Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, ...suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
Background: Emerging data have revealed a negative association between adiposity and muscle quality (MQ). There is a lack of research to examine this interaction among young, healthy individuals, and ...to evaluate the contribution of adiposity to adaptation after resistance exercise (RE). Objective: The purpose of this investigation was to examine the influence of subcutaneous adipose tissue (SAT) on muscle function among non-obese individuals before and after RE. Design: Analyses included 634 non-obese (body mass index <30 kg m−2) subjects (253 males, 381 females; age=23.3+/-5.2 years). SAT and muscle mass (magnetic resonance imaging-derived SAT and biceps muscle volume), isometric and dynamic biceps strength, and MQ (strength/muscle volume), were analyzed at baseline and after 12 weeks of unilateral RE. Results: At baseline, SAT was independently associated with lower MQ for males (beta=-0.55; P<0.01) and females (beta=−0.45; P<0.01), controlling for body mass and age. Adaptation to RE revealed a significant negative association between SAT and changes for strength capacity (beta=−0.13; p=0.03) and MQ (beta=−0.14; P<0.01) among males. No attenuation was identified among females. Post-intervention SAT remained a negative predictor of MQ for males and females (beta=−0.47; P<0.01). Conclusions: The findings reveal that SAT is a negative predictor of MQ among non-obese, healthy adults, and that after 12 weeks of progressive RE this association was not ameliorated. Data suggest that SAT exerts a weak, negative influence on the adaptive response to strength and MQ among males.
Bearing faults are one of the major causes of motor failures. The bearing defects induce vibration, resulting in the modulation of the stator current. In this paper, the stator current is analyzed ...via wavelet packet decomposition to detect bearing defects. The proposed method enables the analysis of frequency bands that can accommodate the rotational speed dependence of the bearing defect frequencies. The wavelet packet decomposition also provides a better treatment of nonstationary stator current than currently used Fourier techniques.
Adjustable-speed drives perform many vital control functions in the industry, serving in such diverse applications as rolling mills, variable-speed compressors, fans, and pumps. When an ...adjustable-speed drive fails due to a bearing failure, it is usually catastrophic. Bearing defects introduce vibration anomalies that alter the current characteristic frequencies. This paper addresses the application of motor current signature analysis using wavelet packet decomposition to detect bearing faults in adjustable-speed drives.
Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. ...Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 RyR2).
In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders.
Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of ...circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS).
Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay.
The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007).
We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
Increasing evidence suggests that aberrant DNA methylation changes may contribute to prostate cancer (PCa) ethnic disparity. To comprehensively identify DNA methylation alterations in PCa disparity, ...we used the Illumina 450K methylation platform to interrogate the methylation status of 485,577 CpG sites focusing on gene-associated regions of the human genome. Genomic DNA from African-American (AA; 7 normal and 3 cancers) and Caucasian (Cau; 8 normal and 3 cancers) was used in the analysis. Hierarchical clustering analysis identified probe-sets unique to AA and Cau samples, as well as common to both. We selected 25 promoter-associated novel CpG sites most differentially methylated by race (fold change > 1.5-fold; adjusted P < 0.05) and compared the β-value of these sites provided by the Illumina, Inc. array with quantitative methylation obtained by pyrosequencing in 7 prostate cell lines. We found very good concordance of the methylation levels between β-value and pyrosequencing. Gene expression analysis using qRT-PCR in a subset of 8 genes after treatment with 5-aza-2′-deoxycytidine and/or trichostatin showed up-regulation of gene expression in PCa cells. Quantitative analysis of 4 genes, SNRPN, SHANK2, MST1R, and ABCG5, in matched normal and PCa tissues derived from AA and Cau PCa patients demonstrated differential promoter methylation and concomitant differences in mRNA expression in prostate tissues from AA vs. Cau. Regression analysis in normal and PCa tissues as a function of race showed significantly higher methylation prevalence for SNRPN (P = 0.012), MST1R (P = 0.038), and ABCG5 (P < 0.0002) for AA vs. Cau samples. We selected the ABCG5 and SNRPN genes and verified their biological functions by Western blot analysis and siRNA gene knockout effects on cell proliferation and invasion in 4 PCa cell lines (2 AA and 2 Cau patients-derived lines). Knockdown of either ABCG5 or SNRPN resulted in a significant decrease in both invasion and proliferation in Cau PCa cell lines but we did not observe these remarkable loss-of-function effects in AA PCa cell lines. Our study demonstrates how differential genome-wide DNA methylation levels influence gene expression and biological functions in AA and Cau PCa.
Cystic fibrosis is characterised in the lungs by high levels of neutrophil elastase (NE). NE induces interleukin-8 (IL-8) expression via an IL-1 receptor-associated kinase signalling pathway. Here, ...we show that these events involve the cell surface membrane bound toll-like receptor 4 (TLR4). We demonstrate that human embryonic kidney (HEK)293 cells transfected with a TLR4 cDNA (HEK-TLR4) express TLR4 mRNA and protein and induce IL-8 promoter activity in response to NE. Treatment of both HEK-TLR4 and human bronchial epithelial cells with NE decreases TLR4 protein expression. Furthermore, a TLR4 neutralising antibody abrogates NE-induced IL-8 production, and induces tolerance to a secondary lipopolysaccharide stimulus. These data implicate TLR4 in NE induced IL-8 expression in bronchial epithelium.
Background In 2007 we began a hybrid program for hypoplastic left heart syndrome (HLHS) variants to potentially improve outcome in high-risk patients. During implementation we offered both hybrid and ...Norwood approaches to all risk categories. The purpose of this study was to perform a comparative analysis of intermediate survival. Methods Newborns were evaluated jointly for high-risk characteristics, including birth weight less than 2.5 kg, prematurity (especially < 35 weeks), central nervous system abnormalities, multiorgan failure, intact or severely restrictive atrial septum, severe ventricular dysfunction, and severe atrioventricular valve regurgitation. We prefer Norwood for standard risk and hybrid for high risk, but all groups crossed over into all treatment pathways resulting in the following 5 treatment groups: standard risk Norwood; high-risk Norwood; standard risk hybrid ductal stent (HDS); high-risk hybrid DS; and high-risk hybrid prostaglandin E1 (HPGE). We reviewed all consecutive patients from 2007 to 2012, obtained follow-up, and analyzed the results. Results Sixty-eight newborns presented (median 2.96 kg, 8 days); 29 (43%) were high and 39 (57%) were standard risk. There were 14 stage I hospital deaths strongly associated with risk: 3 of 39 standard (7.7%) and 11 of 29 high (38%, p = 0.002). Stage I discharge mortality was highest for high-risk Norwood and high-risk HPGE groups ( p < 0.001). Actuarial survival up to 5 years demonstrated superior survival for Norwood versus hybrid (78.1% vs 56.4%, p = 0.0182). With risk stratification there was suboptimal survival for all 3 high-risk groups ( p = 0.003); HDS fared better than HPGE but had higher birth weight ( p < 0.001). Conclusions While a risk-stratified approach for HLHS variant patients with selective use of hybrid palliation resulted in acceptable stage I mortality, the longer term mortality for high-risk patients remains higher than for standard risk regardless of treatment modality. Intrinsic patient risk factors (rather than treatment modality) likely determine long-term outcome in experienced centers. Our current high-risk approach has evolved to HPGE application with Norwood conversion whenever deemed medically possible.
1 Department of Exercise Science, University of Massachusetts, Amherst, Massachusetts; 2 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC; 3 Division of ...Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, Connecticut; 4 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut; 5 Child, Family and Community Sciences, University of Central Florida, Orlando, Florida; 6 Division of Exercise Physiology, School of Medicine, West Virginia University, Morgantown, West Virginia; 7 Department of Sport Science and Health, Dublin City University, Dublin, Ireland; 8 School of Allied Health, University of Connecticut, Storrs, Connecticut; 9 Human Performance Laboratory, Central Michigan University, Mount Pleasant, Michigan; and 10 Department of Exercise Science and Health Promotion, Florida Atlantic University, Davie, Florida
Submitted 11 October 2004
; accepted in final form 9 February 2005
The -actinin 3 (ACTN3) gene encodes a protein of the Z disk of myofibers, and a polymorphism of ACTN3 results in complete loss of the protein. The ACTN3 genotype (R577X) has been found to be associated with performance in Australian elite athletes (Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, and North K. Am J Hum Genet 73: 627631, 2003). We studied associations between ACTN3 genotype and muscle size cross-sectional area of the biceps brachii via magnetic resonance imaging (MRI) and elbow flexor isometric (MVC) and dynamic 1-repetition maximum (1-RM) strength in a large group of men ( N = 247) and women ( N = 355) enrolled in a 12-wk standardized elbow flexor/extensor resistance training program of the nondominant arm at one of eight study centers. We found no association between ACTN3 R577X genotype and muscle phenotype in men. However, women homozygous for the ACTN3 577X allele (XX) had lower baseline MVC compared with heterozygotes ( P < 0.05) when adjusted for body mass and age. Women homozygous for the mutant allele (577X) demonstrated greater absolute and relative 1-RM gains compared with the homozygous wild type (RR) after resistance training when adjusted for body mass and age ( P < 0.05). There was a trend for a dose-response with genotype such that gains were greatest for XX and least for RR. Significant associations were validated in at least one ethnic subpopulation (Caucasians, Asians) and were independent of training volume. About 2% of baseline MVC and of 1-RM strength gain after training were attributable to ACTN3 genotype (likelihood-ratio test P value, P = 0.01), suggesting that ACTN3 is one of many genes contributing to genetic variation in muscle performance and adaptation to exercise.
quantitative trait loci; muscle genetics; alpha-actinin
Address for reprint requests and other correspondence: P. M. Clarkson, Dept. of Exercise Science, 110 Totman Bldg., Univ. of Massachusetts, Amherst, MA 01003 (E-mail: clarkson{at}excsci.umass.edu )
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