European surveillance of antimicrobial consumption (ESAC) : systemic antiviral use in Europe

Objectives: To assess the total systemic antiviral use in Europe and to identify the antiviral substances most commonly used.Methods: Within the European Surveillance of Antimicrobial Consumption (ESAC; www.esac.ua.ac.be), using the anatomical therapeutic chemical (ATC) classification and defined daily dose (DDD) measurement unit, data on total (out- and inpatient) systemic antiviral use (ATC J05), aggregated at the level of the active substance, were collected for 2008, and use was expressed in DDD (WHO ATC/DDD, version 2010) per 1000 inhabitants per day (DID). Antiviral substances were grouped according to their main indication.Results: In Europe, 12 countries (Belgium, Croatia, Denmark, Estonia, Finland, France, Hungary, Italy, Luxembourg, Russia, Slovenia and Sweden) provided total (out- and inpatient) data and 4 countries (Austria, the Netherlands, Portugal and Norway) provided outpatient data only. Total systemic antiviral use varied by a factor of 10.95 between the country with the highest (3.53 DID in France) and the country with the lowest (0.32 DID in Croatia) use. HIV/AIDS antivirals represented more than 50% of the total antiviral use in most countries. The amount and spectrum of antivirals used varied greatly between countries.Conclusions: Our study demonstrated a wide variation of total systemic antiviral use in several European countries, as striking as that of outpatient systemic antibiotic, antimycotic and antifungal use. The variation is mainly determined by the use of HIV/AIDS antivirals. These observations should stimulate further analysis to understand the variation of specific antiviral substances. The ESAC data facilitate auditing of antiviral prescriptions and evaluation of the implementation of guidelines and public health policies.peer-reviewe

Identification of protein tyrosine phosphatases associating with the PDGF receptor

Protein tyrosine phosphatase (PTP) in-gel assays were used to explore association of PTPs with the platelet-derived growth factor beta-receptor (PDGFbetaR). Five PTP activity bands of approximately 120, approximately 70, approximately 60, approximately 53, and approximately 45 kDa could be detected in PDGFbetaR immunoprecipitates and were identified by immunodepletion experiments as PTP-PEST, SHP-2, an active fragment of SHP-2, PTP-1B, and T-cell PTP, respectively. The PTP pattern that was obtained was similar in PDGFbetaR immunoprecipitates from HEK 293 cells overexpressing the human PDGFbetaR and from murine fibroblasts. Association of PTP-1B with the PDGFbetaR was stabilized by pretreatment of the cells with hydrogen peroxide. The epidermal growth factor receptor (EGFR) immunoprecipitated from fibroblasts, and c-Kit isolated from CHRF myeloid cells, were associated with partially overlapping but quantitatively different patterns of PTPs. PTP-PEST was the predominant PTP in EGFR immunoprecipitates, and SHP-1 appeared in c-Kit immunoprecipitates. We propose that the differential association of PTPs with different RTKs is related to their respective contributions to regulation of RTK signaling

New Variant of CTX-M-Type Extended-Spectrum β-Lactamases, CTX-M-71, with a Gly238Cys Substitution in a Klebsiella pneumoniae Isolate from Bulgaria▿

A single Klebsiella pneumoniae strain isolated in a Bulgarian hospital was found to produce CTX-M-71, a new CTX-M variant characterized by one amino acid substitution from glycine to cysteine at position 238 in comparison to CTX-M-15. This exchange decreased the hydrolytic activity of the β-lactamase for cefotaxime, ceftazidime, and cefepime

Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPα promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants