Paediatric treatment costs and the HIV epidemic

A CAJM on pediatric treatment costs and the effects of HIV pandemic in Malawi.As the AIDS epidemic puts additional strains on the already overburdened health care systems in sub-Saharan Africa, it becomes more important to estimate the cost of the epidemic in terms of health personnel and drug treatments. A retrospective review of 250 randomly selected paediatric admissions to a referral hospital in Malawi was undertaken. Groupings of “pos- sible/probable AIDS” and “probably not AIDS” were used in a comparative analysis of treatment costs. Estimated costs of treatments were significantly lower than those calculated in a study from Zimbabwe using different methodology. Meningitis was the most expensive condition to treat and accounted for a greater percentage of overall cost than either acute respiratory infection, diarihoeal disease or measles

Reactivation of the mitosis-promoting factor in postmitotic cardiomyocytes

Cardiomyocytes cease to divide shortly after birth and an irreversible cell cycle arrest is evident accompanied by the downregulation of cyclin-dependent kinase activities. To get a better understanding of the cardiac cell cycle and its regulation, the effect of functional recovery of the mitosis-promoting factor (MPF) consisting of cyclin B1 and the cyclin-dependent kinase Cdc2 was assessed in primary cultures of postmitotic ventricular adult rat cardiomyocytes ( ARC). Gene transfer into ARC was achieved using the adenovirus-enhanced transferrinfection system that was characterized by the absence of cytotoxic events. Simultaneous ectopic expression of wild-type versions of cyclin B1 and Cdc2 was sufficient to induce MPF activity. Reestablished MPF resulted in a mitotic phenotype, marked by an abnormal condensation of the nuclei, histone H3 phosphorylation and variable degree of decay of the contractile apparatus. Although a complete cell division was not observed, the results provided conclusive evidence that cell cycle-related events in postmitotic cardiomyocytes could be triggered by genetic intervention downstream of the G1/S checkpoint. This will be of importance to design novel strategies to overcome the proliferation arrest in adult cardiomyocytes

Cellular engineering of ventricular adult rat cardiomyocytes

Objective: Preparation of viable cultured adult cardiomyocytes (vARCs) is a prerequisite for cell-based transplantation and tissue engineering. Ectopic gene expression is important in this context. Here, we present an in vitro cell replating strategy using Accutase™ for cultured vARCs, allowing ectopic gene expression. Methods: Cultured vARCs from 6- to 8-week-old rats were used. Transfections with EGFP (enhanced green fluorescent protein) constructs, Mlc-3f-EGFP or α-actinin-EGFP were performed using adenovirus-enhanced transferrin-mediated infection (AVET). Accutase™ (PAA Laboratories, Linz, Austria) was used for the detachment of cultured cells. Immunohistochemical analysis, together with confocal laser microscopy was used for structural analysis of the cells. Results: Cultured vARCs could be detached with a high yield (40 to 60%) from primary cultures using Accutase™. The cultivation period plays an important role in the yield of viable cells. Resultant replated vARCs (rep-vARCs) rapidly (1-2 h) acquired a rounded up shape without degradation of their contractile apparatus, which is in contrast to the rod-shaped freshly isolated vARCs (fi-vARCs). The detached cells survived passage through a narrow syringe needle. After seeding, detached cells rapidly attached to various substrates, increased their content of the contractile apparatus, and formed cell-cell contacts within 3 days after reseeding. The detached cells survived passage through a narrow syringe needle. The high recovery of cells after replating enabled the use of the AVET system for gene delivery. AVET is free of infectious particles and does not lead to expression of viral proteins. Transfection of vARCs prior to detachment had a small effect on cell recovery and ectopically synthesized proteins were properly localized after replating. Conclusions: Detachment of cultured vARCs using Accutase™ is well compatible with ectopic gene expression and yields a viable transgenic population of vARCs that eventually may be suitable as transgenic cardiomyocyte graft

Cellular engineering of ventricular adult rat cardiomyocytes

ISSN:1755-3245ISSN:0008-636

Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function

INTRODUCTION: Sepsis may impair mitochondrial utilization of oxygen. Since hepatic dysfunction is a hallmark of sepsis, we hypothesized that the liver is more susceptible to mitochondrial dysfunction than the peripheral tissues, such as the skeletal muscle. We studied the effect of prolonged endotoxin infusion on liver, muscle and kidney mitochondrial respiration and on hepatosplanchnic oxygen transport and microcirculation in pigs. METHODS: Twenty anesthetized pigs were randomized to receive either endotoxin or saline infusion for 24 hours. Muscle, liver and kidney mitochondrial respiration was assessed. The cardiac output (thermodilution) and the carotid, superior mesenteric and kidney arterial, portal venous (ultrasound Doppler) and microcirculatory blood flow (laser Doppler) were measured, and systemic and regional oxygen transport and lactate exchange were calculated. RESULTS: Endotoxin infusion induced hyperdynamic shock and impaired the glutamate-dependent and succinate-dependent mitochondrial respiratory control ratio in the liver (glutamate, median (range) endotoxemia 2.8 (2.3–3.8) vs controls 5.3 (3.8–7.0); P < 0.001; succinate, endotoxemia 2.9 (1.9–4.3) vs controls 3.9 (2.6–6.3), P = 0.003). While the ADP added/oxygen consumed ratio was reduced with both substrates, the maximal ATP production was impaired only in the succinate-dependent respiration. Hepatic oxygen consumption and extraction, and the liver surface laser Doppler blood flow remained unchanged. Glutamate-dependent respiration in the muscle and kidney was unaffected. CONCLUSION: Endotoxemia reduces the efficiency of hepatic mitochondrial respiration but neither skeletal muscle nor kidney mitochondrial respiration, independent of regional and microcirculatory blood flow changes

Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the EPIC-Potsdam Study

OBJECTIVE — We investigated whether metabolic biomarkers and single nucleotide poly-morphisms (SNPs) improve diabetes prediction beyond age, anthropometry, and lifestyle risk factors. RESEARCH DESIGN AND METHODS — A case-cohort study within a prospective study was designed. We randomly selected a subcohort (n 2,500) from 26,444 participants, of whom 1,962 were diabetes free at baseline. Of the 801 incident type 2 diabetes cases identified in the cohort during 7 years of follow-up, 579 remained for analyses after exclusions. Prediction models were compared by receiver operatoring characteristic (ROC) curve and integrated dis-crimination improvement. RESULTS — Case-control discrimination by the lifestyle characteristics (ROC-AUC: 0.8465) im-proved with plasma glucose (ROC-AUC: 0.8672, P 0.001) and A1C (ROC-AUC: 0.8859, P 0.001). ROC-AUC further improved with HDL cholesterol, triglycerides, -glutamyltransferase, and alanine aminotransferase (0.9000, P 0.002). Twenty SNPs did not improve discrimination beyond these characteristics (P 0.69). CONCLUSIONS — Metabolic markers, but not genotyping for 20 diabetogenic SNPs, im-prove discrimination of incident type 2 diabetes beyond lifestyle risk factors. Diabetes Care 32:2116–2119, 2009 A ccurate identification of individualswho are at increased risk for type 2diabetes is a requirement for a tar-geted prevention. We therefore tested whether metabolic and genetic markers add substantial prognostic information to age, anthropometry, and lifestyle characteristics

Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.

Elevated blood pressure has been implicated as a risk factor for renal cell carcinoma (RCC), but prospective studies were confined to men and did not consider the effect of antihypertensive medication. The authors examined the relation among blood pressure, antihypertensive medication, and RCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). Blood pressure was measured in 296,638 women and men, recruited in eight European countries during 1992-1998, 254,935 of whom provided information on antihypertensive medication. During a mean follow-up of 6.2 years, 250 cases of RCC were identified. Blood pressure was independently associated with risk of RCC. The relative risks for the highest versus the lowest category of systolic (>/=160 mmHg vs. /=100 mmHg vs. <80 mmHg) blood pressures were 2.48 (95% confidence interval: 1.53, 4.02) and 2.34 (95% confidence interval: 1.54, 3.55). Risk estimates did not significantly differ according to sex or use of antihypertensive medication. Individuals taking antihypertensive drugs were not at a significantly increased risk unless blood pressure was poorly controlled. These results support the hypothesis that hypertension, rather than its medications, increases the risk of RCC in both sexes, while effective blood pressure control may lower the risk. Udgivelsesdato: 2008-Feb-1

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

OBJECTIVE: First, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk. METHODS: We conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011. RESULTS: Compared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10-0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33-0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12-0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98-1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90-1.27; p for heterogeneity: 0.098)]. CONCLUSION: The well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation