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D St Clair

Publications and source records attributed to D St Clair.

At least 55 records · Page 3Linked to original sources
PubMed1999

No evidence of linkage disequilibrium between a CAG repeat in the SCA1 gene and schizophrenia in Caucasian and Chinese schizophrenic subjects.

Several recent studies have reported evidence for a schizophrenia locus on chromosome 6p, with a variety of linked markers spanning a approximately 40 cM region between D6S470 and D6S291. However because of the wide region implicated and the difficulty of inferring phenotype from genotype in complex disorders, it is difficult to define its location precisely using linkage data. An alternative approach is to search for linkage disequilibrium. On chromosome 6p, allelic association with a (CAG)29 allele of a triplet repeat marker in the SCA1 gene has been reported, and we have attempted to replicate this finding using a Caucasian case-control sample of 211 affected subjects and 204 controls, and a Han Chinese sample of 100 affected family trios. In the case-control sample, the frequency of the (CAG)29 allele was similar in cases and controls (35%), and no other alleles provided evidence for allelic association. Likewise, there was no evidence for preferential transmission of the (CAG)29 allele to affected offspring in the Chinese sample, although a different allele, (CAG)26, was more often transmitted to the affected offspring. However this data did not reach statistical significance (P = 0.1). We conclude that our data does not support the notion that there is a locus for schizophrenia close to the SCA1 gene. However, since linkage disequilibrium will vary between distinct populations, we cannot exclude this possibility.

Asian People↗
PubMed1999

Tentative association of the serotonin transporter with schizophrenia and unipolar depression but not with bipolar disorder in Han Chinese.

The serotonin transporter gene (SERT) plays an important role in the serotonin uptake into neurons. Recently, several polymorphisms including a variable-number-tandem-repeat (VNTR) in the second intron and an insertion/deletion polymorphism (5-HTT linked polymorphic region, 5-HTTLPR) were identified and reported to be associated with a variety of mental illnesses, including major depression, bipolar disorder, anxiety-related traits, and autism. In our study, we performed an association study between the SERT VNTR polymorphism and schizophrenia (n = 260), bipolar disorder (n = 137), and unipolar depression (n = 33) in the Han Chinese. A large group of ethnically matched control individuals (n = 362) were also genotyped. Allele 12 of the VNTR polymorphism was associated with schizophrenia (P = 0.007) and unipolar depression (P = 0.011). Bipolar disorder was not associated with the VNTR (P = 0.93). Thus, we conclude that the SERT VNTR polymorphism may be a risk factor for both schizophrenia and unipolar depression, but not for bipolar disorder, in the Han Chinese.

Alleles↗
PubMed1998

Manganese superoxide dismutase overexpression attenuates MPTP toxicity.

There is substantial evidence implicating mitochondrial dysfunction and free radical generation in the neurotoxicity of MPTP. Manganese superoxide dismutase (MnSOD) is the primary antioxidant enzyme protecting against superoxide radicals produced within mitochondria. Overexpression of human MnSOD in transgenic mice resulted in increased MnSOD localized to mitochondria in neurons and a 50% increase in total MnSOD activity in brain homogenates. We found that MPTP toxicity was significantly attenuated in the MnSOD transgenic mice which overexpress the human manganese superoxide dismutase gene, with these mice showing threefold greater dopamine levels than controls following MPTP. There were no alterations in MPP+ levels, suggesting that the effects were not due to altered metabolism of MPTP. A significant increase in 3-nitrotyrosine levels was seen in littermate controls but not in transgenic mice overexpressing human MnSOD. These results provide further evidence implicating mitochondrial dysfunction and oxidative damage in the pathogenesis of MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Use of transfected liver cells to evaluate potential mechanisms of alcohol-induced liver injury.

There is increased activity of the proinflammatory cytokine, tumor necrosis factor (TNF) in alcoholic liver disease (ALD). Hepatic neutrophil infiltration is a principal injurious manifestation of ALD. TNF can induce cellular oxidative injury directly, and indirectly by inducing neutrophil chemotactic factor (IL-8) production by hepatocytes. IL-8 activates and chemotactically attracts neutrophils to the liver where they release oxidizing substances. Patients with ALD also have decreased protective factors for cellular oxidative injury. Manganous superoxide dismutase (MnSOD) is an antioxidant protective factor. The objectives of these studies were to investigate mechanisms for induction of an injurious factor (IL-8) and a protective factor (MnSOD) in the HepG2 human hepatoma cell line. In the first set of experiments, IL-8 gene reporter constructs were used to transiently transfect a derivative (MVh2E1-9) of the HepG2 cell line which expresses P-4502E1 and metabolizes ethanol. Inactivation of the NF-kappaB and 3'NF-IL-6 DNA binding sites decreased IL-8 gene transcriptional activation in response to TNF while inactivation of the 5'NF-IL-6 binding site increased IL-8 gene transcriptional activity in response to TNF. This system may be useful to assess the effects of ethanol on TNF-induced hepatocyte IL-8 production. In the second set of experiments, HepG2 cells were cultured in 25 to 100 mmol concentrations of ethanol. Both TNF and ethanol increased HepG2 cell MnSOD activity in short-term (72 hr) cultures with ethanol. However, after long-term (10 weeks) culture with ethanol, there was no induction of MnSOD by ethanol and there was a diminished induction of MnSOD in response to TNF. Further studies are needed to assess the effect of this diminished induction of MnSOD with chronic ethanol culture on HepG2 cell susceptibility to TNF cytotoxicity. We conclude that transfected liver cell lines can be used to evaluate mechanisms for increased injurious factors and decreased protective factors in alcoholic liver injury.

Animals↗
PubMed1997

A polymorphism in the presenilin 1 gene does not modify risk for Alzheimer's disease in a cohort with sporadic early onset.

Mutations in the presenilin 1 gene account for many cases of early onset familial Alzheimer's disease. Homozygosity for the 'T' allele of a polymorphism in the presenilin 1 gene has previously been reported to double the risk for Alzheimer's disease in a late onset Caucasian sample. Here we report that this polymorphism does not incur risk in a case control sample of early onset Alzheimer's disease, possibly suggesting a different disease etiology between the early and late onset forms.

Adult↗
PubMed1997

Apolipoprotein E gene in Parkinson's disease, Lewy body dementia and Alzheimer's disease.

Apolipoprotein E (Apo E) epsilon 4 allele is a risk factor for early and late onset Alzheimer's disease. This prompted us to examine other neurophyschiatric phenotypes. Epsilon 4 allele was significantly enriched in Lewy body dementia (n = 39) but not in Parkinson's disease (n = 50) or Schizophrenia (n = 175) compared to aged non-demented controls (n = 47) and the Scottish population (n = 400). We conclude that Lewy body disease should be regarded as a variant of Alzheimer's but not Parkinson's disease.

Aged↗
PubMed1997

Lack of association between schizophrenia and a polymorphism close to the cytosolic phospholipase A2 gene.

Biochemical studies have shown that a proportion of schizophrenics have an abnormal fatty acid composition in their red blood-cell membrane phospholipids and it has been suggested that this might be due to altered levels of the enzyme phospholipase A2 (PLA2). A recent report indicated that there was an association between schizophrenia and alleles of a poly-A repeat polymorphism close to the 5' end of the PLA2 gene. We report the analysis of this polymorphism in a series of 58 schizophrenic patients and 56 controls and find no evidence for allelic association.

Alleles↗
PubMed1995

Pediatric arsenic ingestion.

Acute arsenic toxicity is rare, and there have been no pediatric cases of acute arsenic poisoning in the recent literature. We report a pediatric case of acute arsenic ingestion treated initially with British antilewisite (BAL) and D-penicillamine (DP), and later with dimercaptosuccinic acid (DMSA). A 22-month-old girl ingested 1 oz 2.27% sodium arsenate and developed immediate vomiting and diarrhea. The patient presented to a community emergency department with the following vital signs: blood pressure 96/72 mm Hg, pulse 160 beats/min, respirations 22 breaths/min. She was pale and lethargic. Gastric lavage was performed, and abdominal X-ray was normal. She continued to have gastrointestinal symptoms and received 3 mg/kg BAL. Sinus tachycardia persisted, with heart rate increasing to 200 beats/min. In 12 hours, she was asymptomatic and was started on oral DP. On day 1, 24-hour urine arsenic was 4,880 micrograms/L. She remained asymptomatic and was discharged on day 6 on oral DP. She did well except for a rash that could have been a side effect of DP. On day 8, when the day 5 24-hour urine arsenic level was returned at 650 micrograms/L, the patient was readmitted and started on DMSA. After 4 days on DMSA, the 24-hour urine arsenic level was 96 micrograms/L. White blood cell count and renal and hepatic function remained normal. The excretion half-life was approximately 2.5 days, which is at least 2 to 3 times faster than the spontaneous excretion half-life expected in adults. Long-term follow-up was unavailable.(ABSTRACT TRUNCATED AT 250 WORDS)

Arsenates↗
PubMed1995

Hereditary multi-infarct dementia unlinked to chromosome 19q12 in a large Scottish pedigree: evidence of probable locus heterogeneity.

Hereditary multi-infarct dementia is a rare autosomal dominant disorder that predominantly affects the cerebral white matter. A locus was recently mapped in French pedigrees to chromosome 19q12. We have examined a large Scottish pedigree with neuropathologically confirmed hereditary multi-infarct dementia using polymorphic DNA markers spanning the 19q12 region and found no evidence of linkage. This suggests that, as in familial Alzheimer's disease, there is more than one locus.

Adult↗
PubMed1995

Apolipoprotein E epsilon 4 allele is a risk factor for familial and sporadic presenile Alzheimer's disease in both homozygote and heterozygote carriers.

While apoliprotein E (ApoE) epsilon 4 allele is now a well established risk factor for familial and sporadic senile Alzheimer's disease (AD), its role in the development of the rarer presenile or early onset type is controversial. Early studies showed no association; later ones found enrichment for the epsilon 4 allele in familial or sporadic types or both. We have ApoE genotyped a series of Scottish people (n = 85) with early onset AD. We find highly significant enrichment for both homozygote and heterozygote ApoE epsilon 4 allele carriers in familial and sporadic early onset AD with a pattern closely resembling that in late onset AD.

Age of Onset↗
PubMed1995

High-resolution mapping of SNCA encoding alpha-synuclein, the non-A beta component of Alzheimer's disease amyloid precursor, to human chromosome 4q21.3-->q22 by fluorescence in situ hybridization.

The human alpha-synuclein gene (SNCA) was previously identified as the non-A beta component of Alzheimer's disease amyloid precursor (NACP). A cosmid clone containing this gene has been isolated and mapped by FISH and high-resolution fluorescence banding to human chromosome 4q21.3-->q22.

Amyloid↗
PubMed1995

Seeding of YACs over regions 1q41-q42.3 and 11q14.3-q23 with microdissection clones.

We describe the use of pooled, region-specific hybridisation probes to screen high-density replica filters of a human genome YAC library. The probes were derived by microdissection of an approximately 30-Mbp region subtending the translocation breakpoint on a der(1)(1;11)(q42.1;q14.3) chromosome. Of 70 microdissection clones used in pools of 4-10, 47 identified a total of 77 YAC recombinants, representing over 50% of the microdissected region. This strategy can easily be adapted to other poorly mapped subchromosomal regions of the human or other mammalian genomes and will provide a solid framework for detailed contig map constructions.

Chromosomes, Artificial, Yeast↗
PubMed1995

Apolipoprotein E genotype and its effect on duration and severity of early and late onset Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele is associated with an increased risk of senile and probably presenile Alzheimer's disease. It is not yet clear whether the epsilon 4 allele also influences the duration/rate of progress of illness and the severity of the dementia. METHOD: We have retrospectively examined a series of ApoE genotyped presenile and senile autopsy cases of Alzheimer's disease (AD) for length of illness and severity of pathology. RESULTS: We find no evidence that ApoE genotype affects the rate of progress of AD, but the degree of pathology at death may be increased. CONCLUSION: It appears that the rate of progress of AD as a whole is independent of the ApoE genotype.

Adult↗
PubMed1994

Apolipoprotein E epsilon 4 allele frequency in patients with Lewy body dementia, Alzheimer's disease and age-matched controls.

Genotypes of apolipoprotein E (ApoE) were determined by polymerase-chain reaction (PCR) amplification and restriction-sizing of brain DNA from 39 cases of Lewy body dementia (LBD), 68 senile Alzheimer's disease (AD) patients and 47 neuropathologically validated non-demented controls. There was a 3-fold increase in the epsilon 4 allele frequency in both LBD and AD groups compared with controls. These results indicate that LBD and AD share the epsilon 4 allele of ApoE as a major risk factor for the development of disease and suggest a similarity in disease aetiology.

Aged↗
PubMed1994

Molecular biology of schizophrenia.

To date, the molecular biology of and the genes responsible for schizophrenia are unknown. However, the powerful techniques for gene mapping and mutation analysis now available mean the situation should change and it is likely that a variety of genes involved in schizophrenia are likely to be mapped, cloned and characterized within the next few years. Initial over-optimism should not be replaced by pessimism as to the future prospects.

Genetic Linkage↗
PubMed1994

Synuclein proteins and Alzheimer's disease.

In Alzheimer's disease, synuclein/NAC (non-amyloid beta component of Alzheimer's disease amyloid) proteins are found in presynaptic cholinergic nerve terminals that degenerate early in Alzheimer's disease, and they are also found closely linked to beta-amyloid fibrils in senile plaques. Synuclein/NAC proteins provide a potential molecular link between the degeneration of cholinergic nerve terminals, and the formation of plaques, and might have a primary role in their development.

Alzheimer Disease↗
PubMed1994

Screening schizophrenic patients for mutations in the amyloid precursor protein gene.

A limited number of rare missense mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene have been reported. They are associated with a variety of phenotypes including cerebral haemorrhage, multi-infarct dementia and Alzheimer's disease. We recently reported an alanine to valine mutation in codon 713 in a single case of chronic familial schizophrenia with cognitive deficits. Using denaturing gradient gel electrophoresis (DGGE) we have screened a cohort of 250 chronic schizophrenics for further mutations of exons 7, 16 and 17. None were found. Nevertheless recent evidence suggests that the 713 mutation is indeed pathogenic for the clinical phenotype observed; the mechanisms involved are outlined.

Amyloid beta-Protein Precursor↗