The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.

P-glycoprotein (Pgp) is an ATP-dependent efflux transporter and plays a major role in anti-cancer drug resistance by pumping a chemically diverse range of cytotoxic drugs from cancerous tumors. Despite numerous studies with the transporter, the molecular features that drive anti-cancer drug efflux are not well understood. Even subtle differences in the anti-cancer drug molecular structure can lead to dramatic differences in their transport rates. To unmask these structural differences, this study focused on two closely-related anthracycline drugs, daunorubicin (DNR), and doxorubicin (DOX), with mouse Pgp. While only differing by a single hydroxyl functional group, DNR has a 4 to 5-fold higher transport rate than DOX. They both non-competitively inhibited Pgp-mediated ATP hydrolysis below basal levels. The Km of Pgp-mediated ATP hydrolysis extracted from the kinetics curves was lower for DOX than DNR. However, the dissociation constants (KDs) for these drugs determined by fluorescence quenching were virtually identical. Acrylamide quenching of Pgp tryptophan fluorescence to probe the tertiary structure of Pgp suggested that DNR shifts Pgp to a "closed" conformation, while DOX shifts Pgp to an "intermediate" conformation. The effects of these drugs on the Pgp conformational distributions in a lipid bilayer were also examined by atomic force microscopy (AFM). Analysis of AFM images revealed that DNR and DOX cause distinct and significant shifts in the conformational distribution of Pgp. The results were combined to build a conformational distribution model for anthracycline transport by Pgp.

Intake of polyunsaturated fat in relation to mortality among statin users and non-users in the Southern Community Cohort Study.

BACKGROUND AND AIMS: Consumption of polyunsaturated fatty acids (PUFA), especially the n3-series, may protect against cardiovascular disease (CVD), but recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that PUFA intake may not confer benefits beyond those provided by statins, but studies comparing statin users to non-users with regard to effects of PUFA are lacking. METHODS AND RESULTS: Black and white men and women (n = 69,559) in the Southern Community Cohort Study were studied. Cox regression models adjusting for age, sex, race, BMI, recruitment site, education, income, smoking, diabetes, and dietary variables were used. RESULTS: At baseline the mean ± SD age was 52 ± 9 years, 60% of participants were women, 54% had hypertension and 16% used statins. We observed modest inverse associations between n3-PUFA and n6-PUFA intake with mortality among non-statin users but not among statin users. In adjusted analyses, the HRs (95% CIs) for all-cause mortality (6,396 deaths over a median of 6.4 years) comparing the highest to the lowest quintile were 0.90 (0.82-1.00) for n3-PUFA and 0.80 (0.70-0.92) for n6-PUFA among non-statin users, whereas they were 1.06 (0.87-1.28) and 0.96 (0.78-1.19) for n3-PUFA and n6-PUFA, respectively, among statin users. CONCLUSIONS: Our results suggest potential benefits of PUFA consumption on mortality which are only apparent in the absence of statin therapy. It seems prudent to consider the potential benefit of PUFA consumption in the primary prevention of CVD among patients who are not candidates for statin therapy but are at increased risk for CVD and mortality.

Antimicrobial residues in foods of animal origin in Africa: public health risks.

The authors report on the current status of work on residues of veterinary medicinal products and, in particular, antimicrobial residues in foods of animal origin. This review focuses on residues of veterinary antimicrobials, antimicrobials used in livestock production, the concept of residues, and antimicrobial residues in foods of animal origin. Only one antimicrobial substance has been approved in the West African Economic and Monetary Union, compared with 16 substances in Benin and 56 in the European Union. The issue of antimicrobial residues in foods of animal origin has rarely been a serious concern in developing countries, in contrast to the situation in Europe. However, while the prevalence of veterinary drug residues in foods of animal origin is less than 1% in Europe, in some African countries it can be as high as 94%. Antimicrobial residues in foods of animal origin can cause allergies, cancer, alterations in the intestinal flora, bacterial resistance and the inhibition of fermentation in the dairy industry. The harmonisation of regulations in Africa could reduce the circulation of prohibited antimicrobials and lead to the implementation of a plan for the control and surveillance of residues from veterinary medicinal products in foods of animal origin.

A review on aflatoxin contamination and its implications in the developing world: a sub-Saharan African perspective.

Mycotoxins contamination in some agricultural food commodities seriously impact human and animal health and reduce the commercial value of crops. Mycotoxins are toxic secondary metabolites produced by fungi that contaminate agricultural commodities pre- or postharvest. Africa is one of the continents where environmental, agricultural and storage conditions of food commodities are conducive of Aspergillus fungi infection and aflatoxin biosynthesis. This paper reviews the commodity-wise aetiology and contamination process of aflatoxins and evaluates the potential risk of exposure from common African foods. Possible ways of reducing risk for fungal infection and aflatoxin development that are relevant to the African context. The presented database would be useful as benchmark information for development and prioritization of future research. There is need for more investigations on food quality and safety by making available advanced advanced equipments and analytical methods as well as surveillance and awareness creation in the region.

The 2011 United Nations high-level meeting on non-communicable diseases: the Africa agenda calls for a 5-by-5 approach.

The High Level Meeting of the 66th Session of the United Nations General Assembly was held in September 2011. The Political Declaration issued at the meeting focused the attention of world leaders and the global health community on the prevention and control of noncommunicable diseases (NCDs). The four major NCDs (cardiovascular diseases, cancer, diabetes and chronic respiratory diseases) and their four risk factors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol) constitute the target of the '4-by-4' approach, which is also supported by national and international health organisations. We argue that while preventing these eight NCDs and risk factors is also important in Africa, it will not be enough. A '5-by-5' strategy is needed, addressing neuropsychiatric disorders as the fifth NCD; and transmissible agents that underlie the neglected tropical diseases and other NCDs as the fifth risk factor. These phenomena cause substantial preventable death and disability, and must therefore be prioritised.

Ischaemic heart disease in Africa.

Ischaemic heart disease (IHD), previously considered rare in sub-Saharan Africa, now ranks 8th among the leading causes of death in men and women in the region. Furthermore, the prevalence of IHD and related morbidity may be increasing as a result of adverse behavioural and lifestyle changes associated with urbanisation and the epidemiological transition. The major risk factors for IHD in sub-Saharan Africa include hypertension, smoking, diabetes, abdominal obesity and dyslipidaemia. In the INTERHEART Africa study, these risk factors contributed a population-attributable risk of nearly 90% for acute myocardial infarction. Many cost-effective interventions exist at the individual and population levels, and they are likely to have a significant health impact in Africa. An aggressive approach that combines environmental, policy and legislative interventions for health promotion and primary prevention, coupled with improved access to evaluation, treatment and control of hypertension and other major risk factors, provides the best strategy for averting an epidemic of IHD in sub-Saharan Africa.

Epidemiology of stroke and high blood pressure in Africa.

Stroke and high blood pressure are major causes of death and disability worldwide. Although comprehensive stroke surveillance data for Africa are lacking, the available data show that age-standardised mortality, case fatality and prevalence of disabling stroke in Africa are similar to or higher than those measures in most high-income regions. In Africa, more than 90% of patients with haemorrhagic stroke and more than half with ischaemic stroke are found to have high blood pressure. However, awareness of hypertension and its prevention, treatment and control remain very low in Africa even though recent surveys show an increasing prevalence of the disease consistent with the nutritional and epidemiological transition in the region. Renewed emphasis on improved surveillance and the prevention and control of high blood pressure and stroke in Africa is needed.

The relation of obesity throughout life to carotid intima-media thickness in adulthood: the Bogalusa Heart Study.

OBJECTIVE: Although obese children are at increased risk for coronary heart disease in later life, it is not clear if this association results from the persistence of childhood obesity into adulthood. We examined the relation of adiposity at various ages to the carotid intima-media thickness (IMT) at age 35 y. DESIGN: Prior to the determination of IMT by B-mode ultrasound, subjects (203 men, 310 women) had, on average, six measurements of body mass index (BMI) and triceps skinfold thickness (TSF) between the ages of 4 and 35 y. Mixed regression models for longitudinal data were used to assess the relation of these characteristics to adult IMT. RESULTS: Overall, adult IMT was associated with levels of both BMI and TSF (P<0.001), with the magnitudes of the associations with childhood adiposity comparable to those with adult levels of BMI and TSF. Furthermore, adult obesity modified the association between childhood adiposity and IMT: high IMT levels were seen only among overweight (BMI > or =95th percentile) children who became obese (BMI > or =30 kg/m2) adults (P<0.01 for linear trend). In contrast, IMT levels were not elevated among (1) overweight children who were not obese in adulthood, or among (2) thinner children who became obese adults. CONCLUSIONS: These results emphasize the adverse, cumulative effects of childhood-onset obesity that persists into adulthood. Since many overweight children become obese adults, the prevention of childhood obesity should be emphasized.

Sudden cardiac death in the United States, 1989 to 1998.

BACKGROUND: Sudden cardiac death (SCD) is a major clinical and public health problem. METHODS AND RESULTS: United States (US) vital statistics mortality data from 1989 to 1998 were analyzed. SCD is defined as deaths occurring out of the hospital or in the emergency room or as "dead on arrival" with an underlying cause of death reported as a cardiac disease (ICD-9 code 390 to 398, 402, or 404 to 429). Death rates were calculated for residents of the US aged >/=35 years and standardized to the 2000 US population. Of 719 456 cardiac deaths among adults aged >/=35 years in 1998, 456 076 (63%) were defined as SCD. Among decedents aged 35 to 44 years, 74% of cardiac deaths were SCD. Of all SCDs in 1998, coronary heart disease (ICD-9 codes 410 to 414) was the underlying cause on 62% of death certificates. Death rates for SCD increased with age and were higher in men than women, although there was no difference at age >/=85 years. The black population had higher death rates for SCD than white, American Indian/Alaska Native, or Asian/Pacific Islander populations. The Hispanic population had lower death rates for SCD than the non-Hispanic population. From 1989 to 1998, SCD, as the proportion of all cardiac deaths, increased 12.4% (56.3% to 63.9%), and age-adjusted SCD rates declined 11.7% in men and 5.8% in women. During the same time, age-specific death rates for SCD increased 21% among women aged 35 to 44 years. CONCLUSIONS: SCD remains an important public health problem in the US. The increase in death rates for SCD among younger women warrants additional investigation.

Exercise in sickle cell anemia: effect on inflammatory and vasoactive mediators.

The aim of this study was to determine the response of inflammatory and vasoactive mediators to 3 consecutive days of exercise in African-American women with and without sickle cell anemia (SCA). Circulating inflammatory mediators [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha)] were measured before, and vasoactive mediators [endothelin-1 (ET-1), nitric oxide metabolites (NOx)] before and after each exercise bout in ten subjects with SCA and ten controls. Exercise did not affect ET-1, IL-6 or CRP concentrations (p >.05). TNFalpha was higher in SCA than controls (p < or = .0005) at all times; however, the response pattern was similar for the groups: no change from day 1 to day 2, but a decrease from day 2 to day 3 (p < or = .05). NOx increased significantly after exercise (p < or = .0001) but returned to baseline by 24 h afterward. On the 3rd day, NOx increased after exercise in SCA but not in the controls (p < or = .05). In conclusion, exercise did not cause a harmful inflammatory response in these individuals with SCA. However, NOx increased after exercise on all 3 days in SCA but appeared attenuated after 2 days in controls.

Body composition in women with sickle cell disease.

INTRODUCTION: Adults with sickle cell disease (SCD) have increased morbidity and low perceived health status, similar to patients with other chronic conditions. These patients may be sedentary due to exercise intolerance, physical incapacity due to sickle cell-related complications or medical conservatism. Obesity is an indicator of low health status and overall well-being in the general population, and we hypothesize that adults with SCD will have a high total body fat (%BF). The purpose of this study was to assess body composition in women with SCD using dual-energy X-ray absorptiometry (DXA). METHODS: Baseline medical examination, laboratory assessments, and seven-day activity recall to estimate energy expenditure (EE) were obtained for 22 women with SCD. BMI was calculated and whole body DXA was performed [fat mass (FM), fat-free soft tissue (FFST), and bone mineral content (BMC)]. Descriptive statistics were obtained and associations between body composition indices, total hemoglobin (Hb), treatment with hydroxyurea (HU), and EE were determined. RESULTS: Patient age was 30.5+/-9.3 years and total Hb was 8.85+/-1.92 g/dL (mean+/-SD). Mean body mass index (BMI) (22.6 kg/m2) was in the 'acceptable' range, while DXA measurement of mean % fat (32.6%) indicated obesity. Fat-free mass (FFM) was 40.0+/-5.62 and bone mineral density (BMD) was 1.13+/-0.14 g/cm2 (mean+/-SD). There were no correlations between body composition indices and total Hb, HU, or EE. CONCLUSIONS: This is the first report of high levels of adiposity, low FFM, and low BMD in normal weight women with SCD. The findings were not affected by total Hb, EE, HU. Further studies are needed to better define body composition, body composition determinants, and their impact on overall health status in adults with SCD.

Prognostic implications of the compensatory nature of left ventricular mass in arterial hypertension.

OBJECTIVE: To test whether inappropriate echocardiographic left ventricular (LV) mass (i.e. higher than predicted by individual body size, sex and cardiac load [delta%LVM]) is associated with an increased rate of cardiovascular events, and whether values of LV mass lower than appropriate confer protection. DESIGN: Prospective, longitudinal. SETTING: Institutional, hospital outpatient clinic. PATIENTS: A total of 294 hypertensive patients, 84 with inappropriate and 21 with low LV mass (lower than appropriate). MAIN OUTCOME MEASURES: Cardiovascular fatal and non-fatal events. RESULTS: Baseline delta%LVM was higher in patients with follow-up total (n = 50) or fatal (n = 14) events than in event-free survivors (all P < 0.0001) and predicted events independently of age and systolic pressure (all P < 0.0001). Although the performance was not better than with use of more traditional definition of LV hypertrophy, delta%LVM remained a predictor even in the subgroup of 126 patients (32 total events, 13 deaths) with clear-cut LV hypertrophy (P < 0.009). Patients with low LV mass exhibited supranormal LV chamber and midwall function, slightly higher heart rate and higher cardiac index (all P< 0.01). These patients had the same rate of events as those with appropriate LV mass. CONCLUSIONS: In hypertensive patients, increase in LV mass beyond values required to compensate cardiac workload at a given body size and sex predicts cardiovascular risk independently of age and blood pressure, in the whole population as well as in the subset of patients with LV hypertrophy. Hypertensive patients with levels of LV mass lower than needed to compensate cardiac workload exhibit hyperdynamic circulatory status and the same risk pattern as patients with higher values of LV mass, possibly due to activation of the sympathetic system.

Race, ethnicity, and geography: disparities in heart disease in women of color.

Cardiovascular disease (CVD) is the leading cause of death in women. Misconceptions about the importance of CVD still persist. These myths affect awareness of CVD and the urgency with which women present for treatment after symptoms develop. Modifiable and nonmodifiable risk factors are more prevalent among ethnic minority women in concentrated geographical locations. The recent publication of the CDC women's atlas presents a unique opportunity for healthcare providers to use derived county-specific data in education, research, and delivery of health promotion and disease prevention services to women of color. Specific recommendations for the nursing profession are provided to assist in eliminating CVD disparities for all women.

Using angiotensin converting enzyme inhibitors in African-American hypertensives: a new approach to treating hypertension and preventing target-organ damage.

Angiotensin converting enzyme (ACE) inhibitors have been avoided as an initial therapeutic option in the treatment of hypertension in African-Americans. A major reason for this has been the widespread perception of clinicians that these agents have poor blood pressure (BP) lowering efficacy in this population. Remarkably uniform and pervasive interpretations of clinical trial data have formed the basis of this clinical perception and can be summarised as follows: (1) there has been a lesser BP lowering effect of ACE inhibitors in African-Americans compared to whites, particularly at low doses; and (2) short-acting ACE inhibitors like captopril prescribed at the midpoint of its maximal total daily dose lower BP less effectively than higher doses of calcium antagonists in African-Americans. A reinterpretation of published data from these same clinical trials suggests that: (1) the majority of African-Americans have meaningful BP responses to ACE inhibitors, albeit at a higher average dose than in whites; and (2) high levels of dietary sodium intake appear to explain a significant portion of the racial differences in BP response at the lower doses of ACE inhibitors. Thus, ACE inhibitors can effectively lower BP in African-Americans. These data suggest that the clinician should not avoid these agents in African-Americans because of a presumed lack of BP lowering efficacy. Rather, we should recognise the importance of adequate drug dosing and modest reductions in dietary sodium intake in augmenting the BP lowering effect of ACE inhibitors in hypertensive African-Americans.

Race, baseline characteristics, and clinical outcomes after coronary intervention: The New Approaches in Coronary Interventions (NACI) registry.

BACKGROUND: The impact of race and sex on clinical outcomes after percutaneous coronary interventions remains incompletely understood. Specific data on patient demographics, lesion characteristics, and outcomes of black versus white patients are poorly described. To further evaluate these issues, we analyzed the New Approaches in Coronary Interventions (NACI) registry. METHODS: Patients (200 black, 4279 white) undergoing coronary interventions in the NACI trial were compared. A Cox proportional hazards model was used to determine which baseline demographics were independent risk factors for the combined end point of death, Q-wave myocardial infarction, and coronary artery bypass grafting at 1 year. RESULTS: Black patients were significantly younger (age 59 +/- 11 vs 63 +/- 11 years; P <.001), more often obese (29.6 +/- 6 vs 27.5 +/- 4.8 kg/m(2); P <.001), female (50% vs 34%; P <.001), diabetic (34% vs 21%; P <.001), and hypertensive (71% vs 52%; P <.001). Black patients were significantly more likely to have single-vessel disease (48% vs 40%; P <.05) and less likely to have undergone coronary artery bypass grafting (26% vs 34%; P <.05). Blacks were significantly more likely to have a discrete lesion (85% vs 62%; P <. 001) with less thrombus (7% vs 12%; P <.05), tortuosity (17% vs 25%; P <.05), and an ulcerated appearance (5% vs 10%; P <.05). Despite these significant baseline differences, no significant difference was seen in the procedural success (80% vs 82%) or major adverse events (death, Q-wave myocardial infarction, any revascularization) at 1 year (39% vs 34%). Predictors of adverse events for white patients included diabetes (relative risk [RR] = 1.24; confidence intervals [CI], 1.0-1.5) and high-risk status (RR = 1.58; CI, 1.26-1. 91). Predictive characteristics of adverse events for black patients included only sex (RR = 3.45; CI, 1.27-9.35; P =.02). CONCLUSIONS: There are significant differences in baseline characteristics of black patients compared with white patients. Despite these differences in traditional risk factors, they do not affect procedural success or 1-year outcome. In black patients, only sex predicted adverse events. Additional investigation is required to understand the mechanisms for this difference.

Racial differences in endothelin-1 at rest and in response to acute stress in adolescent males.

Blacks exhibit greater vasoconstriction-mediated blood pressure (BP) increases in response to stress than do whites. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, has been proposed as having a role in racial differences in stress reactivity. We evaluated the hemodynamic and plasma ET-1 levels of 41 (23 whites, 18 blacks, mean age 18.6 years) normotensive adolescent males at rest and in response to a video game challenge and forehead cold stimulation. Measurements were performed at catheter insertion and before and immediately after the 2 stressors, which were separated by 20-minute rest periods. Blacks exhibited higher absolute levels of diastolic blood pressure, total peripheral resistance index, or both in response to catheter insertion and to the video game challenge and during recovery from video game challenge and cold stimulation (P<0. 05 for all). Blacks exhibited higher absolute levels of ET-1 at every evaluation point (P<0.05 for all) and greater increases in ET-1 in response to both stressors (ps<0.05). These findings suggest that altered endothelial function may be involved in racial differences in hemodynamic reactivity to stress and possibly in the development of essential hypertension.

Refining strategies for the prevention and control of hypertension and related complications.

Hypertension is the leading preventable cause of premature morbidity and mortality from coronary heart disease, chronic heart failure, stroke and kidney failure. Despite the remarkable advances made in the design, development, and distribution of antihypertensive drugs and the plethora of published guidelines for hypertension treatment over the last two decades, blood pressure control rates remain rather disappointing. In the United States, Canada, and the United Kingdom, as well as in countries with far less resources devoted to health care, fewer than one in four hypertensives are controlled. This observation remains a major source of frustration for clinicians and health policy makers alike and serves as a constant reminder for more refined strategies for hypertension treatment and control. The 14th International Interdisciplinary Conference on Hypertension in Blacks (ISHIB99), held in Toronto, Canada on July 10-14, 1999 provided a unique forum for the discussion of this issue. The recommendations discussed are summarized herein under 10 specific headings that include: (1) Renewed emphasis on health education for patients and their families; (2) Increased involvement of non-physician health care providers; (3) Aggressive detection, evaluation and control of attendant cardiovascular risk factors; (4) Renewed determination for clinicians to set and achieve blood pressure targets; (5) Increased patient involvement in management decisions; (6) Improved access to quality care for the "working poor" and indigent; (7) Renewed commitment to community participation; (8) Partnership with managed care and professional organizations; (9) Renewed emphasis on the importance of psychosocial factors; (10) Enhanced communication and networking among hypertension care providers and between providers and patients.