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Biomedical subjects

M Walker

Publications and source records attributed to M Walker.

At least 37 records · Page 2Linked to original sources
PubMed2005

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects.

AIMS/HYPOTHESIS: The aim of this prospective study was to investigate predictors of deteriorating glucose tolerance in subjects of British extraction. METHODS: A total of 156 non-diabetic subjects (86 with a family history of type 2 diabetes) underwent a 75-g OGTT and anthropometric assessment at baseline and 5 years later. Pancreatic beta cell function and whole-body insulin sensitivity were studied by model assessment. Subjects were classified as progressors if glucose tolerance moved one or more steps from normal, impaired fasting glucose, impaired glucose tolerance and diabetes over the follow-up period. RESULTS: At baseline, the progressors (n=22) had increased adiposity and a higher proportion of familial diabetes and abnormal glucose tolerance than non-progressors. Baseline pancreatic beta cell sensitivity to changes in glucose (p<0.02) and whole-body insulin sensitivity (p<0.0001) were decreased in the progressors. Logistic regression revealed that baseline and follow-up changes in beta cell glucose sensitivity and insulin sensitivity, rather than the classical clinical predictors (adiposity, familial diabetes and glucose levels), were the key independent predictors of progression (explaining over 50% of the progression). CONCLUSIONS/INTERPRETATION: Impaired pancreatic beta cell glucose sensing and whole-body insulin sensitivity predict progression to hyperglycaemia. Strikingly, these pathophysiological changes override the importance of the clinical risk factors and highlight potential metabolic targets for prevention strategies.

Adult↗
PubMed2005

Tracing the origins of "fetal origins" of adult diseases: programming by oxidative stress?

Too small size at birth (due to poor fetal growth and/or preterm delivery) has been associated with substantially elevated risks of the metabolic syndrome (dislipidemia, insulin resistance, hypertension), type 2 diabetes and cardiovascular disease in adulthood. The mechanisms of such "fetal origins" or "programming" of disease phenomenon remain unresolved. Too large size at birth seems also associated with an increased risk. Many known or suspected causes of or conditions associated with adverse (poor or excessive) fetal growth or preterm birth have been associated with oxidative stress. Plausibly, oxidative stress may be a common link underlying the superficial "programming" associations between adverse fetal growth or preterm birth and elevated risks of certain chronic diseases. The mechanisms of oxidative stress programming may be through directly modulating gene expression or indirectly through the effects of certain oxidized molecules. Experimental investigations have well demonstrated the role of redox balance in modulating gene expression, and recent studies indicate that both the insulin functional axis and blood pressure could be sensitive targets to oxidative stress programming. Adverse programming may occur without affecting fetal growth, but more frequently among low birth weight infants merely because they more frequently experienced known or unknown conditions with oxidative insults. As oxidative stress levels are easily modifiable during pregnancy and early postnatal periods (which are plausible critical windows), the hypothesis, if proved valid, will suggest new measures that could be very helpful on fighting the increasing epidemic of the metabolic syndrome, type 2 diabetes and cardiovascular disease. Currently, there are several ongoing large randomized trials of antioxidant supplementation to counter oxidative stress during pregnancy for the prevention of preeclampsia. It would be invaluable if long-term follow-ups of infants born to women in such trials could be realized to test the oxidative stress programming hypothesis in such experimental trial settings.

Birth Weight↗
PubMed2005

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.

AIMS/HYPOTHESIS: The proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources. MATERIALS AND METHODS: The G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls. RESULTS: There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16). CONCLUSIONS/INTERPRETATION: The present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.

Adult↗
PubMed2005

Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia.

Reduced density of calbindin-containing interneurons in the prefrontal cortex in schizophrenia has been reported (Beasley et al 2002; Biol Psych 52:708-715). Calbindin is a calcium-binding protein (CBP) present in a subpopulation of GABAergic neurons restricted mainly to layer II of the cortex. A paraffin-embedded, 10-mum-thick section from the planum temporale (PT) of each hemisphere was prepared from 12 patients with schizophrenia and 12 controls. Calbindin-containing cells were stained using an antibody (D-28K). Counting frames were superimposed to sample within layer II of the PT. A bilateral reduction (20%) in calbindin cell density was found in patients (controlling for fixation time). Furthermore, mean calbindin cell cross-sectional area was increased in female patients and reduced in male patients. Reduced CBP expression (reducing the excitability of interneurons) or reduced number of CBP-containing cells may cause disinhibition of pyramidal cells. The majority of calbindin-containing cells in the mature brain are double-bouquet cells with vertically oriented dendrites and axon bundles. By exercising inhibitory modulation of pyramidal cells in a columnar arrangement, they make possible cohesive vertical inhibition of minicolumns. Loss of columnar inhibition may result in reduced minicolumnar segregation and altered cell size may reflect altered minicolumn size.

Adult↗
PubMed2005

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10.

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50-70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

Chromosomes, Human, Pair 10↗
PubMed2005

Calpain inhibition and insulin action in cultured human muscle cells.

Variation in the calpain 10 gene has been reported to increase susceptibility to type 2 diabetes. Part of this susceptibility appears to be mediated by a decrease in whole body insulin sensitivity. As skeletal muscle is the primary tissue site of the peripheral insulin resistance in type 2 diabetes, the aim of this study was to use a human skeletal muscle cell culture system to explore the effects of calpain inhibition on insulin action. Calpain 10 mRNA and protein expression was examined in cultured myoblasts, myotubes, and whole skeletal muscle from non-diabetic subjects using RT-PCR and Western blotting. Changes in insulin-stimulated glucose uptake and glycogen synthesis in response to the calpain inhibitors ALLN and ALLM were measured. Calpain 10 expression was confirmed in cultured human myoblasts, myotubes, and native skeletal muscle. Insulin-stimulated glucose uptake was significantly decreased following preincubation with ALLN [404+/-40 vs 505+/-55 (mean+/-SEM)pmol/mg/min; with vs without ALLN: p = 0.04] and ALLM [455+/-38 vs 550+/-50 pmol/mg/min; with vs without ALLM: p = 0.025] in day 7 fused myotubes, but not in myoblasts. Neither ALLN nor ALLM affected insulin-stimulated glycogen synthesis in myoblasts or myotubes. These studies confirm calpain 10 expression in cultured human muscle cells and support a role for calpains in insulin-stimulated glucose uptake in human skeletal muscle cells that may be relevant to the pathogenesis of the peripheral insulin resistance in type 2 diabetes.

Base Sequence↗
PubMed2005

Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases.

BACKGROUND: The treatment of brain metastasis is generally palliative, with whole brain radiation therapy (WBRT), since the majority have uncontrollable systemic cancer. In certain circumstances, such as single brain metastases, death may be more likely from brain involvement than systemic disease. In this group, surgical resection has been proposed to relieve symptoms and prolong survival. OBJECTIVES: To assess the clinical effectiveness of surgical resection plus WBRT versus WBRT alone in the treatment of single brain metastasis. SEARCH STRATEGY: The Cochrane Cancer Network Specialised trials register (July 2003), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1 2003), MEDLINE (1966 to July 2003), EMBASE (1980 to July 2003), CANCERLIT (1980 to July 2003), BIOSIS (1985 to July 2003) and SCIENCE CITATION INDEX (1981 to July 2003) were searched. References of identified studies were hand searched, as was the Journal of Neuro-Oncology over the previous 10 years and Neuro-Oncology over the past 2 years, including all conference abstracts. Specialists in neuro-oncology were also contacted. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing surgery and WBRT with WBRT alone, in patients with single brain metastasis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Three RCTs were identified, with 195 patients in total. No significant difference in survival was noted hazard ratio (HR) 0.74 (95% confidence interval (CI) 0.39 to 1.40, p = 0.35), although there was a high degree of heterogeneity between trials. One trial has shown surgery and WBRT to increase the duration of functionally independent survival (FIS) HR 0.42 (95% CI 0.22 to 0.80, p < 0.008). There is a trend for surgery and WBRT to reduce the number of deaths due to neurological cause odds ratio (OR) 0.57 (95% CI 0.29 to 1.10, p = 0.09). Adverse effects were not found to be statistically more common in any group. AUTHORS' CONCLUSIONS: Surgery and WBRT may improve FIS but not overall survival. There is a trend that it may reduce the proportion of deaths due to neurological cause. All these results were in a highly selected group of patients. Operating on metastases does not confer significantly more adverse effects.

Brain Neoplasms↗
PubMed2005

Examining the relationships between the Pro12Ala variant in PPARG and Type 2 diabetes-related traits in UK samples.

AIMS: The Pro12Ala polymorphism in the PPARG gene alters amino acid sequence and has shown consistent association with susceptibility to Type 2 diabetes in several populations. The present study makes use of large, well-characterized case-control resources to enhance understanding of this susceptibility effect by examining related traits, such as body mass index (BMI), waist-hip ratio and age at diagnosis. METHODS: The Pro12Ala variant was genotyped in two UK case samples, ascertained for positive family history and/or early onset of Type 2 diabetes (combined n=971); and in 1257 ethnically matched control subjects. RESULTS: There were significant associations of the Pro12Ala single nucleotide polymorphism (SNP) genotypes with diabetes in both case-control comparisons (P=0.025 and P=0.039). Comparing individuals homozygous for the Pro allele, with those carrying an Ala allele, the combined odds ratio for diabetes was 1.40 (95% CIs, 1.12-1.76, P=0.0031). There was no association between the variant and either waist-hip ratio or age at diagnosis. Proline homozygosity was associated with increased BMI in one patient group (P=0.013) and decreased BMI in the other (P=0.038). CONCLUSIONS: This study confirms that variation within PPARG influences susceptibility to Type 2 diabetes in UK samples. However, the relationship between PPARG variation and BMI is more complex, and studies in much larger sample sets will be required to more precisely characterize the effect of this variant on adiposity.

Age of Onset↗
PubMed2005

Inequalities in coronary revascularisation during the 1990s: evidence from the British regional heart study.

OBJECTIVE: To investigate the influence of age and social circumstances on probability of revascularisation among British men. DESIGN: Prospective population based study SETTING: 24 medium sized British towns, none of which contained a hospital undertaking coronary artery bypass surgery. SUBJECTS: 5814 surviving participants of the BRHS (British regional heart study), aged 52-73 years, with no history of revascularisation when responding to a questionnaire in November 1992. MAIN OUTCOMES: Incident coronary revascularisations, as documented in general practitioner records, over the following 7.1 years and coronary angiography investigations reported by men in a further questionnaire in November 1996. RESULTS: 160 men underwent at least one revascularisation during this period (4.2/1000 person-years). In multifactorial analysis, which included adjustment for incidence of major coronary heart disease or angina, a lower incidence of revascularisation was found among men aged over 65 years in November 1992 (hazard ratio 0.62, 95% confidence interval (CI) 0.44 to 0.87), among men with manual occupations (0.73, 95% CI 0.53 to 1.02), among men living in households possessing no car (0.44, 95% CI 0.24 to 0.80) or one car (0.60, 95% CI 0.42 to 0.87) compared with two or more cars, among council tenants (0.49, 95% CI 0.25 to 0.97), and among men living outside southern England (0.71, 95% CI 0.51 to 0.99). Only car ownership was related to the incidence of diagnostic angiography: the odds ratio for angiography for those owning fewer than two cars was 0.62 (95% CI 0.42 to 0.89). CONCLUSION: During the 1990s, there were major inequalities in the probability of undergoing coronary revascularisation between British men according to socioeconomic status, age, and geographic location.

Age Factors↗
PubMed2004

Analysis of the contribution to type 2 diabetes susceptibility of sequence variation in the gene encoding stearoyl-CoA desaturase, a key regulator of lipid and carbohydrate metabolism.

AIMS/HYPOTHESIS: Stearoyl-CoA desaturase (SCD) is emerging as a key regulator of lipid and carbohydrate metabolism. Scd-null mice display a beneficial metabolic phenotype characterised by resistance to obesity, diabetes and hyperlipidaemia. The human homologue, SCD, maps to a region of chromosome 10 linked to type 2 diabetes, and SCD activity correlates with insulin sensitivity. Given this strong positional and biological candidacy, the present study sought to establish whether sequence variation in SCD influences susceptibility to type 2 diabetes and related traits. METHODS: The SCD gene was resequenced in 23 diabetic subjects. Six variants within coding and adjacent sequence, including a non-synonymous SNP in exon 5 (M224L), were selected for genotyping in a primary set of 608 diabetic subjects and 600 control subjects. RESULTS: There was no association (at the allele, genotype or haplotype level) with type 2 diabetes, although genotype frequencies at the +14301 A>C SNP in the 3' untranslated region showed borderline association (p~0.06) when evidence for linkage was taken into account. However, replication studies (350 young-onset diabetic patients; 747 controls) failed to confirm any relationship with diabetes for this variant. No significant associations were seen for diabetes-related traits including BMI and waist-to-hip ratio. CONCLUSIONS/INTERPRETATION: The present study, the first reported analysis of this gene, indicates that the SCD variants typed do not explain chromosome-10-encoded susceptibility to type 2 diabetes. Although this study provided no evidence that SCD sequence variation influences diabetes susceptibility or related traits, SCD remains a major target for pharmaceutical and/or environmental manipulation.

Adult↗
PubMed2004

The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and objectives.

AIMS/HYPOTHESES: Insulin resistance is thought to be a key predictor for the development of Type 2 diabetes mellitus and cardiovascular disease (CVD), a leading cause of morbidity and premature mortality in Europe. Insulin resistance is influenced by both genetic and lifestyle factors (e.g. obesity and physical inactivity). The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is using the infrastructure of an extended European collaborative research group to study insulin resistance and CVD risk in 1500 healthy people aged 30 to 60 years from 20 centres in 13 countries. METHODS: Baseline measurements of glucose tolerance and insulin sensitivity are made by the oral glucose tolerance test and the euglycaemic insulin clamp, respectively; carotid artery intima-medial thickness (by ultrasound), ankle/brachial pressure index and electrocardiography will enable evaluation of subclinical CVD at baseline and at follow-up. Classic CVD risk factors, as well as socioeconomic and lifestyle factors will be recorded at baseline; samples for measurement of biochemical and genetic markers will be collected and stored for future analyses. Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis as measured by carotid artery intima-media thickness. Development of Type 2 diabetes, dyslipidaemia, obesity, hypertension and cardiovascular events are additional endpoints. CONCLUSIONS: This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies.

Adult↗
PubMed2004

The Mouse Genome Database (MGD): integrating biology with the genome.

The Mouse Genome Database (MGD) is one component of the Mouse Genome Informatics (MGI) system (http://www.informatics.jax.org), a community database resource for the laboratory mouse. MGD strives to provide a comprehensive knowledgebase about the mouse with experiments and data annotated from both literature and online sources. MGD curates and presents consensus and experimental data representations of genetic, genotype (sequence) and phenotype information including highly detailed reports about genes and gene products. Primary foci of integration are through representations of relationships between genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse and to build and implement the data and semantic standards that are essential for comparative genome analysis. Recent developments in MGD discussed here include an extensive integration of the mouse sequence data and substantial revisions in the presentation, query and visualization of sequence data.

Animals↗