Compartmentation of hexokinase in rat heart. A critical factor for tracer kinetic analysis of myocardial glucose metabolism.

Radiolabeled analogues of 2-deoxyglucose are widely used to trace glucose metabolism in cell cultures, whole organs, and intact animals, although kinetic differences in transport and phosphorylation between these compounds and glucose exist. The present studies were undertaken to determine the effects of insulin stimulation on the phosphorylation of 2-deoxyglucose compared to glucose in the intact, saline-perfused working rat heart. Rates of glucose utilization determined from tritiated glucose differed from rates estimated from the accumulation of [14C]2-deoxyglucose in a nonconstant manner when comparing rates in the absence or presence of physiologic levels of insulin (13 microU/ml). The fraction of monophosphorylated hexoses that was accounted for by [14C]2-deoxyglucose 6-phosphate was dramatically decreased in hearts perfused in the presence of insulin. Additionally, hexokinase activity associated with the mitochondrial fraction of tissue extracts was increased in hearts stimulated by insulin. While this redistribution of hexokinase to the mitochondria did not affect the apparent affinity constant for glucose, hexokinase bound to mitochondria exhibited an 8.5-fold decrease in the affinity for 2-deoxyglucose when compared with hexokinase present in the cytosolic fraction. The findings are consistent with an insulin-mediated preferential uptake and phosphorylation of glucose compared to deoxyglucose. The results also imply that the redistribution of hexokinase and the differential effect of insulin on its affinity for tracer and tracee are responsible for changes in the "lumped constant" (i.e., the correction factor used to equate 2-deoxyglucose to glucose uptake). These changes must be taken into account when regional myocardial glucose metabolism is assessed by the 2-deoxyglucose method.

The cost-effectiveness of elective Cesarean delivery for HIV-infected women with detectable HIV RNA during pregnancy.

OBJECTIVES: To determine the net health consequences, costs, and cost-effectiveness of alternative delivery strategies for HIV-infected pregnant women with detectable HIV RNA in the USA. DESIGN: Cost-effectiveness analysis using a probabilistic decision model. METHODS: The model compared two strategies: elective Cesarean section and vaginal delivery. Data for HIV transmission rate, maternal death rate, health-related quality of life and costs were obtained from the literature, national databases, and a tertiary hospital's cost accounting system. Model outcomes included total lifetime costs, quality-adjusted life expectancy, maternal death rate, HIV transmission rate, and incremental cost-effectiveness ratios. RESULTS: Elective Cesarean section resulted in a vertical HIV transmission rate of 34.9 per 1000 births compared with 62.3 per 1000 births for vaginal delivery. Elective Cesarean section was more effective (38.7 quality adjusted life years per mother and child pair) and less costly ($10600 per delivery) than trial of labor (38.2 combined quality adjusted life years at a cost of $14500 per delivery). However, elective Cesarean section increased maternal mortality by 2.4 deaths per 100000 deliveries. The results were consistent over a wide range of the variables, but were sensitive to the risk of HIV transmission with vaginal delivery and the relative risk of HIV transmission with elective Cesarean section. CONCLUSIONS: In pregnant HIV-infected women with detectable HIV RNA, elective Cesarean section would reduce total costs and increase overall quality-adjusted life expectancy for the mother-child pair, albeit at a slight loss of quality adjusted life expectancy to the mother.

Fasting and lactate unmask insulin responsiveness in the isolated working rat heart.

We have previously reported that the nutritional state in vivo results in differential insulin responses by the perfused heart in vitro. To further assess the effects of insulin on glucose uptake at physiological work loads, hearts from fed and fasted (16-20 h) rats were perfused with buffer containing 2-[18F]fluoro-2-deoxy-D-glucose (2-FDG) and glucose (10 mM) alone or plus lactate (10 mM) as a competing substrate, with insulin (10 mU/ml) added after a control period. When glucose was the only substrate, the addition of insulin decreased the fractional rate of 2-FDG uptake in hearts from either fed or fasted rats. The effect of insulin on increasing myocardial 2-FDG uptake was immediate and sustained only in hearts from fasted rats in the presence of lactate, despite no change in cardiac work. At the same time, the increase in 2-FDG uptake and phosphorylation was associated with an increase in the tissue content of glycogen in hearts from fasted rats. We conclude that lactate unmasks insulin sensitivity in heart muscle at physiological work loads but that this unmasking of insulin-mediated glucose uptake is dependent on the nutritional state of the animal. The glucose up as a result of insulin stimulation is preferentially utilized for glycogen repletion and does not enter the glycolytic pathway. This observation also suggests that myocardial glycogen synthesis in vitro is affected by the nutritional state in vivo and that lactate provides a substrate for oxidative phosphorylation while glucose is preferentially utilized for glycogen synthesis.

An extracorporeal perfusion system to bridge pediatric liver transplant candidates.

An extracorporeal liver perfusion system was designed to maintain cadaver livers in an oxygenated, normothermic state for bridging procedures for hepatic transplantation. Nonpulsatile high flow and pulsatile low flow blood are supplied to the portal venous (PV) and hepatic arterial (HA) circulations. Controlled low blood flow (5-10 cc/kg [patient]/min) is exchanged between the high flow extracorporeal perfusion circuit (1 cc/g [liver]/min) and the patient. The system was evaluated in perfusions of fresh, excised pig livers (n = 5). The average oxygen consumption was 9 +/- 3 microliters/g/min, and bile production averaged 4.7 microliters/g/hr. Perfusion pressures and flows were normal in both the HA and PV circulations for about 4 hr. Pressures then gradually rose, especially in the HA circulation, causing flow to decrease, with subsequent mottling and discoloration of the liver. Red blood cell, platelet, and white blood cell counts fell continuously. Maintenance of liver function was assessed by clearance of an 80 mg taurocholic acid challenge. An average of 56% of injected acid was cleared from the perfused livers (n = 5) in the first half hour, compared with 90% and 25% for the in situ (n = 3) and unperfused (n = 3) control livers, respectively. The system consistently maintained livers in a moderately well functioning state through the first 4 hr of perfusion. Adequate support of animals with induced hepatic failure must now be demonstrated.

Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis.

Studies have shown that rates of liver disease are higher in persons who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) than they are in persons with HCV alone, but estimates of risk vary widely and are based on data for dissimilar patient populations. We performed a meta-analysis to quantify the effect of HIV coinfection on progressive liver disease in persons with HCV. Eight studies were identified that included outcomes of histological cirrhosis or decompensated liver disease. These studies yielded a combined adjusted relative risk (RR) of 2.92 (95% confidence interval [CI], 1.70-5.01). Of note, studies that examined decompensated liver disease had a combined RR of 6.14 (95% CI, 2.86-13.20), whereas studies that examined histological cirrhosis had a pooled RR of 2.07 (95% CI, 1.40-3.07). There is a significantly elevated RR of severe liver disease in persons who are coinfected with HIV and HCV. This has important implications for timely diagnosis and consideration of treatment in coinfected persons.