Biomedical subjects

Lesley Jones

Publications and source records attributed to Lesley Jones.

15 recordsLinked to original sources

PubMed2005

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Age of Onset↗

PubMed2005

'The edge effect': an exploratory study of some factors affecting referrals to cancer genetic services in rural Wales.

This exploratory study examines the role of rurality in referrals from primary care to the Cancer Genetics Service for Wales (CGSW) through a case study of referrals from Montgomeryshire, a predominantly rural area in mid-Wales located adjacent to the English border. Awareness of CGSW amongst practitioners is low. We found that rurality plays a role in referral behaviour as distance, time travelling and accessibility by car and public transport are all perceived to have an impact on the patient's decision to attend a clinic appointment. Some patients are being referred outside Wales as ease of access to services is considered more important than distance.

Awareness↗

PubMed2005

Exploring the relationship between homelessness and risk factors for heroin-related death--a qualitative study.

The aim of this study was to explore the relationship between housing status, associated social networks and risk factors for heroin-related death. We used semi-structured face-to-face qualitative interviews, recorded, transcribed and analysed thematically by framework techniques at three centres providing services to homeless people in a large cosmopolitan city. Different types of accommodation for homeless people have differing social cultures which have an impact upon the amount of heroin used, likelihood of injecting alone or likelihood of achieving abstinence. Hostel accommodation appeared to be linked with a culture of group injecting, which tends to increase the amount of heroin taken. Those with experience of rough sleeping described heroin use to ameliorate the uncomfortable realities of outdoor sleeping, although the overall amount used tended to be less due to having less money to spend on drugs. The prison setting was described as a setting where heroin use was reduced or stopped. Moving away from homelessness towards sustaining an independent tenancy appeared to be associated with a move towards solitary use. We postulate that a progression towards solitary use in a housed environment is one explanation for previous research findings showing the average age of heroin-related death to be increasing despite a decrease in the average age of initiation into heroin use. Hostel accommodation should form a priority setting for future health promotion interventions aimed to reduce heroin-related death. They appear to be linked with an increase in heroin use in the presence of a third party. Drug users sleeping rough in cold climates need to be made aware of the dangers of medicating with heroin to address problems of insomnia due to cold weather.

Adult↗

PubMed2005

Exploring risk perception and behaviour of homeless injecting drug users diagnosed with hepatitis C.

Injecting drug users (IDUs) are at the greatest risk of hepatitis C infection by using any item of injecting equipment that has come into contact with contaminated blood. Alongside this, homeless IDUs have been identified as being at increased risk of harm in their illicit drug taking behaviour. This study interviewed 17 hepatitis C positive homeless IDUs about their injecting practices. In-depth interviews explored the impact of a positive hepatitis C diagnosis on their injecting and identified their risk behaviours and perceptions. The interviews were tape-recorded, transcribed and analysed using the framework approach. Homeless IDUs engaged in both high risk and unhygienic injecting practices, such as using drugs outside and in public places, sharing injecting equipment and re-using cleaned needles. Excessive needle reuse whilst in prison was also identified. However, the findings were not universally bleak as a positive diagnosis of hepatitis C did lead to some behaviour change towards safer injecting and some adopted other lifestyle and behaviour changes. It was, however, common for homeless people to devolve responsibility for preventing hepatitis C transmission to their peers, especially when injecting with others. Knowledge regarding possible transmission through injecting paraphernalia appeared to make users more careful to reduce it through these routes. Placing a continuous emphasis on health promotion is therefore important in educating IDUs about the hepatitis C transmission risks associated with injecting drug use. Information regarding safer and hygienic use, including accurate information regarding the most effective methods to clean used equipment, must be re-enforced by people working with homeless injecting drug users.

Blood-Borne Pathogens↗

PubMed2005

A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease.

Huntington's disease is a genetic disease caused by a single mutation. It is characterized by progressive movement, emotional and cognitive deficits. R6/2 mice transgenic for exon 1 of the HD gene with 150+ CAG repeats have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed at boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up- or down-regulated in untreated R6/2 mice had returned towards normal levels after treatment, though a minority were further dysregulated. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated.

Age Factors↗

PubMed2005

Impact of a positive hepatitis C diagnosis on homeless injecting drug users: a qualitative study.

BACKGROUND: Increasing numbers of injecting drug users are presenting to primary care and a growing number of general practices are specifically providing care for homeless people. Injecting drug users are at the greatest risk of hepatitis C infection and homeless drug misusers, because of their drug-taking behaviour and patterns, have been identified as being at greater risk of harm of blood-borne diseases than the general population. However, little work has been conducted with injecting drug users or homeless people who have hepatitis C and little is known about how the virus may affect them. AIM: To explore the impact of a positive hepatitis C diagnosis on homeless injecting drug users. DESIGN OF STUDY: This study employed qualitative research. In-depth interviews allowed the exploration of the impact of a potentially life-threatening diagnosis within the context of a person's expressed hierarchy of needs. SETTING: A primary care centre for homeless people in the north of England. METHOD: In-depth interviews about the impact of a positive hepatitis C diagnosis on their lives were conducted with 17 homeless injecting drug users who had received a positive hepatitis C diagnosis. The interviews were audiotaped, transcribed, and analysed using the framework approach. RESULTS: Receiving a positive diagnosis for hepatitis C resulted in feelings of shock, devastation, disbelief, anger, and questioning. A positive diagnosis had lasting social, emotional, psychological, behavioural, and physical effects on homeless injecting drug users, even years after the initial diagnosis. Most responders were diagnosed by a doctor in primary care or by hospital staff; however, not all had sought testing and a number were tested while inpatients and were unaware that blood had been taken for hepatitis C virus serology. CONCLUSIONS: The implications for clinical policy and primary care practice are discussed, including the issues of patient choice, confidentiality, and pre- and post-test discussions. Posttest discussions should be followed up with additional social, psychological, and medical support and counselling.

Adult↗

PubMed2004

Endophilin A3 forms filamentous structures that colocalise with microtubules but not with actin filaments.

Endophilin A3 is a member of the endophilin family of proteins, thought to play a role in the formation of clathrin-coated vesicles from the plasma membrane in the process of clathrin-mediated endocytosis. We investigated the localisation of both endogenous and overexpressed endophilin A3 within mammalian cells. Endophilin A3 demonstrated a complex cellular distribution with bright punctate structures and filamentous strands superimposed on a diffuse cytoplasmic background. The endophilin A3 structures did not colocalise with mitochondria, endoplasmic reticulum or lysosomes. Direct immunolocalisation and cytoskeletal perturbation studies showed that the filamentous structures were more likely to be colocalised with microtubules than actin filaments. We therefore propose that endophilin A3 has a role in transport along or as part of the structure of microtubules, in addition to its suggested role in endocytosis.

Actin Cytoskeleton↗

PubMed2004

Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD.

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.

Aged↗

PubMed2004

Extravasation.

Explore the source record for details and available documents.

Adverse Drug Reaction Reporting Systems↗

PubMed2004

Can a simple measure of vigorous physical activity predict future mortality? Results from the OXCHECK study.

BACKGROUND: As epidemiological studies have become more complex, demands for short, easily administered measures of risk factors have increased. This study investigates whether such a measure of physical activity is associated with the risk of death from all causes and death from specific causes. METHODS: A prospective follow-up study of 11,090 men and women, aged 35-64 years, recruited from five UK general practices who responded to a postal questionnaire in 1989. Self-reported frequency of vigorous-intensity physical activity and data on confounding factors were collected at baseline survey. Death notifications up to 31 December 2001 were provided by the Office for National Statistics. The relative risk (and 95% confidence interval) of dying associated with each level of exposure to physical activity was estimated by the hazard ratio in a series of Cox regression models. RESULTS: After >10 years' follow-up there were 825 deaths among the 10 522 subjects with no previous history of angina or myocardial infarction. Participation in vigorous exercise was associated with a significantly lower risk of all-cause mortality. Similar associations were found for ischaemic heart disease and cancer mortality, although the relationships were not significant at the 5% level. CONCLUSIONS: Simple measures of self-reported vigorous physical activity are associated with the risk of future mortality, at least all-cause mortality in a somewhat selected group. Interpretation of the finding should be treated with caution due to the reliance on self-report and the possibility that residual confounding may underlie the associations. Because moderate-intensity physical activity is also beneficial to health, short physical activity questionnaires should include measures of such physical activity in the future.

Adult↗

PubMed2004

Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease.

The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.

Aged↗

PubMed2003

Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease.

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.

Aged↗

PubMed2003

Transgenic rat model of Huntington's disease.

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.

Animals↗

PubMed2002

Full genome screen for Alzheimer disease: stage II analysis.

We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).

Alzheimer Disease↗

PubMed2002

Being deaf and being other things: young Asian people negotiating identities.

This paper explores how Asian deaf young people negotiate identity claims against the backdrop of deaf politics, ethnicity, religion, gender and age. The paper is based on a qualitative study of Asian (mainly Pakistani Muslim) deaf young people and their parents in the UK. The findings provide little support for notions of singular or primary identities (as, for example, 'Deaf' people or 'Muslims') which may make other identity claims irrelevant. Instead, young people's identifications were multiple, complex and contingent. However, resources and structures remained important for identifications to be cultivated and gaining legitimisation.

Adolescent↗