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Biomedical subjects

J A Buchanan

Publications and source records attributed to J A Buchanan.

At least 37 records · Page 2Linked to original sources
PubMed1995

Association study between the dopamine D4 receptor gene and schizophrenia.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Female↗
PubMed1995

Linkage analysis of the nail-patella syndrome.

Nail-patella syndrome (NPS) is an autosomal dominant disorder characterized by dysplasia of nails and patella, decreased mobility of the elbow, iliac horns, and, in some cases, nephropathy. The disorder has been mapped to the long arm of chromosome 9, but the precise localization and identity of the NPS gene are unknown. Linkage analysis in three NPS families, using highly informative dinucleotide repeat polymorphisms on 9q33-q34, confirmed linkage of NPS to this chromosome. Recombinations were detected, by two-point linkage analysis, between NPS and the centromeric markers D9S60 and the gelsolin gene and the telomeric markers D9S64 and D9S66, in one of the families. Haplotype analysis suggested an additional recombination between NPS and the argininosuccinate synthetase (ASS) gene. These results localize the NPS gene to an interval on 9q34.1, distal to D9S60 and proximal to ASS, comprising a genetic distance of approximately 9 cM. This represents a significant refinement in the localization of the NPS gene.

Chromosome Mapping↗
PubMed1994

Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex.

Spectrin is a major component of a membrane-associated cytoskeleton involved in the maintenance of membrane structural integrity and the generation of functionally distinct membrane protein domains. Here, we show that a homolog of erythrocyte beta-spectrin (beta I sigma*) co-localizes with markers of the Golgi complex in a variety of cell types, and that microinjected beta-spectrin codistributes with elements of the Golgi complex. Significantly, we show a dynamic relationship between beta-spectrin and the structural and functional organization of the Golgi complex. Disruption of both Golgi structure and function, either in mitotic cells or following addition of brefeldin A, is accompanied by loss of beta-spectrin from Golgi membranes and dispersal in the cytoplasm. In contrast, perturbation of Golgi structure without a loss of function, by the addition of nocodazole, results in retention of beta-spectrin with the dispersed Golgi elements. These results indicate that the association of beta-spectrin with Golgi membranes is coupled to Golgi organization and function.

Animals↗
PubMed1994

Molecular genetic predictive testing for Alzheimer's disease: deliberations and preliminary recommendations.

Forty-one participants representing diverse professional back-grounds attended a workshop on genetic predictive testing for familial Alzheimer's disease (FAD) on January 23, 1993 at Surrey Place Centre in Toronto, Canada. Rapidly emerging molecular genetic findings in AD indicate that predictive testing is now technologically feasible for selected individuals, although defining eligibility criteria remains problematic. Legal, ethical, biomedical, and psychosocial issues related to establishing predictive testing programs for AD were discussed at the workshop. This article reflects these discussions, provides the current biomedical background for them and examines the Huntington's disease (HD) predictive testing experience. Observations concerning molecular genetic predictive testing for AD in light of its genetic heterogeneity and clinical characteristics, such as usual later age of onset than HD, are presented. It is proposed that predictive testing for AD can now be cautiously offered in a research setting primarily according to the recommendations contained within the Ethical Issues Policy Statement on Huntington's Disease Molecular Genetics Predictive Test. However, in their application to AD, some points in the statement are considered to require emphasis, modification, or currently to be of uncertain applicability. This represents an initial step in an on-going process of debate concerning AD that will be required as new advances occur in genetic and clinical research and in bioethics.

Aged↗
PubMed1994

Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development.

Between 1980 and 1988, displacement bone-marrow transplantation was performed on 25 children with Hurler's syndrome (type-1 mucopolysaccharidosis). We describe the musculoskeletal development of 11 of the 12 surviving children and the orthopaedic procedures undertaken to treat progressive thoracolumbar kyphosis, hip subluxation and carpal tunnel syndrome. We found abnormal bone modelling, focal failures of ossification and an avascular disorder of the femoral head in every patient and offer an explanation for these phenomena. Increasing valgus deformity of the knees and progressive generalised myopathy caused loss of mobility as the children entered adolescence. The benefit of bone-marrow transplantation as a treatment for the skeletal disorders of Hurler's syndrome is limited by the poor penetration of the musculoskeletal tissues by the enzyme derived from the leucocytes.

Bone Marrow Transplantation↗
PubMed1993

Mortality of workers at the Hanford site: 1945-1986.

Updated analyses of mortality of workers at the Hanford site provide little evidence of a positive correlation of cumulative occupational radiation dose and mortality from leukemia and from all cancer except leukemia. Estimates of the excess relative risk per 10 mSv were negative for both disease categories, but these estimates are consistent both with no risk and with estimates obtained through extrapolation from high-dose data. For all cancer except leukemia, the upper limit for a two-sided 90% confidence interval was about 1.5 times the prediction of the BEIR V model, but several times the estimate recommended by the ICRP 60 committee. For leukemia, the comparable upper limit was very close to that predicted by either BEIR V or ICRP 60. The all-cancer risk estimate, from a recent report on updated analyses of data for Oak Ridge National Laboratory workers, was strongly rejected based on the Hanford data. Of 24 specific cancer categories evaluated, only cancer of the pancreas and Hodgkin's disease showed positive correlations with radiation dose that approached statistical significance with one-tailed p values of 0.07 and 0.04, respectively; these correlations are interpreted as probably spurious. For multiple myeloma, for which a correlation was reported previously, the p value was 0.10. However, a significant correlation (p < .05) was obtained when analyses were expanded to include deaths with multiple myeloma listed on the death certificate but not considered to be the underlying cause, when analyses were expanded to include deaths occurring in Washington State during the time period 1987-1989, or when a 2-y latency period (instead of 10-y) was assumed.

Adult↗
PubMed1991

Isolation and regional localization of 25 anonymous DNA probes on a chromosome 13 hybrid panel.

Clones were isolated from two flow-sorted chromosome 13 libraries. Twenty-five clones were localized to various regions of chromosome 13, using a well-characterized panel of rodent x human hybrid cell lines. Eight DNA markers were localized to 13q14.2----q22, where the gene for Wilson disease, a recessive disorder of copper metabolism, was previously assigned. The new markers will be useful for the diagnosis of presymptomatic sibs of Wilson disease patients. We isolated six DNA clones proximal to the retinoblastoma gene, a region in which a translocation associated with rhabdomyosarcoma has been observed. Probes for both of these regions will be useful for the cloning of the genes involved in these diseases.

Animals↗
PubMed1990

A case-cohort study of lung cancer, ionizing radiation, and tobacco smoking among males at the Hanford Site.

Results of several epidemiological studies of workers exposed occupationally to low levels of radiation have been reported but have not included data on smoking. The authors conducted a case-cohort study of male workers at the Hanford Site with an objective of investigating the association between lung-cancer risk and occupational radiation exposure with appropriate adjustment for tobacco use. Eighty-six lung-cancer deaths for the period 1965-1980 and a stratified random sample of 445 subcohort members were included in the study. Tobacco-use data were obtained from medical records collected over each subject's period of employment. Data from this study were analyzed using methods that took into account both the case-cohort design and changes over time in the quality of the tobacco-use data collected. Tobacco use was not strongly related to the level of radiation exposure, and adjustment for tobacco use did not greatly modify results of analyses assessing the association between lung-cancer risk and cumulative dose equivalent. With or without adjustment for tobacco use, the estimated risks per unit of cumulative dose equivalent were negative, but the 95% confidence intervals were wide and included values several times those estimated from populations with high levels of irradiation.

Cohort Studies↗
PubMed1990

Transformed sweat gland and nasal epithelial cell lines from control and cystic fibrosis individuals.

We undertook to extend the in vitro lifespan of epithelial cell cultures useful for the study of the cellular defect underlying cystic fibrosis (CF). Primary cultures from sweat glands of four CF and four non-CF and from nasal polyps of one non-CF and two CF individuals were transformed using a chimaeric virus, Ad5/SV40 1613 ori-. The extended lifespans ranged from 20 to more than 250 population doublings beyond that of the primary cultures. Despite some degree of aneuploidy (as assayed by total cellular DNA content) all samples tested retained at least one copy of the region of chromosome 7 containing the CF gene (as assayed by probing with flanking DNA markers). Epithelial characteristics, including an epithelioid morphology, tight junctions and desmosomes, apical microvilli, keratin networks, and dome formation were positive in the majority of cells examined, although variably expressed. All cells tested demonstrated outwardly rectifying chloride channels by patch clamp, with some from non-CF cells responsive to the catalytic subunit of cyclic AMP-dependent protein kinase. The cells were used for DNA transfection assays with selectable marker genes in appropriate vectors, in order to develop methodology for assaying the function of the CF gene product and the effects of mutations.

Cell Division↗
PubMed1990

Part II: Sex differences in persons found not guilty by reason of insanity: analysis of data from the Connecticut NGRI Registry.

Thirty-one female insanity acquittess from Connecticut were matched to a group of 31 male NGRIs. The samples were compared with regard to demographic, criminal, and clinical characteristics. Logistic regression analyses were used to determine predictors of criminal recidivism for the sample. Results indicated that women NGRIs were older, more likely to be married, less likely to be substance abusers, had less extensive criminal records, and were released from hospitals sooner than the men. A significant racial difference was noted: white women had less extensive criminal records and were hospitalized for shorter periods than minority women. Results of the logistic regression analyses showed that the strongest independent predictors of criminal recidivism were race and having a diagnosis other than psychosis (schizophrenia, affective or organic disorders). Findings support recent APA policy guidelines on the insanity defense.

Adult↗
PubMed1989

Identification of the cystic fibrosis gene: genetic analysis.

Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.

Alleles↗
PubMed1989

Mortality of workers at the Hanford site: 1945-1981.

Analyses of mortality of workers at the Hanford Site were updated to include an additional three years of data (1979-81). Deaths occurring in the state of Washington in the years 1982-85 were also evaluated. Hanford workers continued to exhibit a strong healthy worker effect with death rates substantially below those of the general U.S. population. Comparisons by level of radiation exposure within the Hanford worker population provided no evidence of a positive correlation of radiation exposure and mortality from all cancers combined or of mortality from leukemia. Estimates of cancer risk due to radiation were negative, but confidence intervals were wide, indicating that the data were consistent with no risk and with risks several times larger than estimates provided by major groups concerned with risk assessment. Of 18 categories of cancer analyzed, a correlation of borderline statistical significance was identified for female genital cancers (p = 0.05), but was interpreted as probably spurious. The previously identified correlation for multiple myeloma persisted (p = 0.002).

Environmental Exposure↗
PubMed1989

DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis.

Patients with cystic fibrosis (CF) generally suffer from chronic obstructive lung disease, pancreatic insufficiency (PI), and a number of other exocrine malfunctions. Approximately 15% of CF patients are, however, pancreatic sufficient. To investigate whether the two clinical subgroups, PI and pancreatic sufficiency (PS), are caused by different CF mutant alleles, we have performed linkage disequilibrium and haplotype association analysis with three DNA markers that are tightly linked to the CF locus. The study showed that the allelic and haplotype distributions for these RFLPs are significantly different between the two groups. The data suggest that most of the CF-PI patients are probably descendants of a single mutational event at the CF locus and that the CF-PS patients resulted from multiple, different mutations. While final interpretation of these data awaits molecular cloning of the CF gene, the information on haplotype association in CF may be useful in genetic counseling and disease prognosis, in identifying the gene itself, and in defining the mutations.

Adolescent↗