Mechanisms of a reduced cardiac output and the effects of milrinone and levosimendan in a model of infant cardiopulmonary bypass

OBJECTIVES: A low cardiac output state is an important cause of morbidity after pediatric cardiopulmonary bypass. The objectives of our study were to define the early precipitants of the reduced cardiac output and to investigate the effects on these of milrinone and levosimendan in a model of pediatric cardiopulmonary bypass. DESIGN: Experimental study. SETTING:: Research laboratory at a university-affiliated, tertiary pediatric center. SUBJECTS: Eighteen piglets. INTERVENTIONS: Piglets, instrumented with systemic, pulmonary arterial, and coronary sinus catheters, pulmonary and circumflex arterial flow probes, and a left ventricular conductance-micromanometer-tipped catheter, underwent cardiopulmonary bypass with aortic cross-clamp and cardioplegic arrest. At 120 mins, they were assigned to control, milrinone, or levosimendan groups and studied for a further 120 mins. MEASUREMENTS AND MAIN RESULTS: In controls, between 120 and 240 mins, cardiac output decreased by 15%. Systemic vascular resistance was unchanged, but pulmonary vascular resistance increased by 19%. Systemic arterial elastance increased by 17%, indicating increased afterload. End-systolic elastance was unchanged, and coronary sinus oxygen tension decreased by 4.0 +/- 1.7 mm Hg. In animals receiving milrinone cardiac output was preserved, and in animals receiving levosimendan cardiac output increased by 14%. Both drugs prevented an increase in arterial elastance and pulmonary vascular resistance after cardiopulmonary bypass. Systemic vascular resistance decreased by 31% after levosimendan, and end-systolic elastance increased by 48%, indicating improved contractility. Both agents prevented a decrease in coronary sinus oxygen tension. CONCLUSIONS: Increased afterload, which is not matched by an equivalent elevation in contractility, contributes to the reduced cardiac output early after pediatric cardiopulmonary bypass in this model. This increase is prevented by milrinone and levosimendan. Both agents exert additional beneficial effects on pulmonary vascular resistance and myocardial oxygen balance, although levosimendan has greater inotropic properties.     

Immunization with a Plasmodium falciparum merozoite surface antigen induces a partial immunity in monkeys.

Saimiri monkeys immunized with a Plasmodium falciparum merozoite polypeptide of 41 kD mol wt are resistant to a blood challenge infection that induces a fulminant infection in control monkeys. The sera of the immunized monkeys reacted, as shown by the indirect immunofluorescence technique, with the apical part of the merozoites from five isolates or clones of P. falciparum. Whether the immunogen was dissolved in nonionic detergent (NP-40) or in sodium dodecyl sulfate (SDS) had a marked influence on the level of protection in immunized monkeys. Thus, monkeys immunized with the antigen solubilized in a nonionic detergent developed much lower parasitemia than monkeys immunized with denatured antigen (antigen eluted from SDS polyacrylamide gel electrophoresis).     

Abrupt climate change in the computer: is it real?

Models suggest that dramatic changes in the ocean circulation are responsible for abrupt climate changes during the last ice age and may possibly alter the relative climate stability of the last 10,000 years.     

Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults

Endothelial dysfunction is thought to be an important early event in atherogenesis, related in part to reduced bioavailability of nitric oxide in the arterial wall. Endothelial function may be impaired in the presence of oxidised low density lipoprotein. The use of vitamin E as an anti-oxidant might enhance the bioavailability of nitric oxide in this situation. The effect of vitamin E 1000 IU/day on arterial endothelial physiology was studied in 20 asymptomatic older subjects, aged 45-70 years, who showed evidence of age-related endothelial dysfunction. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. A double-blind, placebo-controlled, randomised crossover design was employed. After 3 weeks of stabilisation on a standard fat-reduced diet, subjects received vitamin E or placebo for 10 weeks in random order, separated by a washout period of 8 weeks. There were no significant changes in blood pressure, plasma lipid or lipoprotein concentrations. Plasma alpha-tocopherol increased from 50+/-3 (mean+/-S.E.M.) to 91+/-6 micromol/l (P < 0.001) with vitamin E ingestion. Total plasma F2alpha-isoprostanes, a measure of free radical-induced lipid peroxidation, were not altered by vitamin E ingestion (0.86+/-0.26 versus 0.82+/-0.25 nmol/l, P > 0.6). FMD was not significantly different between the placebo and vitamin E periods (2.7+/-0.6% versus 2.4+/-0.4%). Variation in FMD was not correlated with change in plasma alpha-tocopherol (r = - 0.03, P > 0.8). The study was powered to detect a minimum change in FMD of 2%. Glyceryl trinitrate endothelium-independent dilatation was not significantly changed with vitamin E (13.7+/-1.3% versus 13.6+/-1.4%,). These results exclude a major impact of medium-term supplementation with vitamin E on arterial endothelial function when age-related dysfunction is already present.     

High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors.

Analysis of untreated fresh blood plasma from healthy, fasting donors revealed that high density lipoprotein (HDL) particles carry most (approximately 85%) of the detectable oxidized core lipoprotein lipids. Low density lipoprotein (LDL) lipids are relatively peroxide-free. In vitro the mild oxidation of gel-filtered plasma from fasting donors with a low, steady flux of aqueous peroxyl radicals initially caused preferential oxidation of HDL rather than LDL lipids until most ubiquinol-10 present in LDL was consumed. Thereafter, LDL core lipids were oxidized more rapidly. Isolated lipoproteins behaved similarly. Preferential accumulation of lipid hydroperoxides in HDL reflects the lack of antioxidants in most HDL particles compared to LDL, which contained 8-12 alpha-tocopherol and 0.5-1.0 ubiquinol-10 molecules per particle. Cholesteryl ester hydroperoxides (CEOOHs) in HDL and LDL were stable when added to fresh plasma at 37 degrees C for up to 20 hr. Transfer of CEOOHs from HDL to LDL was too slow to have influenced the in vitro plasma oxidation data. Incubation of mildly oxidized LDL and HDL with cultured hepatocytes afforded a linear removal of CEOOHs from LDL (40% loss over 1 hr), whereas a fast-then-slow biphasic removal was observed for HDL. Our data show that HDL is the principal vehicle for circulating plasma lipid hydroperoxides and suggest that HDL lipids may be more rapidly oxidized than those in LDL in vivo. The rapid hepatic clearance of CEOOHs in HDL could imply a possible beneficial role of HDL by attenuating the build-up of oxidized lipids in LDL.     

Reduction of RNA A-to-I editing in Drosophila acclimated to heat shock

Although an increasing number of RNA adenosine-to-inosine (A-to-I) editing sites are being discovered, how the editing frequencies of these sites are modulated to fine-tune protein function in adaptive responses is not well understood. A previous study screening for heat tolerance in Drosophila mutants discovered a hypnos-2 mutant strain that was later found to be defective in dADAR, the Drosophila gene encoding the A-to-I editing enzyme. This supports the hypothesis that cells and organisms respond to stressful environments by ADAR (adenosine deaminase acting on RNA)-mediated RNA editing. Here, we investigated changes in the RNA A-to-I editing frequencies of 30 Drosophila nervous system targets in response to heat shock, a stress acclimatization that requires the dADAR function. To our surprise, most of these nervous system editing targets showed reduced editing. Our results suggest that a change in RNA editing pattern is a mechanism by which organisms acclimate to drastic environmental change. However, how RNA editing confers heat resistance is more complicated and requires further investigation.     

Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: a randomized,controlled, double-blind clinical trial

Introduction

There are limited data on the efficacy of early fluid resuscitation with third-generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported.

Methods

In this randomized, controlled, double-blind trial, 48 patients with severe burn injury were assigned to receive either lactated Ringer’s solution plus 6% HES 130/0.4 in a ratio of 2:1 or lactated Ringer’s solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality.

Results

Three-day totals of administered resuscitation fluid (medians) were 21,190 mL in the lactated Ringer’s group and 19,535 mL in the HES group (HES: −1,213 mL; P = 0.39). Creatinine levels from day 1 to 3 (HES: +0.4 μmol/L; 95% confidence interval (CI) −18.7 to 19.5; P = 0.97) and urinary outputs from day 1 to 3 (HES: −58 mL; 95% CI −400 to 283; P = 0.90) were not different. Six patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P = 0.95). Length of ICU stay (HES vs. lactated Ringer’s: 28 vs. 24 days; P = 0.80) and length of hospital stay (31 vs. 29 days; P = 0.57) were similar. Twenty-eight-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P = 0.95), and in-hospital mortality was 8 in the HES group vs. 5 patients in the lactated Ringer’s group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P = 0.31).

Conclusions

There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to lactated Ringer’s solution would lead to a volume-sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus lactated Ringer’s solution could not be considered superior to lactated Ringer’s solution alone.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01012648","term_id":"NCT01012648"}}NCT01012648     

Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066)

Introduction

There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions.

Materials and methods

The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies).

Conclusion

The review presented here is a translation of a short version of the German–Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.

     

The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity

Background:

Cannabinoid type-1 (CB1) receptor inverse agonists improve type 2 diabetes and dyslipidaemia but were discontinued due to adverse psychiatric effects. Δ⁹-Tetrahydrocannabivarin (THCV) is a neutral CB1 antagonist producing hypophagia and body weight reduction in lean mice. We investigated its effects in dietary-induced (DIO) and genetically (ob/ob) obese mice.

Methods:

We performed two dose-ranging studies in DIO mice; study 1: 0.3, 1, 2.5, 5 and 12.5 mg kg⁻¹, oral twice daily for 30 days and study 2: 0.1, 0.5, 2.5 and 12.5 mg kg⁻¹, oral, once daily for 45 days. One pilot (study 3: 0.3 and 3 mg kg⁻¹, oral, once daily) and one full dose-ranging (study 4: 0.1, 0.5, 2.5 and 12.5 mg kg⁻¹, oral, once daily) studies in ob/ob mice for 30 days. The CB1 inverse agonist, AM251, oral, 10 mg kg⁻¹ once daily or 5 mg kg⁻¹ twice daily was used as the positive control. Cumulative food and water intake, body weight gain, energy expenditure, glucose and insulin levels (fasting or during oral glucose tolerance tests), plasma high-density lipoprotein and total cholesterol, and liver triglycerides were measured. HL-5 hepatocytes or C₂C₁₂ myotubes made insulin-resistant with chronic insulin or palmitic acid were treated with 0, 1, 3 and 10 μℳ THCV or AM251.

Results:

THCV did not significantly affect food intake or body weight gain in any of the studies, but produced an early and transient increase in energy expenditure. It dose-dependently reduced glucose intolerance in ob/ob mice and improved glucose tolerance and increased insulin sensitivity in DIO mice, without consistently affecting plasma lipids. THCV also restored insulin signalling in insulin-resistant hepatocytes and myotubes.

Conclusions:

THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.