High-density lipoprotein subclasses and esterification rate of cholesterol in children: effect of gender and age

Since the development of coronary heart disease (CAD) is affected by a specific pattern of plasma high density lipoprotein (HDL) effects it may be useful to know whether this occurs already in childhood. In this study we evaluated particle size distribution of HDL by gradient gel electrophoresis and the determination of cholesterol esterification rate (FER_HDL) in plasma depleted of apo B lipoproteins in 221 children (108 boys and 113 girls) aged 4 months to 20 years. Total plasma- (TC), low-density lipoprotein- (LDL-C) and HDL- (HDL-C) cholesterol, HDL unesterified cholesterol (HDL-UC) and plasma triglycerides (TG) were also measured. There were no significant gender and age differences with respect to the plasma TC, LDL-TC and TG but concentration of HDL-TC increased with age. Post-pubertal girls had significantly higher relative concentrations of HDL_2b compared to boys (30.4% vs 17.2%), while HDL_3b,c was lower in post-pubertal girls (8.7% vs. 16.5 %). FER_HDL correlated inversely with HDL_2b and positively with HDL_3b,c particles and was significantly higher in boys of the post-pubertal group compared to girls (16.9%/h vs 12.5%/h). While in girls there was a positive correlation between age and HDL-C, HDL-UC and the relative concentration of HDL_2b no significant correlation were observed in boys. In girls the increase in TC showed a significant correlation with a simultaneous increase in HDL-C, HDL-UC and HDL_2b. In boys TC correlated significantly with changes in TG only. When HDL_2b and HDL_3b,c cholesterol levels are calculated from HDL-C concentration and per cent distribution the differences between males and females are further emphasized. These data indicate that HDL particle size distribution is age- and gender-dependent.     

Hypoglycémie hyperinsulinémique persistante du nouveau-né et du nourrisson

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Low-dose dopexamine in patients undergoing hemihepatectomy: an evaluation of effects on reduction of hepatic dysfunction and ischaemic liver injury

BACKGROUND: Hepatic dysfunction is a common problem in patients after hemihepatectomy. Treatment with low-dose dopamine has been shown to be beneficial in hemihepatectomy patients. We hypothesized that dopexamine, a synthetic vasoactive catecholamine, due to its specific pharmocodynamic profile may be more effective in reducing hidden ischaemic episodes in the hepato-splanchnic region during and after temporary total cross-clamping of hepatic inflow in these patients. METHODS: The effects of low-dose dopexamine on hepatic venous haemoglobin oxygen saturation (ShvO2), hepatic venous lactate level, monoethylglycinxylid (MEGX) formation, hepatic synthetic function and indicators for hepatic cell damage were studied during hemihepatectomy and for 16 h postoperatively in hemihepatectomy patients and compared to those of low-dose dopamine. In a prospective, double-blind clinical study 20 patients received randomly either dopexamine (DPX) 0.5 microg kg(-1) min(-1) (n=10) or dopamine (DO) 2.5 microg kg(-1) min(-1) (n= 10). Infusions were started after induction of anaesthesia and continued 16 h postoperatively. Hepatic vein, radial and pulmonary artery were catheterized. Measurements were carried out after induction of anaesthesia, after total cross-clamping of hepatic inflow, and at 2 h and 16 h postoperatively. RESULTS: There were no differences in systemic haemodynamics, oxygenation, ShvO2, serum aminotransferases or MEGX levels between the groups. At 16 h postoperatively prothrombin and antithrombin III levels were significantly lower while hepatic venous lactate was significantly higher in the DPX group compared to the DO group. CONCLUSION: In patients undergoing hemihepatectomy, we could not reveal superior hepatoprotective effects of low-dose dopexamine compared to low-dose dopamine.     

Preconditioning with short cycles improves ischemic tolerance in rat fast- and slow-twitch skeletal muscle

AIM: The aim of this study was to investigate whether the efficacy of ischemic preconditioning (IP) in rat skeletal muscle depends on the duration of the preconditioning cycles. METHODS: Rats were divided into four groups (n = 10 each). The right hindlimb of rats in group A were subjected to 2.5 h of tourniquet ischemia followed by 2 h of reperfusion (I-R). Thereafter, muscular function was analyzed in vitro and high-energy phosphates (HEP) were determined by HPLC. Before I-R, right hindlimbs of rats in groups B-D subjected to IP with three cycles each consisting of 2.5, 5 or 10 min of ischemia followed by reperfusion for the same duration. RESULTS: Postischemic function of the extensor muscle was significantly improved with all three preconditioning protocols. Postischemic function of the soleus muscle was only improved by IP with three cycles of 5 min of ischemia and 5 min of reperfusion. Postischemic HEP tissue levels were not influenced by IP. CONCLUSION: This study shows for the first time that IP increases ischemic tolerance not only of fast-twitch but also of slow-twitch skeletal muscle. The efficacy of IP seems to be less dependent on the duration of the single preconditioning cycle than on the number of cycles performed. Three cycles each of 2.5, 5 or 10 min ischemia and reperfusion significantly improved postischemic skeletal muscle function. Tissue levels of HEPs, however, were not influenced by IP indicating that preservation of HEPs does not play a major role in the effects of IP on rodent skeletal muscle.     

Interpreting the improved outcome of patients with central nervous system metastases managed in clinical trials compared with standard hospital practice*

The aims were to determine the median survival and prognostic factors of patients with central nervous system (CNS) metastases managed with whole‐brain radiation therapy (WBRT), and to explore selection criteria in recently published clinical trials using aggressive interventions in CNS metastases. A retrospective audit was performed on patients managed with WBRT for CNS metastases. Potential prognostic factors were recorded and analysed for their association with survival duration. The proportion of patients with these factors was also compared with those of patients managed under three recently reported studies investigating aggressive interventions, such as radiosurgery and chemotherapy for CNS metastases. Seventy‐three patients were treated with WBRT for cerebral metastases over a 12‐month period. The median survival of the population was 3.4 months (95% confidence interval: 2.7–4.1), with 6‐ and 12‐month survival rates of 30 and 18%, respectively. Significant prognostic factors for prolonged median survival were Eastern Cooperative Oncology Group status 0–2 (P = 0.015), Medical Research Council neurological functional status 0–1 (P = 0.006), and Recursive Partitioning Analysis Class 2 versus Class 3 (P = 0.020). On multivariate analysis, younger patient age (P = 0.02) and better performance status (P < 0.01) were associated with improved outcome. When comparing these characteristics with selected published studies, our study cohort demonstrated a higher proportion of patients with poor performance status, a greater number of metastases per patient and a higher incidence of extracranial disease. This reflects the selected nature of patients in these published studies. Central nervous system metastases confer a poor prognosis and, for the majority of patients, aggressive interventions are unlikely to improve survival. The use of potentially toxic and expensive treatments should be reserved for those few in whom these studies have shown a potential benefit.     

PCSK9-Inhibitoren

The 2 or 4?week subcutaneous therapy with the recently approved antibodies alirocumab and evolocumab for inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces low-density lipoprotein cholesterol (LDL-C) in addition to statins and ezetimibe by 50–60?%. The therapy is well-tolerated. The safety profile in the published studies is comparable to placebo. Outcome data and information on long-term safety and the influence on cardiovascular events are not yet available but the results of several large trials are expected in 2016–2018. At present (spring 2016) PCSK9 inhibitors represent an option for selected patients with a high cardiovascular risk and high LDL-C despite treatment with the maximum tolerated oral lipid-lowering therapy. This group includes selected patients with familial hypercholesterolemia and high-risk individuals with statin-associated muscle symptoms (SAMS).