PubMed Health⌕ Search

Biomedical subjects

C Fletcher

Publications and source records attributed to C Fletcher.

At least 19 recordsLinked to original sources
PubMed2006

Changes in sleep quality and brain wave patterns following initiation of an efavirenz-containing triple antiretroviral regimen.

BACKGROUND: Initiation of efavirenz is commonly associated with sleep disturbances. Assessment of sleep using the electroencephalogram and electromyogram enables sleep staging to be performed and changes following the introduction of therapy to be evaluated. METHODOLOGY: Using standardized sleep-staging methodology, we investigated sleep staging and sleep quality by patient self-report in an open-label cohort pilot study. Assessments were performed prior to the initiation of efavirenz, 2 weeks after the initiation of efavirenz and 3 months after the initiation of efavirenz. The study included HIV-positive individuals without central neurological disease who were naive to antiretroviral treatment. All patients initiated treatment with two nucleoside reverse transcriptase inhibitors in combination with efavirenz. RESULTS: Ten patients completed all three study visits. Patients reported an increase in recollection of dreams and morning sluggishness after the initiation of efavirenz which persisted for 3 months. Sleep-staging data indicated a modest reduction in stage 2 sleep with a corresponding increase in deep sleep stage 4 and a modest increase in rapid eye movement (REM) sleep. Overall sleep maintenance efficiency did not significantly change from baseline. Changes in sleep staging were most marked 2 weeks after the initiation of efavirenz but remained different from baseline patterns at 3 months. CONCLUSION: The data indicate that efavirenz has a modest but persistent impact on the time spent in several key sleep stages. Patients reported persistence of dream recollection but remained satisfied with sleep quality and overall quality of life.

Alkynes↗
PubMed2005

Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial.

AIM: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy. METHODS: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a 12-week leptin or placebo treatment period. A total of 284 overweight and obese (body mass index 27-37.0 kg/m(2)) predominantly white (98%) women (66%) and men (34%) with a mean (+/-s.d.) 46.8+/-10.4 years of age were randomized into three treatment groups with three matching placebo groups. Recombinant leptin was administered by subcutaneous injection [10 mg/morning, 10 mg/evening or 20 mg/day (10 mg twice daily)]. Patients were counselled at baseline to reduce dietary intake by 2,100 kJ/day (500 kcal/day), and dietary advice was reinforced every 2-4 weeks. RESULTS: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. No clinically significant adverse effects were observed with the exception of an increase in injection-site reactions in patients treated with recombinant leptin (83%) vs. placebo (36%). CONCLUSIONS: Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy-restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. The hypothesis that nocturnal administration of recombinant leptin might have a specific effect on weight loss was not supported.

Adult↗
PubMed2004

Analysis of candidate modifier loci for the severity of colonic familial adenomatous polyposis, with evidence for the importance of the N-acetyl transferases.

BACKGROUND: We have recently shown that the severity of human colonic familial adenomatous polyposis (FAP) varies in a manner consistent with the action of modifier genes. These modifier genes may harbour common alleles which increase the risk of colorectal cancer (CRC) in the general population. Analyses have suggested several common polymorphisms as risk alleles for CRC. METHODS: We determined the association between the severity of colonic FAP (151 patients) and polymorphisms in MTHFR, NAT1, NAT2, GSTM, GSTT, cyclin D1, E-cadherin, and APC. All of these loci have been suggested as influencing the risk of CRC. Colonic FAP severity was quantitated as the number of polyps per colectomy specimen, standardised for colon size. We analysed the relationship between disease severity and genotype at the polymorphic site, making allowance for the position of the germline APC mutation. RESULTS: We identified significant associations between more severe disease and the absence of the NAT1*10 genotype in the whole group of patients. In a subset of patients with germline mutations in the so-called "mutation cluster region", there was an association between more severe disease and the presence of NAT2*fast alleles. In the whole patient set, a relatively strong association existed between more severe disease and possession of both the NAT1*non-10 and NAT2*fast genotypes. There was weak evidence for an association between the APCT1493C allele and more severe disease in the whole patient group. No consistent association with disease severity was found for the other polymorphisms. CONCLUSION: The severity of colonic FAP may be modified by alleles at the NAT1 and/or NAT2 loci. The identity of any functional variation remains unknown as NAT1*10 appears to be non-functional and there is linkage disequilibrium between alleles at multiple sites within these loci which are adjacent on chromosome 8p22. While evidence from this study cannot be conclusive, our data suggest that NAT1 and NAT2 variants may explain an approximately twofold increase in polyp number in the FAP colon.

Acetyltransferases↗
PubMed2001

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

Chromosome Mapping↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗
PubMed2001

The complete genome of the crenarchaeon Sulfolobus solfataricus P2.

The genome of the crenarchaeon Sulfolobus solfataricus P2 contains 2,992,245 bp on a single chromosome and encodes 2,977 proteins and many RNAs. One-third of the encoded proteins have no detectable homologs in other sequenced genomes. Moreover, 40% appear to be archaeal-specific, and only 12% and 2.3% are shared exclusively with bacteria and eukarya, respectively. The genome shows a high level of plasticity with 200 diverse insertion sequence elements, many putative nonautonomous mobile elements, and evidence of integrase-mediated insertion events. There are also long clusters of regularly spaced tandem repeats. Different transfer systems are used for the uptake of inorganic and organic solutes, and a wealth of intracellular and extracellular proteases, sugar, and sulfur metabolizing enzymes are encoded, as well as enzymes of the central metabolic pathways and motility proteins. The major metabolic electron carrier is not NADH as in bacteria and eukarya but probably ferredoxin. The essential components required for DNA replication, DNA repair and recombination, the cell cycle, transcriptional initiation and translation, but not DNA folding, show a strong eukaryal character with many archaeal-specific features. The results illustrate major differences between crenarchaea and euryarchaea, especially for their DNA replication mechanism and cell cycle processes and their translational apparatus.

Cell Cycle Proteins↗
PubMed2001

Functional annotation of a full-length mouse cDNA collection.

The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.

Animals↗
PubMed2000

Risk of HIV transmission from patients to surgeons in the era of post-exposure prophylaxis.

The HIV prevalence, among patients either undergoing, or with the potential to undergo, surgery were estimated using data from unlinked anonymous HIV surveys of patients in Glasgow hospitals during 1992-1997 in order to quantify the risk of surgeons acquiring HIV occupationally in the era of post-exposure prophylaxis (PEP) availability. A range of prevalence rates was applied to data on other factors influencing risk; these comprised, i) the probability of a percutaneous injury from a sharp instrument used on an HIV infected patient resulting in HIV transmission, ii) the number of injuries sustained and iii) whether or not PEP was administered. On the basis of, for example, a surgeon sustaining three percutaneous injuries over 12 months and not taking PEP after each, the annual risks ranged from 1 in 2,000,000 for urological/renal surgeons to 1 in 200,000 for those performing general surgery/ENT/gynaecological procedures. The administration of PEP after each injury would reduce these rates to 1 in 10,000,000 and 1 in 1,000,000 respectively. The risk of surgeons acquiring HIV occupationally in a city which has an HIV prevalence typical of most urban areas in the UK, is 'minimal' or 'negligible'. In the context of such low risk and our limited knowledge of the adverse effects of PEP, the risk assessment to decide whether or not to give PEP should be well informed and consistent. Current guidelines to help physicians and affected healthcare workers in their decision making need to be improved.

Adolescent↗
PubMed2000

Unlinked anonymous HIV study of hospital patients and general practice attenders in Glasgow, 1991-1997.

AIM: To determine whether HIV is spreading from injecting drug users and homosexual/bisexual males into lower risk heterosexual populations in Glasgow, Scotland, and to pilot a method of monitoring HIV prevalence which involves testing routine biochemistry specimens. METHODS: An unlinked anonymous HIV testing study of hospital patients and general practice attenders was conducted during January 1992 to December 1997. Testing was performed on routine biochemistry specimens from patients aged 16-49 years attending two hospitals with catchment areas covering the north and the east of the city. RESULTS: 78,260 specimens were tested in the study period and no patient objected to their samples being tested anonymously. HIV prevalence rates among male and female subjects were 0.63% and 0.01%, respectively; the large difference in prevalence resulted, in part, from the inclusion of HIV infected haemophiliac patients who attended one of the hospitals. Prevalence among male general practice patients ranged between 0.1% and 0.2%, while that for male patients attending surgical or surgically related specialties was 0.1%. CONCLUSIONS: The prevalence data indicate that HIV has not seeded from the high risk groups into the wider heterosexual population, and that the risk of a surgeon acquiring HIV occupationally is extremely low in a city which has an HIV prevalence similar to or greater than that seen in most other parts of the United Kingdom. Large numbers of residual specimens from busy biochemistry laboratories can be processed for unlinked anonymous testing without interfering with the laboratories' routine functions. This survey approach might be best suited to monitoring HIV trends in developing countries with relatively high prevalence rates and where transmission is principally heterosexual.

Adolescent↗
PubMed2000

Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.

NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

The role of causal discourse structure in narrative writing.

All writers produce text content and ideally connect it together according to discourse conventions. We investigate whether a particularly strong discourse convention, the need for causal coherence in narratives, can predict the kind of text writers will produce. Causality has been found to be a significant discourse factor in reading comprehension and hence can be expected to determine also what writers produce during composition. In Experiment 1, writers composed short continuations at various points throughout a simple narrative, whereas in Experiment 2, writers composed continuations to complete several narratives. The results indicate that causality indeed plays a major role in composition. Writers tend to produce new text in such a way that it is causally connected to the prior text. Furthermore, writers favored causal relations of necessity or of necessity and sufficiency while largely avoiding relations of sufficiency alone, which suggests a general discourse constraint to be maximally informative (e.g., Grice, 1975).

Communication↗
PubMed1998

Terminal differentiation of human breast cancer through PPAR gamma.

We have previously demonstrated that PPAR gamma stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPAR gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPAR gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPAR gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.

Breast Neoplasms↗
PubMed1998

Differentiation and reversal of malignant changes in colon cancer through PPARgamma.

PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.

Adenocarcinoma↗
PubMed1998

Body-type stereotyping in therapeutic judgments.

23 professional psychotherapists and 25 graduate student trainees rated line drawings of three clients' body types on 21 clinically relevant personal characteristics. Professionals and students alike rated ectomorphic and endomorphic clients less favorably than mesomorphic clients.

Humans↗