Biomedical subjects

Lesley Jones

Publications and source records attributed to Lesley Jones.

At least 19 recordsLinked to original sources

PubMed2006

Homeless drug users' awareness and risk perception of peer "take home naloxone" use--a qualitative study.

BACKGROUND: Peer use of take home naloxone has the potential to reduce drug related deaths. There appears to be a paucity of research amongst homeless drug users on the topic. This study explores the acceptability and potential risk of peer use of naloxone amongst homeless drug users. From the findings the most feasible model for future treatment provision is suggested. METHODS: In depth face-to-face interviews conducted in one primary care centre and two voluntary organisation centres providing services to homeless drug users in a large UK cosmopolitan city. Interviews recorded, transcribed and analysed thematically by framework techniques. RESULTS: Homeless people recognise signs of a heroin overdose and many are prepared to take responsibility to give naloxone, providing prior training and support is provided. Previous reports of the theoretical potential for abuse and malicious use may have been overplayed. CONCLUSION: There is insufficient evidence to recommend providing "over the counter" take home naloxone" to UK homeless injecting drug users. However a programme of peer use of take home naloxone amongst homeless drug users could be feasible providing prior training is provided. Peer education within a health promotion framework will optimise success as current professionally led health promotion initiatives are failing to have a positive impact amongst homeless drug users.

Adult↗

PubMed2006

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2006

Assessment of the relationship between pre-chip and post-chip quality measures for Affymetrix GeneChip expression data.

BACKGROUND: Gene expression microarray experiments are expensive to conduct and guidelines for acceptable quality control at intermediate steps before and after the samples are hybridised to chips are vague. We conducted an experiment hybridising RNA from human brain to 117 U133A Affymetrix GeneChips and used these data to explore the relationship between 4 pre-chip variables and 22 post-chip outcomes and quality control measures. RESULTS: We found that the pre-chip variables were significantly correlated with each other but that this correlation was strongest between measures of RNA quality and cRNA yield. Post-mortem interval was negatively correlated with these variables. Four principal components, reflecting array outliers, array adjustment, hybridisation noise and RNA integrity, explain about 75% of the total post-chip measure variability. Two significant canonical correlations existed between the pre-chip and post-chip variables, derived from MAS 5.0, dChip and the Bioconductor packages affy and affyPLM. The strongest (CANCOR 0.838, p < 0.0001) correlated RNA integrity and yield with post chip quality control (QC) measures indexing 3'/5' RNA ratios, bias or scaling of the chip and scaling of the variability of the signal across the chip. Post-mortem interval was relatively unimportant. We also found that the RNA integrity number (RIN) could be moderately well predicted by post-chip measures B_ACTIN35, GAPDH35 and SF. CONCLUSION: We have found that the post-chip variables having the strongest association with quantities measurable before hybridisation are those reflecting RNA integrity. Other aspects of quality, such as noise measures (reflecting the execution of the assay) or measures reflecting data quality (outlier status and array adjustment variables) are not well predicted by the variables we were able to determine ahead of time. There could be other variables measurable pre-hybridisation which may be better associated with expression data quality measures. Uncovering such connections could create savings on costly microarray experiments by eliminating poor samples before hybridisation.

Artifacts↗

PubMed2006

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Adult↗

PubMed2006

A single nucleotide polymorphism in CHAT influences response to acetylcholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegeneration with a characteristic deficit in cholinergic neurotransmission. Treatment with acetylcholinesterase (AChE) inhibitors aims to reverse this deficit and does ameliorate the decline in cognition in some AD patients, although response is variable. OBJECTIVE: To examine whether sequence variation in the gene encoding choline acetyltransferase (CHAT), which encodes the major catalytic enzyme of the cholinergic pathway, predicts response to AChE inhibitors. METHODS: Alzheimer's disease patients (121) were treated with cholinesterase inhibitors and the effect of treatment on cognition was measured using the Mini Mental State Examination (MMSE). Six polymorphisms in CHAT were analysed for association with change in MMSE score. RESULTS: After correction for multiple testing, we found one SNP, rs733722, in a promoter region of CHAT, is associated with response of AD patients to cholinesterase inhibitors (P = 0.03) and accounts for 6% of the variance in response to AChE inhibitors. CONCLUSION: Rs733722 represents a putative marker of response to AChE inhibitors in AD patients.

Aged↗

PubMed2005

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Alleles↗

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↗