Biomedical subjects
Publications and source records attributed to F Bennett.
We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
Hypertension remains the most common cardiovascular risk factor in developing countries, yet the majority of patients have no access to pharmacological therapy. Population-wide preventive strategies, such as salt restriction, are an attractive alternative, but experience in resource-poor settings is limited. To address this question, we conducted a randomized crossover study of salt restriction in adults living in Nigeria and Jamaica in order to estimate the mean blood pressure (BP) response. After a 4-week run-in period to determine willingness to adhere to a low-salt diet, 56 Jamaicans and 58 Nigerians completed an 8-week crossover study of low-salt and high-salt intake. Baseline BPs were in the normotensive range (systolic=125 mmHg in Jamaica, 114 mmHg in Nigeria). Baseline urinary sodium excretion was 86.8 and 125.6 mEq/day in Nigeria and Jamaica, respectively. The mean difference between urinary sodium excretion at baseline and at the end of the 3-week low-sodium phase was 33.6 mEq/day in Nigeria and 57.5 mEq/day in Jamaica. During the high-sodium phase, mean change in urinary sodium excretion from baseline to week 3 was 35.0 and 5.5 mEq/day in Nigeria and Jamaica, respectively. The mean change in systolic BP ('high' vs 'low' sodium phase) was approximately 5 mmHg in both groups. This study suggests that the efficacy of sodium reduction in developing countries equals those noted in more affluent cultures. If promoted on a wide scale, sodium reduction could be used to treat persons with established hypertension, and more importantly, to prevent age-related increases in BP in poor communities.
OBJECTIVE: To describe the influence of maternal weight and weight gain, placental volume and the rate of placental growth in early pregnancy on fetal dimensions measured sonographically. DESIGN: In a prospective study, 712 women were recruited from the antenatal clinic of the University Hospital of the West Indies. Data analysis was confined to 374 women on whom measurements of the placental volume at 14, 17 and 20 weeks gestation were complete. Measurements of maternal anthropometry and fetal size (by ultrasound) were performed. Weight gain in pregnancy between the first antenatal visit (8-10 weeks) and 20 weeks gestation, and the rate of growth of the placenta between 14-17 and 17-20 weeks gestation were calculated. MAIN OUTCOME MEASURES: Fetal anthropometry (abdominal and head circumferences, femoral length, and biparietal diameter) at 35 weeks gestation. RESULTS: Lower maternal weight at the first antenatal visit was associated with a significantly smaller placental volume at 17 and 20 weeks gestation (P<0.002 and <0.0001 respectively). In all women, maternal weight gain was directly related to fetal anthropometry. Placental volume at 14 weeks gestation and the rate of growth of the placenta between 17 and 20 weeks gestation were significantly related to all four fetal measurements. CONCLUSION: This study has provided evidence that both placental volume, and the rate of placental growth may influence fetal size. These effects are evident in the first half of pregnancy, and appear to be mediated through maternal weight and weight gain.
OBJECTIVE: This study compares how income is related to obesity vs two obesity-related cardiovascular disease (CVD) risk factors-diabetes and hypertension-in adults from Jamaica. DESIGN: A cross-sectional population-based survey was used. In total, 847 men and 1249 women aged 25-74 y were randomly recruited from a periurban area in 1993-1998. MEASUREMENTS: Trained interviewers measured anthropometry and blood pressure, obtained fasting blood and collected self-reported data on income and disease history. RESULTS: Income was strongly and positively associated with obesity in men. In women, obesity levels were high even among the very poor, and the income gradient was more moderate. Although obesity-and particularly central fatness-was strongly associated with diabetes and hypertension prevalence, income was not significantly related to these disorders. CONCLUSIONS: Future research in developing countries should independently explore associations between income and obesity vs obesity-related disorders, and identify factors that explain any disparities.
Removal of the N-terminal formyl group from newly synthesized proteins by the enzyme peptide deformylase (PDF) is essential for normal growth of bacteria but not higher organisms. Recently, PDF has been explored as a target for novel antibiotics. Screening a collection of natural products for antimicrobial activity identified actinonin and two matlystatin analogs as potent PDF inhibitors. A number of synthetic analogs of these natural products were prepared and their inhibitory potency determined. Previous work has shown that PDF is an iron metalloproteinase also containing a catalytic glutamic acid residue. Ligation of the ferrous cation is an essential feature of potent inhibitors. The structures of actinonin, a matlystatin analog and a synthetic inhibitor complexed with PDF were determined by crystallography. A quantum mechanics/molecular mechanics (QM/MM) method was used to reproduce the geometry of known complexes, to predict the protonation state in the active site and to predict the geometry of additional complexes. The requirement for protonation of the active site glutamate anion is an important factor in understanding the potency of inhibitors with acidic iron-ligating groups such as hydroxamate and carboxylate. Even though potent inhibitors of PDF have been discovered, their bacteriostatic mechanism of action and the rapid development of resistance in vitro may limit their potential as antibacterial drugs.
AIM: To investigate the relationship between anthropometry at birth and glucose/insulin metabolism in childhood using the response to an oral glucose challenge. METHOD: Four hundred mother/child pairs on whom gestational and birth data were available were studied. After an overnight fast, anthropometric measurements were made on the children and an oral glucose tolerance test performed. The plasma concentrations of insulin, pro-insulin and 32-33 split pro-insulin were also measured. Skinfold thicknesses were used to calculate percentage body fat and fat mass was derived from the percentage fat and absolute weight. RESULTS: The mean age of the children was 8 y (range 7.5-10.5), and six exhibited impaired glucose tolerance based on WHO criteria. Insulin concentration 120 min after the oral glucose load (a measure of insulin resistance) was inversely related to length at birth (P<0.005). The children who were in the shortest quartile at birth and were heaviest at 8 y old had the highest insulin concentration. CONCLUSION: Shortness at birth is related to insulin resistance. Such insensitivity to the action of insulin is greater in heavier children.
Circulating angiotensin I-converting enzyme (ACE) levels are influenced by a major quantitative trait locus (QTL) that maps to the ACE gene. Phylogenetic and measured haplotype analyses have suggested that the ACE-linked QTL lies downstream of a putative ancestral breakpoint located near to position 6435. However, strong linkage disequilibrium between markers in the 3' portion of the gene has prevented further resolution of the QTL in Caucasian subjects. We have examined 10 ACE gene polymorphisms in Afro-Caribbean families recruited in JAMAICA: Variance components analyses showed strong evidence of linkage and association to circulating ACE levels. When the linkage results were contrasted with those from a set of British Caucasian families, there was no evidence for heterogeneity between the samples. However, patterns of allelic association between the markers and circulating ACE levels differed significantly in the two data sets. In the British families, three markers [G2215A, Alu insertion/deletion and G2350A] were in complete disequilibrium with the ACE-linked QTL. In the Jamaican families, only marker G2350A showed strong but incomplete disequilibrium with the ACE-linked QTL. These results suggest that additional unobserved polymorphisms have an effect on circulating ACE levels in Jamaican families. Furthermore, our results show that a variance components approach combined with structured, quantitative comparisons between families from different ethnic groups may be a useful strategy for helping to determine which, if any, variants in a small genomic region directly influence a quantitative trait.
LC-NMR and LC-MS were used to characterize the structures of four major degradation products of SCH 56592, an antifungal drug candidate in clinical trials. These compounds were formed under stress conditions in which the bulk drug substance was heated in air at 150 degrees C for 12 days, and were separated from SCH 56592 as a mixture using a semi-preparative HPLC method. The data from LC-NMR, LC-ESI-MS (electrospray ionization mass spectrometry) and LC-ESI-MS/MS indicate that the oxidation occurred at the piperazine ring in the center of the drug molecule. The structures of the degradation products were determined from the 1H NMR spectra obtained via LC-NMR, which were supported by LC-ESI-MS and LC-ESI-MS/MS analyses. A novel degradation pathway of SCH 56592 was proposed based on these characterized structures.
In vitro studies have suggested that targeting interleukin (IL)-1 and tumor necrosis factor (TNF) can be used to regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and potentially treat kidney inflammation. We therefore evaluated ICAM-1 and VCAM-1 regulation in knockout (KO) mice deficient in both IL-1 receptor 1 (R1) and TNF-R1 during renal ischemia reperfusion injury. ICAM-1 and VCAM-1 mRNA expression was measured with specific murine probes and Northern blotting (n =4/group). Protein expression was measured using immunohistochemistry. Serum creatinine (SCr), tubular histology, and neutrophil infiltration into postischemic kidneys were also quantified. ICAM-1 and VCAM-1 mRNA expression increased in both wild-type (WT) and KO mice at 2, 6, and 24 h. Protein expression of ICAM-1 and VCAM-1 was also increased at 24 h postischemia. SCr levels and tubular necrosis scores were comparable in WT and KO mice at 24 and 48 h. Neutrophil migration in KO mice was decreased at 24 h but comparable to WT at 48 h. These data demonstrate that IL-1 and TNF are not essential for postischemic increases in ICAM-1 and VCAM-1.
CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediated costimulation. We assessed the contributions of these two mechanisms using a panel of T cell lines expressing human CTLA-4 with mutations in the cytoplasmic region. Under conditions of B7-independent costimulation, inhibition of IL-2 production following CTLA-4 engagement required the CTLA-4 cytoplasmic region. In contrast, under B7-dependent costimulation, inhibition of IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA-4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinct functional outcomes: rapid inhibition of T cell activation or induction of T cell anergy.
AIMS: To characterize the prevalence of diabetes and associated risk attributes in the Jamaican population. METHODS: A random population sample was recruited by door-to-door canvassing (n = 1303). A final participation of 60% was achieved. Oral glucose tolerance testing was conducted after an overnight fast and standard anthropometric and demographic data were collected. RESULTS: The prevalence of Type 2 diabetes mellitus was 9.8% (95% confidence interval (CI) 7.2-12.4) among men and 15.7% (95% CI 13.1-18.3) among women with an overall prevalence of 13.4% (95% CI 11.5-15.2). Impaired glucose tolerance was found among 12.3% of men and 14.7% of women. The sex patterns were consistent with a fourfold excess of obesity in women compared to men. The odds ratios for diabetes, fourth vs. first quartiles were 5.42 (95% CI 2.02-16.88) in men and 3.32 (95% CI 1.73-6.63) in women for body mass index (BMI) and 17.39 (95% CI 3.86-78.27) in men and 5.48 (95% CI 2.84-11.00) in women for WHR in a logistic model controlling for age. The population attributes risk percentage, for diabetes, of being overweight and having waist-to-hip ratio (WHR) greater than the median (0.80) were 66% and 80%, respectively. The contribution of central obesity, as characterized by WHR, was also significant in sex-specific multivariate models that included age and BMI. Prevalent hypertension and family history of diabetes were likewise associated with increased odds of having the disease. CONCLUSIONS: The prevalence of diabetes in Jamaica now exceeds that observed among European-origin populations and reflects the emerging epidemic of obesity. The excess risk for this population could not be attributed entirely to relative weight. The pronounced sexual dimorphism in diabetes prevalence most likely reflects the substantial excess of obesity among women compared to men. Like many other island nations, Caribbean societies now appear to be at substantial risk of diabetes.
OBJECTIVE: To compare the prevalence of glucose intolerance in genetically similar African-origin populations within Cameroon and from Jamaica and Britain. RESEARCH DESIGN AND METHODS: Subjects studied were from rural and urban Cameroon or from Jamaica, or were Caribbean migrants, mainly Jamaican, living in Manchester, England. Sampling bases included a local census of adults aged 25-74 years in Cameroon, districts statistically representative in Jamaica, and population registers in Manchester. African-Caribbean ethnicity required three grandparents of this ethnicity. Diabetes was defined by the World Health Organization (WHO) 1985 criteria using a 75-g oral glucose tolerance test (2-h > or = 11.1 mmol/l or hypoglycemic treatment) and by the new American Diabetes Association criteria (fasting glucose > or = 7.0 mmol/l or hypoglycemic treatment). RESULTS: For men, mean BMIs were greatest in urban Cameroon and Manchester (25-27 kg/m2); in women, these were similarly high in urban Cameroon and Jamaica and highest in Manchester (27-28 kg/m2). The age-standardized diabetes prevalence using WHO criteria was 0.8% in rural Cameroon, 2.0% in urban Cameroon, 8.5% in Jamaica, and 14.6% in Manchester, with no difference between sexes (men: 1.1%, 1.0%, 6.5%, 15.3%, women: 0.5%, 2.8%, 10.6%, 14.0%), all tests for trend P < 0.001. Impaired glucose tolerance was more frequent in Jamaica. CONCLUSIONS: The transition in glucose intolerance from Cameroon to Jamaica and Britain suggests that environment determines diabetes prevalence in these populations of similar genetic origin.
Studies involving modifications to the P3 position of previously described HIV-protease inhibitors containing beta-hydroxyether and thioether dipeptide isostere replacements led to the discovery of pseudopeptides 8o and 8p with improved antiviral activities.
The Trp64Arg mutation of the beta3-adrenergic receptor (beta3-AR) has been linked to earlier onset of non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, abdominal obesity, and an increased capacity to gain weight in some European and Japanese populations. We studied the prevalence of the mutation and its association with NIDDM and obesity in our population, in which both rates are high, especially in women. The frequency of the homozygous mutation was 1.53%, and of the Arg allele, 10.5%. Rates were similar in men and women. Significantly higher body mass index (BMI), weight, hip circumference, and fasting and postchallenge 2-hour blood glucose concentrations were associated with the presence of the Arg allele in women but not in men. The association with weight and hip measurements and with hyperglycemia was present only in women aged less than 55 years. In multivariate analysis, the mutation was associated with the BMI and sex in a model that also included age. The variation in fasting and 2-hour blood glucose levels was predicted by beta3-AR, gender, age, and BMI. These results suggest that the presence of the mutation contributes to obesity and hyperglycemia in our female population.
OBJECTIVE: To investigate the relationship between blood pressure (BP), renal haemodynamics, anthropometric measures of obesity and urinary albumin excretion in hypertension and in a control group. METHODS: Urinary albumin, BP and anthropometric measurements were carried out in patients attending the hypertension clinic of the University Hospital of the West Indies. A randomised stratified sample was then selected for renal haemodynamic assessment. A normoalbuminuric control group without hypertension or diabetes was also selected. Renal haemodynamics was assessed by measuring glomerular filtration rate using 51-chromium edetic acid (51Cr-EDTA) and renal blood flow using 125-iodohippurate (125-PAH). RESULTS: Urinary albumin excretion was positively and significantly correlated with systolic pressure (beta = 0.011, P < 0.003, R = 0.22), current body weight (beta = 0.014, P < 0.04, R = 0.15) and the presence of diabetes (beta = 0.9, P < 0.001, R = 0.3). In the sample selected for renal haemodynamics, patients with microalbuminuria had lower age-adjusted corrected renal blood flow (P < 0.006), effective renal plasma flow (P < 0.006) and higher filtration fraction (P < 0.006) when compared with patients without microalbuminuria. Glomerular filtration rate in patients with microalbuminuria was not different from those without. Urinary albumin excretion was positively and significantly correlated with systolic pressure (beta = 0.016, P < 0.003, R = 0.40) and inversely related to corrected renal blood flow (beta = -1.13, P < 0.0002, R = 0.46). Waist:hip ratio was inversely related to corrected renal blood flow (beta = -1.74, P < 0.02, adjusted R = 0.48). CONCLUSION: Systolic BP, diabetes and body weight were significant predictors of albuminuria in our patients. Microalbuminuria and body fat distribution as assessed by waist:hip ratio were important determinants of renal haemodynamics in this population.
Mortality statistics show that there has been a significant change in the leading causes of death in Jamaica over the last 50 years, characterized by a decrease in the infectious diseases and those due to undernutrition and an increase in the non-communicable diseases. The various patterns of this epidemiological transition worldwide are outlined and the characteristics of this 'new' epidemic are discussed. Data are presented from the findings of the recent multi-country study of hypertension and diabetes, including Jamaica, which shows that as the body mass index (BMI) increases across the African diaspora, so does the prevalence of hypertension and diabetes. Among the Jamaican population studied, the prevalence of hypertension was 19.1% among males and 28.2% among females. Reported prevalence of previously diagnosed diabetes was 5.3% in men and 10.4% in females. The gender differences are in part explained by the differences in mean BMI which were 23.8 and 27.9, respectively, for males and females. 30.6% of males and 64.7% of females were either overweight or obese, with obesity prevalent in 7.2% of the males and 31.5% of the females studied. The increasing prevalence of obesity across the Caribbean is cause for concern as it significantly impacts on the demand for health and medical care. The identification of these reversible risk factors should be used to inform public policy to tackle what will be a growing concern.
A method is presented to estimate a cutoff for hemoglobin concentration appropriate for estimating the prevalence of iron deficiency anemia in poor Jamaican girls 13-14 y of age. Iron deficiency was determined from a three-variable model of iron status (serum ferritin, erythrocyte protoporphyrin, and mean corpuscular volume). The most appropriate hemoglobin cutoff was considered the one that minimized misclassification of iron deficiency: that yielding the maximum kappa coefficient for correctly classifying iron deficiency between 100 and 120 g/L, at 1-g/L intervals. By using this method, a hemoglobin cutoff of 107 g/L was considered most appropriate. This cutoff and the other indicators were used to estimate prevalence of iron deficiency and iron deficiency anemia in the Jamaican girls: 7.6% and 4.3%, respectively. This approach should be appropriate for determining hemoglobin cutoffs for iron deficiency anemia in other populations.
OBJECTIVES: This study was undertaken to describe the distribution of blood pressures, hypertension prevalence, and associated risk factors among seven populations of West African origin. METHODS: The rates of hypertension in West Africa (Nigeria and Cameroon), the Caribbean (Jamaica, St. Lucia, Barbados), and the United States (metropolitan Chicago, Illinois) were compared on the basis of a highly standardized collaborative protocol. After researchers were given central training in survey methods, population-based samples of 800 to 2500 adults over the age of 25 were examined in seven sites, yielding a total sample of 10014. RESULTS: A consistent gradient of hypertension prevalence was observed, rising from 16% in West Africa to 26% in the Caribbean and 33% in the United States. Mean blood pressures were similar among persons aged 25 to 34, while the increase in hypertension prevalence with age was twice as steep in the United States as in Africa. Environmental factors, most notably obesity and the intake of sodium and potassium, varied consistently with disease prevalence across regions. CONCLUSION: The findings demonstrate the determining role of social conditions in the evolution of hypertension risk in these populations.