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Biomedical subjects

K Silver

Publications and source records attributed to K Silver.

At least 37 records · Page 2Linked to original sources
PubMed1996

Molecular scanning for mutations in the beta 3-adrenergic receptor gene in Nauruans with obesity and noninsulin-dependent diabetes mellitus.

We recently identified a mutation in the human beta 3-adrenergic receptor (beta 3AR) gene (codon 64 TGGTrp -> CGGArg; TRP64ARG) that associates with features of the insulin resistance syndrome and an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM). We scanned the beta 3AR gene for mutations by single stranded conformational polymorphism analysis in 20 Nauruans with obesity and NIDDM. No mutations were identified. Sixty-five Nauruan subjects were genotyped for the TRP64ARG beta 3AR. All subjects were homozygous for the normal allele. We genotyped Samoans and Asians for the TRP64ARG beta 3AR. Seven of 52 Samoans were heterozygous for the mutant arginine allele (allele frequency, 0.07). Of these, 5 were diabetic and 2 were nondiabetic (by Fisher's exact test, P = 0.4). There were trends toward increased body mass indices, waist to hip ratios, and 2-h insulin levels during oral glucose tolerance tests in Samoans with the mutation; however, the limited number of subjects available for study precluded rigorous statistical analysis. The TRP64ARG beta 3AR was also detected in Chinese, Chinese Americans, and subjects from the Indian subcontinent. In conclusion, the TRP64ARG beta 3AR mutation or any other mutation in the beta 3AR gene is not a major contributor to genetic susceptibility to NIDDM and obesity likely in Nauruans.

Adult↗
PubMed1995

A mutation in the beta 3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects.

The Trp 64 Arg mutation in the beta 3-adrenergic receptor (beta 3AR) gene was investigated in 350 Japanese subjects. This mutation was not associated with non-insulin-dependent diabetes mellitus (NIDDM). In 191 subjects without NIDDM, body mass index (BMI) was significantly higher in subjects homozygous for this mutation than in those homozygous for the normal allele (24.7 +/- 1.4 vs 22.1 +/- 0.2 kg/m2, p = 0.009). Moreover, the frequency of the mutant allele in obese subjects (BMI > 26.4) was significantly higher than that in non-obese subjects (BMI < 22) (0.37 vs 0.15, p = 0.009). The presence of this mutation was also accompanied by significantly higher fasting (p = 0.000) and 2 hrs (p = 0.018) serum insulin levels during an oral glucose tolerance test. The beta 3AR may be one of the loci contributing to obesity and hyperinsulinemia/insulin resistance in Japanese subjects.

Adult↗
PubMed1995

Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene.

BACKGROUND: The beta 3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis. METHODS: To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). RESULTS: A missense mutation was identified in the gene for the beta 3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/- SD) age at the onset of NIDDM was significantly lower (36 +/- 10 years) than in Trp64Arg heterozygotes (40 +/- 10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance). CONCLUSIONS: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Adult↗
PubMed1995

Pelizaeus-Merzbacher disease in a family of Portuguese origin caused by a point mutation in exon 5 of the proteolipid protein gene.

Single-strand conformational polymorphism analysis of an affected male with Pelizaeus-Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G-->A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435-442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes.

Child, Preschool↗
PubMed1995

Association of cerebral dysgenesis and lactic acidemia with X-linked PDH E1 alpha subunit mutations in females.

We describe an infant girl who presented at age 4 1/2 months with developmental delay, infantile spasms, hypotonia, and elevated lactate levels in the blood and cerebrospinal fluid. She had minor dysmorphic features. Muscle phosphorus magnetic resonance spectroscopy demonstrated reduced phosphocreatine and increased inorganic phosphate, suggesting a defect in oxidative energy metabolism. Pyruvate dehydrogenase activity in cultured fibroblasts was reduced (0.35 nmol/mg mitochondrial protein/min; controls 0.7-1.1 nmol/mg mitochondrial protein/min). Immunoblotting demonstrated a reduced amount of pyruvate dehydrogenase (PDH) E1 alpha immunoreactive protein with normal amounts of E2 protein. Single-strand conformational polymorphism analysis of E1 alpha cDNA prepared from fibroblasts disclosed an abnormal migration pattern, suggesting heterozygosity for a mutant allele. Dideoxy-fingerprinting of PCR-amplified genomic DNA was used to localize the mutation to exon 10. Direct sequencing demonstrated a novel 13-bp insertion mutation that would lead to premature termination of the protein product. This study further extends the allelic heterogeneity underlying PDH deficiency. The demonstration of bioenergetic abnormalities in muscle emphasizes that hypotonia in PDH deficiency may have combined peripheral and central etiologies. The results further suggest that the association of cerebral dysgenesis with lactic acidemia in females may be a useful clue to PDH deficiency.

Acidosis, Lactic↗
PubMed1995

Imaging of axonal damage in vivo in Rasmussen's syndrome.

We obtained magnetic resonance spectroscopic images (MRSIs) in three patients with Rasmussen's syndrome. The relative resonance intensity of N-acetylaspartate (NAA) to creatine (NAA:Cr), an index of neuronal loss or damage, was determined for various regions within the brain, and the affected:unaffected hemisphere asymmetry ratio was determined. All three patients had decreased relative NAA signal intensity over the entire affected hemisphere. The decrease in NAA:Cr involved cortex and white matter, was most prominent in the anterior periventricular region, and showed a tendency to be worse in patients with longer duration of disease. 1 year follow-up MRSI showed further reduction of the relative NAA signal in all patients, indicating progression of the disease. All patients were free of seizures for at least 48 h before the first MRSI, but two of them had epilepsia partialis continua (EPC) during the follow-up examination. There was no significant increase of the lactate resonance intensity, except in the two MRSIs performed during EPC. This indicates that lactate accumulation results from repetitive seizures rather than from the disease process itself. The spatial distribution of the metabolic abnormality on MRSI was more widespread than that of the structural abnormality on MRI. The relative NAA resonance intensity was not reduced in the contralateral hemisphere. Our findings indicate that MRSI can identify and quantify neuronal damage and loss throughout the affected hemisphere of patients with Rasmussen's syndrome, including areas that appear normal on conventional MRI.

Adolescent↗
PubMed1995

Lack of IRS-1 codon 513 and 972 polymorphism in Pima Indians.

Insulin receptor substrate-1 (IRS-1), an endogenous substrate for the insulin receptor tyrosine kinase, mediates many or all of the metabolic actions of insulin. Recently, polymorphism at codons 513 and 972 of the IRS-1 gene resulting in 2 amino acid substitutions that were associated with type II diabetes were found in a Caucasian population. Using allele specific oligonucleotide (ASO) hybridization, we screened 242 diabetic and 190 nondiabetic Pima Indians, a population with a very high prevalence of type II diabetes. Neither of the two mutations was present in either diabetic or nondiabetic subjects. We conclude that polymorphism at codons 513 and 972 of the IRS-1 gene observed in certain Caucasian populations is very rare or absent in Pima Indians.

Adult↗
PubMed1994

Fulminant hepatic failure associated with status epilepticus in children: three cases and a review of potential mechanisms.

Fulminant hepatic failure is a rare complication of status epilepticus. Although many of the anticonvulsants used to treat the seizures are known to have hepatotoxic properties, the exact mechanism leading to massive destruction of the liver following a prolonged seizure remains unclear. Three children are presented who developed fulminant hepatic failure following status epilepticus and subsequently died of multiple organ failure. The literature is reviewed with particular attention to the possible interaction between the anticonvulsants and the metabolic consequences of status epilepticus. We postulate that it is a combination of hypoxia and ischemia that occurs during a prolonged seizure with altered metabolism of free radicals secondary to the anticonvulsant drugs which leads to widespread hepatocyte membrane damage.

Anticonvulsants↗
PubMed1994

Human interindividual variability--a major source of uncertainty in assessing risks for noncancer health effects.

For noncancer effects, the degree of human interindividual variability plays a central role in determining the risk that can be expected at low exposures. This discussion reviews available data on observations of interindividual variability in (a) breathing rates, based on observations in British coal miners; (b) systemic pharmacokinetic parameters, based on studies of a number of drugs; (c) susceptibility to neurological effects from fetal exposure to methyl mercury, based on observations of the incidence of effects in relation to hair mercury levels; and (d) chronic lung function changes in relation to long-term exposure to cigarette smoke. The quantitative ranges of predictions that follow from uncertainties in estimates of interindividual variability in susceptibility are illustrated.

Disease Susceptibility↗
PubMed1994

Benign familial nocturnal alternating hemiplegia of childhood.

In infancy, two brothers developed recurrent attacks of alternating or bilateral hemiplegia arising exclusively out of sleep. The episodes were terminated by even brief sleep. Neither child had hypotonia, dystonic attacks, paroxysmal eye movement abnormalities, or other features characteristic of the now-classic form of alternating hemiplegia of childhood (AHC). The development of the brothers has so far remained normal. Both parents have a history of migraine. In the older boy, magnetic resonance spectroscopy (MRS) of muscle showed increased inorganic phosphate similar to what is found in children with AHC. In the younger brother and parents, MRS of muscle was normal. Other investigations were unrevealing. Flunarizine greatly reduced the duration of attacks. This genetically determined disorder represents a specific entity that is probably migraine-related and is easily misdiagnosed as AHC. Because of its benign course, particularly as far as mental development is concerned, it must be distinguished from classic AHC, which has a terrible prognosis.

Adult↗
PubMed1994

Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients.

We treated 19 patients with Rasmussen's syndrome (chronic encephalitis and epilepsy)--a rare progressive disorder of unknown etiology causing focal epilepsy, hemiparesis, and intellectual deterioration--with intravenous immunoglobulins, high-dose steroids, or both, to control seizures and improve the end point of the disease. Ten of 17 patients receiving steroids, and eight of nine patients receiving immunoglobulins, had some reduction of seizure frequency in the short term. Improvement in hemiparesis was slight. The effect of these drugs in ameliorating the end point of the disease in the long term remains unknown, and further multicenter studies with standardized protocols are warranted.

Adolescent↗
PubMed1993

Evidence for mitochondrial dysfunction in patients with alternating hemiplegia of childhood.

Phosphorus magnetic resonance spectra of resting muscle were obtained from 4 patients with alternating hemiplegia of childhood. All patients had abnormally high resonance intensities from inorganic phosphate and an abnormally low calculated cytosolic phosphorylation potential. Two of the 4 patients had abnormally low resonance intensities from phosphocreatine and an abnormally high calculated cytosolic free adenosine diphosphate concentration. These abnormalities are indicative of mitochondrial dysfunction. The combination of a central nervous system disorder and evidence of mitochondrial dysfunction in muscle suggests that alternating hemiplegia of childhood may represent a previously unrecognized phenotype of mitochondrial disease.

Adenosine Diphosphate↗
PubMed1993

Pulmonary artery hypertension in severe aortic stenosis: incidence and mechanism.

We investigated the incidence and mechanism of pulmonary artery hypertension (PAH) in a consecutive series of patients with aortic stenosis who were undergoing diagnostic cardiac catheterization. Forty-five patients with severe aortic stenosis were divided into two groups: group 1 comprised 13 patients (29%) with PAH (pulmonary artery systolic pressure > 50 mm Hg); group 2 comprised 32 patients (71%) without PAH. Group 1 patients had a higher incidence of congestive heart failure, a lower left ventricular ejection fraction and cardiac index, and more mitral regurgitation as compared with group 2 patients. Of the 13 group 1 patients, 8 had a transpulmonary gradient (pulmonary artery mean pressure--pulmonary capillary wedge pressure) > or = 10 mm Hg, consistent with reactive PAH. We conclude that PAH frequently accompanies aortic stenosis and is often reactive.

Acute Disease↗
PubMed1993

Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies.

Localized brain proton MR spectra were acquired from patients with different mitochondrial encephalomyopathies (myoclonus epilepsy with ragged-red fibers [MERRF], Kearns-Sayre syndrome [KSS], and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS]). The regional brain metabolic abnormalities in patients with these syndromes showed different features consistent with the distinct phenotypes. In MERRF, only one of four patients showed an increase in the lactate/creatine resonance intensity ratio (an index of impairment of oxidative metabolism) in spectra from central (supraventricular) or occipital brain volumes, and this was small. There were significant decreases in N-acetylaspartate/creatine (a measure of neuronal loss or dysfunction) in central cerebral volumes of demented patients and, more prominently, in occipital volumes. In the one patient in whom it was studied, the cerebellum also showed a decreased N-acetylaspartate/creatine. Spectra from two patients with KSS both showed large (four- to sevenfold) increases in lactate/creatine and large decreases in N-acetylaspartate/creatine in central brain volumes. Yet another pattern of regional metabolic abnormality was present in the MELAS syndrome, where proton spectroscopic imaging demonstrated focal localization of abnormally increased lactate/creatine and decreased N-acetylaspartate/creatine to the regions of the stroke-like lesions on conventional MR images. Serial studies emphasized that the regional metabolic abnormalities in MELAS are highly variable as the stroke-like lesions appear and evolve.

Aspartic Acid↗