOI: 10.1101/gr.6086307
PMCID: PMC1855176
PMID: 17387144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24059450 | 1. J Cardiothorac Surg. 2013 Sep 24;8:191. doi: 10.1186/1749-8090-8-191.
The impact of academic calendar cycle on coronary artery bypass outcomes: a
comparison of teaching and non-teaching hospitals.
Gopaldas RR(1), Overbey DM, Dao TK, Markley JG.
Author information:
(1)Division of Cardiothoracic Surgery, University of Missouri-Columbia,
Columbia, MO, USA. [email protected].
BACKGROUND: The commencement of new academic cycle in July is presumed to be
associated with poor patient outcomes, although supportive evidence is limited
for cardiac surgery patients. We sought to determine if the new academic cycle
affected the outcomes of patients undergoing Coronary Artery Bypass Grafting.
METHODS: A retrospective analysis was performed on 10-year nationwide
in-hospital data from 1998-2007. Only patients who underwent CABG in the first
and final academic 3-month calendar quarter were included. Generalized
multivariate regression was used to assess indicators of hospital quality of
care such as risk-adjusted mortality, total complications and "failure to
rescue" (FTOR) - defined as death after a complication.
RESULTS: Of the 1,056,865 CABG operations performed in the selected calendar
quarters, 698,942 were at teaching hospitals. The risk-adjusted mortality,
complications and FTOR were higher in the beginning of the academic year [Odds
ratio = 1.14, 1.04 and 1.19 respectively; p < 0.001 for all] irrespective of
teaching status. However, teaching status was associated with lower mortality
(OR 0.9) despite a higher complication rate (OR 1.02); [p < 0.05 for both]. The
July Effect thus contributed to only a 2.4% higher FTOR in teaching hospitals
compared to 19% in non teaching hospitals.
CONCLUSIONS: The July Effect is reflective of an overall increase in morbidity
in all hospitals at the beginning of the academic cycle and it had a pronounced
effect in non-teaching hospitals. Teaching hospitals were associated with lower
mortality despite higher complication rates in the beginning of the academic
cycle compared to non-teaching hospitals. The July effect thus cannot be
attributed to presence of trainees alone.
ULTRAMINI ABSTRACT: This study compares the July effect in teaching and
non-teaching hospitals and demonstrates that this effect is not unique to
teaching hospitals for CABG patients. In fact, teaching hospitals have somewhat
better outcomes at the beginning of the academic cycle and the July effect is a
much broader seasonal variation.
DOI: 10.1186/1749-8090-8-191
PMCID: PMC3849646
PMID: 24059450 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11078926 | 1. Neurosci Lett. 2000 Dec 1;295(1-2):17-20. doi: 10.1016/s0304-3940(00)01580-9.
In vivo regulation of precursor cells in the subventricular zone of adult rat
brain by thyroid hormone and retinoids.
Giardino L(1), Bettelli C, Calzà L.
Author information:
(1)Department of Veterinary Morphophysiology and Animal Production (DIMORFIPA),
University of Bologna, Via Tolara di Sopra 50, 40064, Ozzano dell'Emilia, Italy.
[email protected]
The mature central nervous system contains precursor cells in the subventricular
zone of the lateral ventricle. In this study we examined the possibility to
affect fate of precursor cells through exogenous manipulations. The results
indicate that administration of thyroid hormone and retinoic acid increases the
expression of Ki67, a nuclear antigen associated with cell proliferation, and of
nestin, a marker protein for precursor cells in the subventricular zone of adult
male rats. Moreover, retinoic acid increases polysialated-neural cell adhesion
molecules (PSA-NCAM)-immunoreactivity. These data suggest that nuclear receptor
ligands are potential candidates for fate determination of precursor cells in
the subventricular zone also in the adult brain.
DOI: 10.1016/s0304-3940(00)01580-9
PMID: 11078926 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20348135 | 1. Nucleic Acids Res. 2010 Jul;38(13):4313-24. doi: 10.1093/nar/gkq187. Epub 2010
Mar 25.
Targeting of 5-aza-2'-deoxycytidine residues by chromatin-associated DNMT1
induces proteasomal degradation of the free enzyme.
Patel K(1), Dickson J, Din S, Macleod K, Jodrell D, Ramsahoye B.
Author information:
(1)Breakthrough Research Unit, Institute of Genetics and Molecular Medicine,
University of Edinburgh, Edinburgh, UK.
5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and
DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal
degradation of free (non-chromatin bound) DNMT1 through a mechanism which is
dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues
by DNMT1 itself. Thus, 5-aza-dC induces Dnmt1 degradation in wild-type mouse ES
cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express Dnmt1 but
lack DNA methylation (<0.7% of CpG methylated) and contain few hemi-methylated
CpG sites, these being the preferred substrates for Dnmt1. We suggest that
adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3
ligase activity which preferentially targets free DNMT1 molecules for
degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1
degradation and reduces hypomethylation induced by 5-aza-dC.
DOI: 10.1093/nar/gkq187
PMCID: PMC2910061
PMID: 20348135 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19173286 | 1. J Cell Biochem. 2009 Mar 1;106(4):521-8. doi: 10.1002/jcb.22071.
Dimerization of DNA methyltransferase 1 is mediated by its regulatory domain.
Fellinger K(1), Rothbauer U, Felle M, Längst G, Leonhardt H.
Author information:
(1)Department of Biology II, Center for Integrated Protein Science, Ludwig
Maximilians University Munich, Planegg-Martinsried, Germany.
DNA methylation is a major epigenetic modification and plays a crucial role in
the regulation of gene expression. Within the family of DNA methyltransferases
(Dnmts), Dnmt3a and 3b establish methylation marks during early development,
while Dnmt1 maintains methylation patterns after DNA replication. The
maintenance function of Dnmt1 is regulated by its large regulatory N-terminal
domain that interacts with other chromatin factors and is essential for the
recognition of hemi-methylated DNA. Gelfiltration analysis showed that purified
Dnmt1 elutes at an apparent molecular weight corresponding to the size of a
dimer. With protein interaction assays we could show that Dnmt1 interacts with
itself through its N-terminal regulatory domain. By deletion analysis and
co-immunoprecipitations we mapped the dimerization domain to the targeting
sequence TS that is located in the center of the N-terminal domain (amino acids
310-629) and was previously shown to mediate replication independent association
with heterochromatin at chromocenters. Further mutational analyses suggested
that the dimeric complex has a bipartite interaction interface and is formed in
a head-to-head orientation. Dnmt1 dimer formation could facilitate the
discrimination of hemi-methylated target sites as has been found for other
palindromic DNA sequence recognizing enzymes. These results assign an additional
function to the TS domain and raise the interesting question how these functions
are spatially and temporarily co-ordinated.
DOI: 10.1002/jcb.22071
PMID: 19173286 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19698106 | 1. Genome Biol. 2009;10(8):R86. doi: 10.1186/gb-2009-10-8-r86. Epub 2009 Aug 21.
Synorth: exploring the evolution of synteny and long-range regulatory
interactions in vertebrate genomes.
Dong X(1), Fredman D, Lenhard B.
Author information:
(1)Computational Biology Unit, Bergen Center for Computational Science,
University of Bergen, Thormøhlensgate 55, N-5008 Bergen, Norway.
[email protected]
Genomic regulatory blocks are chromosomal regions spanned by long clusters of
highly conserved noncoding elements devoted to long-range regulation of
developmental genes, often immobilizing other, unrelated genes into long-lasting
syntenic arrangements. Synorth http://synorth.genereg.net/ is a web resource for
exploring and categorizing the syntenic relationships in genomic regulatory
blocks across multiple genomes, tracing their evolutionary fate after teleost
whole genome duplication at the level of genomic regulatory block loci,
individual genes, and their phylogenetic context.
DOI: 10.1186/gb-2009-10-8-r86
PMCID: PMC2745767
PMID: 19698106 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20820192 | 1. Cell Res. 2010 Nov;20(11):1201-15. doi: 10.1038/cr.2010.128. Epub 2010 Sep 7.
BRCA1 affects global DNA methylation through regulation of DNMT1.
Shukla V(1), Coumoul X, Lahusen T, Wang RH, Xu X, Vassilopoulos A, Xiao C, Lee
MH, Man YG, Ouchi M, Ouchi T, Deng CX.
Author information:
(1)Genetics of Development and Disease Branch, 10/9N105, National Institute of
Diabetes, Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892, USA.
Global DNA hypomethylation at CpG islands coupled with local hypermethylation is
a hallmark for breast cancer, yet the mechanism underlying this change remains
elusive. In this study, we showed that DNMT1, which encodes a methylation
maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the
promoter of the DNMT1 gene through a potential OCT1 site and the binding is
required for maintaining a transcriptional active configuration of the promoter
in both mouse and human cells. We further demonstrated that impaired function of
BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an
open chromatin configuration in several types of tissues examined in a BRCA1
mutant mouse model at premaligant stages. BRCA1 deficiency is also associated
with significantly increased expression levels of several protooncogenes,
including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while
premalignant mammary epithelial cells displayed an intermediate state between
tumors and controls. In human clinical samples, reduced expression of BRCA1
correlates with decreased levels of DNMT1, and reduced methylation of CpG
islands. Thus, BRCA1 prevents global DNA hypomethylation through positively
regulating DNMT1 expression, and this provides one of mechanisms for
BRCA1-associated breast cancer formation.
DOI: 10.1038/cr.2010.128
PMCID: PMC9423198
PMID: 20820192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17929180 | 1. Cell Biol Toxicol. 2008 Jun;24(3):265-72. doi: 10.1007/s10565-007-9035-9. Epub
2007 Oct 11.
Age and gender affect DNMT3a and DNMT3b expression in human liver.
Xiao Y(1), Word B, Starlard-Davenport A, Haefele A, Lyn-Cook BD, Hammons G.
Author information:
(1)Division of Personalized Nutrition and Medicine, National Center for
Toxicological Research, Jefferson, AR 72079, USA.
DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs)
including the maintenance enzyme DNMT 1 and de novo methyltransferases DNMT 3a
and DNMT 3b. Elevated levels of DNMTs have been found in cancer cells and in
several types of human tumors. A polymorphism found in DNMT3b has been
associated with increased risk for several cancers. The factors influencing DNMT
expression in human tissues have not been clearly determined. he present study
examined TDNMT3a and DNMT3b levels in human liver tissue samples and compared
the effect of ageing, cigarette smoking, and gender. DNMT3a and DNMT3b
expression levels in the samples from older individuals (56-78 years, n = 28)
were both significantly higher than those of the younger group (16-48 years, n =
27) (73.2 +/- 3.4 vs 8.3 +/- 2.8 and 56.1 +/- 1.9 vs 17.5 +/- 5.7, respectively;
p < 0.05). Levels of DNMT3b in females were significantly higher than those in
males (75.4 +/- 2.2 vs 16.3 +/- 4.7; p < 0.05); however, DNMT3a levels were
similar for females and males (52.7 +/- 2.7 vs 48.4 +/- 2.0). Expression levels
of DNMT3a and DNMT3b were similar in smokers and nonsmokers (58.1 +/- 3.5 vs
60.8 +/- 3.1 and 54.5 +/- 2.3 vs 48.3 +/- 1.8, respectively). Genotyping for
DNMT3b (C-->T) variant in this sample pool showed a frequency distribution of CC
(41%), CT (50%), and TT (9%). The findings from this study suggest that ageing
and gender may be important factors influencing DNA methylation status.
DOI: 10.1007/s10565-007-9035-9
PMID: 17929180 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22704242 | 1. Trends Genet. 2012 Oct;28(10):474-9. doi: 10.1016/j.tig.2012.05.006. Epub 2012
Jun 14.
De novo DNA methyltransferases: oncogenes, tumor suppressors, or both?
Fernandez AF(1), Huidobro C, Fraga MF.
Author information:
(1)Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del
Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo 33006,
Spain.
Aberrant promoter DNA hypermethylation of tumor suppressor genes is a hallmark
of cancer. This alteration is largely dependent on the action of de novo DNA
methyltransferases (DNMTs) early during tumor progression, which supports the
oncogenic role for these enzymes. However, recent research has identified
several inactivating mutations of de novo DNMTs in various types of tumor. In
addition, it has been shown that loss of de novo DNA methylation activity at
advanced tumor stages leads to the promoter DNA demethylation-dependent
expression of specific oncogenes. These new data support the notion that de novo
DNMTs also have an important role in the maintenance of DNA methylation and
suggest that, in addition to acting as oncogenes, they also behave as tumor
suppressors. This potential dual role might have clinical implications, as DNMTs
are currently considered bona fide targets in cancer therapy.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tig.2012.05.006
PMID: 22704242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2237235 | 1. Sb Lek. 1990 Jul;92(6-7):194-202.
[The effect of corticoids on bone tissue in myasthenia gravis].
[Article in Czech]
Zejkan AD(1), Bakosová M, Vrbová H, Pesková M, Bejcek Z, Horejs J.
Author information:
(1)I. chirurgická klinika fakulty vseobecného lékarství Univerzity Karlovy,
Praha.
Myasthenia gravis is an autoimmune disease where corticoids are the basis of
therapy. They are taken for short periods in large amounts, as well as for
prolonged periods in medium or small doses. The authors investigated in the
described groups the effect of corticoids on bone tissue. They provided evidence
of a significant effect on the diffraction pattern, geometrical arrangement of
the apatite grid and ion changes in relation to the period of corticoid
administration without significant clinical manifestations of osteoporosis, when
respecting therapeutic principles.
PMID: 2237235 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11328209 | 1. Acta Neurol Scand. 2001 May;103(5):320-2. doi:
10.1034/j.1600-0404.2001.103005320.x.
Osteoporosis prevention in myasthenia gravis: a reminder.
Lewis SJ(1), Smith PE.
Author information:
(1)Department of Neurology, University Hospital of Wales, Cardiff, UK.
OBJECTIVES: Consensus guidelines for bone management of patients taking
corticosteroids suggest two main interventions: Dual energy X-ray absorptiometry
(DEXA) scanning in those taking prednisolone > or =7.5 mg daily for > or =6
months (repeated every 1-3 years as indicated). Bisphosphonate therapy for those
taking prednisolone > or =15 mg daily for > or =6 months regardless of DEXA
result, and also for patients with known or high risk of developing osteoporosis
(including those aged >65 years).
MATERIAL AND METHODS: We audited adherence to these guidelines in all adults
with myasthenia gravis (MG) attending our neurology service.
RESULTS: Of 80 patients with MG (47 male, mean age 63.3 years), 34 (43%) had
received corticosteroids for > or =6 months. Eighteen were taking prednisolone >
or =7.5 mg daily (mean dose 16.6 mg) yet only 4 of these (22%) had undergone
DEXA scanning. Of the 13 patients meeting the guideline criteria to receive
bisphosphonate therapy, this was prescribed to only 7 (54%). Two others were
prescribed vitamin D, 2 a calcium supplement and 2 were receiving no
prophylaxis.
CONCLUSION: In these MG patients the guidelines were followed in only a
minority. Neurologists need greater awareness of the bone health consequences of
prescribing long-term corticosteroids.
DOI: 10.1034/j.1600-0404.2001.103005320.x
PMID: 11328209 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8479464 | 1. N Engl J Med. 1993 May 20;328(20):1450-6. doi: 10.1056/NEJM199305203282004.
Vitamin E consumption and the risk of coronary heart disease in men.
Rimm EB(1), Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC.
Author information:
(1)Department of Epidemiology, Harvard School of Public Health, Boston, MA
02115.
Comment in
N Engl J Med. 1993 May 20;328(20):1487-9. doi: 10.1056/NEJM199305203282012.
N Engl J Med. 1993 Nov 4;329(19):1425; author reply 1425-6.
N Engl J Med. 1993 Nov 4;329(19):1424-5; author reply 1425-6. doi:
10.1056/NEJM199311043291914.
N Engl J Med. 1993 Nov 4;329(19):1425; author reply 1425-6.
BACKGROUND: The oxidative modification of low-density lipoproteins increases
their incorporation into the arterial intima, an essential step in
atherogenesis. Although dietary antioxidants, such as vitamin C, carotene, and
vitamin E, have been hypothesized to prevent coronary heart disease, prospective
epidemiologic data are sparse.
METHODS: In 1986, 39,910 U.S. male health professionals 40 to 75 years of age
who were free of diagnosed coronary heart disease, diabetes, and
hypercholesterolemia completed detailed dietary questionnaires that assessed
their usual intake of vitamin C, carotene, and vitamin E in addition to other
nutrients. During four years of follow-up, we documented 667 cases of coronary
disease.
RESULTS: After controlling for age and several coronary risk factors, we
observed a lower risk of coronary disease among men with higher intakes of
vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of
vitamin E, the multivariate relative risk was 0.64 (95 percent confidence
interval, 0.49 to 0.83) as compared with those consuming less than 7.5 IU per
day. As compared with men who did not take vitamin E supplements, men who took
at least 100 IU per day for at least two years had a multivariate relative risk
of coronary disease of 0.63 (95 percent confidence interval, 0.47 to 0.84).
Carotene intake was not associated with a lower risk of coronary disease among
those who had never smoked, but it was inversely associated with the risk among
current smokers (relative risk, 0.30; 95 percent confidence interval, 0.11 to
0.82) and former smokers (relative risk, 0.60; 95 percent confidence interval,
0.38 to 0.94). In contrast, a high intake of vitamin C was not associated with a
lower risk of coronary disease.
CONCLUSIONS: These data do not prove a causal relation, but they provide
evidence of an association between a high intake of vitamin E and a lower risk
of coronary heart disease in men. Public policy recommendations with regard to
the use of vitamin E supplements should await the results of additional studies.
DOI: 10.1056/NEJM199305203282004
PMID: 8479464 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15567903 | 1. Indian J Med Sci. 2004 Nov;58(11):465-71.
Association of serum antioxidants and risk of coronary heart disease in South
Indian population.
Rajasekhar D(1), Srinivasa Rao PV, Latheef SA, Saibaba KS, Subramanyam G.
Author information:
(1)Departments of Cardiology, Sri Venkateswara Institute of Medical Sciences,
Tirupati - 517 507, Andhra Pradesh, India. [email protected]
BACKGROUND AND AIM: Higher prevalence of coronary heart disease (CHD) has been
reported in south Indian population, which cannot be accounted for by the
traditional risk factors like hyperlipidemia. Identification of new risk factors
may help in treatment and prevention of CHD in this part of the world. In an
attempt to investigate the causes of increased incidence of CHD in this part of
the world, we intended to look for oxidative stress in our patients as a
possible risk factor. As an initial step in this perspective, a case- control
study was conducted to find out the serum antioxidant levels and their
association with CHD in south Indian population.
SETTINGS AND DESIGN: A tertiary care hospital; Case--control study.
MATERIALS AND METHODS: One hundred thirty nine angiographically proven CHD
patients (aged 29-75 years) were studied against 59 population based healthy
controls (aged 29-72 years) free of CHD. Fasting serum cholesterol,
triglycerides, HDL cholesterol, erythrocyte and plasma glutathione peroxidase
and superoxide dismutase were estimated on automated clinical chemistry
analyzer. LDL cholesterol and VLDL cholesterol were calculated. Vitamins A and E
were estimated using high performance liquid chromatography (HPLC).
STATISTICAL ANALYSIS: Unpaired t test was used to compare means. Binary logistic
regression was done to find out the association between dependent and
independent variables.
RESULTS: Significantly higher levels of Total Cholesterol/HDL cholesterol and
LDL cholesterol/HDL cholesterol ratio and lower HDL cholesterol levels were
observed in patients when compared to controls. No significant difference of
plasma and erythrocyte glutathione peroxidase and superoxide dismutase activity
was observed between patients and controls. Significantly lower levels of
vitamin E in patients than in controls was observed (P<0.001). Serum vitamin E
was inversely associated with coronary heart disease even after controlling for
age and other coronary risk factors (Odds ratio 0.898, 95% CI 0.826-0.976
P=0.01).
CONCLUSIONS: The results of present study suggest that deficiency of vitamin E
may be an independent risk factor of CHD. This study brings out the need for
long- term monitoring of vitamin E supplementation as a preventive measure for
CHD in the population studied.
PMID: 15567903 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16690366 | 1. Bone. 2006 Sep;39(3):658-65. doi: 10.1016/j.bone.2006.03.009. Epub 2006 May
11.
Immune system and bone metabolism: Does thymectomy influence postmenopausal bone
loss in humans?
D'Amelio P(1), Grimaldi A, Bernabei P, Pescarmona GP, Isaia G.
Author information:
(1)Department of Internal Medicine, Research-University of Torino, Italy.
[email protected]
Recent studies of animal models have suggested that an increase in the number of
T cells due to both peripheral expansion and increased thymic T cell output
plays a key role in the regulation of bone loss after ovariectomy.
Osteoclastogenic cytokines which are either produced by T cells or activate T
cells have also been implicated in ovx induced bone loss. Among them are TNF
alpha and IL-7. The present study investigates the role of thymectomy (THX) and
IL-7 in bone metabolism in humans. We studied T cells subsets, cytokine
production and bone metabolism in 13 women thymectomized for Myasthenia gravis
as compared to healthy controls. Our data demonstrate that the number of CD4+
and TNF-producing T cells is lower in THX women as compared to euthymic
controls. However in THX women the residual T cells produce higher levels of
IL-7 and RANKL. Furthermore, flow cytometry shows that IL-7 is produced by T and
B cells. Serum levels of TNF alpha were unaffected by THX and both serum TNF
alpha and the RANKL/OPG correlated inversely with BMD. There were no differences
in bone turnover and bone mineral density between THX women and the controls.
These data suggest that THX decreases the number of TNF-producing CD4+ T cells
but does not alters serum TNF levels. The RANKL/OPG ratio and indices of bone
metabolisms are also not affected by THX, although THX increases the levels of
IL-7 and RANKL. Further studies are needed to clarify the role of thymus in bone
metabolism and osteoclastogenesis in postmenopausal women.
DOI: 10.1016/j.bone.2006.03.009
PMID: 16690366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2949917 | 1. Diabet Med. 1986 Jul-Aug;3(4):312-5. doi: 10.1111/j.1464-5491.1986.tb00770.x.
Hypotensive therapy reduces microvascular albumin leakage in insulin-dependent
diabetic patients with nephropathy.
Parving HH, Smidt UM.
The effect of hypotensive therapy on the transcapillary escape rate of albumin
(TERalb) was studied in eight hypertensive insulin-dependent diabetic patients
(mean age 29, range 19-42 years) with nephropathy and retinopathy.
Transcapillary escape rate of albumin (initial disappearance of intravenously
injected 125I-labelled human serum albumin), urinary albumin excretion rate
(radial immunodiffusion), and glomerular filtrate rate (single bolus 51-Cr-EDTA
technique) were measured. After hypotensive treatment (mean duration, 23 months,
range 7-39 months) with combinations of metoprolol, hydralazine, and frusemide
or thiazide diuretics, arterial blood pressure fell from 152/103 +/- 18/6 mmHg
(mean +/- SD) to 133/81 +/- 12/10 mmHg (p less than 0.01), transcapillary escape
rate of albumin from 10.2 +/- 1.8 to 8.1 +/- 1.8% of intravascular mass of
albumin/h (p less than 0.01), albuminuria from 1803 (370-5066) micrograms/min to
940 (101-2676) micrograms/min (median and range, p less than 0.05), and
glomerular filtration rate from 103 +/- 23 to 84 +/- 22 ml/min/1.73 m2 (p less
than 0.01). Our study suggests that effective hypotensive treatment reduces the
abnormally elevated albumin leakage characteristically found in
insulin-dependent diabetic patients with clinical microangiopathy. This may be
due to a reduction in the hydrostatic pressure in the microcirculation.
DOI: 10.1111/j.1464-5491.1986.tb00770.x
PMID: 2949917 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19016755 | 1. Cancer Sci. 2008 Oct;99(10):1960-6. doi: 10.1111/j.1349-7006.2008.00913.x.
Interaction between DNMT1 and DNA replication reactions in the SV40 in vitro
replication system.
Shimamura S(1), Ishikawa F.
Author information:
(1)Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto
University, Kyoto, Japan.
In contrast to normal cells, cancer cells exhibit both genetic and epigenetic
instability. These unique properties give rise to genetic and epigenetic
heterogeneity in a given population of cancer cells and provide a means for the
population to undergo phenotypic progression by clonal selection. DNA
methylation at CpG dinucleotides is one of the epigenetic marks that are
frequently disturbed in cancer cells. To understand how the CpG methylation
pattern is changeable in cancer cells, it is necessary to know how it is
faithfully maintained in normal cell proliferation. Toward this goal, we have
developed a novel in vitro system that is based on the well-established SV40 in
vitro replication system and functions to reconstitute concurrent DNA
replication and DNA maintenance methylation reactions. We found that DNA
methylation was maintained only when exogenous DNA methyltransferase 1 (DNMT1)
and S-adenosyl methionine (SAM) were added to the reaction. We demonstrated that
DNMT1 associates with replicating and/or replicated chromatin irrespective of
the DNA methylation status of template DNA. Moreover, the PCNA-binding domain
(PBD) of DNMT1 is not required for the association. Taken together, we suggest
that DNMT1 is recruited to replicating and/or replicated chromatin in a
constitutive manner independent of the DNA methylation reaction. The in vitro
system described in this report is very useful for analyzing the molecular
mechanism underlying the DNA maintenance methylation reaction.
DOI: 10.1111/j.1349-7006.2008.00913.x
PMCID: PMC11158606
PMID: 19016755 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23124387 | 1. Pediatr Cardiol. 2013 Apr;34(4):887-92. doi: 10.1007/s00246-012-0565-4. Epub
2012 Nov 4.
Response to intravenous potassium chloride supplementation in pediatric cardiac
intensive care patients.
Knudson JD(1), Lowry AW, Price JF, Moffett BS.
Author information:
(1)Division of Pediatric Cardiology, Department of Pediatrics, University of
Mississippi Medical Center/Batson Children's Hospital, 2500 North State Street,
Jackson, MS 39216, USA. [email protected]
Potassium chloride (KCl) supplementation is common among critically ill
children. Intravenous (IV) KCl supplementation for pediatric patients is poorly
characterized. This study aimed to examine the efficacy and safety of IV KCL and
to determine factors affecting patient responses to IV KCL in the pediatric
cardiac intensive care unit (CICU). A retrospective review of 211 children (794
KCl doses) undergoing cardiac surgery or a hospital stay for heart failure in
the CICU of a tertiary care teaching and referral children's hospital in 2011
was performed. Demographic data, weight, height, creatinine, and concomitant
medications during each KCl dose were recorded and analyzed. Body surface area
(BSA), creatinine clearance, and change in [K(+)] were calculated. The median
age of the children was 4 months (range, 10 days-18 years). In this study, 151
KCl doses were administered to neonates (19 %), 307 doses (39 %) to females, and
510 doses (64 %) to patients with a BSA smaller than 0.33 m(2) (a group with
relative renal insufficiency). The mean KCl dose was 0.97 ± 0.006 mEq/kg. No
adverse events were associated with IV KCl administration. Blood/plasma [K(+)]
increased 0.8 ± 0.02 mEq/L. The responses to KCl did not differ significantly
between males and females, between neonates and children, or between patients
with a BSA smaller than 0.33 m(2) and those with a BSA of 0.33 m(2) or larger.
The responses to IV KCl were attenuated by concomitant furosemide (p = 0.01),
amphotericin B (p < 0.01), and KCl in parenteral nutrition (p < 0.01). The
responses were augmented by concomitant enalapril (p = 0.03), ethacrynic acid (p
< 0.001), and hemodialysis (p < 0.01). Intravenous KCl can be administered
safely for CICU patients. Responses to KCl are altered when it is given with
certain medications. Intravenous KCl should be used cautiously in children
receiving angiotensin-converting enzyme inhibitors. Future studies are needed
for further characterization of factors affecting responses to IV KCl in
children.
DOI: 10.1007/s00246-012-0565-4
PMID: 23124387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1318542 | 1. Pediatr Cardiol. 1992 Jul;13(3):129-35. doi: 10.1007/BF00793943.
Acute hemodynamic effects of converting enzyme inhibition in children with
intracardiac shunts.
Webster MW(1), Neutze JM, Calder AL.
Author information:
(1)Cardiology Department, Green Lane Hospital, Auckland, New Zealand.
The short-term hemodynamic effects of intravenous enalaprilat were assessed in
26 infants and children, aged 6 months to 15 years, with intracardiac shunts
undergoing cardiac catheterization. Pulmonary and systemic pressure, flow, and
resistance indices were measured by the direct Fick method before and 30 min
after enalaprilat at 0.06 mg/kg. Aortic and pulmonary artery pressure decreased
15 and 20%, respectively, by 10 min, with little further change at 30 min. The
heart rate did not change significantly and there was no reduction in systemic
flow. In those with a large ventricular septal defect and normal or near-normal
pulmonary resistance (less than 3.5 u.m2, n = 8), the mean pulmonary-systemic
flow ratio decreased from 2.9 +/- 0.3 to 2.4 +/- 0.3 (p less than 0.05) and the
mean left-to-right shunt from 7.4 +/- 0.8 to 5.9 +/- 0.7 L/min/m2 (p less than
0.02). Those with an elevated pulmonary vascular resistance (greater than 5
u.m2, n = 8) showed a varied response. Two children, both with Down's syndrome,
an atrioventricular canal defect, and reversible pulmonary hypertension (as
assessed by an infusion of isoproterenol), had no decrease in pulmonary vascular
resistance with enalaprilat. There were no adverse effects. Converting enzyme
inhibitors may benefit "heart failure" associated with large ventricular septal
defects and normal or mildly elevated pulmonary resistance.
DOI: 10.1007/BF00793943
PMID: 1318542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9315539 | 1. Circulation. 1997 Sep 2;96(5):1507-12. doi: 10.1161/01.cir.96.5.1507.
Enalapril does not enhance exercise capacity in patients after Fontan procedure.
Kouatli AA(1), Garcia JA, Zellers TM, Weinstein EM, Mahony L.
Author information:
(1)Department of Pediatrics, University of Texas Southwestern Medical Center at
Dallas, 75235-9063, USA.
BACKGROUND: Angiotensin-converting enzyme inhibitors improve exercise capacity
in adults with congestive heart failure by decreasing systemic vascular
resistance and improving ventricular diastolic function. Patients who have
undergone the Fontan procedure have decreased cardiac output, increased systemic
vascular resistance, abnormal diastolic function, and decreased exercise
capacity compared with normal people.
METHODS AND RESULTS: To test the hypothesis that afterload reduction therapy
alters hemodynamic variables and augments exercise capacity in patients after a
Fontan procedure, we compared the results of graded exercise with maximal effort
from 18 subjects (14.5+/-6.2 years of age, 4 to 19 years after Fontan procedure)
in a randomized, double-blind, placebo-controlled crossover trial using
enalapril (0.2 to 0.3 mg x kg[-1] x d[-1], maximum 15 mg). Each treatment was
administered for 10 weeks. Diastolic filling patterns at rest were assessed by
Doppler determination of the systemic atrioventricular valve flow velocity at
the conclusion of each therapy. No difference was detected in resting heart
rate, blood pressure, or cardiac index. Diastolic filling patterns were also
similar. Exercise duration was not different (6.4+/-2.6 [enalapril] versus
6.7+/-2.6 minutes [placebo]). The mean percent increase in cardiac index from
rest to maximum exercise was slightly but significantly decreased in subjects
after 10 weeks of enalapril therapy (102+/-34% [enalapril] versus 125+/-34%
[placebo]; P<.02). At maximal exercise, cardiac index (3.5+/-0.9 [enalapril]
versus 3.8+/-0.9 L x min[-1] x m2 [placebo]), oxygen consumption (18.3+/-9
[enalapril] versus 20.5+/-7 mL x min[-1] x kg[-1] [placebo]), minute ventilation
(57.5+/-17 [enalapril] versus 55.4+/-19 L/min [placebo]), and total work
(247+/-181 [enalapril] versus 261+/-197 W [placebo]) were not different.
CONCLUSIONS: We conclude that enalapril administration for 10 weeks does not
alter abnormal systemic vascular resistance, resting cardiac index, diastolic
function, or exercise capacity in patients who have undergone a Fontan
procedure.
DOI: 10.1161/01.cir.96.5.1507
PMID: 9315539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15003307 | 1. Clin Neurol Neurosurg. 2004 Mar;106(2):139-41. doi:
10.1016/j.clineuro.2003.12.001.
Bone density in myasthenia gravis patients receiving long-term prednisolone
therapy.
Wakata N(1), Nemoto H, Sugimoto H, Nomoto N, Konno S, Hayashi N, Araki Y,
Nakazato A.
Author information:
(1)Fourth Department of Internal Medicine, Toho University School of Medicine,
2-17-6 Ohashi, Meguro-ku, Tokyo 153-8151, Japan. [email protected]
Osteoporosis is an adverse effect of prednisolone therapy, although no study has
been conducted on myasthenia gravis patients receiving high-dose prednisolone.
We measured bone density in 36 patients (26 females and 10 males) who had
undergone long-term prednisolone administration, and found a decrease in bone
density in 31% of female patients and osteoporosis in only 11.5% (three cases).
This frequency is lower than the presumptive rate of the general population in
Japan (22.6%). No osteoporosis was detected in male patients. In conclusion,
prednisolone-treated patients with myasthenia gravis have an acceptable risk of
bone loss if prophylactic medication is administered.
DOI: 10.1016/j.clineuro.2003.12.001
PMID: 15003307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18548846 | 1. Biomed Environ Sci. 2008 Apr;21(2):91-7. doi: 10.1016/S0895-3988(08)60012-4.
Kale juice improves coronary artery disease risk factors in hypercholesterolemic
men.
Kim SY(1), Yoon S, Kwon SM, Park KS, Lee-Kim YC.
Author information:
(1)Graduate School of Human Environmental Science, College of Human Ecology,
Yonsei Health Center Yonsei University, 134 Shinchon-dong, Sudaemun-ku, 120-749,
Seoul, Korea. [email protected]
OBJECTIVE: To evaluate the effect of 3-month kale (Brassica oleracea acephala)
juice supplementation on coronary artery disease risk factors among
hypercholesterolemic men.
METHODS: Thirty-two men with hypercholesterolemia (> 200 mg/dL) were recruited
after annual health examinations among the faculty and staff at university. The
subjects consumed 150 mL of kale juice per day for a 12-week intervention
period. Dietary and anthropometric assessments were performed and blood samples
were collected to evaluate biochemical profiles before and after
supplementation.
RESULTS: Serum concentrations of HDL-cholesterol, and HDL- to LDL-cholesterol
ratio were significantly increased by 27% (P<0.0001) and 52% (P<0.0001),
respectively. The LDL-cholesterol concentration and the atherogenic index were
significantly reduced by 10% (P=0.0007) and 24.2% (P<0.0001), respectively
without affecting body mass index, waist and hip circumferences, or nutrient
intakes after three months of supplementation. While there was no difference in
the concentration of malondialdehyde, significant increase in glutathione
peroxidase activity (P=0.0005) were accompanied by a significant increase in the
serum selenium level (P=0.0132). It was also found that the responses of these
risk factors to kale juice administration were dependent on smoking status.
CONCLUSION: Regular meals supplementation with kale juice can favorably
influence serum lipid profiles and antioxidant systems, and hence contribute to
reduce the risks of coronary artery disease in male subjects with
hyperlipidemia.
DOI: 10.1016/S0895-3988(08)60012-4
PMID: 18548846 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8602181 | 1. N Engl J Med. 1996 May 2;334(18):1156-62. doi: 10.1056/NEJM199605023341803.
Dietary antioxidant vitamins and death from coronary heart disease in
postmenopausal women.
Kushi LH(1), Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM.
Author information:
(1)Division of Epidemiology, University of Minnesota School of Public Health,
Minneapolis 55454-1015, USA.
Comment in
N Engl J Med. 1996 May 2;334(18):1189-90. doi: 10.1056/NEJM199605023341810.
N Engl J Med. 1996 Oct 3;335(14):1066; author reply 1068-9.
BACKGROUND: The role of dietary antioxidant vitamins in preventing coronary
heart disease has aroused considerable interest because of the knowledge that
oxidative modification of low-density lipoprotein may promote atherosclerosis.
METHODS: We studied 34,486 postmenopausal women with no cardiovascular disease
who in early 1986 completed a questionnaire that assessed, among other factors,
their intake of vitamins A, E, and C from food sources and supplements. During
approximately seven years of follow-up (ending December 31, 1992), 242 of the
women died of coronary heart disease.
RESULTS: In analyses adjusted for age and dietary energy intake, vitamin E
consumption appeared to be inversely associated with the risk of death from
coronary heart disease. This association was particularly striking in the
subgroup of 21,809 women who did not consume vitamin supplements (relative risks
from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and
0.42; P for trend 0.008). After adjustment for possible confounding variables,
this inverse association remained (relative risks from lowest to highest
quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend, 0.004). There was little
evidence that the intake of vitamin E from supplements was associated with a
decreased risk of death from coronary heart disease, but the effects of
high-dose supplementation and the duration of supplement use could not be
definitely addressed. Intake of vitamins A and C did not appear to be associated
with the risk of death form coronary heart disease.
CONCLUSIONS: These results suggest that in postmenopausal women the intake of
vitamin E from food is inversely associated with the risk of death from coronary
heart disease and that such women can lower their risk without using vitamin
supplements. By contrast, the intake of vitamins A and C was not associated with
lower risks of dying from coronary disease.
DOI: 10.1056/NEJM199605023341803
PMID: 8602181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19923434 | 1. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20806-11. doi:
10.1073/pnas.0905668106. Epub 2009 Nov 18.
Identification of a region of the DNMT1 methyltransferase that regulates the
maintenance of genomic imprints.
Borowczyk E(1), Mohan KN, D'Aiuto L, Cirio MC, Chaillet JR.
Author information:
(1)Department of Microbiology and Molecular Genetics, University of Pittsburgh
School of Medicine, Pittsburgh, PA 15261, USA.
Reprogramming of DNA methylation patterns during mammalian preimplantation
development involves the concurrent maintenance of methylation on differentially
methylated domains (DMDs) of imprinted genes and a marked reduction of global
(non-DMD) genomic methylation. In the developing mammalian embryo, one allele of
a DMD is unmethylated, and the opposite parental allele is methylated, having
inherited this methylation from the parental gamete. The maintenance of DMDs is
important for monoallelic imprinted gene expression and normal development of
the embryo. Because the DNMT1 cytosine methyltransferase governs maintenance
methylation in mammals, rearrangements of non-DMD, but not DMD methylation in
preimplantation embryos suggest that the preimplantation DNMT1-dependent
maintenance mechanism specifically targets DMD sequences. We explored this
possibility using an engineered mouse ES cell line to screen for mutant DNMT1
proteins that protect against the loss of DMD and/or global (non-DMD)
methylation in the absence of the wild-type endogenous DNMT1 methyltransferase.
We identified DNMT1 mutants that were defective in maintenance of either DMD
and/or non-DMD methylation. Among these, one mutant maintained non-DMD
methylation but not imprinted DMD methylation and another mutant maintained just
DMD methylation. The mutated amino acids of these mutants reside in a
mammal-specific, disordered region near the amino terminus of DNMT1. These
findings suggest that DNMT1 participates in epigenetic reprogramming through its
ability to distinguish different categories of methylated sequences.
DOI: 10.1073/pnas.0905668106
PMCID: PMC2791569
PMID: 19923434 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/19932585 | 1. Biomed Pharmacother. 2010 Apr;64(4):254-8. doi: 10.1016/j.biopha.2009.06.008.
Epub 2009 Oct 21.
Increased CXCR4 expression in AsPC1 pancreatic carcinoma cells with RNA
interference-mediated knockdown of DNMT1 and DNMT3B.
Przybylski M(1), Kozłowska A, Pietkiewicz PP, Lutkowska A, Lianeri M,
Jagodzinski PP.
Author information:
(1)Department of Biochemistry and Molecular Biology, Poznań University of
Medical Sciences, 6, Swiecickiego Street, 60-781 Poznań, Poland.
The effect of DNA methylation on CXCR4 expression has been demonstrated in
pancreatic cancer and melanoma cells, but little is known about the effect of
DNA methyltransferases 1 and 3 (DNMT1 and DNMT3B) on CXCR4 expression. Employing
lentiviral vectors, we created stable RNA interference-mediated knockdown of
DNMT1 and DNMT3B in AsPC1 pancreatic cancer cells. Using reverse transcription
real-time quantitative PCR and flow cytometric analysis, we evaluated the
increase in the expression of CXCR4 transcript and protein levels in these
cells. Bisulfite sequencing analysis showed that the level of promoter
demethylation appeared more effective in cells with knockdown of DNMT1 than in
those with DNMT3B knockdown. Furthermore, the combined RNA interference
knockdown of both DNMT1 and DNMT3B increased promoter demethylation, leading to
a slight increase in CXCR4 expression. However, the demethylating agent
5-Aza-2'-deoxycytidine exhibited the strongest effect on promoter demethylation,
which correlated with the highest production of CXCR4 transcript and protein in
AsPC1 cells. Our results indicate that DNMT1 plays the main role in maintenance
of methylation of CXCR4 promoter, while DNMT3B may function as an accessory DNA
methyltransferase to modulate CXCR4 expression in AsPC1 cells.
(c) 2009 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.biopha.2009.06.008
PMID: 19932585 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11192356 | 1. Basic Res Cardiol. 2000;95 Suppl 1:I65-71. doi: 10.1007/s003950070012.
Coronary artery disease--free radical damage, antioxidant protection and the
role of homocysteine.
Maxwell SR(1).
Author information:
(1)Department of Medical Sciences, The University of Edinburgh, Western General
Hospital, UK. [email protected]
Traditional risk factors for coronary artery disease (CAD) can only explain
approximately two thirds of the observed clinical events. This has maintained
interest in other nutritional and biochemical factors that might contribute to
the underlying pathophysiology of vascular disease. Two such factors are dietary
antioxidants and plasma homocysteine. Established risk factors such as
hypertension, smoking and diabetes mellitus are all associated with increased
oxidative stresses due to excess free radical activity in the vascular wall.
This may facilitate the development of vascular disease because of (i) increased
oxidation of low-density lipoprotein (LDL) particles which increases their
propensity to deposition in the vascular wall, (ii) inactivation of
endothelium-derived nitric oxide, and (iii) direct cytotoxicity to endothelial
cells. Protective antioxidant molecules include vitamin C and vitamin E of which
the latter is lipid soluble and is the primary antioxidant defence in
circulating LDL particles. Epidemiological studies have suggested strongly that
individuals who have high circulating concentrations or dietary intake of
natural antioxidant vitamins are protected against vascular disease events (18).
Furthermore, many studies have demonstrated a beneficial effect of natural and
synthetic antioxidants on surrogate markers of vascular disease such as
endothelial function and lipoprotein oxidation. However, large prospective
randomized controlled intervention trials, mostly involving vitamin E (e.g.
CHAOS, HOPE (22)), have failed to demonstrate any beneficial effect upon
vascular mortality in high risk individuals. Possible reasons for these
disappointing results include the pro-oxidant effects of high dose antioxidant
supplements, particularly in patients with established vascular disease.
Homocysteine is a sulphydryl-containing amino acid derived from the
demethylation of dietary methionine. Epidemiological studies over 30 years have
shown that increased concentrations of homocysteine are associated with vascular
disease. This link is independent of other risk factors, is consistent across
many studies and is strongly dose-related. Recently, evidence has accumulated to
suggest that this link is also biologically plausible because homocysteine
promotes oxidant injury to the vascular endothelium, impairs
endothelium-dependent vasomotor regulation and may also alter the coagulant
properties of the blood. Plasma homocysteine levels can be reduced by dietary
supplements of folic acid and B vitamins. Studies are currently being undertaken
to examine the impact of these vitamins in high risk patients and, thereby,
establish a causative role for homocysteine in promoting vascular events.
DOI: 10.1007/s003950070012
PMID: 11192356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20139415 | 1. Nucleic Acids Res. 2010 May;38(9):e107. doi: 10.1093/nar/gkq047. Epub 2010 Feb
5.
A real-time assay for CpG-specific cytosine-C5 methyltransferase activity.
Wood RJ(1), McKelvie JC, Maynard-Smith MD, Roach PL.
Author information:
(1)School of Chemistry, University of Southampton, Southampton, Hampshire, SO17
1BJ, UK.
A real-time assay for CpG-specific cytosine-C5 methyltransferase activity has
been developed. The assay applies a break light oligonucleotide in which the
methylation of an unmethylated 5'-CG-3' site is enzymatically coupled to the
development of a fluorescent signal. This sensitive assay can measure rates of
DNA methylation down to 0.34 +/- 0.06 fmol/s. The assay is reproducible, with a
coefficient of variation over six independent measurements of 4.5%. Product
concentration was accurately measured from fluorescence signals using a linear
calibration curve, which achieved a goodness of fit (R(2)) above 0.98. The
oligonucleotide substrate contains three C5-methylated cytosine residues and one
unmethylated 5'-CG-3' site. Methylation yields an oligonucleotide containing the
optimal substrate for the restriction enzyme GlaI. Cleavage of the fully
methylated oligonucleotide leads to separation of fluorophore from quencher,
giving a proportional increase in fluorescence. This method has been used to
assay activity of DNMT1, the principle maintenance methyltransferase in human
cells, and for the kinetic characterization of the bacterial cytosine-C5
methyltransferase M.SssI. The assay has been shown to be suitable for the
real-time monitoring of DNMT1 activity in a high-throughput format, with low
background signal and the ability to obtain linear rates of methylation over
long periods, making this a promising method of high-throughput screening for
inhibitors.
DOI: 10.1093/nar/gkq047
PMCID: PMC2875032
PMID: 20139415 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18712042 | 1. Hypertens Res. 2008 May;31(5):873-9. doi: 10.1291/hypres.31.873.
Vascular permeability, blood pressure, and organ damage in primary hypertension.
Viazzi F(1), Leoncini G, Ratto E, Parodi A, Falqui V, Conti N, Tomolillo C,
Ravera G, Deferrari G, Pontremoli R.
Author information:
(1)Department of Internal Medicine and Cardionephrology, Azienda Universitaria
Ospedale San Martino, Genoa, Italy.
Sub-clinical organ damage is a strong independent predictor of cardiovascular
mortality in primary hypertension, and its changes over time parallel those in
risk of cardiovascular events. A better understanding of the pathogenetic
mechanisms underlying the development of target organ damage may help us devise
more effective therapeutic strategies. We therefore investigated the
relationship between the presence of organ damage and some of its potential
determinants, such as blood pressure severity and early atherosclerotic
abnormalities. Thirty-seven untreated, non-diabetic hypertensive patients were
enrolled. Target organ damage was assessed by albuminuria and left ventricular
mass index; systemic vascular permeability was evaluated by transcapillary
escape rate of albumin (TERalb); and blood pressure was measured by 24h
ambulatory blood pressure monitoring. The albumin-to-creatinine ratio and left
ventricular mass index were directly related to TERalb (r = 0.48, p = 0.003 and
r = 0.39, p < 0.020, respectively) and 24-h systolic blood pressure values (r =
0.54, p < 0.001; r = 0.60, p < 0.001). The simultaneous occurrence of increased
blood pressure load and TERalb was associated with higher left ventricular mass
index values (p = 0.012) and entailed an increased risk of having at least one
sign of damage (chi2 = 17.4; p < 0.001). Logistic regression analysis showed
that the risk of presenting at least one sign of organ damage increased more
than ten-fold when TERalb was above the median and more than five-fold with each
10 mmHg increase in 24-h systolic blood pressure. Blood pressure load and
vascular permeability are potentially modifiable factors that are independently
associated with the occurrence of sub-clinical signs of renal and cardiac damage
in hypertensive patients.
DOI: 10.1291/hypres.31.873
PMID: 18712042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8479463 | 1. N Engl J Med. 1993 May 20;328(20):1444-9. doi: 10.1056/NEJM199305203282003.
Vitamin E consumption and the risk of coronary disease in women.
Stampfer MJ(1), Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC.
Author information:
(1)Channing Laboratory, Boston, MA 02115.
Comment in
N Engl J Med. 1993 May 20;328(20):1487-9. doi: 10.1056/NEJM199305203282012.
N Engl J Med. 1993 Nov 4;329(19):1425; author reply 1425-6.
N Engl J Med. 1993 Nov 4;329(19):1424-5; author reply 1425-6. doi:
10.1056/NEJM199311043291914.
N Engl J Med. 1993 Nov 4;329(19):1425; author reply 1425-6.
BACKGROUND: Interest in the antioxidant vitamin E as a possible protective
nutrient against coronary disease has intensified with the recognition that
oxidized low-density lipoprotein may be involved in atherogenesis.
METHODS: In 1980, 87,245 female nurses 34 to 59 years of age who were free of
diagnosed cardiovascular disease and cancer completed dietary questionnaires
that assessed their consumption of a wide range of nutrients, including vitamin
E. During follow-up of up to eight years (679,485 person-years) that was 97
percent complete, we documented 552 cases of major coronary disease (437
nonfatal myocardial infarctions and 115 deaths due to coronary disease).
RESULTS: As compared with women in the lowest fifth of the cohort with respect
to vitamin E intake, those in the top fifth had a relative risk of major
coronary disease of 0.66 (95 percent confidence interval, 0.50 to 0.87) after
adjustment for age and smoking. Further adjustment for a variety of other
coronary risk factors and nutrients, including other antioxidants, had little
effect on the results. Most of the variability in intake and reduction in risk
was attributable to vitamin E consumed as supplements. Women who took vitamin E
supplements for short periods had little apparent benefit, but those who took
them for more than two years had a relative risk of major coronary disease of
0.59 (95 percent confidence interval, 0.38 to 0.91) after adjustment for age,
smoking status, risk factors for coronary disease, and use of other antioxidant
nutrients (including multi-vitamins).
CONCLUSIONS: Although these prospective data do not prove a cause-and-effect
relation, they suggest that among middle-aged women the use of vitamin E
supplements is associated with a reduced risk of coronary heart disease.
Randomized trials of vitamin E in the primary and secondary prevention of
coronary disease are being conducted; public policy recommendations about the
widespread use of vitamin E should await the results of these trials.
DOI: 10.1056/NEJM199305203282003
PMID: 8479463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15585762 | 1. Am J Clin Nutr. 2004 Dec;80(6):1508-20. doi: 10.1093/ajcn/80.6.1508.
Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9
cohorts.
Knekt P(1), Ritz J, Pereira MA, O'Reilly EJ, Augustsson K, Fraser GE, Goldbourt
U, Heitmann BL, Hallmans G, Liu S, Pietinen P, Spiegelman D, Stevens J, Virtamo
J, Willett WC, Rimm EB, Ascherio A.
Author information:
(1)National Public Health Institute, Helsinki, Finland. [email protected]
BACKGROUND: Epidemiologic studies have suggested a lower risk of coronary heart
disease (CHD) at higher intakes of fruit, vegetables, and whole grain. Whether
this association is due to antioxidant vitamins or some other factors remains
unclear.
OBJECTIVE: We studied the relation between the intake of antioxidant vitamins
and CHD risk.
DESIGN: A cohort study pooling 9 prospective studies that included information
on intakes of vitamin E, carotenoids, and vitamin C and that met specific
criteria was carried out. During a 10-y follow-up, 4647 major incident CHD
events occurred in 293 172 subjects who were free of CHD at baseline.
RESULTS: Dietary intake of antioxidant vitamins was only weakly related to a
reduced CHD risk after adjustment for potential nondietary and dietary
confounding factors. Compared with subjects in the lowest dietary intake
quintiles for vitamins E and C, those in the highest intake quintiles had
relative risks of CHD incidence of 0.84 (95% CI: 0.71, 1.00; P=0.17) and 1.23
(1.04, 1.45; P=0.07), respectively, and the relative risks for subjects in the
highest intake quintiles for the various carotenoids varied from 0.90 to 0.99.
Subjects with higher supplemental vitamin C intake had a lower CHD incidence.
Compared with subjects who did not take supplemental vitamin C, those who took
>700 mg supplemental vitamin C/d had a relative risk of CHD incidence of 0.75
(0.60, 0.93; P for trend <0.001). Supplemental vitamin E intake was not
significantly related to reduced CHD risk.
CONCLUSIONS: The results suggest a reduced incidence of major CHD events at high
supplemental vitamin C intakes. The risk reductions at high vitamin E or
carotenoid intakes appear small.
DOI: 10.1093/ajcn/80.6.1508
PMID: 15585762 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16603825 | 1. Prev Cardiol. 2006 Spring;9(2):75-81. doi: 10.1111/j.1520-037x.2006.4424.x.
Antioxidant vitamin intake and subclinical coronary atherosclerosis.
Hatzigeorgiou C(1), Taylor AJ, Feuerstein IM, Bautista L, O'Malley PG.
Author information:
(1)Department of Medicine, Walter Reed Army Medical Center, Washington, DC
20307, USA.
Numerous studies have evaluated the association between antioxidants and
coronary atherosclerosis but have been limited by its study among individuals
with advanced atherosclerosis. The authors studied 865 consecutive patients,
39-45 years of age, without known coronary artery disease and presenting for a
periodic physical examination. Antioxidant intake was assessed with the Block
Dietary Questionnaire, and coronary atherosclerosis was identified by measuring
coronary artery calcification using electron beam computed tomography. The mean
age was 42 (+/-2), 83% were male, and the prevalence of coronary artery
calcification was 20%. Vitamin supplements were used by 56% of the participants,
and the mean (+/-SD) daily intake (dietary plus supplemental) of vitamins A, C,
and E were 1683 mg (+/-1245), 371 mg (+/-375), and 97 mg (+/-165), respectively.
There was no significant correlation between coronary artery calcification score
and individual vitamin or total antioxidant vitamin intake, even after adjusting
for traditional cardiac risk factors. The highest quartile of vitamin E was
positively associated with calcification (odds ratio=1.77; 95% confidence
interval, 1.02-3.06). Antioxidant vitamin intake is not significantly related to
coronary artery calcification, implying that there is no effect on the
development of early coronary atherosclerosis. High doses of vitamin E may
confer an increased risk of calcified atherosclerosis.
DOI: 10.1111/j.1520-037x.2006.4424.x
PMID: 16603825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12741415 | 1. J Womens Health (Larchmt). 2003 Mar;12(2):123-36. doi:
10.1089/154099903321576510.
Does vitamin E supplementation prevent cardiovascular events?
Manson JE(1), Bassuk SS, Stampfer MJ.
Author information:
(1)Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
02115, USA. [email protected]
In recent years, vitamin E has been investigated as a cardioprotective agent.
Experimental studies have identified potential mechanisms by which vitamin E may
inhibit the development of atherosclerosis, and observational studies of
individuals without coronary disease suggest that vitamin E intake may prevent
future cardiovascular events. Secondary prevention trials to date have
demonstrated little benefit from vitamin E supplementation. It remains possible,
however, that supplementation may be useful among certain high-risk groups,
including those with nutritional deficiencies. Limited data from completed
primary prevention trials also indicate minimal cardioprotection from vitamin E,
but large-scale trials now in progress may yet show benefit. Results from
ongoing trials will contribute powerfully to the totality of evidence on which
to formulate both appropriate clinical recommendations for individual patients
and a rational public health policy for the population as a whole. At this time,
there is insufficient evidence for issuing a public health recommendation to use
vitamin E supplements to prevent cardiovascular disease (CVD). Rather, increased
intake of fruits, vegetables, and other antioxidant-rich foods should be
promoted as part of a healthy diet because they provide nutritional benefits
beyond any potential antioxidant effect. Moreover, even if found to reduce CVD
risk, vitamin supplement use should be considered an adjunct, not an
alternative, to established cardioprotective measures, such as smoking
abstention, avoidance of obesity, adequate physical activity, and control of
high blood pressure and hyperlipidemia.
DOI: 10.1089/154099903321576510
PMID: 12741415 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23055813 | 1. Int J Med Sci. 2012;9(8):621-6. doi: 10.7150/ijms.4768. Epub 2012 Sep 19.
Correlations between oxidative DNA damage, oxidative stress and coenzyme Q10 in
patients with coronary artery disease.
Kaya Y(1), Çebı A, Söylemez N, Demır H, Alp HH, Bakan E.
Author information:
(1)Kafkas University, Faculty of Medicine Department of Cardiology, Kars,
Turkey.
The correlation of coronary artery disease (CAD) with pro-oxidant/antioxidant
balance and oxidative DNA damage was investigated. Seventy-seven patients with
CAD and 44 healthy individuals as control were included in this study. The
comparative ratios of ubiquinol-10/ubiquinone-10,
8-hydroxy-2(')-deoxyguanosine/deoxyguanosine and the level of MDA measured by
HPLC and the activities of GPX and SOD by colorimetric approach in blood samples
obtained from patients with CAD were unraveled.8-OHdG/dG ratios, serum MDA level
and GPX activity were found significantly elevated level in serum of CAD
patients compared to control group. The SOD activity was observed in stable
levels in CAD patients. Ubiquinol-10/ubiquinone-10 ratio was significantly lower
in patients with CAD than the controls. The positive correlation was observed
between 8-OHdG/dG ratios in both MDA levels and GPX activity, while the
significant negative correlation was seemed between the ratio of 8-OHdG/dG and
ubiquinol-10/ubiquinone-10 as well as MDA levels and ubiquinol-10/ubiquinone-10
ratio. We conclude that, both the disruption of pro-oxidant/antioxidant balance
and oxidative stress in DNA may play an important role in the pathogenesis of
coronary artery disease.
DOI: 10.7150/ijms.4768
PMCID: PMC3465845
PMID: 23055813 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/10386507 | 1. Arch Intern Med. 1999 Jun 28;159(12):1313-20. doi:
10.1001/archinte.159.12.1313.
Vitamin E and coronary artery disease.
Spencer AP(1), Carson DS, Crouch MA.
Author information:
(1)Medical University of South Carolina, Charleston 29425, USA.
Comment in
Arch Intern Med. 1999 Jun 28;159(12):1279-80. doi:
10.1001/archinte.159.12.1279.
Various studies have evaluated the antioxidant effects of vitamin E in the
prevention or treatment of coronary artery disease (CAD). In vitro data suggest
that vitamin E protects against oxidation of low-density lipoprotein and
decreases the deposition of atherogenic oxidized low-density lipoprotein in
arterial walls. Various observational and epidemiological studies also suggest a
relationship between vitamin E serum concentrations or intake and CAD. One
prospective, randomized trial suggested that low-dosage vitamin E
supplementation (50 IU/d) decreases the risk of angina in patients without
previously diagnosed CAD. Another study, using high-dosage vitamin E
supplementation (400 or 800 IU/d), demonstrated a decrease in the combined end
point of nonfatal myocardial infarction and cardiovascular death in patients
with established CAD. Discordant data, however, have been published that imply
no cardiovascular benefit of low-dosage vitamin E supplementation (50 IU/d) and
detrimental effects if vitamin E is combined with beta carotene. At this point,
clinicians should emphasize a low-fat diet with high intake of fruits and
vegetable sources containing vitamin E. Supplemental vitamin E may be considered
in patients at high risk for CAD or with documented CAD, but the potential
beneficial effects should be weighed against possible long-term adverse effects.
If vitamin E supplementation is initiated, the literature suggests dosages of
100 to 400 IU/d, with the higher dosage considered in patients with documented
CAD. Additional investigation is warranted to further define the role of vitamin
E supplementation in CAD and to critically evaluate the optimal dosage, duration
of use, and method of consumption (dietary vs supplemental).
DOI: 10.1001/archinte.159.12.1313
PMID: 10386507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7977015 | 1. Am Heart J. 1994 Dec;128(6 Pt 2):1333-6. doi: 10.1016/0002-8703(94)90256-9.
Platelet inhibitors and antioxidant vitamins in cardiovascular disease.
Hennekens CH(1).
Author information:
(1)Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215.
Considerable research attention has focused on the possible roles of platelet
inhibition, principally using aspirin, and antioxidant vitamins in reducing the
risks of cardiovascular disease. Data from large-scale randomized trials
indicate that aspirin reduces subsequent vascular events among patients with
prior myocardial infarction, stroke, transient ischemic attacks, or unstable
angina, as well as among patients with acute evolving myocardial infarction. In
primary prevention trials, the Physicians' Health Study showed a clear benefit
in decreasing risk of a first myocardial infarction in men; the data on stroke
and total number of deaths from vascular causes are inadequate. The Women's
Health Study, a trial now under way among apparently healthy women, will provide
direct evidence on the balance of risks and benefits of aspirin in primary
prevention. Antioxidant vitamins are hypothesized to decrease cardiovascular
disease risk by several mechanisms, including inhibition of oxidation of
low-density lipoprotein cholesterol and decreasing uptake into the coronary
endothelium. Promising results have emerged from observational studies, which
show that people with high intakes of antioxidant vitamins through diet or
supplements have lowered risks of cardiovascular disease; however, unknown or
unmeasured factors associated with high antioxidant vitamin intake may explain
all or part of the observed associations. Randomized trials to provide reliable
data are now ongoing among apparently healthy men and women, as well as among
survivors of prior cardiovascular disease events.
DOI: 10.1016/0002-8703(94)90256-9
PMID: 7977015 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12675072 | 1. Clin Excell Nurse Pract. 1998 Jan;2(1):10-22.
A review of vitamins A, C, and E and their relationship to cardiovascular
disease.
Brown DJ(1), Goodman J.
Author information:
(1)University of Florida, College of Nursing, J. Hillis Miller Health Sciences
Center, Gainesville, Florida, USA.
Cardiovascular disease (CVD), particularly in the form of coronary artery
disease, is the leading cause of death in the United States. Research in the
past 10 years links pathogenic low-density lipoprotein (LDL) modification to
oxidation damage by free radicals. This review summarizes the major findings of
CVD-related epidemiologic research and clinical trials conducted in the past 5
years on vitamins A, C, and E. Vitamin supplementation behaviors are discussed.
In prospective studies, the intake of vitamins A, C, and E has been correlated
with lower mortality rates. When recent clinical trials and oxidation studies
are analyzed, the weight of evidence suggests that 100-400 IU of daily vitamin E
over 2 years or more may be most efficacious in reducing low-density lipoprotein
oxidation and positively influencing mortality rates from CVD in primary care.
Research also supports vitamin E supplementation in patients with known CAD or a
history of transient ischemic attacks. Persons with diabetes or hypertension as
well as smokers may benefit from supplemental vitamin C intake. Targeted
antioxidant vitamin intake should be included in CVD risk assessment and primary
preventive counseling efforts.
PMID: 12675072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12242302 | 1. Mol Cell Biol. 2002 Oct;22(20):7268-78. doi: 10.1128/MCB.22.20.7268-7278.2002.
Highly selective actions of HuR in antagonizing AU-rich element-mediated mRNA
destabilization.
Chen CY(1), Xu N, Shyu AB.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Texas Medical
School, Houston, Texas 77030, USA.
Human RNA-binding protein HuR, a nucleocytoplasmic shuttling protein, is a
ubiquitously expressed member of the family of Hu proteins, which consist of two
N-terminal RNA recognition motifs (RRM1 and RRM2), a hinge region, and a
C-terminal RRM (RRM3). Although in vitro experiments showed indiscriminate
binding of Hu proteins synthesized in bacterial systems to many different
AU-rich elements (AREs), in vivo studies have pointed to a cytoplasmic role for
HuR protein in antagonizing the rapid decay of some specific ARE-containing
mRNAs, depending on physiological situations. By ectopically overexpressing HuR
and its mutant derivatives in NIH 3T3 cells to mimic HuR upregulation of
specific ARE-containing mRNAs in other systems, we have examined the in vivo
ARE-binding specificity of HuR and dissected its functionally critical domains.
We show that in NIH 3T3 cells, HuR stabilizes reporter messages containing only
the c-fos ARE and not other AREs. Two distinct binding sites were identified
within the c-fos ARE, the 5' AUUUA-containing domain and the 3'
U-stretch-containing domain. These actions of HuR are markedly different from
those of another ARE-binding protein, hnRNP D (also termed AUF1), which in vivo
recognizes AUUUA repeats found in cytokine AREs and can exert both stabilizing
and destabilizing effects. Further experiments showed that any combination of
two of the three RRM domains of HuR is sufficient for strong binding to the
c-fos ARE in vitro and to exert an RNA stabilization effect in vivo comparable
to that of intact HuR and that the hinge region containing nucleocytoplasmic
shuttling signals is dispensable for the stabilization effect of HuR. Our data
suggest that the ARE-binding specificity of HuR in vivo is modulated to interact
only with and thus regulate specific AREs in a cell type- and physiological
state-dependent manner.
DOI: 10.1128/MCB.22.20.7268-7278.2002
PMCID: PMC139819
PMID: 12242302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21996047 | 1. Nutrition. 2012 Mar;28(3):250-5. doi: 10.1016/j.nut.2011.06.004. Epub 2011 Oct
12.
Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant
enzyme activity in patients with coronary artery disease.
Lee BJ(1), Huang YC, Chen SJ, Lin PT.
Author information:
(1)School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
OBJECTIVE: The purpose of this study was to investigate the effect of coenzyme
Q10 supplementation on oxidative stress and antioxidant enzyme activity in
patients with coronary artery disease (CAD).
METHODS: This was an intervention study. Patients who were identified by cardiac
catheterization as having at least 50% stenosis of one major coronary artery or
receiving percutaneous transluminal coronary angioplasty (n = 51) were randomly
assigned to the placebo group (n = 14) or one of the two coenzyme
Q10-supplemented groups (60 mg/d, n = 19 [Q10-60 group]; 150 mg/d, n = 18
[Q10-150 group]). Intervention was administered for 12 wk. Patients' blood
samples were analyzed every 4 wk for plasma coenzyme Q10 concentrations,
malondialdehyde (MDA), and antioxidant enzyme (catalase [CAT], superoxide
dismutase [SOD], glutathione peroxidase) activity.
RESULTS: Forty-three subjects with CAD completed intervention study. Plasma
coenzyme Q10 concentration increased significantly after coenzyme the Q10-150
intervention (P < 0.01). The MDA levels were significantly lower than baseline
in the Q10-150 group at week 4 (P = 0.03). The Q10-150 group had significantly
lower MDA levels than the placebo group at week 8 (P = 0.03). With respect to
antioxidant enzyme activity, subjects in the Q10-150 group had significantly
higher CAT (P = 0.03) and SOD (P = 0.03) activity than the placebo group at week
12. The plasma coenzyme Q10 concentration was significantly correlated with MDA
levels (r = -0.35, P = 0.02) and CAT (r = 0.43, P = 0.01) and SOD activity (r =
0.39, P = 0.01). The ratio of plasma coenzyme Q10 to total cholesterol was
significantly correlated with SOD activity (r = 0.39, P = 0.02). The ratio of
plasma coenzyme Q10 to low-density lipoprotein was significantly correlated with
CAT (r = 0.35, P = 0.04) and SOD (r = 0.45, P = 0.01) activity. However, there
was no relation between coenzyme Q10 concentration and glutathione peroxidase
activity.
CONCLUSION: Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative
stress and increase antioxidant enzyme activity in patients with CAD. A higher
dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable
antioxidation in patients with CAD.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nut.2011.06.004
PMID: 21996047 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10077397 | 1. Int J Cardiol. 1999 Jan;68(1):23-9. doi: 10.1016/s0167-5273(98)00323-4.
Serum concentration of lipoprotein(a) decreases on treatment with hydrosoluble
coenzyme Q10 in patients with coronary artery disease: discovery of a new role.
Singh RB(1), Niaz MA.
Author information:
(1)Centre of Nutrition, Medical Hospital and Research Centre, Moradabad, India.
OBJECTIVE: To examine the effect of coenzyme Q10 supplementation on serum
lipoprotein(a) in patients with acute coronary disease.
STUDY DESIGN: Randomized double blind placebo controlled trial.
SUBJECTS AND METHODS: Subjects with clinical diagnosis of acute myocardial
infarction, unstable angina, angina pectoris (based on WHO criteria) with
moderately raised lipoprotein(a) were randomized to either coenzyme Q10 as Q-Gel
(60 mg twice daily) (coenzyme Q10 group, n=25) or placebo (placebo group, n=22)
for a period of 28 days.
RESULTS: Serum lipoprotein(a) showed significant reduction in the coenzyme Q10
group compared with the placebo group (31.0% vs 8.2% P<0.001) with a net
reduction of 22.6% attributed to coenzyme Q10. HDL cholesterol showed a
significant increase in the intervention group without affecting total
cholesterol, LDL cholesterol, and blood glucose showed a significant reduction
in the coenzyme Q10 group. Coenzyme Q10 supplementation was also associated with
significant reductions in thiobarbituric acid reactive substances,
malon/dialdehyde and diene conjugates, indicating an overall decrease in
oxidative stress.
CONCLUSION: Supplementation with hydrosoluble coenzyme Q10 (Q-Gel) decreases
lipoprotein(a) concentration in patients with acute coronary disease.
DOI: 10.1016/s0167-5273(98)00323-4
PMID: 10077397 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15693087 | 1. J Rheumatol. 2005 Feb;32(2):275-82.
Effects of vitamins C and E on oxidative stress markers and endothelial function
in patients with systemic lupus erythematosus: a double blind, placebo
controlled pilot study.
Tam LS(1), Li EK, Leung VY, Griffith JF, Benzie IF, Lim PL, Whitney B, Lee VW,
Lee KK, Thomas GN, Tomlinson B.
Author information:
(1)Department of Medicine and Therapeutics, Department of Radiology, and the
Clinical Immunology Unit, Hong Kong Cancer Institute, Hong Kong.
[email protected]
OBJECTIVE: Patients with systemic lupus erythematosus (SLE) experience excess
morbidity and mortality due to coronary artery disease (CAD) that cannot be
fully explained by the classical CAD risk factors. Among emerging CAD risk
factors, oxidative stress is currently being emphasized. We evaluated the
effects of longterm antioxidant vitamins on markers of oxidative stress and
antioxidant defense and endothelial function in 39 patients with SLE.
METHODS: Patients were randomized to receive either placebo or vitamins (500 mg
vitamin C and 800 IU vitamin E daily) for 12 weeks. Markers of oxidative stress
included malondialdehyde (MDA) and allantoin. Antioxidants measured included
erythrocyte superoxide dismutase and glutathione peroxidase, plasma total
antioxidant power (as FRAP value), and ascorbic acid and vitamin E
concentrations. Endothelial function was assessed by flow-mediated dilatation
(FMD) of the brachial artery and plasma concentration of von Willebrand factor
(vWF) and plasminogen activator inhibitor type 1 (PAI-1). Primary outcome of the
study included the change in lipid peroxidation as revealed by MDA levels.
Secondary outcomes included changes in allantoin and antioxidant levels and
change in endothelial function.
RESULTS: After treatment, plasma ascorbic acid and alpha-tocopherol
concentrations were significantly (p < 0.05) increased only in the
vitamin-treated group, associated with a significant decrease (p < 0.05) in
plasma MDA. Other oxidative stress markers and antioxidant levels remained
unchanged in both groups. FMD and vWF and PAI-1 levels remained unchanged in
both groups.
CONCLUSION: Combined administration of vitamins C and E was associated with
decreased lipid peroxidation, but did not affect endothelial function in
patients with SLE after 3 months of therapy.
PMID: 15693087 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17275460 | 1. Am J Med. 2007 Feb;120(2):180-4. doi: 10.1016/j.amjmed.2006.03.039.
Risk of mortality with vitamin E supplements: the Cache County study.
Hayden KM(1), Welsh-Bohmer KA, Wengreen HJ, Zandi PP, Lyketsos CG, Breitner JC;
Cache County Investigators.
Author information:
(1)Department of Psychiatry and Behavioral Sciences, Duke University Medical
Center, Durham, NC, USA. [email protected]
PURPOSE: A recent meta-analysis reported increased mortality in clinical trial
participants randomized to high-dose vitamin E. We sought to determine whether
these mortality risks with vitamin E reflect adverse consequences of its use in
the presence of cardiovascular disease.
METHODS: In a defined population aged 65 years or older, baseline interviews
captured self- or proxy-reported history of cardiovascular illness. A medicine
cabinet inventory verified nutritional supplement and medication use. Three
sources identified subsequent deaths. Cox proportional hazards methods examined
the association between vitamin E use and mortality.
RESULTS: After adjustment for age and sex, there was no association in this
population between vitamin E use and mortality (adjusted hazard ratio [aHR]
0.93; 95% confidence interval [CI], 0.74-1.15). Predictably, deaths were more
frequent with a history of diabetes, stroke, coronary artery bypass graft
surgery, or myocardial infarction, and with the use of warfarin, nitrates, or
diuretics. None of these conditions or treatments altered the null main effect
with vitamin E, but mortality was increased in vitamin E users who had a history
of stroke (aHR 3.64; CI, 1.73-7.68), coronary bypass graft surgery (aHR 4.40;
CI, 2.83-6.83), or myocardial infarction (aHR 1.95; CI, 1.29-2.95) and,
independently, in those taking nitrates (aHR 3.95; CI, 2.04-7.65), warfarin (aHR
3.71; CI, 2.22-6.21), or diuretics (aHR 1.83; CI, 1.35-2.49). Although not
definitive, a consistent trend toward reduced mortality was seen in vitamin E
users without these conditions or treatments.
CONCLUSIONS: In this population-based study, vitamin E use was unrelated to
mortality, but this apparently null finding seems to represent a combination of
increased mortality in those with severe cardiovascular disease and a possible
protective effect in those without.
DOI: 10.1016/j.amjmed.2006.03.039
PMID: 17275460 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25394660 | 1. Am J Physiol Gastrointest Liver Physiol. 2015 Jan 15;308(2):G100-11. doi:
10.1152/ajpgi.00287.2014. Epub 2014 Nov 13.
Deletion of intestinal epithelial insulin receptor attenuates high-fat
diet-induced elevations in cholesterol and stem, enteroendocrine, and Paneth
cell mRNAs.
Andres SF(1), Santoro MA(1), Mah AT(2), Keku JA(1), Bortvedt AE(1), Blue RE(1),
Lund PK(3).
Author information:
(1)Department of Cell Biology and Physiology, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina; and.
(2)Department of Nutrition, University of North Carolina at Chapel Hill, Chapel
Hill, North Carolina.
(3)Department of Cell Biology and Physiology, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina; and [email protected].
The insulin receptor (IR) regulates nutrient uptake and utilization in multiple
organs, but its role in the intestinal epithelium is not defined. This study
developed a mouse model with villin-Cre (VC) recombinase-mediated intestinal
epithelial cell (IEC)-specific IR deletion (VC-IR(Δ/Δ)) and littermate controls
with floxed, but intact, IR (IR(fl/fl)) to define in vivo roles of IEC-IR in
mice fed chow or high-fat diet (HFD). We hypothesized that loss of IEC-IR would
alter intestinal growth, biomarkers of intestinal epithelial stem cells (IESC)
or other lineages, body weight, adiposity, and glucose or lipid handling. In
lean, chow-fed mice, IEC-IR deletion did not affect body or fat mass, plasma
glucose, or IEC proliferation. In chow-fed VC-IR(Δ/Δ) mice, mRNA levels of the
Paneth cell marker lysozyme (Lyz) were decreased, but markers of other
differentiated lineages were unchanged. During HFD-induced obesity, IR(fl/fl)
and VC-IR(Δ/Δ) mice exhibited similar increases in body and fat mass, plasma
insulin, mRNAs encoding several lipid-handling proteins, a decrease in Paneth
cell number, and impaired glucose tolerance. In IR(fl/fl) mice, HFD-induced
obesity increased circulating cholesterol; numbers of chromogranin A
(CHGA)-positive enteroendocrine cells (EEC); and mRNAs encoding Chga,
glucose-dependent insulinotrophic peptide (Gip), glucagon (Gcg), Lyz, IESC
biomarkers, and the enterocyte cholesterol transporter Scarb1. All these effects
were attenuated or lost in VC-IR(Δ/Δ) mice. These results demonstrate that
IEC-IR is not required for normal growth of the intestinal epithelium in lean
adult mice. However, our findings provide novel evidence that, during
HFD-induced obesity, IEC-IR contributes to increases in EEC, plasma cholesterol,
and increased expression of Scarb1 or IESC-, EEC-, and Paneth cell-derived
mRNAs.
Copyright © 2015 the American Physiological Society.
DOI: 10.1152/ajpgi.00287.2014
PMCID: PMC4297856
PMID: 25394660 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19252527 | 1. Oncogene. 2009 Apr 16;28(15):1782-91. doi: 10.1038/onc.2009.16. Epub 2009 Mar
2.
RNase L downmodulation of the RNA-binding protein, HuR, and cellular growth.
Al-Ahmadi W(1), Al-Haj L, Al-Mohanna FA, Silverman RH, Khabar KS.
Author information:
(1)Program in BioMolecular Research, King Faisal Specialist Hospital and
Research Center, Riyadh, Saudi Arabia.
Ribonuclease L (RNase L) is an intracellular enzyme that is vital in innate
immunity, but also is a tumor suppressor candidate. Here, we show that
overexpression of RNase L decreases cellular growth and downmodulates the
RNA-binding protein, HuR, a regulator of cell-cycle progression and
tumorigenesis. The effect is temporal, occurring in specific cell-cycle phases
and correlated with the cytoplasmic localization of RNase L. Both cellular
growth and HuR were increased in RNASEL-null mouse fibroblast lines when
compared to wild-type cells. Moreover, the stability of HuR mRNA was enhanced in
RNASEL-null cells. The HuR 3' untranslated region (UTR), which harbors U-rich
and adenylate-uridylate-rich elements, was potently responsive to RNase L when
compared to control 3' UTR. Our results may offer a new explanation to the tumor
suppressor function of RNase L.
DOI: 10.1038/onc.2009.16
PMCID: PMC3071643
PMID: 19252527 [Indexed for MEDLINE] |