Evaluation of activity and emergence of resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing Klebsiella pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MICPMB], 0.5 mg/liter; MIC of fosfomycin [MICFOF], 32 mg/liter) and BRKP67 (MICPMB, 8 mg/liter; MICFOF, 32 mg/liter) at an initial inoculum of 107 CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h infusion) regimens alone and in combination. Population analysis profiles (PAPs) and MIC testing were performed to assess emergence of resistance...

An essential receptor for adeno-associated virus infection.

Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.

Meta-analysis of the effectiveness of smoking cessation interventions in community pharmacy.

WHAT IS KNOWN AND OBJECTIVE: With the emerging and promising role of healthcare professionals in implementing smoking cessation services, community pharmacists, in particular, can play a pivotal role. The aim of this meta-analysis is to evaluate the effectiveness of smoking cessation interventions delivered by community pharmacists in assisting smokers to quit. METHODS: PubMed, EMBASE, Scopus, International Pharmaceutical Abstracts and ISI Web of Knowledge were searched from inception to May 2013. Original research articles were selected for review, if they addressed the effectiveness of pharmacy-based interventions in smokers vs. a control group and reported smoking abstinence rates as an outcome. Obtained studies were assessed for methodological quality using the Cochrane Effective Practice and Organization of Care Group risk of bias tool. The primary outcome of measure was smoking abstinence based on the 'most rigorous criterion'. Pooled relative risks (RR) with 95% confidence interval (CI) were estimated using the Dersimonian and Laird random-effects models. Corresponding subgroup met-analysis was performed. RESULTS: Of the 1168 articles extracted, five studies (three randomized controlled trials and two controlled before-after studies) met the inclusion criteria, involving a total of 1426 smokers. Pharmacist interventions showed better abstinence rates as compared with controls (RR 2·21, 95% CI 1·49-3·29). Compared with the control group, the RR (95% CI) in the intervention group was 3·21 (1·81-5·72) for clinically validated abstinence and 1·66 (1·08-2·54) for self-reported abstinence. In the intervention group, the RR for short-term and long-term abstinence was 2·48 (1·15-5·31) and 2·40 (1·37-4·23), respectively. WHAT IS NEW AND CONCLUSIONS: Pharmacist-led interventions can significantly impact abstinence rates in smokers. Health policymakers should direct incentives for community pharmacists to provide such services.

Real-time computer-generated hologram by means of liquid-crystal television spatial light modulator.

A novel use of liquid-crystal television (LCTV) is described. It is shown that, if the phase nonuniformity of the LCTV is corrected by a liquid gate, then a simple computer-generated hologram can be written and coherently reconstructed.

Variable nature of cartilage proteoglycans.

Cartilage proteoglycan aggregates are separated from collagen and other non-proteoglycan protein by preparative rate zonal sedimentation under associative conditions. Dissociative rate zonal sedimentation produces sedimented proteoglycan of lower protein content with a corresponding increase in the amount of less sedimentable protein-rich proteoglycan. An extensive number of sequential rate zonal sedimentations discloses that the proceess of disaggregation involves the separation of proteoglycans varying continuously in composition with no apparent discontinuities in distribution to indicate the presence of distinctively different macromolecules. The variations encompass proteoglycans of low protein content containing less than 2% keratan sulfate and proteoglycans with keratan sulfate as the predominant polysaccharide (present in concentrations greater than 2-fold that of the chondroitin sulfate) and more than a 10-fold increase in protein content.

Distribution studies of proteoglycan aggregates by ultracentrifugation.

The tendency forcartilage proteoglycans to aggregate or disperse in ultracentrifugation at high ionic strength is influenced by cations. Guanidinum, Li+ and Ca++ promote disaggregation and Na+, K+ and Cs+ support aggregation. The process of disaggregation is fundamentally the separation of low density from high density proteoglycans, the density being an inverse function of the protein content. PPL 5 pellet formation is a packing or aggregation phenomenon occurring well below the isopycnic density of proteoglycan which accounts for its difference from the isopycnic density equilibrated complex. Cations which promote disaggregation result in shifts in distribution of the proteoglycans on equilibrated density gradients. Comparisons of the desulfated products of the high density aggregated and disaggregated complexes and of more selective high and low density proteoglycan fractions clearly show the heterogeneity of proteoglycans related to protein content. It is suggested that the nature of the variable population of proteoglycan macromolecules permits its existence as a self aggregating system.