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Biomedical subjects

A Carey

Publications and source records attributed to A Carey.

At least 19 recordsLinked to original sources
PubMed2006

Estimating the duration of common elective operations: implications for operating list management.

Over-running operating lists are known to be a common cause of cancellation of operations on the day of surgery. We investigated whether lists were overbooked because surgeons were optimistic in their estimates of the time that operations would take to complete. We used a questionnaire to assess the estimates of total operation time of 22 surgeons, 35 anaesthetists and 16 senior nursing staff for 31 common, general surgical and urological procedures. The response rate was 66%. We found no difference between the estimates of these three groups of staff, or between these estimates and times obtained from theatre computer records (p = 0.722). We then applied the average of the surgeons' estimates prospectively to 50 consecutive published surgical lists. Surgical estimates were very accurate in predicting the actual duration of the list (r2= 0.61; p < 0.001), but were poor at booking the list to within its scheduled duration: 50% of lists were predictably overbooked, 50% over-ran their scheduled time, and 34% of lists suffered a cancellation. We suggest that using the estimates of operating times to plan lists would reduce the incidence of predictable over-runs and cancellations.

Anesthesiology↗
PubMed2003

Analysis of the IBD5 locus and potential gene-gene interactions in Crohn's disease.

BACKGROUND AND AIMS: Genetic variation in the chromosome 5q31 cytokine cluster (IBD5 risk haplotype) has been associated with Crohn's disease (CD) in a Canadian population. We studied the IBD5 risk haplotype in both British and Japanese cohorts. Disease associations have also been reported for CARD15/NOD2 and TNF variants. Complex interactions between susceptibility loci have been shown in animal models, and we tested for potential gene-gene interactions between the three CD associated loci. METHODS: Family based association analyses were performed in 457 British families (252 ulcerative colitis, 282 CD trios) genotyped for the IBD5 haplotype, common CARD15, and TNF-857 variants. To test for possible epistatic interactions between variants, transmission disequilibrium test analyses were further stratified by genotype at other loci, and novel log linear analyses were performed using the haplotype relative risk model. Case control association analyses were performed in 178 Japanese CD patients and 156 healthy controls genotyped for the IBD5 haplotype. RESULTS: The IBD5 haplotype was associated with CD (p=0.007), but not with UC, in the British Caucasian population. The CARD15 variants and IBD5 haplotype showed additive main effects, and in particular no evidence for epistatic interactions was found. Variants from the IBD5 haplotype were extremely rare in the Japanese. CONCLUSIONS: The IBD5 risk haplotype is associated with British CD. Genetic variants predisposing to CD show heterogeneity and population specific differences.

Adult↗
PubMed2001

Alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons.

The rates of uptake and oxidation of [U-(14)C]lactate and [U-(14)C]glucose were determined in primary cultures of astrocytes and neurons from rat brain, in the presence and absence of the monocarboxylic acid transport inhibitor alpha-cyano-4-hydroxycinnamate (4-CIN). The rates of uptake for 1 mM lactate and glucose were 7.45 +/- 1.35 and 8.80 +/- 1.0 nmol/30 sec/mg protein in astrocytes and 2.36 +/- 0.19 and 1.93 +/- 0.16 nmol/30 sec/mg protein in neuron cultures, respectively. Lactate transport into both astrocytes and neurons was significantly decreased by 0.25-1.0 mM 4-CIN; however, glucose uptake was not affected. The rates of (14)CO(2) formation from 1 mM lactate and glucose were 12.49 +/- 0.77 and 3.42 +/- 0.67 nmol/hr/mg protein in astrocytes and 29.32 +/- 2.81 and 10.04 +/- 1.79 nmol/hr/mg protein in neurons, respectively. Incubation with 0.25 mM 4-CIN decreased the oxidation of lactate and glucose to 57.1% and 54.1% of control values in astrocytes and to 13.2% and 41.6% of the control rates in neurons, respectively. Preincubation with 4-CIN further decreased the oxidation of both glucose and lactate. Studies with glucose specifically labeled in the one and six positions demonstrated that 4-CIN decreased mitochondrial glucose oxidation but did not impair the metabolism of glucose via the pentose phosphate pathway in the cytosol. The lack of effect of 4-CIN on glutamate oxidation demonstrated that overall mitochondrial metabolism was not impaired. These findings suggest that the impaired neuronal function and tissue damage in the presence of 4-CIN observed in other studies may be due in part to decreased uptake of lactate; however, the effects of 4-CIN on mitochondrial transport would significantly decrease the oxidative metabolism of pyruvate derived from both glucose and lactate.

Animals↗
PubMed2001

Isolation, expression, and characterization of fully functional nontoxic BiP/GRP78 mutants.

Mammalian BiP/GRP78 and Escherichia coli DnaK belong to the highly conserved hsp70 family and function as molecular chaperones in the endoplasmic reticulum or the cytosol, respectively. Induction of murine BiP/GRP78 expression in E. coli leads to growth arrest and cell death, independent of the bacterial strain and vector used. Analysis of various BiP constructs and mutants shows that the dominant-lethal phenotype is induced specifically by the expression of the 13.7-kDa C-terminal domain and abolished by a single substitution in that region. Deletion of that region also results in nontoxic gene products that can be overexpressed and purified to homogeneity. The nontoxic mutants are highly expressed in E. coli, representing up to 20% of the soluble fraction. They are catalytically active, depolymerize upon binding ATP or synthetic peptide, and interact with the J-domain of the DnaJ-like accessory protein, MTJ1, with near wild-type affinity. Our data indicate that the cytotoxic effect encountered during overexpression of recombinant proteins can be caused by a single domain and can be alleviated by a specific mutation or deletion in that region without altering the catalytic properties of the enzyme.

Adenosine Triphosphatases↗
PubMed2001

A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11).

We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138). A positional cloning approach supported by bioinformatics identified PRPF31 comprising 14 exons and encoding a protein of 499 amino acids. The level of sequence identity to the yeast PRP31 gene indicates that PRPF31 is also likely to be involved in pre-mRNA splicing. Mutations that include missense substitutions, deletions, and insertions have been identified in four RP11-linked families and three sporadic RP cases. The identification of mutations in a pre-mRNA splicing gene implicates defects in the splicing process as a novel mechanism of photoreceptor degeneration.

Alleles↗
PubMed2001

Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3).

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. A number of genome scans have been conducted in cohorts of IBD families with affected sibling pairs (ASPs) to identify chromosomal regions that harbour IBD susceptibility genes. Several putative linked loci have been identified, including two loci on chromosomes 16 and 12, IBD1 and IBD2, which have subsequently been replicated by independent region-specific studies. We have conducted both a replication study on another linkage region, chromosome 6p (IBD3), and extension studies on two other regions, chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD ASPs from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to chromosome 6p (IBD3). Nominal evidence of linkage was observed at both the 3p and 7q regions.

Chromosome Mapping↗
PubMed2000

Extent and distribution of linkage disequilibrium in three genomic regions.

The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.

Computer Simulation↗
PubMed2000

Case management for dually diagnosed individuals involved in the criminal justice system.

A case-management model for individuals with substance abuse and mental health disorders who are involved in the criminal justice system is described, based on the experience of a rural demonstration project. Detailed descriptions of case-management activities and the philosophy underlying this model of case management are provided. A major goal of these case-management services was to improve access to appropriate treatment for the target population. Evaluation data describing the population served, case-management implementation, and outcomes are presented along with a case vignette. Six-month follow-up data revealed significantly fewer legal problems and apparent symptom relief for participants in the project. Participants reported improvement in most life areas measured compared to the year before, and were generally satisfied with the case-management services. Barriers observed in implementing these types of services and issues for replication are outlined and discussed.

Adult↗
PubMed1999

Applications of comparative genomic hybridisation in constitutional chromosome studies.

G band cytogenetic analysis often leads to the discovery of unbalanced karyotypes that require further characterisation by molecular cytogenetic studies. In particular, G band analysis usually does not show the chromosomal origin of small marker chromosomes or of a small amount of extra material detected on otherwise normal chromosomes. Comparative genomic hybridisation (CGH) is one of several molecular approaches that can be applied to ascertain the origin of extra chromosomal material. CGH is also capable of detecting loss of material and thus is also applicable to confirming or further characterising subtle deletions. We have used comparative genomic hybridisation to analyse 19 constitutional chromosome abnormalities detected by G band analysis, including seven deletions, five supernumerary marker chromosomes, two interstitial duplications, and five chromosomes presenting with abnormal terminal banding patterns. CGH was successful in elucidating the origin of extra chromosomal material in 10 out of 11 non-mosaic cases, and permitted further characterisation of all of the deletions that could be detected by GTG banding. CGH appears to be a useful adjunct tool for either confirming deletions or defining their breakpoints and for determining the origin of extra chromosomal material, even in cases where abnormalities are judged to be subtle. We discuss internal quality control measures, such as the mismatching of test and reference DNA in order to assess the quality of the competitive hybridisation effect on the X chromosome.

Chromosome Banding↗
PubMed1998

Case control study of risk factors for toxic mastitis in 26 dairy herds.

A retrospective case control study of farm level risk factors for toxic mastitis was carried out in November and December 1996. Twenty-six farms from mid-Somerset were visited: 13 case farms (had had a cow with toxic mastitis in the previous year) and 13 geographically matched controls (no case of toxic mastitis). The farmers were interviewed and the buildings were examined. Information was collected on the type and quality of housing, usual milking routines, milk quality and mastitis prevalence in the previous year. All the data were collected on to pretested recording sheets and loaded into a database. Simple and complex analysis was done. The following variable were significantly (P < 0.05) associated with an increased risk of toxic mastitis in the simple analysis: housing cows in October rather than November; a low number of calving boxes per cow; a high proportion of cows with intermediate body condition and low herd bulk milk somatic cell counts (HBMSCC). In the final model low HBMSCC and a high proportion of cows with intermediate body condition remained significant. The authors conclude that, despite the small size sample, the results of this study are consistent, plausible and support the information from previous experimental and observational studies about the role of somatic cell counts in toxic mastitis.

Animal Husbandry↗
PubMed1996

Linkage analyses of schizophrenia to chromosome 6p24-p22: an attempt to replicate.

The present study evaluates evidence for linkage of schizophrenia to chromosome 6p24-p22. An independent sample of 211 families ascertained on the basis of having an affected sib-pair diagnosed with schizophrenia or schizoaffective disorder was assessed with seventeen polymorphic markers spanning a 37cM region. Linkage analysis was performed with parametric and non-parametric methods to test for cosegregation using 4 models of inheritance. Neither two-point nor multipoint non-parametric analyses reached significance at a level less than 0.01 for any markers examined in the region and lod score analyses were not suggestive of linkage. Based on initial findings in the present data set and recently published linkage results, two specific areas were densely covered with markers and tested for linkage disequilibrium. After correcting for multiple comparisons within each locus, no significant deviation from expected allele transmission ratios was observed. The present findings together with the published literature fail to find consistent evidence of a linkage for schizophrenia to a single locus on chromosome 6.

Adult↗
PubMed1996

Hypersecretion of androgens by polycystic ovaries: the role of genetic factors in the regulation of cytochrome P450c17 alpha.

A single base change has been found in the promoter region of CYP17, the gene encoding P450c17 alpha, which appears to be a significant factor in the expression of hyperandrogenism in PCO but which can be excluded as the primary genetic defect. These findings are consistent with the biochemical data from the studies of patients with PCOS reported above, in which the production of ovarian 17 hydroxyprogesterone and androstenedione were observed to be greatly increased but the generation of progesterone was also exaggerated in PCO theca. Thus, genetic factors may well be involved in the observed dysregulation of 17 hydroxylase/17,20 lyase, but this does not appear to be the whole story. It remains a tenable hypothesis that a single-gene effect is the major cause of PCOS and that a gene involved in the expression of androgen production will be implicated. On the other hand, increased androgen production may be a reflection of an 'upstream' abnormality in the ovary, perhaps involving the fundamental processes of proliferation, differentiation and atresia in ovarian follicles. It is also possible that PCOS is truly polygenic and that CYP17 is one of several genes-including those related to insulin secretion and action-that contribute to the PCOS phenotype. Further candidate genes will need to be investigated using well-characterized, large families, but if several predisposing genes are involved, other approaches may be applicable, for example analysis of shared alleles by affected sibling pairs, which has proved valuable in understanding the genetics of type 1 diabetes (Davies et al, 1994). In conclusion, PCOS--one of the most common endocrinopathies--remains an enigmatic condition but one which may prove to be an important model for understanding the interaction of genetic and environmental factors in the aetiology of endocrine disorders.

Alleles↗
PubMed1996

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Alleles↗
PubMed1994

Cutaneous warts in butchers.

Several studies have indicated a high prevalence of hand warts in meat handlers, although the reasons for this are not clear. The high prevalence may be partly due to HPV7, a virus found almost exclusively in meat handlers, but the source of HPV7 is not known. We have carried out a cross-sectional survey of hand warts in male meat workers and controls from other occupational groups, to investigate the reasons for the high prevalence of warts, and particularly of HPV7, in butchers. We studied 240 abattoir workers, 246 retail and wholesale butchers, 308 engineering fitters and 292 office workers. Each subject was interviewed using a standard questionnaire, and his hands were examined by a dermatologist. Scrapings from the warts were tested for HPV1, HPV2 and HPV7 by a polymerase chain reaction method. The prevalence of hand warts was 33.3% in the abattoir workers, 34.1% in the butchers, 19.5% in the engineers and 14.7% in the office workers. Scrapings were taken from 247 of 267 subjects with warts, and HPV DNA was detected in 151 samples. The most common viruses were HPV2 (94 men) and HPV7 (76 men). The excess of warts in meat workers was largely due to HPV7, which was found in only two of the office workers, and was not found in any of the engineers. Logistic regression analysis showed no association between the prevalence of hand warts (or HPV2 and HPV7 specifically) and hand trauma, cold and wet working conditions, smoking, atopy, or handling any particular kind of meat. We suggest that some constituent of animal flesh predisposes to replication of HPV7 in keratinized epithelium.

Abattoirs↗
PubMed1994

Butchers' warts: no evidence for person to person transmission of HPV7.

The distribution of warts due to HPV7 in workers in six abattoirs and 103 retail and wholesale butcheries has been studied to determine whether the high prevalence of HPV7 in the meat trade is the result of enhanced person to person transmission, or whether it is a ubiquitous virus which is activated by an unknown factor in meat. Warts were detected in 164 of 486 men. Scrapings were taken from 156 men, and HPV DNA was found in 112 samples, 74 of which contained HPV7. HPV7 was found in 36 workplaces, and there was no evidence of clustering of cases, as would be expected if person to person transmission was occurring in the workplace. This suggests that HPV7 is widely distributed in the community, but only causes clinical disease under specific conditions. We suggest that some unknown factor in meat enhances viral replication.

Abattoirs↗
PubMed1993

Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11.

The velo-cardio-facial syndrome (VCFS) and DiGeorge sequence (DGS) have many similar phenotypic characteristics, suggesting that in some cases they share a common cause. DGS is known to be associated with monosomy for a region of chromosome 22q11, and DNA probes have been shown to detect these deletions even in patients with apparently normal chromosomes. Twelve patients with VCFS were examined and monosomy for a region of 22q11 was found in all patients. The DNA probes used in this study could not distinguish the VCFS locus and the DGS locus, indicating that the genes involved in these haploinsufficiencies are closely linked, and may be identical. The phenotypic variation of expression in VCFS and DGS may indicate that patients without the full spectrum of VCFS abnormalities but with some manifestations of the disorder may also have 22q11 deletions.

Abnormalities, Multiple↗