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Biomedical subjects

E Green

Publications and source records attributed to E Green.

At least 19 recordsLinked to original sources
PubMed2006

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

Adult↗
PubMed2005

Health professionals, their medical interventions and uncertainty: a study focusing on women at midlife.

Health professionals face a tension between focusing on the individual and attending to health issues for the population as a whole. This tension is intrinsic to medicine and gives rise to medical uncertainty, which here is explored through accounts of three medical interventions focused on women at midlife: breast screening, hormone replacement therapy and bone densitometry. The accounts come from interviews with UK health professionals using these medical interventions in their daily work. Drawing on the analysis of Fox [(2002). Health and Healing: The public/private divide (pp. 236-253). London: Routledge] we distinguish three aspects of medical uncertainty and explore each one of them in relation to one of the interventions. First is uncertainty about the balance between the individual and distributive ethic of medicine, explored in relation to breast screening. Second is the dilemma faced by health professionals when using medical evidence generated through studies of populations and applying this to individuals. We explore this dilemma for hormone replacement therapy. Thirdly there is uncertainty because of the lack of a conceptual framework for understanding how new micro knowledge, such as human genetic information, can be combined with knowledge of other biological and social dimensions of health. The accounts from the bone denistometry clinic indicate the beginnings of an understanding of the need for such a framework, which would acknowledge complexity, recognising that factors from many different levels of analysis, from heredity through to social factors, interact with each other and influence the individual and their health. However, our analysis suggests biomedicine continues to be dominated by an individualised, context free, concept of health and health risk with individuals alone responsible for their own health and for the health of the population. This may continue to dominate how we perceive responsibilities for health until we establish a conceptual framework that recognises the complex interaction of many factors at macro and micro level affecting health.

Absorptiometry, Photon↗
PubMed2005

Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741.

BACKGROUND: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. PATIENTS AND METHODS: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated. RESULTS: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. CONCLUSIONS: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Adult↗
PubMed2005

Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22.

Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS> or =1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22.

Bipolar Disorder↗
PubMed2005

Identification of a potential bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4.

The gene encoding the transcription factor RFX4 represents an excellent neurobiological and positional candidate gene for Bipolar disorder due to the potential involvement of RFX4 proteins in the regulation of circadian rhythms and the proximity of the locus to numerous linkage signals on chromosome 12q23. In this study we have sought to identify common variants within the gene, which might confer risk to the disease in our large UK Caucasian sample of Bipolar patients (676 DSMIV Bipolar I probands, 690 controls). RFX4 was screened for sequence variants and the LD block structure across the genomic region determined using 22 biallelic polymorphisms (minor allele frequency >or=0.1). Through analysis of 10 haplotype-tagging markers and using a two-stage approach (subset I: 347 cases, 374 controls; subset II: 329 cases, 316 controls), we identified a haplotype at rs10778502 and ss24735177, which showed nominally significant disease association in our full sample (haplotype-specific P=0.002, global P=0.017; subset I: haplotype-specific P=0.0002, global P=0.0008; subset II: haplotype-specific P=0.572, global P=0.109). Evidence for potential disease association with mutations across the RFX4 region came also from the analysis of the nearby microsatellite D12S2072 (empirical P=0.009 in our full sample). Investigation of RFX4 brain cDNA tagged by rs10778502 provided evidence for significant allelic differences in expression (P<0.001), where some of the variance was accounted for by the genotype at ss24735177. Our findings thus indicate the potential functional relevance of the associated haplotype and now require replication in independent samples.

Adult↗
PubMed2005

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved.

Amino Acid Substitution↗
PubMed2003

Reducing domestic exposure to environmental tobacco smoke: a review of attitudes and behaviours.

This paper reviews research on attitudes and behaviours towards environmental tobacco smoke (ETS), with a special focus on child health and the indoor environment. Research needs and ways forward to encourage reductions in domestic ETS levels are discussed. Published material was identified through online literature searches (Medline, Toxline, Cancerlit, Biosis, Embase, Enviroline, Sociological Abstracts, Social Science Citation Index, Academic Index and Psychinfo). The literature search strategy employed search terms such as "passive smoking" or "environmental tobacco smoke" with "attitude" or "awareness" and other synonyms. Additional publications were identified by citation chasing and expert advice. Focusing on the UK, studies that provided survey-derived data about attitudes and behaviours in relation to ETS exposure in the indoor environment were selected for review. Published studies from other countries were also included when they provided information pertinent to this review. Most people are aware of the health risks associated with ETS exposure, and there is a high level of support for smoking restrictions in public places to protect non-smokers from ETS. However, although there is concern among both non-smoking and smoking parents about children and second-hand smoke, many people allow children to be exposed to ETS in the home. The review suggests that traditional health promotion campaigns have had only limited success in encouraging ETS risk reduction measures in the home. Because ETS is a public health priority, particularly in relation to child health, the barriers to the uptake of such measures need to be explored in detail to inform the future promotion of reductions in domestic levels of ETS.

Attitude to Health↗
PubMed2003

Estimation of the impact on children's health of environmental tobacco smoke in England and Wales.

In this paper, the population attributable risk (PAR), a measure of the excess risk of disease associated with a risk factor, is calculated for some of the common adverse health effects that have been associated with exposure of children to environmental tobacco smoke (ETS): childhood lower respiratory illness, chronic middle ear disease, asthma and sudden infant death syndrome (SIDS). Published data on both risk estimates and the percentage of children exposed to ETS in the home (prevalence of ETS) have been utilised. The percentage of childhood lower respiratory illness and middle ear disease typically attributable to ETS from either parent smoking ranged from 9% for asthma prevalence and for referral for glue ear, to 25% for hospital admission for lower respiratory illness. Where data were available to calculate PARs separately for mother only smoking and father only smoking, the PARs were generally larger for mothers only smoking, due mainly to higher odds ratios for mothers only smoking. The PAR for SIDS attributable to ETS from mother only smoking was 11%. Although based on a small number of studies, the PAR for SIDS attributable to smoking of fathers only was similar to that attributable to the smoking of mothers only, largely due to the higher prevalence of households where only the father smokes. This study has shown that the impact of ETS on childhood illness can be considerable, emphasising the importance of the need to develop effective strategies for reducing the risk of ETS exposure in the home and elsewhere.

Adolescent↗
PubMed2001

No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD.

Adolescent↗
PubMed2001

Mutational analysis of the peroxisome proliferator-activated receptor gamma gene in human malignancies.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in adipocyte differentiation and is expressed in many human malignancies, including those from prostate, breast, as well as colon. It regulates differentiation and/or cell growth of these cells. However, expression of this nuclear hormone receptor in other types of cancer, especially in hematological malignancies, remains to be fully elucidated. The PPARgamma gene has been mapped to chromosome band 3p25, where chromosomal abnormalities are observed in a variety of human malignancies. Furthermore, a recent study revealed that the PPARgamma gene is functionally mutated in sporadic colon cancer cells. Therefore, PPARgamma could be an important tumor suppressor gene. This prompted us to investigate the expression and mutational status of the PPARgamma gene in cancers of a variety of tissues. A total of 159 samples were interrogated for their expression of PPARgamma as measured by reverse transcription-polymerase chain reaction and/or Western blot analysis. In each of the samples, expression of PPARgamma was detectable. In addition, a total of 397 clinical samples and cell lines including colon, prostate, breast and lung cancers, and leukemias were analyzed for mutations of the PPARgamma gene by either reverse transcription-polymerase chain reaction-single-strand conformation polymorphism or polymerase chain reaction-single-strand conformation polymorphism analysis. No abnormalities were detectable in any of the human malignancies. On the other hand, shifted bands were easily detectable when using positive controls, which harbored the same sequence alterations reported previously in colon cancer cells. Taken together, PPARgamma is expressed in a variety of cancers, and mutation of the PPARgamma gene is a very rare event in human malignancies.

Blotting, Western↗
PubMed2001

The biology of cortical granules.

An egg-that took weeks to months to make in the adult-can be extraordinarily transformed within minutes during its fertilization. This review will focus on the molecular biology of the specialized secretory vesicles of fertilization, the cortical granules. We will discuss their role in the fertilization process, their contents, how they are made, and the molecular mechanisms that regulate their secretion at fertilization. This population of secretory vesicles has inherent interest for our understanding of the fertilization process. In addition, they have import because they enhance our understanding of the basic processes of secretory vesicle construction and regulation, since oocytes across species utilize this vesicle type. Here, we examine diverse animals in a comparative approach to help us understand how these vesicles function throughout phylogeny and to establish conserved themes of function.

Amino Acid Sequence↗
PubMed2001

Review of management of drooling problems in neurologically impaired children: a review of methods and results over 6 years at Chailey Heritage Clinical Services.

Drooling can be a difficult problem for a child to endure, both physically and socially, especially if they are also having to cope with physical disabilities. Chailey Heritage Clinical Services and associated School look after a large number of severely physically disabled children and adolescents. This paper reviews the management strategy of the multidisciplinary oral-motor clinic at Chailey Heritage Clinical Services, and reviews the results of children treated between 1990 and 1996. The management ranges from oral-motor skills training through palatal training appliances to surgery. Seventy-eight children, ranging from 3 to 17 years, were treated and there were complete records for 73. Eighteen per cent responded to oral skills training alone. Thirty per cent of children had good results with a palatal training appliance and did not need any further intervention. Forty-seven per cent of patients underwent some form of surgery to control their drooling. Only 8% of children were treated with medication.

Adolescent↗
PubMed2001

An uncommon cause of a destructive vulval lesion.

We present a case of a 39-year-old woman with a vulval lesion, which macroscopically looked consistent with a fungating squamous cell carcinoma of the vulva. However, further investigations demonstrated a less common cause for this presentation.

Adult↗
PubMed2001

Children with organic growth hormone deficiency have elevated cortisol responses to stimuli.

The aim of this study was to investigate hypothalamic-pituitary-adrenal (HPA) function in children with GH deficiency. Ninety-four patients were evaluated for GH deficiency and cortisol (F) deficiency using clinical criteria and L-dopa and insulin-induced hypoglycemia stimulation tests. They were assigned to three diagnostic groups: organic GH deficient (OGHD), idiopathic GH deficient (IGHD), and not GH-deficient (NGHD). Time series, cross-sectional, regression analysis revealed statistically significantly elevated F [>828 nmol/L (30 microg/dL)] in the OGHD group vs. the NGHD group. The value for F in the IGHD group was not different from the NGHD group. This finding suggests that dysregulation of the HPA axis is present in most children with OGH deficiency and significantly less often in children with IGH deficiency or without GH deficiency. Anatomical disruption of the control pathways for the HPA axis or stress may cause the dysregulation.

Blood Glucose↗
PubMed2001

Psychological impact of islet cell antibody screening.

The purpose of this study was to evaluate the psychological impact of autoantibody screening and its results on at-risk individuals and family members. Individuals who were antibody positive (AP) were identified through a large-scale screening program conducted at our institute. The sample consisted of nine families in whom 10 AP youngsters (7 M, 3 F) were identified, ranging in age from 6-18 years (mean 11.8, median 10 yr). Seventeen parents and eight diabetic youngsters (mean age 15.2, median 16 yr) participated in the study. Reaction to autoantibody positivity was assessed with the Impact of Event scale (IES). The IES was answered twice: within a week from the disclosure of the AP status, and 3 months later. Parents scored higher than their diabetic children and AP children on both measures of the IES, Intrusion and Avoidance. Three months later both scores were significantly reduced in both the parents and the AP children; however, parents still scored significantly higher on both scores than the AP children. The results suggest that learning one's AP status induces significant anxiety, especially in parents of AP youngsters. Although this initial anxiety dissipates over time it still remains quite high after 3 months. The results highlight the importance of psychosocial counseling for all members of diabetes mellitus screening and prevention trials.

Adolescent↗
PubMed2000

Protecting environmental quality and human health: strategies for harmonisation.

In September 1999 the MRC Institute for Environment and Health hosted a multidisciplinary seminar on the harmonisation of strategies to protect environmental quality and human health. The objectives of the meeting were to share information about ways in which the protection of the environment and human health can be harmonised, and, by bringing together an audience representing a range of disciplines, interests and sectors, to explore how these may be integrated to inform policy, decision-making and the management of risks. Key conclusions from the seminar focused on the importance of sustainable development, harmonising risk assessment and the role of stakeholder involvement. The necessary move from an expert-based to a dialogue-based process will require concerted efforts on the part of scientists, policy-makers, regulators, industry and the public.

Environmental Pollution↗