Interrogation of related clinical pan-azole-resistant Aspergillus fumigatus strains: G138C, Y431C, and G434C single nucleotide polymorphisms in cyp51A, upregulation of cyp51A, and integration and activation of transposon Atf1 in the cyp51A promoter.

Multiple Aspergillus fumigatus isolates from a patient with two aspergillomas complicating chronic pulmonary aspergillosis were pan-azole resistant. Microsatellite typing was identical for all isolates despite major phenotypic and some growth rate differences. Three different cyp51A mutations were found (G138C, Y431C, and G434C), of which the first two were demonstrated by heterologous expression in a hypersusceptible Saccharomyces cerevisiae strain to be at least partly responsible for elevated MICs. cyp51A and cyp51B gene duplication was excluded, but increased expression of cyp51A was demonstrated in three isolates selected for additional study (7-to 13-fold increases). In the isolate with the greatest cyp51A expression, an Aft1 transposon was found inserted 370 bp upstream of the start codon of the cyp51A gene, an integration location never previously demonstrated in Aspergillus. Two transcription start sites were identified at 49 and 136 bp upstream of the start codon. The role of the Aft1 transposon, if any, in modulating cyp51A expression remains to be established. Increased mRNA expression of the transporters AfuMDR1 and AfuMDR4 also was demonstrated in some isolates, which could contribute to azole resistance or simply represent a stress response. The diversity of confirmed and possible azole resistance mechanisms demonstrated in a single series of isogenic isolates is remarkable, indicating the ability of A. fumigatus to adapt in the clinical setting.

Determinants of school efficiency : The case of primary schools in the State of Geneva, Switzerland

The public primary school system in the State of Geneva, Switzerland, is characterized by centrally evaluated pupil performance measured with the use of standardized tests. As a result, consistent data are collected among the system. The 2010-2011 dataset is used to develop a two-stage data envelopment analysis (DEA) of school efficiency. In the first stage, DEA is employed to calculate an individual efficiency score for each school. It shows that, on average, each school could reduce its inputs by 7% whilst maintaining the same quality of pupil performance. The cause of inefficiency lies in perfectible management. In the second stage, efficiency is regressed on school characteristics and environmental variables;external factors outside of the control of headteachers. The model is tested for multicollinearity, heteroskedasticity and endogeneity. Four variables are identified as statistically significant. School efficiency is negatively influenced by (1) the provision of special education, (2) the proportion of disadvantaged pupils enrolled at the school and (3) operations being held on multiple sites, but positively influenced by school size (captured by the number of pupils). The proportion of allophone pupils; schools located in urban areas and the provision of reception classes for immigrant pupils are not significant. Although the significant variables influencing school efficiency are outside of the control of headteachers, it is still possible to either boost the positive impact or curb the negative impact. Dans le canton de Genève (Suisse), les écoles publiques primaires sont caractérisées par un financement assuré par les collectivités publiques (canton et communes) et par une évaluation des élèves à l'aide d'épreuves standardisées à trois moments distincts de leur scolarité. Cela permet de réunir des informations statistiques consistantes. La base de données de l'année 2010-2011 est utilisée dans une analyse en deux étapes de l'efficience des écoles. Dans une première étape, la méthode d'analyse des données par enveloppement (DEA) est utilisée pour calculer un score d'efficience pour chaque école. Cette analyse démontre que l'efficience moyenne des écoles s'élève à 93%. Chaque école pourrait, en moyenne, réduire ses ressources de 7% tout en conservant constants les résultats des élèves aux épreuves standardisées. La source de l'inefficience réside dans un management des écoles perfectible. Dans une seconde étape, les scores d'efficience sont régressés sur les caractéristiques des écoles et sur des variables environnementales. Ces variables ne sont pas sous le contrôle (ou l'influence) des directeurs d'école. Le modèle est testé pour la multicolinéartié, l'hétéroscédasticité et l'endogénéité. Quatre variables sont statistiquement significatives. L'efficience des écoles est influencée négativement par (1) le fait d'offrir un enseignement spécialisé en classe séparée, (2) la proporition d'élèves défavorisés et (3) le fait d'opérer sur plusieurs sites différents. L'efficience des écoles est influencée positivement par la taille de l'école, mesurée par le nombre d'élèves. La proporition d'élèves allophones, le fait d'être situé dans une zone urbaine et d'offrir des classes d'accueil pour les élèves immigrants constituent autant de variables non significatives. Le fait que les variables qui influencent l'efficience des écoles ne soient pas sous le contrôle des directeurs ne signifie pas qu'il faille céder au fatalisme. Différentes pistes sont proposées pour permettre soit de réduire l'impact négatif soit de tirer parti de l'impact positif des variables significatives.

HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV.

BACKGROUND Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested. RESULTS MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003). CONCLUSIONS Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.

Factors associated with chronic pain in patients with bipolar depression: a cross-sectional study.

BACKGROUND While pain is frequently associated with unipolar depression, few studies have investigated the link between pain and bipolar depression. In the present study we estimated the prevalence and characteristics of pain among patients with bipolar depression treated by psychiatrists in their regular clinical practice. The study was designed to identify factors associated with the manifestation of pain in these patients. METHODS Patients diagnosed with bipolar disorder (n=121) were selected to participate in a cross-sectional study in which DSM-IV-TR criteria were employed to identify depressive episodes. The patients were asked to describe any pain experienced during the study, and in the 6 weeks beforehand, by means of a Visual Analogical Scale (VAS). RESULTS Over half of the bipolar depressed patients (51.2%, 95% CI: 41.9%-60.6%), and 2/3 of the female experienced concomitant pain. The pain was of moderate to severe intensity and prolonged duration, and it occurred at multiple sites, significantly limiting the patient's everyday activities. The most important factors associated with the presence of pain were older age, sleep disorders and delayed diagnosis of bipolar disorder. CONCLUSIONS Chronic pain is common in bipolar depressed patients, and it is related to sleep disorders and delayed diagnosis of their disorder. More attention should be paid to study the presence of pain in bipolar depressed patients, in order to achieve more accurate diagnoses and to provide better treatment options.

Towards closure between measured and modelled UV under clear skies at four diverse sites

The purpose of this work is determine the extent of closure between measurements and models of UV irradiances at diverse sites using state of the art instruments, models, and the best available data as inputs to the models. These include information about aerosol optical depth (unfortunately not extending down as far into the UVB region as desirable because such information is not generally available), ozone column amounts, as well as vertical profiles of temperature. We concentrate on clear-sky irradiances, and report the results in terms of UV Index (UVI)

Neural correlates of alerting and orienting impairment in multiple sclerosis patients.

BACKGROUND A considerable percentage of multiple sclerosis patients have attentional impairment, but understanding its neurophysiological basis remains a challenge. The Attention Network Test allows 3 attentional networks to be studied. Previous behavioural studies using this test have shown that the alerting network is impaired in multiple sclerosis. The aim of this study was to identify neurophysiological indexes of the attention impairment in relapsing-remitting multiple sclerosis patients using this test. RESULTS After general slowing had been removed in patients group to isolate the effects of each condition, some behavioral differences between them were obtained. About Contingent Negative Variation, a statistically significant decrement were found in the amplitude for Central and Spatial Cue Conditions for patient group (p<0.05). ANOVAs showed for the patient group a significant latency delay for P1 and N1 components (p<0.05) and a decrease of P3 amplitude for congruent and incongruent stimuli (p<0.01). With regard to correlation analysis, PASAT-3s and SDMT showed significant correlations with behavioral measures of the Attention Network Test (p<0.01) and an ERP parameter (CNV amplitude). CONCLUSIONS Behavioral data are highly correlated with the neuropsychological scores and show that the alerting and orienting mechanisms in the patient group were impaired. Reduced amplitude for the Contingent Negative Variation in the patient group suggests that this component could be a physiological marker related to the alerting and orienting impairment in relapsing-remitting multiple sclerosis. P1 and N1 delayed latencies are evidence of the demyelination process that causes impairment in the first steps of the visual sensory processing. Lastly, P3 amplitude shows a general decrease for the pathological group probably indexing a more central impairment. These results suggest that the Attention Network Test give evidence of multiple levels of attention impairment, which could help in the assessment and treatment of relapsing-remitting multiple sclerosis patients.

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

BACKGROUND Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. OBJECTIVES In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. RESULTS AND CONCLUSION Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele.

Probabilistic models to assist maintenance of multiple instruments

The paper discusses maintenance challenges of organisations with a huge number of devices and proposes the use of probabilistic models to assist monitoring and maintenance planning. The proposal assumes connectivity of instruments to report relevant features for monitoring. Also, the existence of enough historical registers with diagnosed breakdowns is required to make probabilistic models reliable and useful for predictive maintenance strategies based on them. Regular Markov models based on estimated failure and repair rates are proposed to calculate the availability of the instruments and Dynamic Bayesian Networks are proposed to model cause-effect relationships to trigger predictive maintenance services based on the influence between observed features and previously documented diagnostics

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Networks in Argentine agriculture: a multiple-case study approach

Argentina is among the four largest producers of soybeans, sunflower, corn, and wheat, among other agricultural products. Institutional and policy changes during the 1990s fostered the development of Argentine agriculture and the introduction of innovative process and product technologies (no-till, agrochemicals, GMO, GPS) and new investments in modern, large-scale sunflower and soybean processing plants. In addition to technological changes, a "quiet revolution" occurred in the way agricultural production was carried out and organized: from self-production or ownership agriculture to a contract-based agriculture. The objective of this paper is to explore and describe the emergence of networks in the Argentine crop production sector. The paper presents and describes four cases that currently represent about 50% of total grain and oilseed production in Argentina: "informal hybrid form", "agricultural trust fund", "investor-oriented corporate structure", and "network of networks". In all cases, hybrid forms involve a group of actors linked by common objectives, mainly to gain scale, share resources, and improve the profitability of the business. Informal contracts seem to be the most common way of organizing the agriculture process, but using short-term contracts and sequential interfirm collaboration. Networks of networks involve long-term relationships and social development, and reciprocal interfirm collaboration. Agricultural trust fund and investor-oriented corporate structures have combined interfirm collaboration and medium-term relationships. These organizational forms are highly flexible and show a great capacity to adapt to challenges; they are competitive because they enjoy aligned incentives, flexibility, and adaptability.

Effectiveness of glatiramer acetate compared to other multiple sclerosis therapies.

OBJECTIVE To assess the effectiveness of glatiramer acetate (GA) compared to other multiple sclerosis (MS) therapies in routine clinical practice. MATERIALS AND METHODS Observational cohort study carried out in MS patients treated with GA (GA cohort) or other MS therapies -switched from GA- (non-GA cohort). Study data were obtained through review of our MS patient database. The primary endpoint was the Expanded Disability Status Scale (EDSS) scores reached at the end of treatment/last check-up. RESULTS A total of 180 patients were included: GA cohort n = 120, non-GA cohort n = 60. Patients in the GA cohort showed better EDSS scores at the end of treatment/last check-up (mean ± SD, 2.8 ± 1.8 vs. 3.9 ± 2.2; P = 0.001) and were 1.65 times more likely to show better EDSS scores compared to the non-GA cohort (odds ratio, 0.606; 95%CI, 0.436-0.843; P = 0.003). Patients in the GA cohort showed longer mean time to reach EDSS scores of 6 (209.1 [95%CI, 187.6-230.6] vs. 164.3 [95% CI, 137.0-191.6] months; P = 0.004) and slower disability progression (hazard ratio, 0.415 [95%CI, 0.286-0.603]; P < 0.001). The annualized relapse rate was lower in the GA cohort (mean ± SD, 0.5 ± 0.5 vs. 0.8 ± 0.5; P = 0.001) and patients' quality of life was improved in this study cohort compared to the non-GA cohort (mean ± SD, 0.7 ± 0.1 vs. 0.6 ± 0.2; P = 0.01). CONCLUSIONS GA may slow down the progression of EDSS scores to a greater extent than other MS therapies, as well as achieving a greater reduction in relapses and a greater improvement in patients' quality of life. Switching from GA to other MS therapies has not proved to entail a better response to treatment.

Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers.

Plasma concentrations of the enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) were measured at days 7, 14, and 23 of oral administration of 20 mg of racemic fluoxetine in 11 patients who were comedicated with risperidone. Eight patients were genotyped as being cytochrome P4502D6 extensive metabolizers (EMs) and three as cytochrome P4502D6 poor metabolizers (PMs). No statistically significant differences were calculated between EMs and PMs in the concentrations of (R)-FLX and (R)-NFLX for all days examined (day 23, mean +/- SD for (R)-FLX and (R)-NFLX in EMs, 16 +/- 5 and 29 +/- 20 ng/mL, respectively; in PMs, 16 +/- 1 and 20 +/- 2 ng/mL, respectively). However, concentrations of (S)-FLX and (S)-NFLX were higher and lower, respectively, in PMs as compared with EMs (day 7, p = 0.037 and p = 0.036; day 14, p = 0.014 and p = 0.014; day 23, p = 0.068 and p = 0.038). On day 23, mean (S)-FLX and (S)-NFLX in EMs were (mean +/- SD) 39 +/- 26 and 63 +/- 26 ng/mL, and in PMs they were 88 +/- 7 and 19 +/- 2 ng/mL. This study confirms the results of the single-dose studies showing that CYP2D6 is involved in the demethylation of FLX to NFLX, with a stereoselectivity toward the (S)-enantiomer. The data also clearly show that the CYP2D6 genotype has an important influence on the concentrations of the (S)- but not of the (R)-enantiomer of FLX and NFLX after multiple doses.