Oxygen metabolism of the liver during an HA clamp: HV saturation and free radicals

BACKGROUND/AIMS: To clarify changes in the hepatic oxygen metabolism and tissue damage resulting from oxygen-derived free radical generation from polymorphonuclear cells during a hepatic arterial clamp. METHODOLOGY: Subjects were 32 male Wistar rats. Hepatic tissue blood flow, and hepatic venous chemiluminescence, indicating oxygen-derived free radicals from polymorphonuclear cells, and liver lipid peroxide were measured, and hepatic and portal venous blood gas analysis were performed before and after 130 minutes of hepatic arterial clamping. RESULTS: Hepatic tissue blood flow decreased by hepatic arterial clamp. The values of hepatic arterial oxygen pressure (HTBF), hepatic venous oxygen saturation (ShvO2), and O2 contents after hepatic arterial clamp were lower than those before hepatic arterial clamp (P = 0.035, 0.024, and 0.028, respectively). Hepatic venous chemiluminescence decreased and the lipid peroxide level of the liver increased by hepatic arterial clamp (P = 0.001). CONCLUSIONS: ShvO2 is useful for the evaluation of hepatic oxygen metabolism and hepatic tissue blood flow during acute hepatic arterial clamp. This condition should prepare the following tissue damage due to oxygen-derived free radicals from polymorphonuclear cells.     

Effects of conditioning depolarization, repriming, and external calcium reduction on the potassium contractures in frog single twitch muscle fibers

The inactivation of potassium (K) contractures induced by prolonged conditioning depolarization and repriming after 190 mM K+ contractures were studied at both room and low temperatures using frog single twitch muscle fibers. Effects of conditioning K+ depolarization and external Ca2+ reduction on the biphasic K contractures were also studied. When the conditioning depolarization with 15-30 mM K+ was prolonged, the peak tension of test 190 mM K+ contractures was inhibited in parallel with the shortening of plateau duration at both room and low temperatures. Such parallel changes were also observed during the early stage of repriming after 190 mM K+ contracture at both temperatures. On the other hand, the peak tension of the secondary component of the test 80 mM K+ contractures was rather potentiated by the conditioning depolarization, even though the time course of the component was markedly shortened. The foregoing changes were also illustrated in a diagramatic way. These results suggested that the peak tension and the time course of the test K contractures after conditioning depolarization and during repriming may be determined by a balance between the activation and the inactivation processes of the contractures. This view is supported by the results obtained under conditions in which the concentration of external Ca2+ was reduced. Furthermore, based on additional experimental results, it was suggested that the initial component is not accompanied by an inactivation process and that Ca uptake by sarcoplasmic reticulum may partially contribute to determining the spontaneous relaxation phase of the secondary component, at least at room temperature.     

Predicting the development of diabetes in older adults: the derivation and validation of a prediction rule

OBJECTIVE: To create a simple prediction rule that could perform as well as the 2-h postchallenge plasma glucose (PCPG) test to predict those at risk for diabetes. We created a prediction rule in one sample and prospectively validated it for incident diabetes in a separate cohort. RESEARCH DESIGN AND METHODS: A cross-sectional analysis with data from the Rancho Bernardo Study (age 67 +/- 11 years) to derive a rule predicting abnormal PCPG >/=140 mg/dl, using demographic, clinical, and laboratory data of nondiabetic participants with fasting plasma glucose (FPG) <126 mg/dl. Data from the Health, Aging and Body Composition study (age 74 +/- 3 years) were used to prospectively validate this rule for incident diabetes and compare it with the predictive ability of the PCPG test. RESULTS: Of 1,549 RBS participants, 514 (33%) had PCPG >/=140 mg/dl. Female sex, age, triglycerides, and FPG were most significantly associated with abnormal PCPG. Based on standardized beta-coefficients, we allotted 1 point for female sex, triglycerides >/=150 mg/dl, or FPG 95-104 mg/dl. Age >/=70 years or FPG 105-115 mg/dl were given 2 points, and FPG 116-125 mg/dl received 3 points. In the validation cohort, this simple prediction rule was as good as the 2-h PCPG test for predicting incident diabetes (C-statistic: 0.71 for both). CONCLUSIONS: Advanced age, female sex, FPG, and triglycerides were able to predict adults at risk for diabetes equally well as the 2-h PCPG test. Using this rule, clinicians may better identify older persons who should receive intensive lifestyle intervention to prevent type 2 diabetes.     

Combination therapy with oral sildenafil and beraprost for pulmonary arterial hypertension associated with CREST syndrome

Pulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in long-term combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome. Traces of the acute hemodynamic effects of beraprost (20 microg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours. After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 microg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome.     

Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo study cohort

BACKGROUND: A few studies have examined change in cognitive performance by diabetes status with disparate results. We examined the 4-year change in cognitive performance among older adults according to glucose tolerance status. METHODS: Three cognitive tests (Mini-Mental State Examination, Verbal Fluency [VF] test, and Trail-Making Test B) were measured 4 years apart in 999 white men and women aged 42 to 89 years, who were enrolled in the Rancho Bernardo Study. Participants were classified with normal (NGT), impaired (IGT) or diabetic glucose tolerance. Sex-specific linear regression models adjusted for age, education, depression score, apolipoprotein E epsilon4 allele, and current estrogen use. We checked for mediation by further adjusting for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; blood pressure; glycohemoglobin level; and microalbuminuria, retinopathy, stroke, or coronary heart disease. RESULTS: At baseline, mean cognitive function scores did not differ between glucose tolerance groups. Women with diabetes mellitus had a 4-fold increased risk of a major cognitive decline on the VF test after 4 years compared with nondiabetic women. After multivariate adjustment, VF test scores at follow-up for women were 15.2 +/- 0.6 for those with diabetes, 16.7 +/- 0.4 for those with IGT, and 17.2 +/- 0.2 for those with NGT (P =.007). Glycohemoglobin attenuated this effect, but lipid levels, blood pressure, and microvascular or macrovascular disease did not. Performance on Mini-Mental State Examination and Trail-Making Test B did not differ by baseline glucose status. CONCLUSIONS: Elderly white women with diabetes had a more rapid decline in performance on the VF test compared with women with IGT or NGT. Better glucose control might ameliorate this decline.     

Abdominal obesity is an independent risk factor for chronic heart failure in older people

OBJECTIVES: To examine whether total and abdominal adiposity are risk factors for the development of chronic heart failure (CHF) in older men and women. DESIGN: Prospective, longitudinal cohort: The Health, Aging and Body Composition study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania, metropolitan areas. PARTICIPANTS: Three thousand seventy-five well-functioning community-dwelling older adults aged 70 to 79. MEASUREMENTS: Body composition using dual energy X-ray absorptiometry, visceral adipose tissue area using computed tomography, adjudicated CHF. RESULTS: Of the remaining (640 participants excluded from original group of 3,075) 2,435 participants (1,081 men, 1,354 women) without coronary heart disease or CHF at baseline, there were 166 confirmed diagnoses of CHF during the median+/-standard deviation (SD) follow-up of 6.1+/-1.4 years. After adjustment for age, race, sex, site, education, smoking, and chronic obstructive pulmonary disorder, all adiposity variables (body mass index (BMI), adipose tissue mass, percentage body fat, waist-to-thigh ratio, waist circumference, and visceral and subcutaneous abdominal adipose tissue) were significant predictors of the development of CHF. In a model that included waist circumference and BMI, waist circumference was associated with incident CHF (hazard ratio (HR)=1.27, 95% confidence interval (CI)=1.04-1.54 per SD increase, P=.02), but BMI was not (HR=1.08, 95% CI=0.86-1.35). When waist circumference and percentage fat were included together, both variables were significant predictors of CHF (waist: HR=1.17, 95% CI=1.00-1.36 per SD increase, P=.05; percentage fat: HR=1.47, 95% CI=1.16-1.87 per SD increase, P=.002). Stepwise adjustment for inflammation, hypertension, insulin resistance, and diabetes mellitus did not decrease the relative risk of a greater waist circumference for the development of CHF (all HR=1.27-1.32, 95% CI=1.02-1.61 per SD increase). CONCLUSION: Abdominal body fat distribution may be a stronger risk factor for CHF than overall obesity.     

Na+-K+ pump inhibition caused by chronic amiodarone in guinea pig myocardium

Summary Although it is known that amiodarone inhibits myocardial Na⁺-K⁺ pump activity, the potency and the time course of this inhibition are unknown. The aim of this study was to investigate these aspects with reference to digoxin, using guinea pigs treated with either intraperitoneal amiodarone (20mg/kg per week, up to 12 weeks,n = 26) or the same amount of vehicle as a control (n = 24). ECG recording and microelectrode experiments were conducted every 2 weeks. QT interval corrected by heart rate and action potential duration were prolonged as a function of the time of exposure to amiodarone. Hyperpolarization observed immediately after the overdrive (1.0Hz) termination or K⁺-replenishment following K⁺-depletion in the presence of 0.1mM Ba²⁺ was compared in the amiodarone-treated and untreated groups, as an index of the Na⁺-K⁺ pump activity. The resting membrane potential recovery from overdrive-induced depolarization was slower and the amplitude of K⁺-induced hyperpolarization was smaller in the amiodarone-treated group than in the untreated group. These changes were evident as the chronic amiodarone treatment progressed, although the changes in these parameters were greater in the case of acute application of 50µM digoxin. In conclusion, this study indicates that treatment with amiodarone for longer than several weeks moderately inhibits the myocardial Na⁺-K⁺ pump.This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (11877125).     

Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images

We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post‐mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.     

Serum adiponectin and coronary heart disease risk in older Black and White Americans

CONTEXT: Adiponectin may influence the risk of coronary heart disease (CHD) independently of traditional cardiovascular risk factors. OBJECTIVE: Because body composition and adiponectin levels vary by race, we examined the relationship of adiponectin with prevalent and incident CHD in a cohort of older Black and White adults. DESIGN AND SETTING: We conducted a cross-sectional and prospective cohort study at two U.S. clinical centers. PARTICIPANTS: Participants included 3075 well-functioning adults between ages 70 and 79 yr enrolled in the Health, Aging, and Body Composition study. MAIN OUTCOME MEASURES: Prevalent CHD was defined as history of myocardial infarction, coronary artery bypass graft, percutaneous coronary transluminal angioplasty, angina, or major electrocardiogram abnormalities. After excluding those with prevalent CHD, incident CHD was defined as hospitalized myocardial infarction or CHD death. RESULTS: At baseline, 602 participants (19.6%) had CHD. During 6 yr of follow-up, 262 (10.6%) incident CHD events occurred. Whites had higher median adiponectin than Blacks (12 vs. 8 microg/ml, P < 0.001). Race modified the effect of adiponectin (P for interaction was 0.002 for prevalent CHD, and P = 0.02 for incident CHD). Among Whites, an inverse association of adiponectin with CHD was explained by high-density lipoprotein and glucose. Among Blacks, a doubling of adiponectin was associated with a 40% higher risk of both prevalent CHD (odds ratio, 1.41; 95% confidence interval, 1.11-1.78) and incident CHD (hazards ratio, 1.37; 95% confidence interval, 1.01-1.87) after adjusting for explanatory variables. CONCLUSION: High circulating concentrations of adiponectin were associated with higher risk of CHD in older Blacks, even accounting for traditional CHD risk factors.