Therapeutic Strategies for Localized Prostate Cancer II: Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy

Application of improved imaging, diagnostic, and computer techniques is beginning to have an impact on the management of localized prostate cancer. It is possible to perform a range of surgical and radiation procedures with less morbidity than in the past. The changes in therapy for patients with localized disease derive from better knowledge of anatomy for invasive procedures and optimization of virtual planning for noninvasive methods. Perineal prostatectomy and combinations of beam and seed radiation offer both patient and physician reasonable therapeutic options.     

Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains

The human ATP‐binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small α‐helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease‐associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.     

The relation between cartilage biomarkers (C2C,C1,2C,CS846, and CPII) and the long-term outcome of rheumatoid arthritis patients within the CAMERA trial

Introduction  

The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA).     

Interactions between fungal growth, substrate utilization and enzyme production during shallow stationary cultivation of Phanerochaete chrysosporium on cotton stalks

Microbial pretreatment of lignocellulosic feedstocks is an environment friendly alternative to physio-chemical pretreatment methods. A better understanding of the interactive fungal mechanisms in biological systems is essential for enhancing performance and facilitating scale-up and commercialization of this pretreatment technique. In this study, mathematical models were developed for describing cellulose and hemicellulose consumption, lignin degradation, cellulase and ligninolytic enzyme production and oxygen uptake associated with the growth of Phanerochaete chrysosporium during a 14-day shallow stationary submerged fungal pretreatment process on cotton stalks. Model parameters were estimated and validated by Statistics Toolbox in MatLab 7.1. Models yielded sufficiently accurate predictions for cellulose and hemicellulose consumption (R2=0.9772 and 0.9837), lignin degradation (R2=0.9879 and 0.8682) and ligninolytic enzyme production (R2=0. 8135 and 0.9693) under both 1-day and 3-day oxygen flushing conditions, respectively. The predictabilities for fungal growth (R2=0.6397 and 0.5750) and cellulase production (R2=0.0307 and 0.3046) for 1-day and 3-day oxygen flushing, respectively, and oxygen uptake (R2=0.5435) for 3-day oxygen flushing were limited.     

Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine,Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults

Background

Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®).

Methodology/Principal Findings

An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC_0–12h and C_max. Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8–1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C_max, 1.3 (0.99–1.71) and AUC_0–12h, 1.1 (0.87–1.38); lamivudine C_max, 0.8 (0.63–0.98) and AUC_0–12h, 0.8 (0.65–0.99); and nevirapine C_max, 1.1 (0.95–1.23) and AUC_0–12h, 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.

Conclusions/Significant Findings

These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.     

Sex and seasonal differences in the skin lipids of garter snakes

1. This study investigates the skin lipids of male and female red-sided garter snakes both in the breeding season and in the non-breeding season. 2. Skin lipids were analyzed by means of thin-layer chromatography (TLC) and gas chromatography/mass spectrometry (GC/MS). 3. Distinct differences exist in the skin lipids of males and females. 4. Samples obtained during the breeding season were qualitatively different from those acquired during the non-breeding season.     

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol.The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.