Survey of Treponemal Infections in Free-Ranging and Captive Macaques, 1999-2012.

Survey results showed treponemal infection among pet macaques in Southeast Asia, a region with a high prevalence of human yaws. This finding, along with studies showing treponemal infection in nonhuman primates in Africa, should encourage a One Health approach to yaws eradication and surveillance activities, possibly including monitoring of nonhuman primates in yaws-endemic regions

Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii

Quaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. While they are known for their membrane-damaging properties, QAC action has been suggested to extend beyond the surface to intracellular targets. Here we characterize the range of action of the QAC biocide benzalkonium chloride (BZK) against the bacterial pathogen Acinetobacter baumannii. At high concentrations, BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. Resistance to BZK is found to develop through ribosomal protein mutations that protect A. baumannii against BZK-induced protein aggregation. The multifunctional impact of BZK led us to discover that alternative QAC structures, with low human toxicity, retain potent action against multidrug-resistant A. baumannii, Staphylococcus aureus, and Clostridium difficile and present opportunities for their development as antibiotics

Proton Transport Pathway in the ClC Cl−/H+ Antiporter

A fundamental question concerning the ClC Cl−/H+ antiporters is the nature of their proton transport (PT) pathway. We addressed this issue by using a novel computational methodology capable of describing the explicit PT dynamics in the ClC-ec1 protein. The main result is that the Glu203 residue delivers a proton from the intracellular solution to the core of ClC-ec1 via a rotation of its side chain and subsequent acid dissociation. After reorientation of the Glu203 side chain, a transient water-mediated PT pathway between Glu203 and Glu148 is established that is able to receive and translocate the proton via Grotthuss shuttling after deprotonation of Glu203. A molecular-dynamics simulation of an explicit hydrated excess proton in this pathway suggests that a negatively charged Glu148 and the central Cl− ion act together to drive H+ to the extracellular side of the membrane. This finding is consistent with the experimental result that Cl− binding to the central site facilitates the proton movement. A calculation of the PT free-energy barrier for the ClC-ec1 E203V mutant also supports the proposal that a dissociable residue is required at this position for efficient delivery of H+ to the protein interior, in agreement with recent experimental results

Systematic review of purine analog treatment for chronic lymphocytic leukemia: lessons for future trials

A systematic review of purine analogs revealed heterogeneity between trials in treatment effects on response and progression free survival, but not survival, perhaps partly due to variations in analytical methods. In addition, combination treatments required evaluation. Therefore, individual patient data were sought for all randomized trials in untreated chronic lymphocytic leukemia which involved a purine analog, but which did not include antibody therapies. Sixteen trials were found, addressing seven comparisons. Eight trials, with 2,753 patients, showed that single agent purine analog improved progression free survival (odds ratio=0.71; 95% confidence interval=0.63-0.79). Heterogeneity remained substantial. Three trials, with 1,403 patients, showed that progression free survival was further improved by the addition of cyclophosphamide (odds ratio=0.54; 0.47-0.62). Fewer data were available on the addition of other drugs to purine analog, and none showed clear benefit. Two trials, with 544 patients, suggested cladribine improved progression free survival compared to fludarabine (odds ratio=0.77; 0.63-0.95). No differences were seen in overall survival for any comparisons. In conclusion, purine analogs, particularly combined with cyclophosphamide, significantly improve progression free survival but not survival. Some groups, such as the elderly, may not see the same benefits and maximizing doses may be important for all treatments, including chlorambucil. Longer follow up, consistent definitions and detailed reporting of trials should be encouraged