Search PubMed⌕ Search

Biomedical subjects

D Walsh

Publications and source records attributed to D Walsh.

At least 19 recordsLinked to original sources
PubMed2006

Interleukin 3 and schizophrenia: the impact of sex and family history.

Chromosome 5q21-33 has been implicated in harboring risk genes for schizophrenia. In this paper, we report evidence that multiple single nucleotide polymorphisms in and around interleukin 3 (IL3) are associated with the disease in the Irish Study of High-Density Schizophrenia Families (ISHDSF), the Irish Case-Control Study of Schizophrenia (ICCSS) and the Irish Trio Study of Schizophrenia (ITRIO). The associations are sex-specific and depend on the family history (FH) of schizophrenia. In all three samples, rs31400 shows female-specific and FH-dependent associations (P=0.0062, 0.0647 and 0.0284 for the ISHDSF, ICCSS and ITRIO, respectively). Several markers have similar associations in one or two of the three samples. In haplotype analyses, identical risk and protective haplotypes are identified in the ISHDSF and ITRIO samples in several multimarker combinations. For ICCSS, the same haplotypes are implicated; however, the risk haplotypes observed in the family samples become protective. Several significant markers, rs440970, rs31400 and rs2069803, are located in and around known estrogen response elements, promoter and enhancer of the IL3 gene. They may explain the sex-specific associations and be functional for the expression of IL3 gene.

Case-Control Studies↗
PubMed2006

Catechol-O-methyltransferase and the clinical features of psychosis.

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P < 0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

Catechol O-Methyltransferase↗
PubMed2006

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (chi2 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

Alcohol-Related Disorders↗
PubMed2006

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50-60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 x 10(-6), at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0-2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Aged↗
PubMed2005

Meeting the information needs of the 'Health for all' challenge--lessons from Scotland.

OBJECTIVE: To create a public health data resource for Scotland that is based on a socio-ecological model of the determinants of health and would, therefore, meets the needs of the emerging public health agenda. DESIGN: Action research, in which the approach moved logically through stages of action (conception, feasibility study, pilot projects, leading to a national set of integrated health and well-being profiles). Each stage built on the results of the previous research. RESULTS: The conceptual stage identified the need for an approach to public health data that kept pace with the increasingly accepted socio-ecological models of the determinants of health. A feasibility study concluded that sufficient data were available to populate the health fields that represented the important determinants of health. At this time strengths and weakness in data were defined. This led to the articulation of a 'vision' for integrated public heath data in Scotland that was the subject of a wide consultation. Pilot studies provided local stakeholders with imaginatively presented data (on population demographics, health and function, behaviour, social environment, economy, physical environment, morbidity and mortality) for their local communities. The response to these was so positive that a demand was created for a comprehensive set of 'community profiles'. These, in addition to parliamentary constituency profiles, have now been created and widely disseminated. CONCLUSIONS: It has been possible, despite many difficulties, to develop approaches to public health information that are informed by the socio-ecological model of health and create outputs that represent a significant advance on previous approaches to public health data. This is a work in progress and many issues remain unresolved. Interaction with others engaged in parallel tasks will facilitate the next steps.

Community Participation↗
PubMed2005

Why is mortality higher in Scotland than in England and Wales? Decreasing influence of socioeconomic deprivation between 1981 and 2001 supports the existence of a 'Scottish Effect'.

OBJECTIVES: To determine the degree to which changing patterns of deprivation in Scotland and the rest of Great Britain between 1981 and 2001 explain Scotland's higher mortality rates over that period. DESIGN: Cross-sectional analyses using population and mortality data from around the 1981, 1991 and 2001 censuses. SETTING: Great Britain (GB). PARTICIPANTS: Populations of Great Britain enumerated in the 1981, 1991 and 2001 censuses. MAIN OUTCOME MEASURES: Carstairs deprivation scores derived for wards (England and Wales) and postcode sectors (Scotland). Mortality rates adjusted for age, sex and deprivation decile. RESULTS: Between 1981 and 2001 Scotland became less deprived relative to the rest of Great Britain. Age and sex standardized all-cause mortality rates decreased by approximately 25% across Great Britain, including Scotland but mortality rates were on average 12% higher in Scotland in 1981 rising to 15% higher in 2001. While over 60% of the excess mortality in 1981 could be explained by differences in deprivation profile, less than half the excess could be explained in 1991 and 2001. After adjusting for age, sex and deprivation, excess mortality in Scotland rose from 4.7% (95% CI: 3.9% to 5.4%) in 1981 to 7.9% (95% CI: 7.2% to 8.7%) in 1991 and 8.2% (95% CI: 7.4% to 9.0%) in 2001. All deprivation deciles showed excess indicating that populations in Scotland living in areas of comparable deprivation to populations in the rest of Great Britain always had higher mortality rates. By 2001 the largest excesses were found in the most deprived areas in Scotland with a 17% higher mortality rate in the most deprived decile compared to similarly deprived areas in England and Wales. Excess mortality in Scotland has increased most among males aged <65 years. CONCLUSIONS: Scotland's relative mortality disadvantage compared to the rest of Great Britain, after allowing for deprivation, is worsening. By 1991 measures of deprivation no longer explained most of the excess mortality in Scotland and the unexplained excess has persisted during the 1990s. More research is required to understand what is causing this 'Scottish effect'.

Adolescent↗
PubMed2005

Home-like versus conventional institutional settings for birth.

BACKGROUND: Home-like birth settings have been established in or near conventional labour wards for the care of pregnant women who prefer and require little or no medical intervention during labour and birth. OBJECTIVES: Primary: to assess the effects of care in a home-like birth environment compared to care in a conventional labour ward. Secondary: to determine if the effects of birth settings are influenced by staffing or organizational models or geographical location of the birth centre. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (18 May 2004) and handsearched eight journals and two published conference proceedings. SELECTION CRITERIA: All randomized or quasi-randomized controlled trials that compared the effects of a home-like institutional birth environment to conventional hospital care. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration Pregnancy and Childbirth Group were used. Two review authors evaluated methodological quality. Double data entry was performed. Results are presented using relative risks and 95% confidence intervals. MAIN RESULTS: Six trials involving 8677 women were included. No trials of freestanding birth centres were found. Between 29% and 67% of women allocated to home-like settings were transferred to standard care before or during labour. Allocation to a home-like setting significantly increased the likelihood of: no intrapartum analgesia/anaesthesia (four trials; n = 6703; relative risk (RR) 1.19, 95% confidence interval (CI) 1.01 to 1.40), spontaneous vaginal birth (five trials; n = 8529; RR 1.03, 95% CI 1.01 to 1.06), vaginal/perineal tears (four trials; n = 8415; RR 1.08, 95% CI 1.03 to 1.13), preference for the same setting the next time (one trial; n = 1230; RR 1.81, 95% CI 1.65 to 1.98), satisfaction with intrapartum care (one trial; n = 2844; RR 1.14, 95% CI 1.07 to 1.21), and breastfeeding initiation (two trials; n = 1431; RR 1.05, 95% CI 1.02 to 1.09) and continuation to six to eight weeks (two trials; n = 1431; RR 1.06, 95% CI 1.02 to 1.10). Allocation to a home-like setting decreased the likelihood of episiotomy (five trials; n = 8529; RR 0.85, 95% CI 0.74 to 0.99). There was a trend towards higher perinatal mortality in the home-like setting (five trials; n = 8529; RR 1.83, 95% CI 0.99 to 3.38). No firm conclusions could be drawn regarding the effects of staffing or organizational models. AUTHORS' CONCLUSIONS: When compared to conventional institutional settings, home-like settings for childbirth are associated with modest benefits, including reduced medical interventions and increased maternal satisfaction. Caregivers and clients should be vigilant for signs of complications.

Birthing Centers↗
PubMed2004

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study.

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

Alleles↗
PubMed2004

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Chromosome Mapping↗
PubMed2004

Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families.

The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia. Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed. SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative. These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews. Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects. This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele. We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.

Alleles↗
PubMed2004

No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF).

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

Chromosome Mapping↗
PubMed2004

Longitudinal prescribing patterns for psychoactive medications in community-based individuals with developmental disabilities: utilization of pharmacy records.

BACKGROUND: Little is known about longitudinal prescribing practices for psychoactive medications for individuals with intellectual disabilities and developmental disabilities (IDDD) who are living in community settings. METHODS: Computerized pharmacy records were accessed for 2344 community-based individuals with IDDD for whom a total of 3421 prescriptions were written during a 17-month period of study. Forty-two psychoactive medications were rank ordered in terms of prescription frequency. RESULTS: Fifty-two per cent (52%) of all prescriptions written during the study period were for psychoactive medications. Anticonvulsant, antipsychotic and antidepressant medications were the most commonly filled prescriptions among psychoactive medications. Sixty per cent (62%) of the study population was given prescriptions for more than one psychoactive medication and 36% received three or more psychoactive medications. During the study period there was a statistically significant increase in prescriptions filled for olanzapine, risperidone, valproic acid, and clonazepam whereas prescriptions filled for thioridazine, haloperidol, and benzotropine showed a significant decline (P < 0.05-0.001). Distribution of psychoactive drug class by age showed that the majority of prescriptions were filled for individuals between 20 and 50 years with the exception of prescriptions for psychostimulants which peaked for individuals prior to 20 years. CONCLUSIONS: (1) Analysis of pharmacy billing records provides a method for assessing prescribing patterns of psychoactive medications in community-based individuals with IDDD. (2) Polypharmacy for psychoactive medications is prevalent in this setting. (3) The second-generation antipsychotic medications are prominently represented by an increasing number of filled prescriptions during the study period.

Adult↗
PubMed2003

Evaluation of nutritional status in advanced metastatic cancer.

Consecutive cancer referrals to a palliative medicine program were evaluated to assess nutritional status using a standard protocol. The study included 352 patients (180 men, 172 women; median age 61 years, range 22-94 years). The most common diagnosis was lung cancer. All had metastatic disease, 139 with gastrointestinal involvement. The most common gastrointestinal symptoms were weight loss ( n=307), anorexia ( n=285), and early satiety ( n=243). Of those with any weight loss, 71% had lost >or0% of their pre-illness weight. The most common factor identified which might have contributed to weight loss was hypophagia ( n=275/307). Men had lost weight more often and to a greater extent than women. Triceps skinfold (TSF) was measured in 337: 51% had values that suggested severe fat deficiency. Upper mid-arm muscle area (AMA) was measured in 349: 30% had evidence of significant muscle mass reduction. The body mass index (BMI) was normal or increased in most patients. Calculated resting energy expenditure (REE) ( n=324) was high in 41%. C-reactive protein was elevated in 74% of those measured ( n=50). We conclude that: (1).most of this group of cancer patients referred to palliative medicine had severe weight loss; (2).there was a gender difference in the severity and type of weight loss; (3).males lost more weight overall and more muscle than females; (4).males with any degree of weight loss had a higher REE than females; (5).a significant correlation existed between the time from diagnosis to death and the severity of weight loss in the prior month; (6).BMI was normal in most patients, suggesting precancer diagnosis obesity; and (7).both TSF and AMA correlated well with body composition of both fat and protein as determined by bioelectrical impedance.

Adult↗
PubMed2003

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Carrier Proteins↗
PubMed2002

The potential of biomimesis in bone tissue engineering: lessons from the design and synthesis of invertebrate skeletons.

Synthetic bone replacement materials are now widely used in orthopedics. However, to date, replication of trabecular bone structure and mechanical competence has proved elusive. Maximization of bone tissue attachment to replacement materials requires a highly organized porous structure for tissue integration and a template for assembly, combined with structural properties analogous to living bone. Natural structural biomaterials provide an abundant source of novel bone replacements. Animal skeletons have been designed through optimization by natural selection to physically support and physiologically maintain diverse tissue types encompassing a variety of functions. These skeletons possess structural properties that provide support for the complete reconstruction and regeneration of ectodermal, mesodermal, and bone tissues derived from animal and human and are thus suited to a diversity of tissue engineering applications. Increased understanding of biomineralization has initiated developments in biomimetic synthesis with the generation of synthetic biomimetic materials fabricated according to biological principles and processes of self-assembly and self-organization. The synthesis of complex inorganic forms, which mimic natural structures, offers exciting avenues for the chemical construction of macrostructures and a new generation of biologically and structurally related bone analogs for tissue engineering.

Animals↗
PubMed2002

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes.

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.

Chromosome Mapping↗