Structural determinants for histamine H1 affinity,hERG affinity and QTc prolongation in a series of terfenadine analogs

In the late 1980’s reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H₁ binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H₁ assays.     

A multi-dimensional coalescent process applied to multi-allelic selection models and migration models

For a sample of two genes from a population divided into an arbitrary number of allele classes, a general mathematical framework is developed to address the expectation and variance of the time of the most recent common ancestor. Depending on the meaning of allele classes and the manner in which genes can change among them, this framework can be applied to a diversity of population genetic models. By adoption of the infinite sites model, the effect on heterozygosity is modelled for balancing selection among allele classes, mutation between allele classes, migration among populations, and gene conversion between loci. Most results are described for a continuous time approximation to a discrete generation model. It is also shown how the discrete generation model can be used to study the hitch-hiking effect of favorable mutations.     

Do We Know Whether Researchers and Reviewers are Estimating Risk and Benefit Accurately?

Accurate estimation of risk and benefit is integral to good clinical research planning, ethical review, and study implementation. Some commentators have argued that various actors in clinical research systems are prone to biased or arbitrary risk/benefit estimation. In this commentary, we suggest the evidence supporting such claims is very limited. Most prior work has imputed risk/benefit beliefs based on past behavior or goals, rather than directly measuring them. We describe an approach – forecast analysis – that would enable direct and effective measure of the quality of risk/benefit estimation. We then consider some objections and limitations to the forecasting approach.     

Crosslinked fibrous collagen for use as a dermal implant: control of the cytotoxic effects of glutaraldehyde and dimethylsuberimidate

Collagen intended for use as a dermal implant may be crosslinked to increase its strength and persistence in vivo. Sheets of rat fibrous dermal collagen were crosslinked with either glutaraldehyde or dimethylsuberimidate and the cytotoxicity to human dermal fibroblasts resulting from these treatments was measured by following the inhibition of [3H]leucine incorporation into protein. Both agents were cytotoxic at the concentrations required to effect adequate crosslinking (0.005% and 25 mM, respectively). This cytotoxicity could be limited by extensive washing and by incubation with 5 mM L-lysine, with 66 mM (0.25% w/v) sodium borohydride, or with 71.3 mM (1% w/v) dimedone. However, cytotoxicity was most efficiently controlled by treatment with a combination of 66 mM sodium borohydride and 5 mM L-lysine or 66 mM sodium borohydride and 71.3 mM dimedone. [3H]Leucine incorporation by cells exposed to crosslinked collagen treated with these combinations approached 100% of the values recorded with cells exposed to uncrosslinked collagen.