Validation of the French version of the BACS (the brief assessment of cognition in schizophrenia) among 50 French schizophrenic patients.

Schizophrenic patients demonstrate impairments in several key dimensions of cognition. These impairments are correlated with important aspects of functional outcome. While assessment of these cognition disorders is increasingly becoming a part of clinical and research practice in schizophrenia, there is no standard and easily administered test battery. The BACS (Brief Assessment of Cognition in Schizophrenia) has been validated in English language [Keefe RSE, Golberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensibility, and comparison with a standard neurocognitive battery. Schizophr. Res 2004;68:283-97], and was found to be as sensitive to cognitive dysfunction as a standard battery of tests, with the advantage of requiring less than 35 min to complete. We developed a French adaptation of the BACS and this study tested its ease of administration and concurrent validity. Correlation analyses between the BACS (version A) and a standard battery were performed. A sample of 50 stable schizophrenic patients received the French Version A of the BACS in a first session, and in a second session a standard battery. All the patients completed each of the subtests of the French BACS . The mean duration of completion for the BACS French version was 36 min (S.D.=5.56). A correlation analysis between the BACS (version A) global score and the standard battery global score showed a significant result (r=0.81, p<0.0001). The correlation analysis between the BACS (version A) sub-scores and the standard battery sub-scores showed significant results for verbal memory, working memory, verbal fluency, attention and speed of information processing and executive functions (p<0.001) and for motor speed (p<0.05). The French Version of the BACS is easier to use in French schizophrenic patients compared to a standard battery (administration shorter and completion rate better) and its good psychometric properties suggest that the French Version of the BACS may be a useful tool for assessing cognition in schizophrenic patients with French as their primary language.     

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV₂R). Most of these mutations lead to intracellular retention of the hV₂R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV₂Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV₂R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV₂R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV₂R agonist pharmacochaperones promising therapeutic candidates for cNDI.The antidiuretic hormone arginine-vasopressin (AVP) is crucial for osmoregulation, cardiovascular control, and water homeostasis. The human AVP V₂ receptor (hV₂R), localized in the principal cells of the kidney collecting duct, mediates AVP antidiuretic effect and therefore helps in maintaining physiologic plasma osmolality, blood volume, and arterial pressure. Binding of AVP to hV₂R first triggers a cAMP signal through activation of the G protein α_s (Gs) subunit and adenylyl cyclase (AC). Then, the cAMP-activated protein kinase A phosphorylates aquaporin 2 water channels, resulting in their insertion into the luminal membrane of principal cells and finally to water reabsorption.¹ AVP binding to hV₂R also induces arrestin recruitment, receptor internalization,² and mitogen-activated protein kinase (MAPK) activation.³Mutations in the hV₂R gene lead to the X-linked congenital nephrogenic diabetes insipidus (cNDI), a rare disease characterized by the kidney''s inability to concentrate urine despite normal or elevated plasma concentrations of AVP.⁴ More than 200 different mutations have been described and are responsible for polyuria, a main consequence of the disease. Most of the mutant receptors (cNDI-hV₂Rs), trapped in the endoplasmic reticulum (ER), cannot reach the cell surface and interact with AVP.⁵ cNDI is thus referred as a conformational or protein-misfolding disease.⁶Various chaperones,⁷ either chemical (cellular osmolytes such as glycerol or DMSO) or pharmacologic (specific ligands),^8,9 are promising therapeutic agents for future clinical treatment of protein-misfolding disorders. Because a majority of cNDI-hV₂Rs are misfolded and many ligands are available for hV₂R, the pharmacochaperone-based strategy is of particular interest for cNDI. Considering an efficient therapy for this disease, the ideal drug should combine pharmacochaperone properties together with hV₂R agonist and noninternalizing activities, for stimulating AC and maintaining a long-lasting cAMP signal. This would classify such a molecule as a biased agonist or functionally selective compound.¹⁰Small nonpeptide AVP antagonists (commonly named vaptans)—such as the hV₂R-selective antagonists SR121463 (satavaptan), VPA985 (lixivaptan),¹¹ {"type":"entrez-protein","attrs":{"text":"OPC41061","term_id":"1153774258","term_text":"OPC41061"}}OPC41061 (tolpavtan), and {"type":"entrez-protein","attrs":{"text":"OPC31260","term_id":"1153764269","term_text":"OPC31260"}}OPC31260 (mozavaptan)¹²; the V_1a receptor (V_1aR) antagonist SR49059 (relcovaptan); and the nonselective V_1aR/V₂R antagonist YM087 (conivaptan)¹³—were demonstrated to promote adequate maturation and cell surface rescue of cNDI-hV₂Rs, with restoration of their capacity to initiate a cell response upon AVP binding. Although the vaptans display the expected pharmacochaperone beneficial effects, their antagonistic activity limits their use as a result of their inability to stimulate membrane-targeted cNDI-hV₂Rs directly. Comparatively, agonist pharmacochaperones would combine crucial advantages for treating cNDI.Here, we identified the first functionally selective hV₂R agonist pharmacochaperones. The Wyeth-Ayerst WAY-VNA-932 and the Otsuka OPC23h nonpeptide hV₂R antidiuretics,^14,15 as well as a novel compound MCF57, were tested for their capacity to recruit intracellularly trapped cNDI-hV₂Rs and to restore their functionality. In addition, we determined the capacity of the three ligands to act as hV₂R biased agonists (i.e., their behavior in terms of Gs/AC agonism and arrestin antagonism).     

A 1 year surveillance study of glycopeptide-intermediate Staphylococcus aureus strains in a French hospital

OBJECTIVES: Glycopeptides are the drugs of choice to treat infections due to methicillin-resistant Staphylococcus aureus, but since 1995, glycopeptide-intermediate S. aureus (GISA) and heterogeneous GISA (hGISA) have been reported worldwide. Detection of reduced susceptibility to glycopeptides in S. aureus is very difficult in a routine clinical laboratory. The aim of this study was to investigate the prevalence of hGISA/GISA strains using a three-step approach during a 1 year period. METHODS: The following algorithm was adopted: (i) brain heart infusion agar with 4 mg/L teicoplanin was used to screen S. aureus strains for reduced susceptibility to glycopeptides; (ii) for each agar screen-positive strain, an Etest macromethod using modified cut-off values (vancomycin and teicoplanin > or =4 mg/L) was used to detect potential hGISA/GISA; and (iii) the population analysis profile (PAP) method was finally used to confirm the hGISA/GISA phenotype. RESULTS: In total, 2300 strains of S. aureus were screened and 255 (11%) were categorized as hGISA with the PAP method, whereas no GISA strains were detected. Standard MIC values and current MIC breakpoints could not discriminate the hGISA/GISA phenotype from glycopeptide-susceptible S. aureus. Thus laboratories using currently standardized MIC methods cannot be expected to detect S. aureus strains that may exhibit reduced susceptibility to glycopeptides. Molecular typing by PFGE revealed that 238 strains belonged to the same clone. CONCLUSIONS: A clonal hGISA strain has disseminated within our hospital. The method described in this study has to be further investigated to see if it is applicable to other S. aureus strains.     

Genetic environment of quinolone resistance gene qnrB2 in a complex sul1-type integron in the newly described Salmonella enterica serovar Keurmassar

A qnrB2 determinant was described for a new complex sul1-type integron from Salmonella enterica serovar Keurmassar. The genetic structure contained two class 1 integrons surrounding two common regions (CRs) separated by a partial 3' conserved segment. The qnrB2 gene is adjacent to the first CR.