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排序方式: 共有218条查询结果,搜索用时 31 毫秒
1.
Lee L. Eckhardt MD Amanda L. Farley MS Esther Rodriguez MD Karen Ruwaldt BS Daniel Hammill David J. Tester BS Michael J. Ackerman MD PhD Jonathan C. Makielski MD 《Heart rhythm》2007,4(3):323-329
BACKGROUND: Loss-of-function mutations in the KCNJ2 cause approximately 50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? OBJECTIVES: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. METHODS: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. RESULTS: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. CONCLUSIONS: KCNJ2 loss of function mutations were found in approximately 1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations. 相似文献
2.
M J Ackerman B L Siu W Q Sturner D J Tester C R Valdivia J C Makielski J A Towbin 《JAMA》2001,286(18):2264-2269
CONTEXT: Fatal arrhythmias from occult long QT syndrome may be responsible for some cases of sudden infant death syndrome (SIDS). Because patients who have long QT syndrome with sodium channel gene (SCN5A) defects have an increased frequency of cardiac events during sleep, and a recent case is reported of a sporadic SCN5A mutation in an infant with near SIDS, SCN5A has emerged as the leading candidate ion channel gene for SIDS. OBJECTIVE: To determine the prevalence and functional properties of SCN5A mutations in SIDS. DESIGN, SETTING, AND SUBJECTS: Postmortem molecular analysis of 93 cases of SIDS or undetermined infant death identified by the Medical Examiner's Office of the Arkansas State Crime Laboratory between September 1997 and August 1999. Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses. Missense mutations were incorporated into the human heart sodium channel alpha subunit by mutagenesis, transiently transfected into human embryonic kidney cells, and characterized electrophysiologically. MAIN OUTCOME MEASURES: Molecular and functional characterization of SCN5A defects. RESULTS: Two of the 93 cases of SIDS possessed SCN5A mutations: a 6-week-old white male with an A997S missense mutation in exon 17 and a 1-month old white male with an R1826H mutation in exon 28. These 2 distinct mutations occurred in highly conserved regions of the sodium channel and were absent in 400 control patients (800 alleles). Functionally, the A997S and R1826H mutant channels expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. CONCLUSION: Approximately 2% of this prospective, population-based cohort of SIDS cases had an identifiable SCN5A channel defect, suggesting that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS. 相似文献
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David J. Tester Leonie C.H. Wong Pritha Chanana Amie Jaye Jared M. Evans David R. FitzPatrick Margaret J. Evans Peter Fleming Iona Jeffrey Marta C. Cohen Jacob Tfelt-Hansen Michael A. Simpson Elijah R. Behr Michael J. Ackerman 《Journal of the American College of Cardiology》2018,71(11):1217-1227
Background
Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS.Objectives
This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS.Methods
A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of “potentially informative,” ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed.Results
Overall, 53 of 419 (12.6%) SIDS cases had ≥1 “potentially informative,” GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a “potentially informative” GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a “pathogenic” or “likely pathogenic” variant.Conclusions
Less than 15% of more than 400 SIDS cases had a “potentially informative” variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families. 相似文献5.
OBJECTIVES: This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD). BACKGROUND: Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases. METHODS: From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation. RESULTS: Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases. CONCLUSIONS: In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD. 相似文献
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Poonam B. Jaiswal Nicole J. Tester Paul W. Davenport 《The journal of spinal cord medicine》2016,39(1):103-110
Context
Spinal cord injury (SCI) causes disruption of the efferent input to and afferent input from respiratory muscles, which impairs respiratory motor and sensory functions, respectively. This disturbs the injured individual''s ability to respond to ventilatory loads and may alter the respiratory perceptual sensitivity of applied loads. Acute intermittent hypoxia with elevated CO2 (AIH treatment) has been shown to induce ventilatory long-term facilitation in individuals with chronic SCI. This study evaluated the effect of ten days of AIH treatment on ventilatory load compensation and respiratory perceptual sensitivity to inspiratory resistive loads (IRL), in an individual with chronic, incomplete cervical SCI.Methods
Case report and literature review.Findings
We report a case of a 55-year-old female with a C4 chronic, incomplete SCI (American Spinal Injury Association Impairment Scale D). The subject underwent evaluation at four time-points: Baseline, Post Sham, AIH Day 1 and AIH Day 10. Significant improvements in airflow generated in response to applied IRL were found after AIH treatment compared to Baseline. There were no significant changes in the respiratory perceptual sensitivity to applied IRL after AIH treatment.Clinical relevance
Rehabilitative interventions after SCI demand restoration of the respiratory motor function. However, they must also ensure that the respiratory perceptual sensitivity of the injured individual does not hinder their capability to compensate to ventilatory challenges. 相似文献9.
Can alcohol-based hand-rub solutions cause you to lose your driver's license? Comparative cutaneous absorption of various alcohols
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Brown TL Gamon S Tester P Martin R Hosking K Bowkett GC Gerostamoulos D Grayson ML 《Antimicrobial agents and chemotherapy》2007,51(3):1107-1108
We assessed cutaneous ethanol (ETOH) and isopropanol (ISOP) absorption after intensive (30 times per h) use of alcohol-based hand-rub solutions by healthcare workers (HCWs). ETOH was detectable in the breath of 6/20 HCWs (0.001 to 0.0025%) at 1 to 2 min postexposure and in the serum of 2/20 HCWs at 5 to 7 min postexposure. Serum ISOP levels were unrecordable at all time points. 相似文献
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