Structural Evidence for a Bifurcated Mode of Action in the Antibody-Mediated Neutralization of Hepatitis C Virus.

Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus.

Proc Natl Acad Sci U S A. 2013 Apr 15;
Deng L, Zhong L, Struble E, Duan H, Ma L, Harman C, Yan H, Virata-Theimer ML, Zhao Z, Feinstone S, Alter H, Zhang P

Hepatitis C virus (HCV) envelope glycoprotein E2 has been considered as a major target for vaccine design. Epitope II, mapped between residues 427-446 within the E2 protein, elicits antibodies that are either neutralizing or nonneutralizing. The fundamental mechanism of antibody-mediated neutralization at epitope II remains to be defined at the atomic level. Here we report the crystal structure of the epitope II peptide in complex with a monoclonal antibody (mAb#8) capable of neutralizing HCV. The complex structure revealed that this neutralizing antibody engages epitope II via interactions with both the C-terminal ?-helix and the N-terminal loop using a bifurcated mode of action. Our structural insights into the key determinants for the antibody-mediated neutralization may contribute to the immune prophylaxis of HCV infection and the development of an effective HCV vaccine. HubMed – drug


A vitamin-responsive mesoporous nanocarrier with DNA aptamer-mediated cell targeting.

Chem Commun (Camb). 2013 Apr 15;
Li LL, Xie M, Wang J, Li X, Wang C, Yuan Q, Pang DW, Lu Y, Tan W

A smart drug delivery system with cancer cell targeting and bioresponsive controlled drug release has been constructed by taking advantage of a protein-capped mesoporous nanovalve and a DNA aptamer. HubMed – drug


Hepatic veno-occlusive disease resulting in tacrolimus toxicity after allogeneic hematopoietic stem cell transplantation.

Blood Res. 2013 Mar; 48(1): 55-7
Shin SH, Yahng SA, Yoon JH, Lee SE, Cho BS, Kim YJ

Tacrolimus is a widely used immunosuppressive agent for the prophylaxis of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation (HSCT). Since tacrolimus is primarily metabolized by the liver, hepatic dysfunction may affect its metabolism. Hepatic veno-occlusive disease (VOD) is an early complication of HSCT that results in hepatic dysfunction, suggesting that VOD may affect tacrolimus metabolism. We report a case of hepatic VOD accompanied by a sustained high blood trough level of tacrolimus despite its discontinuation. The findings of this case suggest that the elimination of tacrolimus can be markedly delayed in patients with hepatic VOD, and that the clinician should carefully modulate the drug dosage for these patients. HubMed – drug


A Simple Method for Assessment of MDR Bacteria for Over-Expressed Efflux Pumps.

Open Microbiol J. 2013; 7: 72-82
Martins M, McCusker MP, Viveiros M, Couto I, Fanning S, Pagès JM, Amaral L

It is known that bacteria showing a multi-drug resistance phenotype use several mechanisms to overcome the action of antibiotics. As a result, this phenotype can be a result of several mechanisms or a combination of thereof. The main mechanisms of antibiotic resistance are: mutations in target genes (such as DNA gyrase and topoisomerase IV); over-expression of efflux pumps; changes in the cell envelope; down regulation of membrane porins, and modified lipopolysaccharide component of the outer cell membrane (in the case of Gram-negative bacteria). In addition, adaptation to the environment, such as quorum sensing and biofilm formation can also contribute to bacterial persistence. Due to the rapid emergence and spread of bacterial isolates showing resistance to several classes of antibiotics, methods that can rapidly and efficiently identify isolates whose resistance is due to active efflux have been developed. However, there is still a need for faster and more accurate methodologies. Conventional methods that evaluate bacterial efflux pump activity in liquid systems are available. However, these methods usually use common efflux pump substrates, such as ethidium bromide or radioactive antibiotics and therefore, require specialized instrumentation, which is not available in all laboratories. In this review, we will report the results obtained with the Ethidium Bromide-agar Cartwheel method. This is an easy, instrument-free, agar based method that has been modified to afford the simultaneous evaluation of as many as twelve bacterial strains. Due to its simplicity it can be applied to large collections of bacteria to rapidly screen for multi-drug resistant isolates that show an over-expression of their efflux systems. The principle of the method is simple and relies on the ability of the bacteria to expel a fluorescent molecule that is substrate for most efflux pumps, ethidium bromide. In this approach, the higher the concentration of ethidium bromide required to produce fluorescence of the bacterial mass, the greater the efflux capacity of the bacterial cells. We have tested and applied this method to a large number of Gram-positive and Gram-negative bacteria to detect efflux activity among these multi-drug resistant isolates. The presumptive efflux activity detected by the Ethidium Bromide-agar Cartwheel method was subsequently confirmed by the determination of the minimum inhibitory concentration for several antibiotics in the presence and absence of known efflux pump inhibitors. HubMed – drug


Risks of alcohol-attributable hospitalisation and death in Australia over time: Evidence of divergence by region, age and sex.

Australas Med J. 2013; 6(3): 134-51
Pascal R, Liang W, Gilmore W, Chikritzhs T

Past reports on trends of alcohol consumption and related harm have generally been descriptive in nature and have not provided evidence of whether changes over time are significant.We investigated whether: (i) the risk of alcohol-attributable hospitalisation and death between 1994 and 2005 for three different age groups changed significantly across all Australian jurisdictions; and (ii) the relative rates of hospitalisation for males and females changed over time.Estimates of alcohol-attributable hospitalisations and deaths were calculated using the aetiologic fraction method. Hospitalisations and deaths were grouped by age: 15-29 years, 30-44 years and 45+ years. Risk estimates and risk differences were analysed using Poisson regression.Risk of alcohol-attributable hospital separations increased nationally and across most jurisdictions throughout the study period. Male and female rates converged over time. Alcohol-attributable deaths decreased nationally across the three age groups and across several jurisdictions beginning in the mid-1990s.Nationally, alcohol-attributable deaths declined while hospitalisations rose. However, states with higher population density tended to drive national rates, with considerable variation by jurisdiction. The conditions which dominated hospitalisations (e.g. alcohol dependence, falls) differed substantially from those underlying alcoholattributable deaths (e.g. alcoholic liver cirrhosis, road crashes). Jurisdictional variation in death and hospitalisations rates as well as changes over time may be partly due to differences in: regulation of alcohol supply; patterns and levels of alcohol consumption; the nature and effectiveness of law enforcement; demographic characteristics of general and sub-populations; and medical health services and screening for chronic conditions. HubMed – drug