A practical guide to using insulin

Normally, the level of total body water is maintained by natural elimination and intake. However, several variables can influence the rate of water loss, and if mechanisms that regulate thirst malfunction, intake can be affected as well. The resulting water imbalance can cause excessive or deficient sodium levels. Dr Brown describes the interrelationship between water and sodium concentrations, explains how to calculate a given patient's requirements, and presents a safe approach to the various types of imbalance.     

Major Hepatectomy Induces Phenotypic Changes in Circulating Dendritic Cells and Monocytes

Introduction  Patients undergoing major hepatectomy are at increased risk for post-operative morbidity and mortality, and changes in the phenotype of effector cells may predispose these patients to infectious sequelae. Methods  To better understand post-hepatectomy immune responses, peripheral blood from 15 hepatectomy patients was drawn immediately before and after liver resection and on post-operative days 1, 3, and 5. Circulating monocytes and dendritic cells were analyzed by flow cytometry for quantity, phenotype, activation status, human leukocyte antigen DR (HLA-DR) expression, and toll-like receptor-2 and -4 expression. Results  Major hepatectomy increased the numbers of activated CD16^bright blood monocytes and the percentage of activated dendritic cells, although monocyte HLA-DR expression was reduced. These results may represent both dysfunctional antigen presentation and pending anergy, as well as cellular priming of immune effector cells. Better understanding of the alterations in innate immunity induced by hepatectomy may identify strategies to reduce infectious outcomes.     

PBPK modeling of irbesartan: incorporation of hepatic uptake

Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp^®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF_1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF_1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REF_HH) or tissues (REF_tissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REF_HH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd.     

Plasma lipid alterations in leukemia and lymphoma

Plasma lipids and lipoproteins were studied at presentation in 25 patients with acute leukemia and non-Hodgkin's lymphoma. All patients demonstrated an abnormality in at least one plasma lipid fraction, and most exhibited a predictable pattern of lipid alterations that consisted of extremely low levels of high-density lipoprotein cholesterol (median [Xm] = 23), elevated triglyceride (Xm =165) and elevated very-low-density lipoprotein (Xm = 26). Patients restudied during remission demonstrated a return to normal values. The degree of lipid abnormality was directly related to the underlying tumor burden and particularly to the presence of bone marrow involvement. However, even patients with minimal tumor bulk demonstrated plasma lipid abnormalities. The results suggest that an abnormality in systemic lipid metabolism, possibly in triglyceride clearance, is present in these patients and that its incidence in this population is high.     

Effects of statins on vascular structure and function: a systematic review

PURPOSE: Statins reduce cardiovascular events by more than can be explained by their effects on lipids. We conducted a systematic review of how statins affect vascular structure and function, differences among statins, and correlations between the effects of statins on vascular outcomes and either lipid levels or cardiovascular outcomes. METHODS: We primarily searched MEDLINE (1980 to March 2004) to identify all studies with at least 10 subjects that reported the effects of currently available statins on coronary artery stenosis, carotid intima-media thickness, and endothelial function (excluding studies of drug combinations and subjects with organ transplants). Meta-analyses were performed when feasible. RESULTS: Statins decrease the progression and increase the regression of coronary artery lesions and luminal narrowing. Compared with placebo, statins decrease the likelihood of coronary artery restenosis (summary risk ratio = 0.85; 95% confidence interval: 0.77 to 0.95). Statins appear to slow the progression of carotid artery intima-media thickness. Although the effect of statins on coronary endothelial function is uncertain, statins appear to improve peripheral endothelial function. There is no conclusive evidence to suggest that individual statins differ in their effects on these outcomes. Studies generally found weak or no correlation between the effects of statins on vascular outcomes and lipid levels. No study showed a correlation between vascular effect and clinical outcome. CONCLUSION: Statins slow the progression of, and may reverse, atherosclerosis. The magnitude of these effects, however, is small compared with the effects of statins on cardiovascular events. Statins also improve measures of vascular function, which may contribute to their clinical benefits. There is insufficient evidence to suggest that individual statins differ in their vascular effects.     

A Driver Training Program Intervention for Student Drivers with Autism Spectrum Disorder: A Multi-site Randomised Controlled Trial

The purpose of this multi-site randomised controlled trial was to evaluate the effectiveness of a Driving Training Program, an intervention designed for student drivers with autism spectrum disorder (ASD). Participants were 72 student drivers with ASD (ages 16–31) who were randomly assigned to an intervention or control group. Student drivers received ten driving lessons with a professional driving instructor via a standardised driving route. The Driving Performance Checklist was used as the outcome measure to evaluate the driving performance of student drivers during on-road pre- and post-observational drives. Both groups showed an improvement in driving performance, however, the extent of improvement between groups was not significant. Findings showed promising intervention efficacy for training student drivers with ASD to drive.