Biomedical subjects
Publications and source records attributed to M Walker.
Necrotizing fasciitis continues to carry a very high mortality and prolonged morbidity. Gallstones have previously not been reported as a cause of this condition. We report a patient who presented with gallbladder perforation leading to necrotizing fasciitis of the anterior abdominal wall. The only organism isolated was Escherichia Coli, cultured from necrotic issue.
3-Deoxyglucosone (3DG), a reactive dicarbonyl, is an important intermediate in the formation of advanced glycation end products (AGEs). The AGEs are particularly important in diabetes since they have been correlated with the development of diabetic complications. Consequently, measurements of 3DG are likely to provide valuable insights into the role of this metabolite in the etiology of diabetic complications. While several methods of 3DG quantitation in human plasma have been previously published, a significant discrepancy (over 30-fold) exists in the reported values. Knecht et al. (Arch. Biochem. Biophys. 294, 130-137, 1992) have reported the levels of plasma 3DG in normoglycemics to be 61 nM, using a GC/MS procedure. In contrast to this, Niwa et al. (Biochem. Biophys. Res. Commun. 196, 837-843, 1993) reported 3DG levels to be 1800 nM in normoglycemics, using a totally independent GC/MS method. To resolve this disagreement and fill the need for a robust assay for this dicarbonyl, suitable for absolute quantitation, a GC/MS procedure was devised for its measurement. Plasma samples were deproteinized either by ultrafiltration or by addition of ethanol as described by Niwa et al. (Biochem. Biophys. Res. Commun. 196, 837-843, 1993). 3DG in the ultrafiltrate or the supernatant was conjugated with 2,3-diamino-naphthalene to produce a stable adduct which was then converted to a silyl ether and analyzed by GC/MS. The analyte was monitored by selected ion monitoring at an m/z of 295 and 306 and quantitated using an internal standard of [U-13C]3DG. Using this approach, 3DG levels in plasma deproteinized by ultrafiltration were found to be significantly elevated from 58.5 +/- 14 (SD) nM in normoglycemics to 98.5 +/- 34 (SD) nM in type I diabetics. When deproteinization of the plasma was carried out using ethanol, the levels of 3DG from normoglycemic plasma were similar to those reported by Niwa et al. (1710 +/- 750 (SD) nM). These results suggest that 3DG levels measured by ultrafiltration may represent the free circulating 3DG and those obtained by ethanol extraction may represent aform of 3DG bound to a macromolecule (presumbaly protein).
Animals have evolved diverse appendages adapted for locomotion, feeding and other functions. The genetics underlying appendage formation are best understood in insects and vertebrates. The expression of the Distal-less (Dll) homeoprotein during arthropod limb outgrowth and of Dll orthologs (Dlx) in fish fin and tetrapod limb buds led us to examine whether expression of this regulatory gene may be a general feature of appendage formation in protostomes and deuterostomes. We find that Dll is expressed along the proximodistal axis of developing polychaete annelid parapodia, onychophoran lobopodia, ascidian ampullae, and even echinoderm tube feet. Dll/Dlx expression in such diverse appendages in these six coelomate phyla could be convergent, but this would have required the independent co-option of Dll/Dlx several times in evolution. It appears more likely that ectodermal Dll/Dlx expression along proximodistal axes originated once in a common ancestor and has been used subsequently to pattern body wall outgrowths in a variety of organisms. We suggest that this pre-Cambrian ancestor of most protostomes and the deuterostomes possessed elements of the genetic machinery for and may have even borne appendages.
OBJECTIVE: To determine the body mass index associated with the lowest morbidity and mortality. DESIGN: Prospective study of a male cohort. SETTING: One general practice in each of 24 British towns. SUBJECTS: 7735 men aged 40-59 years at screening. MAIN OUTCOME MEASURES: All cause death rate, heart attacks, and stroke (fatal and non-fatal) and development of diabetes, or any of these outcomes (combined end point) over an average follow up of 14.8 years. RESULTS: There were 1271 deaths from all causes, 974 heart attacks, 290 strokes, and 245 new cases of diabetes mellitus. All cause mortality was increased only in men with a body mass index (kg/m2) < 20 and in men with an index > or = 30. However, risk of cardiovascular death, heart attack, and diabetes increased progressively from an index of < 20 even after age, smoking, social class, alcohol consumption, and physical activity were adjusted for. For the combined end point the lowest risks were seen for an index of 20.0-23.9. In never smokers and former smokers, deaths from any cause rose progressively from an index of 20.0-21.9 and for the combined end point, from 20.0-23.9. Age adjusted levels of a wide range of cardiovascular risk factors rose or fell progressively from an index < 20. CONCLUSION: A healthy body mass index in these middle aged British men seems to be about 22.
OBJECTIVE: To identify which patterns of fetal growth, represented by different measurements of size at birth, are associated with increased blood pressure in children aged 8-11 years. DESIGN AND SETTING: School based, cross sectional survey conducted in 10 towns in England and Wales in 1994. SUBJECTS: 3010 singleton children (response rate 75%) with physical measurements and information on birth weight from parental questionnaires. Hospital birth records were examined for 1573. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure at age 8-11 years. RESULTS: In the whole group birth weight was inversely related to systolic pressure (regression coefficient -1.48 mm Hg/kg; 95% confidence interval -2.20 to -0.76) after adjustment for current body size. There was no significant association between birth weight and diastolic pressure. The association with systolic pressure was much stronger in girls (-2.54 mm Hg/kg; -3.60 to -1.48) than in boys (-0.64 mm Hg/kg; -1.58 to 0.30), with a significant difference between the sexes (P = 0.006). Among the other neonatal measures, head circumference and placental weight were inversely associated with subsequent blood pressure in girls, and placental ratio (placental weight:birth weight) was positively associated with blood pressure in boys. Neither ponderal index at birth nor length:head circumference ratio was related to blood pressure in either sex. CONCLUSIONS: In these contemporary children the association between birth weight and blood pressure was apparent only in girls. There was no evidence that measures of size at birth, which may be related to nutrition at critical periods of pregnancy (thinness at birth or shortness in relation to head circumference), are related to blood pressure in the offspring.
The myeloid transforming gene Evi-1 encodes a protein with two zinc finger domains, designated ZF1 and ZF2, with distinct DNA binding specificities. For the first time we demonstrate that Evi-1 has transcriptional repressor activity which is directly proportional to the amount of Evi-1 protein in cells. Repression has been observed with two distinct promoters: the minimal HSV-1 tk promoter and a VP16 inducible adenovirus E1b minimal promoter. Optimal repression is DNA binding dependent and is mediated by either ZF1 or a heterologous GAL4 DNA binding domain (GAL4DBD) but is significantly less efficient through the ZF2 binding site. Both GAL4DBD/Evi-1 fusion and non-fusion proteins have been used to map the repressor activity to a proline-rich region located within amino acids 514-724 between the ZF1 and ZF2 domains. Constitutive expression of mutant proteins lacking the repressor domain are defective for transformation of Rat1 fibroblasts demonstrating that this region is required for the oncogenic activity of the Evi-1 protein. These studies show that the Evi-1 gene encodes a transcriptional repressor and has important implications for the mechanism of action of the Evi-1 protein both in development and in the progression of some myeloid leukaemias.
Maternally inherited diabetes and deafness (MIDD) is a new sub-type of diabetes and results from an A to G substitution at position 3243 of the mitochondrial tRNA(leu(UUR)) gene. This mutation is also associated with a neurological syndrome (MELAS). Recent studies have screened carefully selected diabetic populations and have reported MIDD prevalence rates ranging from undetectable to 60%. The aim of this work was to determine the importance of this sub-type in clinical practice by screening a routine hospital diabetic population. A total of 1440 patients (IDDM and NIDDM) of North European extraction attending two hospital diabetes services were initially screened by questionnaire. This identified 445 patients with one or more features of MIDD and/or MELAS and these subjects were then genotyped. Two patients were identified with the mutation giving a prevalence rate of 0.13% for the whole study population, and 0.45% for the sample with phenotypic features of MIDD. In conclusion, therefore, the 3243 mutation is associated with the phenotypically distinct MIDD sub-type, but this is rare in the routine hospital diabetic population.
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In adults low birthweight and thinness at birth are associated with increased risk of glucose intolerance and non-insulin-dependent diabetes mellitus. We have examined the relations between size at birth (birthweight, thinness at birth) and levels of plasma glucose and serum insulin in children, and compared them with the effects of childhood size. We performed a school-based survey of 10-11-year-old British children (response rate 64%) with measurements made after an overnight fast. One group of children (n = 591) was studied fasting while the other (n = 547) was studied 30 min after a standard oral glucose load (1.75 g/kg). Serum insulin was measured by a highly specific ELISA method. Birthweight was assessed by maternal recall and thinness at birth using birth records. Neither fasting nor post-load glucose levels showed any consistent relationship with birthweight or ponderal index at birth. After adjustment for childhood height and ponderal index, both fasting and post-load insulin levels fell with increasing birthweight. For each kg increase in birthweight, fasting insulin fell by 16.9% (95% confidence limits 7.1-25.8%, p = 0.001) and post-load insulin by 11.6% (95% confidence limits 3.5-19.1%, p = 0.007). However, the proportional change in insulin level for a 1 SD increase in childhood ponderal index was much greater than that for birthweight (27.2% and -8.8%, respectively, for fasting insulin). We conclude that low birthweight is not related to glucose intolerance at 10-11 years, but may be related to the early development of insulin resistance. However, in contemporary children obesity is a stronger determinant of insulin level and insulin resistance than size at birth.
Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3%, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion.
OBJECTIVE: Reports suggest that there is an increased incidence of preeclampsia after a previously normal pregnancy if there is a change in paternity. We hypothesize that there is a higher incidence of preeclampsia (proteinuric hypertension) in women conceiving by intrauterine insemination with donor sperm versus intrauterine insemination with partner sperm. STUDY DESIGN: This was a retrospective cohort study. In women with primary infertility all pregnancies achieved by either partner or donor intrauterine insemination carried to birth of a fetus (> 20 weeks) were identified. The medical records were examined for the maternal and pregnancy outcome data. The relative risk and 95% confidence interval were calculated for the risk of preeclampsia. The baseline data were compared with t tests, chi 2 analysis and Fisher's exact test where appropriate. RESULTS: Forty-four patients in the partner intrauterine insemination group and 37 in the donor insemination group were identified as having primary infertility. Three cases of mild preeclampsia were found in the partner insemination program and nine cases of preeclampsia (five severe, four mild) in the donor insemination program (relative risk 1.85, 95% confidence interval 1.20 to 2.85). CONCLUSIONS: There is a higher incidence of preeclampsia in women conceiving by intrauterine insemination with washed donor sperm compared with intrauterine insemination with washed partner sperm. This supports, indirectly, an immunologic basis for preeclampsia. The antigenic factor would appear to be located on the sperm as opposed to the seminal fluid itself.
Type II (non-insulin-dependent) diabetes mellitus is a metabolically heterogeneous condition, and is invariably preceded by impaired glucose tolerance (IGT). We examined whether metabolic heterogeneity is a feature of IGT. Three subject groups were studied: IGT subjects with two or more living non-insulin-dependent diabetic relatives (IGTWF, n = 17), and IGT subjects (IGTWOF, n = 17) and subjects with normal glucose tolerance (NGT, n = 25) without a family history of diabetes. Glucose tolerance, glucose (KITTG) and nonesterified fatty acid (KITTNEF) insulin sensitivity, and first-phase insulin secretion (FPIS) were assessed by oral glucose tolerance (OGTT), insulin tolerance (ITT), and intravenous glucose tolerance (IVGTT) tests, respectively. Comparison of groups was made by ANOVA and t test. The three groups were matched for age, gender, body mass index (BMI), and waist to hip ratio (WHR). IGTWOF and IGTWF subjects had comparable 2-hour plasma glucose levels on OGTT, and insulin secretion and KITTG were decreased to comparable degrees. However, in comparison to IGTWF subjects, IGTWOF subjects had increased fasting serum triglyceride (geometric mean, 1.8 [range, 0.8 to 4.5] v 1.1 [0.4 to 2.5] mmol. L-1, P = .02) and 2-hour plasma nonesterified fatty acid ([NEFA] mean +/- SD, 0.12 +/- 0.07 v 0.08 +/- 0.03 mmol.L-1, P < .02) levels and decreased KITTNEF values (4.0 [1.7 to 8.9] v 6.2 [2.8 to 12.1]%.min-1, P < .02). Thus, the two IGT groups had comparable changes in glucose metabolism, but IGTWOF subjects had additional abnormalities of lipid metabolism. In conclusion, metabolic heterogeneity is a feature of IGT, and this may reflect underlying etiological heterogeneity.
Previous studies have suggested that polyol-pathway and nonenzymatic glycation may be involved in the development of cardiac myopathy, a well-known manifestation of diabetes. Although the exact etiology of this complication is not fully understood, it is likely to be multifactorial. In this study, we investigated the metabolic consequences of diabetes and the effect of aldose reductase inhibitor (ARI) treatment on cardiac tissues of Sprague-Dawley rats. Perchloric acid (PCA) extracts of hearts from the animals were examined using 31P-nuclear magnetic resonance (NMR), gas chromatography/mass spectrometry (GC/MS), and high-performance liquid chromatography (HPLC). In 31P-NMR spectra of diabetic animals, a peak resonating at the chemical shift of 5.8 ppm with a coupling constant of 10 Hz was identified as fructose-3-phosphate (F3P). Undetectable in controls (< approximately 20 nmol/g), this metabolite was present at a concentration of 81.3 +/- 16.3 nmol/g wet weight (n = 4) in diabetic rat hearts. GC/MS analysis of these extracts from diabetics also identified a decomposition product of F3P, 3-deoxyglucosone (3DG), at a concentration of 9.4 +/- 3.5 nmol/g (n = 3), compared with 0.98 +/- 0.43 nmol/g (n = 3) in controls. No evidence was found for the expected detoxification products of 3-DG, 3-deoxyfructose and 2-keto 3-deoxygluconate. Concomitant with the elevation of F3P and 3DG, fructose and sorbitol levels were also elevated in diabetic animals. Surprisingly, ARI treatment was found to have no effect on the levels of these metabolites. These data suggest that either the heart may be unique in its production of fructose or it may not readily transport the ARI sorbinil. Production of the potent glycating agents F3P and 3DG in diabetics suggests that these compounds may be contributing factors in the glycation of cardiac proteins in the diabetic rat heart.
There is a need to evaluate the permeability of human ulcerated tissue and periulcer tissue in order to assess the possible treatment of such a localized pathological lesion with a topical therapy. In vitro percutaneous absorption studies were undertaken to evaluate an animal model that may mimic this clinical situation. Porcine skin from three anatomical sites, the ear, abdomen, and dorsum; ischaemic skin (porcine and guinea pig); porcine wounds; and human skin (including periulcer and ulcerated tissue) were investigated, utilizing both whole skin and dermal membranes. Dermal membranes were chosen as representative of ulcerated tissue, as there would be no epidermal barrier present, and the thickness of the dermal membrane was not expected to offer any diffusional resistance to topically applied active agents. A range of chemicals with differing physicochemical properties was investigated using a Franz type diffusion cell. For all tissues a permeability coefficient (kp with units of cm h-1) was measured, along with skin thickness and tissue partition coefficient measurements. Under these experimental conditions and for the range of compounds tested, the results suggest that porcine skin, whole skin, and dermal membranes should be considered as good representative in vitro models for the topical delivery of compounds to human skin and ulcerated tissue, respectively.
The current practice of stroke prevention was assessed among UK general practitioners (GPs) using a postal questionnaire. A random sample of 583 GPs (response rate 60%) in practice throughout the UK was examined. Main outcomes were the reported practice in the identification of stroke risk, management of hypertension, and use of other interventions (particularly aspirin treatment) to reduce the risk of stroke. Most respondents (451, 77%) reported that they specifically identified patients at high risk of stroke. However, of these only 301 (67%) used more than one major risk factor to do this and less than one-third used either age or pre-existing cardiovascular disease as an indicator. Thresholds for drug treatment of hypertension increased markedly with patient age with only 68%, 23% and 9% of respondents reporting treating elevated systolic, diastolic and isolated systolic pressures respectively, in accord with the British Hypertension Society (BHS) guidelines for patients aged 70-79 years. Thresholds for blood pressure (BP) treatment in older patients did not differ by region but were higher among respondents who had been in general practice for more than 10 years. The value of aspirin in preventing stroke in patients with pre-existing cardiovascular disease was recognized by almost all (560, 96%) respondents. The results suggest that there is scope for increasing the benefits of stroke prevention in primary care, by focusing on the management of patients at high absolute risk, in whom the greatest treatment benefits are likely to be obtained.
We report on dynamic changes in plasma corticosteroid-binding globulin (CBG) binding and basal hypothalamic-pituitary-adrenal (HPA) activity following acute stress in adult rats. Plasma CBG binding was significantly reduced at 24 and 48 h following a single 60 min period of restraint. Basal levels of plasma ACTH and total corticosterone (B) during the light phase of the cycle were elevated at 24 h following restraint. These effects occurred only when animals were stressed in the light phase of the cycle; animals exposed to restraint stress during the dark phase of the cycle showed no change in plasma CBG binding or in basal HPA activity. Pituitary intracellular transcortin, which is derived from circulating CBG, was also decreased by restraint stress. The decrease in CBG binding was also associated with a significant increase in resting-state free B levels. Together, these effects produced a substantially (i.e. approximately 10-fold) increased 'basal' glucocorticoid signal 24 h following acute stress. These data suggest that the increase in the circulating glucocorticoid signal associated with acute stress endures well beyond the period of increased total B levels.
In May 1993, an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) was identified at our tertiary care teaching center. The epidemic MRSA strain was transmitted efficiently in the hospital environment. Subsequent investigations indicated that the strain had been introduced into western Canada by a patient who had recently been hospitalized for 3 months in the Punjab, India, and had been admitted to a hospital in rural British Columbia shortly after his arrival in Canada. Transfer of the patient to a hospital in Vancouver and subsequent transfer of a colonized patient contact to a hospital in Winnipeg, Manitoba, resulted in major outbreaks of MRSA at these two large tertiary care centers within 6 weeks of the arrival of the index case in Canada. Epidemiological typing of the S. aureus coagulase gene with use of a polymerase chain reaction method and pulsed-field gel electrophoresis documented clonality of this strain. These outbreaks again illustrate both the propensity of certain strains of S. aureus to produce epidemic disease, including rapid spread within the institutional setting, and the global nature of problems with antimicrobial resistance.
Insulin resistance is associated with diabetes mellitus, ischemic heart disease, and hypertension both independently and as part of syndrome X. Environmental influences on SI are incompletely understood. Exercise has a strong beneficial effect and obesity a strong adverse effect. The balance of evidence suggests that a high-fat diet is likely to reduce insulin sensitivity but the effects of dietary carbohydrates are more controversial. Extensive studies in animals showed a detrimental effect of diets very high in fructose or sucrose, particularly in association with induction of hypertriglyceridemia. The more limited studies in humans had conflicting results, partly because of heterogeneity of design. Certain groups of subjects may be more sensitive to adverse effects of high intakes of dietary sucrose or fructose. More carefully controlled studies in humans are needed to provide evidence on which to base public health policies with respect to dietary carbohydrates and SI.