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Biomedical subjects

K Schwartz

Publications and source records attributed to K Schwartz.

At least 73 records · Page 4Linked to original sources
PubMed1999

Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.

The voltage-gated K+ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K+ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the alpha subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA)n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR-single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1: two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts.

Base Sequence↗
PubMed1999

Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II.

Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.

Arrhythmias, Cardiac↗
PubMed1999

Movement and reaction times and fine coordination tasks following pallidotomy.

The effect of a unilateral, microelectrode-guided lesion in the globus pallidum internum (GPi) was evaluated in 41 patients (21 women) with moderately advanced Parkinson's disease (PD). The mean age was 60.3+/-9.0 years (range, 40-74) and the mean symptom duration was 14.7+/-5.3 years (range, 4-25). In addition to clinical ratings, movement time (MT) and reaction time (RT) tests were performed at baseline and 3 months after surgery during the "practically defined off" state (more than 12 hours after the last dose of levodopa). Improvement occurred bilaterally with more robust and statistically significant improvement on the contralateral side in all RT tests. Simple reaction time (SRT) improved by 14.5% (p<0.001) and the choice reaction time (CRT) by 12.2% (p<0.001) when the arm contralateral to the pallidotomy side was tested. There was a trend toward improvement in the ipsilateral arm. The MT, determined by repetitive movement between two adjacent targets, improved by 24% contralaterally (p<0.0001) and by 12% ipsilaterally (p<0.005). In addition, the Purdue Pegboard (PP) test scores, used to evaluate hand dexterity, improved on the contralateral side by 35.5% (p<0.0002) but there was no statistically significant ipsilateral improvement. To the extent that MT and RT are quantitative measures of bradykinesia, our study provides evidence that this parkinsonian feature improves after pallidotomy.

Adult↗
PubMed1999

Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group.

The genetic factors that underlie idiopathic dilated cardiomyopathy (IDCM) have not yet been elucidated. Since beta1-adrenoceptors are downregulated in patients with IDCM, and since beta-blocker therapy is consistently beneficial in this setting, we hypothesized that genetic variation in the beta1-adrenoceptor might affect susceptibility to and/or severity of IDCM. As no intragenic polymorphism was available, a systematic screening of the gene was first performed. The organization and sequence of the human beta1-adrenoceptor gene were established using polymerase chain reaction, single-strand conformation polymorphism analysis and sequencing. The gene comprises 1434 bp and no intron was observed. We found a unique and frequent polymorphism (C1165G) which predicts an Arg389Gly substitution. The association of this polymorphism with IDCM was then analysed using the PCR-restriction fragment length polymorphism method in the CARDIGENE population, a clinically well-characterized population of IDCM. Genotypic distribution was in agreement with Hardy-Weinberg equilibrium. There were no differences in the beta1-adrenoceptor allele frequencies between IDCM (n=426; C/G=0.76/0.24) and age- and sex-matched control subjects (n=395; C/G=0.78/0.22). Within the patient group, no association was observed with the severity of the disease. In conclusion, the genomic organization of beta1-adrenoceptor is described here for the first time. We found a unique and frequent polymorphism in the coding sequence of the gene. No association was observed between IDCM and the genetic variant. Its possible involvement in other cardiac diseases related to the beta1-adrenoceptor remains to be analysed.

Adult↗
PubMed1999

Optimal clip application and intraoperative angiography for intracranial aneurysms.

BACKGROUND: The actual incidence of residual aneurysm after clipping is unknown. The natural history of residual aneurysm can be regrowth and hemorrhage. Intraoperative angiography offers a cost-effective, safe interdiction to the problem of residual aneurysm and parent vessel stenosis. METHODS/RESULTS: Forty consecutive patients harboring 54 aneurysms underwent 42 operative procedures to clip 52 aneurysms, during which 220 intraoperative angiographic runs were performed. Ninety-three percent of the procedures were performed on patients with acute subarachnoid hemorrhage. There were 4 giant (>2.5 cm, 4/52 = 8%, all anterior circulation), 21 large (1.0-2.5 cm, 21/52 = 40%, 16/ 21 = 76% anterior circulation, 6/21 = 28% posterior circulation), and 27 small (<1.0 cm, 27/52-52%, 22/27 = 81% anterior circulation, 5/27 = 18% posterior circulation) aneurysms. Intraoperative angiography led to clip adjustment in 18/52 = 34% of aneurysms (4/18 = 22% for parent artery stenosis, 8/18 = 44% for residual aneurysm and 6/18 = 33% for both). Of the 18 adjustments made, 16 = 88% were made on giant or large aneurysms and two were small (one was a complex anterior communicating and one was a vertebral junction aneurysm). Follow-up angiography was performed on 26/42 = 62% of operative cases. Postoperative angiography confirmed intraoperative angiography in all cases. Two complications occurred during 220 angiographic runs: one embolic stroke and one incident of equipment failure. CONCLUSION: A grading scale was applied to test the relationship between anatomical site and size as they relate to the necessity for clip adjustment for complete aneurysm obliteration and/or parent artery compromise. Significance was related to site (basilar bifurcation, anterior communicating, middle cerebral bifurcation, and ophthalmic) and size (>1.0 cm), both as independent and codependent variables. An analysis of the cost-effectiveness of intraoperative angiography was demonstrated.

Adult↗
PubMed1999

Familial dilated cardiomyopathy: clinical features in French families.

UNLABELLED: The aims of the study were to analyze the clinical features, the penetrance and the mode of inheritance of 13 French families with dilated cardiomyopathy using diagnostic criteria recently established by a European collaboration. METHODS: Screening consisted of physical examination, ECG and Echo of all the probands first degree relatives (n = 118). Using major Echo criteria [ejection fraction (EF) < 45% or FS < 25% and left ventricular diameter (LVD) > 117% of the predictive value], or combined minor Echo/ECG criteria, relatives were classified as affected, unknown or healthy. RESULTS: (1) Adult affected relatives (n = 31) were identified with major Echo criteria in 74% of cases, and with combined minor Echo/ECG criteria in 26% of cases. (2) In the unknown relatives (n = 21), the most common abnormality was an isolated left ventricular dilation (67%). (3) Mode of inheritance was autosomal dominant (AD) in 11 families and possibly autosomal recessive in two. (4) In AD families, the penetrance was incomplete in adults (72%), age-related (O.R.: 1.3 per 10 years; 95% CI 1.03-1.56) and sex-related [greater in men (87%) than in women (61%), actuarial survival curve: P<0.002]. (5) Mortality related to end stage heart failure was 2.2 times as high as mortality related to sudden death (11% vs. 5%). CONCLUSIONS: (1) In the absence of a specific phenotype of FDC, the characterization of relatives appears more accurate when minor criteria were added. (2) Since high mortality (16%) and incomplete penetrance frequently give rise to small nuclei of clinically affected and alive relatives per family, the accurate model of penetrance that we proposed might be helpful in the future to enhance the statistical power of linkage analysis in this disease.

Adult↗
PubMed1999

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.

Amino Acid Sequence↗
PubMed1999

Gene delivery to the myocardium by intrapericardial injection.

Several studies have demonstrated the feasibility of gene transfer into the heart muscle. However, all the available data also indicate that the extent of transfection remains limited. As an alternative method to intravascular administration, we have developed a novel strategy which uses the pericardial sac. When a replication-deficient adenovirus containing the cDNA encoding a bacterial beta-galactosidase is injected into the pericardial sac of adult Wistar rats the staining is exclusively restricted to the pericardial cell layers. However, injecting a mixture of collagenase and hyaluronidase together with the virus, leads to a large diffusion of the transgene activity, reaching up to 40% of the myocardium. Transgene expression is predominant in the left ventricle and the interventricular septum but limited in the right ventricle. In vivo echocardiographic measurements of the left ventricular diameters at end diastolic and end systolic times show no difference between virus- and sham-injected animals, thus indicating a good clinical tolerance to this strategy of virus delivery. The same protocol has been used with the same efficiency in mice, which leads us to propose injection into the pericardial sac as an effective and harmless method for gene transfer into the heart muscle.

Adenoviridae↗
PubMed1999

Myoblast transplantations lead to the expression of the laminin alpha 2 chain in normal and dystrophic (dy/dy) mouse muscles.

Laminin-2 is part of the basement membrane of the skeletal muscle fibers. The laminin alpha 2 chain is absent or drastically reduced in a subgroup of congenital muscular dystrophy patients, and in the severely affected dystrophic dy/dy mouse. We previously reported that heterogeneous primary mouse muscle cell cultures conferred laminin alpha 2 chain expression in dy/dy mice muscles upon cell transplantation. In the present study we investigated whether pure myoblast cell lines were able to confer laminin alpha 2 chain expression in vivo. We observed that: (1) xeno-transplantation of non-immortalized human myoblast in SCID mouse muscles allows human laminin alpha 2 chain expression; (2) allotransplantation of the permanent G8 mouse myoblast cell line in dy/dy muscles allows the expression of the murine laminin alpha 2 chain; and (3) allo-transplantation of the D7 dystrophic dy/dy cell line allows the formation of new and hybrid muscle fibers in dy/dy muscle in the absence of laminin alpha 2 chain expression. We conclude that normal myoblasts are able to restore the expression of an extracellular skeletal muscle protein and that the absence of laminin-2 does not prevent transplanted muscle cells from participating in the formation of myofibers. Myoblasts are, therefore, attractive tools for further exploration of gene complementation strategies in the animal models of congenital muscular dystrophy.

Animals↗
PubMed1999

Short communication: developmental control of Xa21-mediated disease resistance in rice.

The rice resistance gene Xa21 confers resistance against the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). The molecular genetic mechanism controlling the integration of the Xa21-mediated disease resistance response with the developmental program in rice is under study in this model system. Reproducible means of infecting plants at certain developmental stages were designed based on the timing of full expansion of the leaf. Xa21-resistance progressively increases from the susceptible juvenile leaf 2 stage through later stages, with 100% resistance at the adult leaf 9/10 stage. We found that Xa21 expression is independent of plant developmental stage, infection with Xoo, or wounding. Expression of the Xa21 gene transcript is not correlated with expression of Xa21 disease resistance indicating that the developmental regulation of Xa21-resistance is either controlled post-transcriptionally or by other factors.

Gene Expression↗
PubMed1999

Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene. CARDIGENE group.

BACKGROUND: Idiopathic dilated cardiomyopathy is a frequent cause of heart failure, a major concern of public health. Although idiopathic dilated cardiomyopathy may be familial, most cases are sporadic and the disease is considered to be multifactorial, for which genetic factors may account for a significant part. METHODS AND RESULTS: We hypothesized that genetic abnormalities of the endothelin pathway may be involved in idiopathic dilated cardiomyopathy pathophysiology and therefore examined the possible association between idiopathic dilated cardiomyopathy and polymorphisms in genes encoding endothelin 1, endothelin type A and type B receptors, in a case-control study (433 patients and 400 age- and sex-matched control subjects). Analysis of the Exon 8 C/T polymorphism in the endothelin receptor type A gene indicated that individuals who are homozygote for the T allele were at significantly increased risk for the disease (odds ratio: 1.9; 95% confidence interval: 1.2 to 3. 01;P<0.006). Analysis of the other polymorphisms indicated that no significant difference was observed in genotype or allele frequencies between cases and controls. CONCLUSIONS: The variant in the Exon 8 of the endothelin receptor type A gene appears as a genetic risk factor for idiopathic forms of heart failure. These results provide a new approach to the pathophysiology of idiopathic dilated cardiomyopathy.

Adult↗
PubMed1999

The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.

The ABC1 transporter was identified as the defect in Tangier disease by a combined strategy of gene expression microarray analysis, genetic mapping, and biochemical studies. Patients with Tangier disease have a defect in cellular cholesterol removal, which results in near zero plasma levels of HDL and in massive tissue deposition of cholesteryl esters. Blocking the expression or activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured cells, and increasing expression of ABC1 enhances it. ABC1 expression is induced by cholesterol loading and cAMP treatment and is reduced upon subsequent cholesterol removal by apolipoproteins. The protein is incorporated into the plasma membrane in proportion to its level of expression. Different mutations were detected in the ABC1 gene of 3 unrelated patients. Thus, ABC1 has the properties of a key protein in the cellular lipid removal pathway, as emphasized by the consequences of its defect in patients with Tangier disease.

ATP Binding Cassette Transporter 1↗
PubMed1999

Detection of Lawsonia intracellularis in swine using polymerase chain reaction methodology.

The polymerase chain reaction (PCR) was evaluated for its usefulness as a diagnostic tool to detect Lawsonia (ileal symbiont) intracellularis. Porcine ilea were collected from swine cases submitted to the Iowa State University Veterinary Diagnostic Laboratory between December 1, 1994, and June 30, 1995. Sampling was random, with no regard to health status. There were 621 ileum scrapings evaluated using the PCR technique. Thirty-five of the samples were positive, either by PCR or conventional diagnostic methods such as histology and Warthin-Starry silver stain. These 35 samples were further evaluated by Warthin-Starry silver stain and indirect immunofluorescent antibody test (IFAT) to confirm the presence of L. intracellularis in the tissue sections. Of the 26 samples positive by PCR, 22 were positive by IFAT. Sixteen of the 22 were also positive when stained with Warthin-Starry and evaluated microscopically for typical bacteria. Nine of the original samples were negative by all 3 techniques. PCR appears more sensitive and specific for L. intracellularis detection than Warthin-Starry stain and IFAT. This study provides evidence that PCR may be useful as a reference standard for the detection of L. intracellularis. PCR may be an appropriate monitoring tool for swine herds because it is a rapid procedure that could be applied to batch testing. Although the test is currently too laborious and expensive for routine diagnostic use, there may be situations in which it is justified because of the advantages of greater sensitivity and specificity.

Age Factors↗
PubMed1999

Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous autosomal dominant disease, caused by mutations in several sarcomeric protein genes. So far, seven genes have been shown to be associated with the disease with the beta-myosin heavy chain (MYH7) and the cardiac myosin binding protein C (MYBPC3) genes being the most frequently involved. We performed electrocardiography (ECG) and echocardiography in 15 subjects with hypertrophic cardiomyopathy from a French Caribbean family. Genetic analyses were performed on genomic DNA by haplotype analysis with microsatellite markers at each locus involved and mutation screening by single strand conformation polymorphism analysis. Based on ECG and echocardiography, eight subjects were affected and presented a classical phenotype of hypertrophic cardiomyopathy. Two new mutations cosegregating with the disease were found, one located in the MYH7 gene exon 15 (Glu483Lys) and the other in the MYBPC3 gene exon 30 (Glu1096 termination codon). Four affected subjects carried the MYH7 gene mutation, two the MYBPC3 gene mutation, and two were doubly heterozygous for the two mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than in the other affected subjects. We report for the first time the simultaneous presence of two pathological mutations in two different genes in the context of familial hypertrophic cardiomyopathy. This double heterozygosity is not lethal but is associated with a more severe phenotype.

Adult↗