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Biomedical subjects

M Walker

Publications and source records attributed to M Walker.

At least 199 records · Page 11Linked to original sources
PubMed1999

Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study.

BACKGROUND AND PURPOSE: B-mode ultrasound is a noninvasive method of examining the walls of peripheral arteries and provides measures of the intima-media thickness (IMT) at various sites (common carotid artery, bifurcation, internal carotid artery) and of plaques that may indicate early presymptomatic disease. The reported associations between cardiovascular risk factors, clinical disease, IMT, and plaques are inconsistent. We sought to clarify these relationships in a large, representative sample of men and women living in 2 British towns. METHODS: The study was performed during 1996 in 2 towns (Dewsbury and Maidstone) of the British Regional Heart Study that have an approximately 2-fold difference in coronary heart disease risk. The male participants were drawn from the British Regional Heart Study and were recruited in 1978-1980 and form part of a national cohort study of 7735 men. A random sample of women of similar age to the men (55 to 77 years) was also selected from the age-sex register of the general practices used in the original survey. A wide range of data on social, lifestyle, and physiological factors, cardiovascular disease symptoms, and diagnoses was collected. Measures of right and left common carotid IMT (IMTcca) and bifurcation IMT (IMTbif) were made, and the arteries were examined for plaques 1.5 cm above and below the flow divider. RESULTS: Totals of 425 men and 375 women were surveyed (mean age, 66 years; range, 56 to 77 years). The mean (SD) IMTcca observed were 0. 84 (0.21) and 0.75 (0.16) mm for men and women, respectively. The mean (SD) IMTbif were 1.69 (0.61) and 1.50 (0.77) mm for men and women, respectively. The correlation between IMTcca and IMTbif was similar in men (r=0.36) and women (r=0.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very common, affecting 57% (n=239) of men and 58% (n=211) of women. Severe carotid plaques with flow disturbance were rare, affecting 9 men (2%) and 6 women (1.6%). Plaques increased in prevalence with age, affecting 49% men and 39% of women aged <60 years and 65% and 75% of men and women, respectively, aged >70 years. Plaques were most common among men in Dewsbury (79% affected) and least common among men in Maidstone (34% affected). IMTcca showed a different pattern of association with cardiovascular risk factors from IMTbif and was associated with age, SBP, and FEV1 but not with social, lifestyle, or other physiological risk factors. IMTbif and carotid plaques were associated with smoking, manual social class, and plasma fibrinogen. IMTbif and carotid plaques were associated with symptoms and diagnoses of cardiovascular diseases. IMTbif associations with cardiovascular risk factors and prevalent cardiovascular disease appeared to be explained by the presence of plaques in regression models and in analyses stratified by plaque status. CONCLUSIONS: IMTcca, IMTbif, and plaque are correlated with each other but show differing patterns of association with risk factors and prevalent disease. IMTcca is strongly associated with risk factors for stroke and with prevalent stroke, whereas IMTbif and plaque are more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Our analyses suggest that presence of plaque, rather than the thickness of IMTbif, appears to be the major criterion of high risk of disease, but confirmation of these findings in other populations and in prospective studies is required. The association of fibrinogen with plaque appears to be similar to its association with incident cardiovascular disease. Further work elucidating the composition of plaques using ultrasound imaging would be helpful, and more data, analyzed to distinguish plaque from IMTbif and IMTcca, are required to understand the significance of thicker IMT in the absence of plaque.

Age Distribution↗
PubMed1999

Management of acute nontraumatic upper limb ischemia.

A retrospective review of all patients presenting to a tertiary referral center with acute nontraumatic upper limb ischemia between January 1992 and June 1997 was undertaken to examine the role of intraarterial thrombolysis in the management of such cases. Twenty-one patients were identified in the radiology and vascular surgery departments' registers. Twenty (95%) underwent angiography, demonstrating subclavian artery occlusion in four, axillary in two, brachial in 13, and one at the digital level. Intraarterial thrombolysis was attempted in 12 patients. There were three technical failures, all requiring embolectomy. Six had complete lysis and resolution of their symptoms. One patient had partial lysis but experienced no further rest pain. Thrombolysis was unsuccessful in two cases with one subsequently requiring embolectomy and the other surgical bypass. Three patients had surgical intervention as their primary procedure with two favorable outcomes and one ending in above-elbow amputation. Five patients were treated conservatively with heparin, resulting in three partial and two full recoveries. One patient experienced complete resolution of symptoms with an intravenous prostacyclin infusion. Both electrocardiograms (ECG) and echocardiograms (ECHO) were of limited diagnostic aid, and long-term warfarin anticoagulation was prescribed to all patients. There was no recurrence of upper limb ischemia at a median follow up of 18 months. Intraarterial thrombolysis is an effective first line treatment for acute nontraumatic upper limb ischemia in selected cases.

Acute Disease↗
PubMed1999

Permanent effects of neonatal estrogen exposure in rats on reproductive hormone levels, Sertoli cell number, and the efficiency of spermatogenesis in adulthood.

This study aimed to identify the mechanism(s) for impairment of spermatogenesis in adulthood in rats treated neonatally with estrogens. Rats were treated (days 2-12) with 10, 1, or 0.1 microg diethylstilbestrol (DES), 10 microg ethinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle and killed in adulthood. DES/EE caused dose-dependent reductions in testis weight, total germ cell volume per testis, and Sertoli cell volume per testis. Sertoli cell number at 18 days of age in DES-treated rats was reduced dose dependently. GnRHa treatment caused changes in these parameters similar to those in rats treated with 10 microg DES. Plasma FSH levels were elevated (P < 0.001) to similar levels in all treatment groups regardless of differences in Sertoli cell number and levels of inhibin B; the latter reflected Sertoli cell number, but levels were disproportionately reduced in animals treated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa, caused dose-dependent reductions (40-80%) in plasma testosterone levels in adulthood, but did not alter LH levels. Preliminary evidence suggests that the decrease in testosterone levels in estrogen-treated rats is not due to reduced Leydig cell volume per testis. GnRHa-treated rats exhibited a significant increase in germ cell volume per Sertoli cell and a reduction in germ cell apoptosis, probably because of the raised FSH levels. Despite similar raised FSH levels, rats treated with DES (10 or 1 microg) or EE (10 microg) had reduced germ cell volume/Sertoli cell and increased germ cell apoptosis, especially when compared with GnRHa-treated animals. The latter changes were associated with an increase in lumen size per testis, indicative of impaired fluid resorption from the efferent ducts, resulting in fluid accumulation in the testis. Rats treated neonatally with 0.1 microg DES showed reduced germ cell apoptosis comparable to that in GnRHa-treated animals. The changes in apoptotic rate among treatment groups occurred across all stages of the spermatogenic cycle. It is concluded that 1) neonatal estrogen treatment results in dose-dependent alterations in Sertoli cell numbers, germ cell volume, efficiency of spermatogenesis, and germ cell apoptosis in adulthood; 2) the relatively poor spermatogenesis in estrogen-treated animals is most likely due to altered testis fluid dynamics and/or altered Sertoli cell function; 3) as indicated by FSH (LH) and testosterone levels, the hypothalamic-pituitary axis and Leydig cells are probably more sensitive than the Sertoli cells to reprogramming by estrogens neonatally; and 4) elevated FSH levels in adulthood may improve the efficiency of spermatogenesis.

Animals↗
PubMed1999

Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.

The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.

Adult↗
PubMed1998

Adult height, stroke, and coronary heart disease.

An inverse relation between adult height and risk of coronary heart disease (CHD) has been reported in many studies, but the association between adult height and stroke remains uncertain. The authors examined the relation between adult height and risk of stroke and CHD in a prospective study of 7,735 men drawn from general medical practices in 24 towns in England, Wales, and Scotland. The men were followed up for an average of 16.8 years (range, 15.5-18.0 years) between 1978 and 1995. During this period, there were 351 major stroke events (63 fatal, 288 nonfatal) and 1,093 major CHD events (465 fatal, 628 nonfatal). The mean height of the men was 173.3 cm. Total stroke risk was increased only in the men who fell into the lowest quintile of the height distribution (<167.7 cm), with little difference being seen between the other groups. When data were examined separately for fatal and nonfatal events, no relation was seen with nonfatal stroke. An apparent inverse association was seen with fatal stroke, even after adjustment for a wide range of confounding variables, but the number of deaths was small and the trend was not statistically significant (p = 0.17). By contrast, a significant inverse relation was seen between height and risk of major CHD events: Risk decreased progressively with increasing height, even after full adjustment (highest quintile vs. lowest: relative risk (RR) = 0.74, 95% confidence interval (CI) 0.59-0.91; test for trend: p < 0.001). A stronger inverse association was seen with nonfatal CHD events (RR = 0.64, 95% CI 0.49-0.84) than with fatal CHD events (RR = 0.82, 95% CI 0.60-1.11). This study confirms the finding of an inverse association between height and CHD. The inverse association seen for fatal stroke but not nonfatal stroke suggests that height may be related to specific subtypes of stroke. There are different patterns of association between height and stroke and height and CHD. If the apparent association between short stature and increased risk of fatal stroke is confirmed in other prospective studies, this would suggest that different mechanisms underlie the effects of height on stroke and CHD.

Adult↗
PubMed1998

Identification of genetic variation in the human hormone-sensitive lipase gene and 5' sequences: homology of 5' sequences with mouse promoter and identification of potential regulatory elements.

Hormone-sensitive lipase (HSL) plays a crucial role in triglyceride hydrolysis in adipose tissue and exhibits cholesterol hydrolase activity in steroidogenic tissue and macrophages. Thus, common genetic variation in the HSL gene could affect both energy metabolism and atherogenesis. Using overlapping single-strand conformational polymorphism analysis (SSCP), a common single base change (T/C) in intron 4 [allele frequency 0.012 (95% CI 0.007-0. 018)] and a variable CA repeat in intron 6 with 9 alleles (heterozygosity index = 0.66) were identified. Sequence of 1.123 kb upstream from the reported 5'UTR (1) which includes intron B, exon B, and 159 bp of the promoter (2) was obtained and a single common nucleotide change, -60C/G [allele frequency 0.052 (95% CI 0.039-0. 064)], identified. Preliminary in vitro studies show that the -60G construct has 38.5% lower luciferase activity compared to the -60C construct (P = 0.035), suggesting a functional change affecting HSL gene expression. The 5' sequence shows 57-59% homology with the mouse promoter with higher homology at potential regulatory motifs. Thus, the 1.7 kb of 5' sequences is well conserved and may play a part in the regulation of HSL gene expression.

Adipocytes↗
PubMed1998

Changes in physical activity, mortality, and incidence of coronary heart disease in older men.

BACKGROUND: We studied the relations between physical activity and changes in physical activity, all-cause mortality, and incidence of major coronary-heart-disease events in older men. METHODS: In 1978-80 (Q1), 7735 men aged 40-59 were selected from general practices in 24 British towns, and enrolled in a prospective study of cardiovascular disease, which included physical activity data. In 1992 (Q92), 12-14 years later, 5934 of the men (91% of available survivors, mean age 63 years) gave further information on physical activity and were then followed up for a further 4 years. The main endpoints were all-cause mortality during 4 years of follow-up from Q92, and major fatal and non-fatal coronary-heart-disease events during 3 years of follow-up from Q92. FINDINGS: Among 4311 men with no history of coronary heart disease, stroke, or "other heart trouble" by Q92 and who did not report "poor health", there were 219 deaths. In the inactive/occasionally active, light, moderate, and moderately vigorous/vigorous activity groups there were 101 (18.5/1000 person-years) 48 (11.4), 23 (7.3), and 47 (9.1) deaths, respectively (adjusted risk ratios 1.00, 0.61 [95% CI 0.48-0.86], 0.50 [0.31-0.79], 0.65 [0.45-0.94]). Men who were sedentary at Q1 and who began at least light activity by Q92 had significantly lower all-cause mortality than those who remained sedentary, even after adjustment for potential confounders (risk ratio=0.55 [0.36-0.84]). Physical activity improved both cardiovascular mortality (0.66 [0.35-1.23]) and non-cardiovascular mortality (0.48 [0.27-0.85]). The relation between physical activity at Q92, changes in physical activity, and mortality were similar for men with pre-existing cardiovascular disease. INTERPRETATION: Maintaining or taking up light or moderate physical activity reduces mortality and heart attacks in older men with and without diagnosed cardiovascular disease. Our results support public-health recommendations for older sedentary people to increase physical activity, and for active middle-aged people to continue their activity into old age.

Aged↗
PubMed1998

Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis.

The activities of hexokinase isoenzymes I-IV (EC 2.7.1.1) and of N-acetylglucosamine kinase (EC 2.7.1.59) were determined in normal human liver and in alcoholic liver disease and primary biliary cirrhosis after FPLC fractionation of high-speed supernatants on Mono-Q with a linear NaCl gradient. In control human liver the hexokinase activities were: I, 3.6; II, 0.7; III, 3.5, IV, 4.8 (mUnits/mg supernatant protein). The activity of N-acetylglucosamine kinase was 8 mU/mg of protein. In alcoholic liver disease and primary biliary cirrhosis, the activity of hexokinase IV (glucokinase) was suppressed to less than 10% of control activity and the activity of hexokinase I was increased 3-fold. The activity of hexokinase II was increased approximately 7-fold in alcoholic liver disease. The activities of hexokinase III and N-acetylglucosamine kinase were unchanged in cirrhosis. Hexokinase III showed 50% substrate inhibition at 100 mM glucose as compared with 0.5mM glucose. The high activity of hexokinase III in human liver (approximately 50% of the low-Km activity and 70% of glucokinase activity) results in a significant underestimation of glucokinase activity as determined by the conventional spectrometric assay while the activity of N-acetylglucosamine kinase may contribute to an overestimation of glucokinase activity in the radiochemical assay. Furthermore glucokinase is dramatically suppressed in liver disease, which although partly compensated for by the increase in hexokinase I (and II), accounts in part for the well-known glucose intolerance of liver cirrhosis.

Chromatography↗
PubMed1998

Do health and use of services differ in residents of sheltered accommodation? A pilot study.

OBJECTIVE: To compare the rates of mental health problems, disability and use of health and social services of older people living in sheltered accommodation with those of the rest of the community in the same age group. DESIGN: Door-to-door survey in randomly selected enumeration districts. The districts contained three sheltered accommodation complexes. Residents from these addresses were compared with the others. SETTING: London Borough of Islington. SUBJECTS: 700 men and women aged 65 or over. MAIN OUTCOME MEASURES: Short-CARE depression, dementia and activity scales; the Guy's/Age Concern anxiety scale; individual items detailing problems with mobility, vision and hearing; use of a number of health and social services. RESULTS: The only difference in mental health variables on univariate analysis was a greater severity of cognitive impairment and dementia symptoms in sheltered accommodation. When demographic differences were taken into account, the association with cognitive impairment became statistically insignificant. There were significant associations between residence in sheltered accommodation and several of the disability variables. Increased use of health and social services by sheltered residents remained significant after disability and living alone were taken into account. CONCLUSIONS: The residents of sheltered accommodation were more disabled than the general elderly population but, in contrast to those in residential care, did not have a great excess of mental health problems. Indeed, the possibility was raised that sheltered accommodation may protect against depression in people who live alone.

Aged↗
PubMed1998

The use of an oligonucleotide that hybridizes to DNA sequences interspersed in the genome of members of the genus Phytophthora as an adjunct to morphological criteria in species identification.

An oligonucleotide (primer), designed from a conserved region of the multi-allelic b locus of the basidiomycete fungus Ustilago maydis, generated reproducible PCR fingerprints in Phytophthora species. The primer hybridized in a species-specific manner to nucleotide sequences interspersed in the genome of the closely related members of Phytophthora taxonomic group IV. We recommend the use of this PCR procedure as an alternative method for resolving the close taxonomic affinity of some members of the genus Phytophthora.

DNA↗
PubMed1998

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance.

Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.

Adult↗
PubMed1998

Metabolism, excretion and pharmacokinetics of a single dose of [14C]-raltitrexed in cancer patients.

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase and has recently been licensed in Europe for use in the treatment of advanced colorectal carcinoma. This study evaluated the metabolism, excretion and pharmacokinetics after a single dose of 3.0 mg/m2 [14C]-raltitrexed in patients with advanced solid malignancies not amenable to curative therapy. From April 1994 to July 1995, nine patients (six men and three women) were recruited into the study. Pharmacokinetics analysis was performed during the first cycle of treatment in all patients and, in two patients, limited sampling was done prior to and during the second cycle of treatment. The mean observed peak plasma concentration (Cmax) was 700.6 ng/ml and the median time (tmax) to reach maximal raltitrexed concentrations was 15 min after the initiation of the infusion. After reaching Cmax the drug declined in a triexponential manner with a terminal half-life of 257 h. The AUC0-infinity as predicted by the pharmacokinetic model was 2341.7 ng h ml(-1). Clearance was 41.3 ml/min, of which renal clearance accounted for 50-60%. Urinary collection for the measurement of radiolabeled drug revealed that renal excretion extrapolated to infinity accounted for 40% of the total radioactive dose. Faecal excretion accounted for only 3% of the dose when samples were collected to day 5 in the first six patients. Collection was extended to 10 days in the last three patients and faecal elimination accounted for 14% in these patients. Raltitrexed measurements prior to subsequent doses suggest that there was no accumulation of the drug with repeated administration. Low levels of radioactivity measured in the red cell pellets on days 15, 22 and 29 are likely to represent drug retained by newly forming red cells at the time of dosing. Examination of the urine revealed that the drug was excreted unchanged. The toxicities seen were in line with those encountered in previous studies. Grade 3 and 4 thrombocytopenia occurred in three patients and grade 3 neutropenia occurred in two patients.

Adult↗