Search PubMed⌕ Search

Biomedical subjects

J Welch

Publications and source records attributed to J Welch.

At least 37 records · Page 2Linked to original sources
PubMed2001

Evidence for three tumor suppressor loci on chromosome 9p involved in melanoma development.

Cytogenetic and loss of heterozygosity (LOH) studies have long indicated the presence of a tumor suppressor gene (TSG) on 9p involved in the development of melanoma. Although LOH at 9p has been reported in approximately 60% of melanoma tumors, only 5-10% of these tumors have been shown to carry CDKN2A mutations, raising the possibility that another TSG involved in melanoma maps to chromosome 9p. To investigate this possibility, a panel of 37 melanomas derived from 35 individuals was analyzed for CDKN2A mutations by single-strand conformation polymorphism analysis and sequencing. The melanoma samples were then typed for 15 markers that map to 9p13-24 to investigate LOH trends in this region. In those tumors demonstrating retention of heterozygosity at markers flanking CDKN2A and LOH on one or both sides of the gene, multiplex microsatellite PCR was performed to rule out homozygous deletion of the region encompassing CDKN2A. CDKN2A mutations were found in tumors from 5 patients [5 (14%) of 35], 4 of which demonstrated LOH across the entire region examined. The remaining tumor with no observed LOH carried two point mutations, one on each allele. Although LOH was identified at one or more markers in 22 (59%) of 37 melanoma tumors corresponding to 20 (57%) of 35 individuals, only 11 tumors from 9 individuals [9 (26%) of 35] demonstrated LOH at D9S942 and D9S1748 the markers closest to CDKN2A. Of the remaining 11 tumors with LOH 9 demonstrated LOH at two or more contiguous markers either centromeric and/or telomeric to CDKN2A while retaining heterozygosity at several markers adjacent to CDKN2A. Multiplex PCR revealed one tumor carried a homozygous deletion extending from D9S1748 to the IFN-alpha locus. In the remaining eight tumors, multiplex PCR demonstrated that the observed heterozygosity was not attributable to homozygous deletion and stromal contamination at D9S1748, D9S942, or D9S974, as measured by comparative amplification strengths, which indicates that retention of heterozygosity with flanking LOH does not always indicate a homozygous deletion. This report supports the conclusions of previous studies that a least two TSGs involved in melanoma development in addition to CDKN2A may reside on chromosome 9p.

Chromosome Mapping↗
PubMed2001

Experience of nevirapine use in a London cohort of HIV-infected pregnant women.

OBJECTIVE: To describe the experience of four London HIV centres prescribing nevirapine (NVP) to HIV-1 infected pregnant women with respect to immunological and virological response, tolerability and pregnancy outcome. METHODS: We identified all HIV-1-infected women who received NVP as part of a triple antiretroviral regimen during pregnancy between January 1997 and September 1999. Laboratory results, clinical events, side-effects and pregnancy outcome were abstracted using a standardized proforma from the medical records. RESULTS: Forty-six women were identified, 85% of whom were black African. At initiation of NVP, the median age was 29 years and the median baseline CD4 cell count and viral load were 242 cells/microL and 4.15 log10 copies/mL, respectively. Thirty-two out of 36 women who had a plasma sample obtained at, or just prior to, delivery had an undetectable viral load (< 50 to < 400 copies/mL). Adverse events that were definitely attributed to NVP included a generalized rash (n = 2) and hepatitis (n = 2). Obstetric complications occurred in nine women (19.5%), which was not statistically different (P = 0.36) from that found in a historical (1990-96) control group 7/51 (14%). The rate of preterm delivery (13%) was similar to that previously reported in HIV-1 infected pregnant women (18%). CONCLUSIONS: NVP (as part of highly active antiretroviral therapy) reduced plasma viraemia to below the limit of detection in 89% of women. It was generally well tolerated and clinical and laboratory adverse events were infrequent. There was no evidence of an increase in obstetric complications including preterm delivery during the second and third trimesters of pregnancy.

Adult↗
PubMed2000

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Animals↗
PubMed2000

Sensitization to oilseed rape is not due to cross-reactivity with grass pollen.

BACKGROUND: Oilseed rape is an important crop grown in the UK which can cause specific immunological sensitization with clinical symptoms in a relatively small number of the general population. Individuals with immunoglobulin (Ig) E-mediated allergy to oilseed rape have also been found to be sensitized to other pollen allergens, most frequently being grass pollen. Cross-reactivity between common grass and oilseed rape would have important implications, especially as their flowering period coincides. OBJECTIVE: We have investigated whether the cosensitization found in individuals sensitized to both oilseed rape and grass pollen is due to cross-reactivity. METHODS: Cross-reactivity between oilseed rape and grass pollen was determined using RAST, RAST inhibition, Western blotting and inhibition studies with Western blotting. RESULTS: Competitive RAST inhibition studies between pollen of oilseed rape and grass failed to show any cross-reactivity between the pollen types. Self-inhibition with oilseed rape resulted in 90% inhibition, whereas there was less than 10% inhibition with grass pollen. Western blotting revealed allergens of similar molecular weight in both oilseed rape and grass pollen. Despite allergens of similar molecular weights being present in both pollen types, inhibition immunoblot studies confirmed that the allergens in the two allergens were immunologically distinct. CONCLUSION: The allergens of oilseed rape and grass pollen, although similar in molecular weights, are immunologically distinct and there is no evidence of cross-reactivity between them. Individuals allergic to grass pollen will not necessarily develop a specific nasal or airway response to inhaled oilseed rape pollens.

Adult↗
PubMed1999

CDKN2A variants in a population-based sample of Queensland families with melanoma.

BACKGROUND: Mutations in the CDKN2A gene confer susceptibility to cutaneous malignant melanoma (CMM); however, the population incidence of such mutations is unknown. Polymorphisms in CDKN2A have also been described, but it is not known whether they influence melanoma risk. We investigated the association of CDKN2A mutations and polymorphisms with melanoma risk in a population-based sample of families ascertained through probands with melanoma. METHODS: The 482 Queensland, Australia, families in our sample were characterized previously as having high, intermediate, or low family risk of CMM. Unrelated individuals (n = 200 families/individuals) drawn from the Australian Twin Registry served as control subjects. For individuals in the high-risk group, the entire CDKN2A gene coding region was screened for mutations by use of the polymerase chain reaction, agarose gel electrophoresis, allele-specific oligonucleotide (ASO) hybridization, and single-strand conformation polymorphism analysis. The intermediate- and low-risk families and control subjects were analyzed by ASO hybridization for a total of six recurring mutations as well as for polymorphisms at nucleotides (Nts) 442, 500, and 540. RESULTS: CDKN2A mutations were found only in the high-risk families (nine [10.3%] of 87). The prevalence of the Nt500G (guanosine) polymorphism increased linearly with increasing familial risk (two-sided P = .02) and was highest in the nine (primarily Celtic) families with CDKN2A mutations. After adjustment for ethnic origin, the relationship between risk group and the frequency of the Nt500G allele was weakened (P = .25); however, there was no relationship between ethnic origin and Nt500-polymorphism frequency among the control subjects. CONCLUSIONS: CDKN2A mutations are rare in this population (approximately 0.2% of all melanoma cases in Queensland) and appear to be associated with melanoma in only the most affected families. The Nt500G allele appears to be associated with familial risk, but this association probably reflects Celtic ancestry.

Autoradiography↗
PubMed1999

Infants' ability to use object kind information for object individuation.

The present studies investigate infants reliance on object kind information in solving the problem of object individuation. Two experiments explored whether adults, 10- and 12-month-old infants could use their knowledge of ducks and cars to individuate an ambiguous array consisting of a toy duck perched on a toy car into two objects. A third experiment investigated whether 10-month-old infants could use their knowledge of cups and shoes to individuate an array consisting of a cup perched on a shoe into two objects. Ten-month-old infants failed to use object kind information alone to resolve the ambiguity with both pairs of objects. In contrast, infants this age succeeded in using spatiotemporal information to segment the array into two objects, i.e. they succeeded if shown that the duck moved independently relative to the car, or the cup relative to the shoe. Twelve-month-old infants, as well as adults, succeeded at object individuation on the basis of object kind information alone. These findings shed light on the developmental course of object individuation and provide converging evidence for the Object-first Hypothesis [Xu, F., Carey, S., 1996; Xu, F., 1997b]. Early on, infants may represent only one concept that provides criteria for individuation, namely physical object; kind concepts such as duck, car, cup, and shoe may be acquired later in the first year of life.

Adult↗
PubMed1999

Integrated clinical service for sexual assault victims in a genitourinary setting.

BACKGROUND: Reported sexual assault is increasing, and the diverse immediate and longer term needs of the victim are usually met by exposure to a number of healthcare professionals often in different locations, involving delays and travel, increasing the trauma for the victim. OBJECTIVES: To set up a centre to address the immediate and longer term needs of the sexual assault victim and review issues arising during the development of the service. METHODS: Description of setting up the service in the genitourinary medicine department of Kings College Hospital, south London, and the aspects of care offered. RESULTS: The number of victims referred by police increased from 15 in 1992 to 58 in 1996. In 1996, 55 female and three male victims were seen. 23 different police stations brought victims for examination; mean age of the victim was 27 years (range 14-60), median time between assault and examination was 22 hours (range 3 hours-3 months); 23% had genital injuries, 59% had other physical injury, and 11% needed further hospital care. 71% accepted screening for sexually transmitted infection (STI), 21% had an STI diagnosed, 16% of the women required emergency contraception, 26% received prophylactic antibiotics, and 58% saw a health adviser. 70% had a follow up appointment arranged of which 50% attended. CONCLUSION: The high uptake of STI screening, emergency contraception, health adviser consultation, and follow up supports the concept of a comprehensive integrated system to meet the disparate needs of the victim while still obtaining the necessary forensic evidence. The wide catchment area of service users indicates gaps in services available for the assault victim. Earlier genitourinary involvement after sexual assault is becoming increasingly pertinent in relation to HIV prophylaxis.

Adolescent↗
PubMed1998

Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPARgamma is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPARgamma is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPARgamma expression in primary macrophages and monocytic cell lines. PPARgamma mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPARgamma expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPARgamma expression in macrophages. TPA induced the expression of PPARgamma in RAW 264.7 macrophages by increasing transcription from the PPARgamma1 and PPARgamma3 promoters. In concert, these observations provide insights into the regulation of PPARgamma expression in activated macrophages and raise the possibility that PPARgamma ligands may influence the progression of atherosclerosis.

Animals↗
PubMed1998

Instant electronic imaging systems are superior to Polaroid at detecting sight-threatening diabetic retinopathy.

Polaroid photography in diabetic retinopathy screening allows instant image availability to enhance the results of ophthalmoscopy. Retinal cameras are now being developed which use video/digital imaging techniques to produce an instant enlarged retinal image on a computer monitor screen. We aimed to compare one such electronic imaging system, attached to a Canon CR5 45NM, with standard Polaroid retinal photography. Two hundred and thirteen eyes from 107 diabetic patients were photographed through dilated pupils by both systems in random order and the images were analysed blind. Diabetic retinopathy was present in 58 eyes of which 55/58 (95%) were detected on the electronic image and only 49/58 (84%) on the Polaroid. Of 34 eyes requiring ophthalmologist referral according to standard European criteria, 34/34 (100%) were detected on the electronic image and only 24/34 (71%) on the Polaroid. Side by side comparisons showed electronic imaging to be superior to Polaroid at lesion detection. Using linear analogue scales, the patients assessed the electronic imaging photographic flash as less uncomfortable than the Polaroid equivalent (p < 0.0001). Other advantages of electronic imaging include: ready storage of the images with other patient clinical data on the diabetes computerized register/database; potential for image enhancement and analysis using image analysis software and electronic transfer of images to ophthalmologist or general practitioner. Electronic imaging systems represent a potential major advance for the improvement of diabetic retinopathy screening.

Diabetic Retinopathy↗
PubMed1998

Mutation of the transforming growth factor-beta type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations.

The presence of inactivating mutations in the transforming growth factor-beta (TGF-beta) type II receptor (RII) gene in the colon cancer suggests that it may behave like a tumour suppressor gene. RII is mutated in the majority of colon tumours exhibiting widespread microsatellite instability, a characteristic generally referred to as the replication error phenotype (RER+). We investigated the association between RII mutations and various clinicopathological variables and genetic alterations in a large series of sporadic adenocarcinomas arising in the proximal colon. RII mutations were found in 17 per cent (36/210) of right-sided tumours and in 86 per cent (32/37) of those displaying RER+. They were associated with the absence of lymph node invasion (P = 0.04), poor histological differentiation (P = 0.006), and with a trend for improved patient survival. Tumours with an RII mutation also showed non-significant trends for a lower incidence of p53 protein overexpression and of p53, K-ras, and APC gene mutation compared with tumours with normal RII. These results indicate that right-sided colorectal tumours containing RII mutations resemble those with the RER+ phenotype in terms of their clinicopathological features and genetic alterations.

Adenocarcinoma↗