Biomedical subjects
N Williams
Publications and source records attributed to N Williams.
Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia.
People with deletion of the chromosome 22q11 region associated with velo cardio-facial syndrome (VCFS) have a remarkably high risk of developing schizophrenia. Recently, the gene proline dehydrogenase (PRODH) which maps to 22q11 and is also an excellent functional candidate gene for psychosis, has been reported to show genetic association with schizophrenia. We have screened all the exons and adjacent intronic sequences of PRODH for the presence of sequence variation in 14 DSM IV schizophrenic subjects. Similarly, we also screened all putative exons of a sequence that is similar to proline dehydrogenase (PsPRODH) and which also maps within the deleted region. A total of nine single nucleotide polymorphisms (SNPs) were identified in PRODH, eight of which were exonic, while in PsPRODH, five SNPs were identified, one of which was in a putative exon. All samples were tested for association in a pooled sample of 368 DSM IV diagnosed schizophrenic subjects and 368 matched controls. None of the variants identified in PRODH gave even modest evidence for allelic association (P < 0.1). In PsPRODH, two variants (-3864G > A and 226G > A) gave P values < 0.1. These were individually genotyped in the same subjects that had been used to construct the pools. Although a trend for association was confirmed, neither showed evidence for association at the P </= 0.05 level. These results do not suggest that PRODH or PsPRODH contribute to the aetiology of schizophrenia, and that the putative schizophrenia susceptibility gene in 22q11 remains unknown.
Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.
Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.
Association between PRODH and schizophrenia is not confirmed.
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Occupational health management: an audit tool.
BACKGROUND: Organizations must manage occupational health risks in the workplace and the UK Health & Safety Executive (HSE) has published guidance on successful health and safety management. AIMS: This paper describes a method of using the published guidance to audit the management of occupational health and safety, first at an organizational level and, secondly, to audit an occupational health service provider's role in the management of health risks. The paper outlines the legal framework in the UK for health risk management and describes the development and use of a tool for qualitative auditing of the efficiency, effectiveness and reliability of occupational health service provision within an organization. The audit tool is presented as a question set and the paper concludes with discussion of the strengths and weaknesses of using this tool, and recommendations on its use.
Undergraduate occupational health teaching in medical schools--not enough of a good thing?
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Relationship between myocardial counts and patient weight: adjusting the injected activity in myocardial perfusion scans.
It is generally accepted that the quality of myocardial images deteriorates with increasing patient weight. This is attributed to a reduction of counts detected from the myocardium. In this paper we have looked at the count reduction in obese patients and suggest a workable algorithm to increase the injected activity to compensate for this loss of count. In this prospective study, 64 consecutive patients with normal myocardial images were selected to include a weight range of 50-120 kg. The height, weight and gender of patients were noted. Each patient had two studies (total of 128 studies), one at rest and one following stress with adenosine and 20-40 W bicycle exercise. Total myocardial counts were calculated from the back-projected views. The total myocardial counts per MBq of the injected activity were calculated. There was no significant difference in the injected activity and the size of the heart (pixel length of heart) between stress and rest, or gender of the patient. The normalized myocardial counts were not different between men and women, but the counts were slightly, although not significantly, higher ( P=NS) with adenosine and exercise (mean of 243 x 10(3) counts) compared to rest images (229 x 10(3) counts). There was a significant progressive loss of counts in patients with increasing weight, body mass index or body surface area ( P<0.001). There was no significant difference in the changes in counts with weight between male and female, or rest and stress studies. The combined data from all the studies were used to calculate the correlation coefficient and the slope of the line for reduction of cardiac counts with a patient's weight, body mass index, and body surface area. The best correlation was with patient weight ( r=0.58, P<0.001). This was used to calculate the increase in injection activity with increasing weight to maintain the same average counts as achieved in a 70 kg patient with a 400 MBq injection. We suggest that the injection activity should increase from 100% for a 70 kg patient to 140% for 110 kg, 200% for 140 kg, and 250% for a 150 kg patient.
The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population.
Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR). We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation. We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation. In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population.
Toxin clues to beetle relationships.
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Whole gut lavage fluid interleukin-1beta and interleukin-8 in smokers and non-smokers with Crohn's disease in clinical remission.
INTRODUCTION: Smoking in patients with Crohn's disease is associated with more frequent relapse. The mechanism responsible is unknown but a direct pro-inflammatory action on intestinal mucosa has been postulated. Mucosal inflammation in clinically inactive Crohn's disease predicts forthcoming relapse. Whole gut lavage fluid obtained after bowel cleansing with a polyethylene glycol electrolyte solution is an assessment of gut inflammation and immunity. AIM: To assess whether whole gut lavage fluid interleukin-1beta and interleukin-8 differed between smokers and non-smokers with clinically inactive Crohn's disease. METHODS: A total of 34 patients with inactive Crohn's disease (Crohn's disease activity index <150 and whole gut lavage fluid IgG concentration of <10 mg/ml) underwent whole gut lavage with interleukin-1beta and interleukin-8 analysed by enzyme-linked immunosorbent assay. Clinical details and blood markers of inflammation were collected. RESULTS: In this series, 14 patients smoked (10 females, mean age 44.3+/-14.3 years), 20 did not (12 females, mean age 40.7+/-14.3). Surgical resection was more common in smokers (12/14 vs 8/20, p<0.008). Whole gut lavage fluid IgG was significantly lower in smokers (median 1.5 mg/ml (range 1.0-8.0 mg/ml) vs median 3.5 mg/ml (range 1.0-7.0 mg/ml), p<0.05). Whole gut lavage fluid interleukin-1beta was also lower in smokers [median 14.5 pg/ml (range 2-72 pg/ml) vs 26 pg/ml (range 7-1700 pg/ml)], p<0.03. CONCLUSION: Markers of mucosal inflammation in inactive Crohn's disease are lower in smokers than non-smokers. This is against the hypothesis that nicotine exerts a direct pro-inflammatory action via interleukin-1beta and interleukin-8. Further research is required to elucidate the exact mechanisms involved.
The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report.
We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS > or = 0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.
Characterisation, mutation detection, and association analysis of alternative promoters and 5' UTRs of the human dopamine D3 receptor gene in schizophrenia.
The dopamine D(3) receptor gene (DRD3) is a candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder and alcohol and drug abuse. Previous studies have reported associations between polymorphisms in DRD3 and these disorders, but these findings may have reflected linkage disequilibrium with pathogenic variants that are further upstream. We have isolated and sequenced approximately 9 kb of genomic sequence upstream of the human DRD3 translational start site. Using 5' RACE, we have identified within this region three additional exons and two putative promoter regions which show promoter activity in three different cell lines. A 5' UTR identified only in lymphoblasts is spread over three exons and is 353 bp long. A second 5' UTR, found in adult and fetal brain, lymphocytes, kidney and placenta is spread over two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to a previously reported EST, but corresponding mRNA could not be found in the tissues above. The EST, 5' UTRs and putative promoter regions have been analysed for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which were tested for association in a large sample of unrelated patients with schizophrenia and matched controls. No associations were observed with schizophrenia. In addition we failed to replicate previous findings of association with homozygosity of the Ser9Gly variant. The results from this study imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia.
Vitreoretinopathy with phalangeal epiphyseal dysplasia, a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule.
A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding proalpha1(II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.
Clinical and genetic heterogeneity in peroneal muscular atrophy associated with vocal cord weakness.
BACKGROUND: The peroneal muscular atrophy syndrome is the most common inherited disorder of the peripheral nervous system and has extensive clinical and genetic heterogeneity. Cranial nerve involvement is rare, though there are distinct peroneal muscular atrophy syndromes in which vocal cord paralysis is a characteristic feature. Among these dHMN-VII and HMSN-IIC are clinically similar but are differentiated by sensory involvement in HMSN-IIC. The gene for dHMN-VII, designated DHMNVP, has been localised to chromosome 2q14, but the location of the gene for HMSN-IIC is currently unknown. It has been suggested that dHMN-VII and HMSN II-C are allelic disorders. OBJECTIVE: To assess the contribution of the dHMN-VII predisposition gene to peroneal muscular atrophy syndromes associated with vocal cord weakness. METHODS: Linkage analysis of microsatellite markers at chromosome 2q14 was undertaken on two families, one affected by HMSN-IIC and a second manifesting vocal cord paralysis and sensorineural deafness in addition to distal muscular atrophy. RESULTS: Two-point LOD scores at chromosome 2q14 markers encompassing the DHMNVP gene were negative in both families. CONCLUSIONS: These results suggest that at least one further gene predisposing to distal muscular weakness in association with vocal cord paralysis is likely to exist, and that dHMN-VII and HMSN-IIC are unlikely to be allelic disorders. Analyses of further HMSN-IIC families are required to confirm this.
Beefing up the bioweapons treaty.
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Data boost to counter gender inequality.
There's much anecdotal evidence that women get a raw deal if they choose a research career but there are hopes that new data gathered by a team of European Union researchers will help their prospects. Nigel Williams reports.