Genetic Variations and Diseases in UniProtKB/Swiss-Prot: The Ins and Outs of Expert Manual Curation.

During the last few years, next-generation sequencing (NGS) technologies have accelerated the detection of genetic variants resulting in the rapid discovery of new disease-associated genes. However, the wealth of variation data made available by NGS alone is not sufficient to understand the mechanisms underlying disease pathogenesis and manifestation. Multidisciplinary approaches combining sequence and clinical data with prior biological knowledge are needed to unravel the role of genetic variants in human health and disease. In this context, it is crucial that these data are linked, organized, and made readily available through reliable online resources. The Swiss-Prot section of the Universal Protein Knowledgebase (UniProtKB/Swiss-Prot) provides the scientific community with a collection of information on protein functions, interactions, biological pathways, as well as human genetic diseases and variants, all manually reviewed by experts. In this article, we present an overview of the information content of UniProtKB/Swiss-Prot to show how this knowledgebase can support researchers in the elucidation of the mechanisms leading from a molecular defect to a disease phenotype.

Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group.

BACKGROUND: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. METHODS: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. RESULTS: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. CONCLUSIONS: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Estimating uncertainty of alcohol-attributable fractions for infectious and chronic diseases.

Background: Alcohol is a major risk factor for burden of disease and injuries globally. This paper presents a systematic method to compute the 95% confidence intervals of alcohol-attributable fractions (AAFs) with exposure and risk relations stemming from different sources.Methods: The computation was based on previous work done on modelling drinking prevalence using the gamma distribution and the inherent properties of this distribution. The Monte Carlo approach was applied to derive the variance for each AAF by generating random sets of all the parameters. A large number of random samples were thus created for each AAF to estimate variances. The derivation of the distributions of the different parameters is presented as well as sensitivity analyses which give an estimation of the number of samples required to determine the variance with predetermined precision, and to determine which parameter had the most impact on the variance of the AAFs.Results: The analysis of the five Asian regions showed that 150 000 samples gave a sufficiently accurate estimation of the 95% confidence intervals for each disease. The relative risk functions accounted for most of the variance in the majority of cases.Conclusions: Within reasonable computation time, the method yielded very accurate values for variances of AAFs.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.

As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.

Seasonal activity of Dinoponera quadriceps Santschi (Formicidae, Ponerinae) in the semi-arid Caatinga of northeastern Brazil

Seasonal activity of Dinoponera quadriceps Santschi (Formicidae, Ponerinae) in the semi-arid Caatinga of northeastern Brazil. We studied seasonal foraging patterns of the queenless ant D. quadriceps (Formicidae, Ponerinae) for 24 months in a Caatinga area of northeastern Brazil, an ecosystem characterized by strong climatic changes throughout the year, in order to determine if regulation of worker activity is based on environmental conditions (air temperature, relative humidity, precipitation) and/or food resources (potential prey: Coleoptera, Diptera, Hemiptera, Hymenoptera, Lepidoptera, Orthoptera, Araneae, Chilopoda and Diplopoda). Foraging activity of D. quadriceps varied over the course of both years, with the highest frequency occurring from May to August, corresponding to the late rainy season and early dry season. This foraging activity was negatively correlated with temperature and positively correlated with the availability of potential prey, but not with total abundance of soil arthropods or with rainfall and relative humidity. Diet composition, in relation to the main taxonomic prey groups, seems to be common to the species, regardless of habitat. Our results suggest that D. quadriceps workers adjust foraging activity to the most suitable period of the year, to avoid thermal stress and increase efficiency. Thus, they present an appropriate behavioral response to seasonal fluctuations in the Caatinga.

Examining non-response bias in substance use research-Are late respondents proxies for non-respondents?

BACKGROUND: Non-response is a major concern among substance use epidemiologists. When differences exist between respondents and non-respondents, survey estimates may be biased. Therefore, researchers have developed time-consuming strategies to convert non-respondents to respondents. The present study examines whether late respondents (converted former non-participants) differ from early respondents, non-consenters or silent refusers (consent givers but non-participants) in a cohort study, and whether non-response bias can be reduced by converting former non-respondents. METHODS: 6099 French- and 5720 German-speaking Swiss 20-year-old males (more than 94% of the source population) completed a short questionnaire on substance use outcomes and socio-demographics, independent of any further participation in a cohort study. Early respondents were those participating in the cohort study after standard recruitment procedures. Late respondents were non-respondents that were converted through individual encouraging telephone contact. Early respondents, non-consenters and silent refusers were compared to late respondents using logistic regressions. Relative non-response biases for early respondents only, for respondents only (early and late) and for consenters (respondents and silent refusers) were also computed. RESULTS: Late respondents showed generally higher patterns of substance use than did early respondents, but lower patterns than did non-consenters and silent refusers. Converting initial non-respondents to respondents reduced the non-response bias, which might be further reduced if silent refusers were converted to respondents. CONCLUSION: Efforts to convert refusers are effective in reducing non-response bias. However, converted late respondents cannot be seen as proxies of non-respondents, and are at best only indicative of existing response bias due to persistent non-respondents.

The Effect of Amifostine on Acute and Late Radiation Side Effects in Head and Neck Cancer Patients

Objective: We aimed to investigate the effect of amifostine on acute and late side effects, and its tolerability in head and neck cancer patients treated with radiotherapy (RT). Material and Methods: The study included 87 patients with primary head and neck cancers and cervical lymph node metastases from unknown primary cancers treated with RT alone or combined with chemotherapy (CT). Forty-one patients (47%) received amifostine combined with RT (ART group) and 46 patients (52%) received RT without amifostine (RT group). The patients were evaluated every week during the treatment and at month 1 and 2 after the completion of RT for acute side effects and month 3, 6, 9, 12, and 24 after the treatment for late side effects according to SOMA/LENT scale. Amifostine was administered prior to RT, along with anti-emetic prophylaxis. The two groups were compared with the Student's t and Mann-Whitney U and Chi-square tests. Results: The ART group had significantly less toxicity (grade! 1 mucositis, grade 2 fibrosis) than patients in the RT group (p=0.001, p=0.03, respectively). At week 3 of RT grade 2 mucositis developed in two patients (5%) in the ART group and 10 patients (22%) in the RT group (p=0.02). The protective effect of amifostine on skin reactions developed at week 4 of RT (p=0.05). Grade 3 xerostomia at 9, 12, and 15 months of follow-up (p=0.02, p=0.02, and p=0.02, respectively), grade 2 xerostomia at 18 and 24 months (p=0.02 and p=0.01, respectively) and fibrosis at 15, 18 and 24 months (p=0.05, p=0.02 and p=0.02, respectively) decreased markedly in the ART group compared with the RT group. Emesis was the most common adverse effect of amifostine. Conclusion: Daily administration of amifostine during RT was effective in avoiding late grade 2-3 xerostomia, as well as grade 2 fibrosis.

Sex-ratio regulation: the economics of fratricide in ants

In many insect societies, workers can manipulate the reproductive output of their colony by killing kin of lesser value to them. For instance, workers of the mound-building For mica exsecta eliminate male brood in colonies headed by a single-mated queen. By combining an inclusive fitness model and empirical data, we investigated the selective causes underlying these fratricides. Our model examines until which threshold stage in male brood development do the workers benefit from eliminating males to rear extra females instead. We then determined the minimal developmental stage reached by male larvae before elimination in F. exsecta field colonies. Surprisingly, many male larvae were kept until they were close to pupation, and only then eliminated. According to our model, part of the eliminated males were so large that workers would not benefit from replacing them with new females. Moreover, males were eliminated late in the season, so that new females could no longer be initiated, because matings take place synchronously during a short period. Together, these results indicate that workers did not replace male brood with new females, but rather reduced total brood size during late larval development. Male destruction was probably triggered by resource limitation, and the timing of brood elimination suggests that males may have been fed to females when these start to grow exponentially during the final larval stage. Hence, the evolution of fratricides in ants is best explained by a combination of ecological, demographic and genetic parameters.

The zebrafish is an animal model in ophthalmic diseases : Fleck corneal dystrophy and Schorderet-Munier syndrome

RAPPORT DE SYNTHÈSE : Pip5k3 : Pip5k3 is a kinase responsible for fleck corneal dystrophy when mutated. It is a well conserved gene that has only been characterized in human and mouse. Characterization of pip5k3 in zebrafish was necessary before using it as a model. The protein is 70 % similar to the human homologue. The full coding sequence encompasses 6303 by and presented four isoforms. They were differentially expressed during development. All the analyzed organs of the adult zebrafish expressed pip5k3. The adult eye expressed pip5k3 in the cornea, lens, ganglion cell layer (GCL), inner nuclear layer (INL) and outer limiting membrane (OLM). During development, pip5k3 was first uniformly expressed before to be restricted to the head region and to the somites. The expression of pip5k3 in the cornea of the larval eye could make possible the study of fleck corneal dystrophy on this animal. NkxS-3 : NKXS-3 is a transcription factor responsible for a new oculo-auricular syndrome in human when mutated. This recessive disorder is characterized by defects in ear lobule and multiple defects in eye, including microphthalmia and cataract. During development, the zebrafish expressed nkx5-3 in the lens, in the anterior retina and in otic vesicles. Knockdown experiments partially phenocopied the human disease. Microphthalmia and cataract were reproduced, but zebrafish showed also defects in the cartilage of the jaw associated with a microcephaly and fins abnormalities. The retinal cell differentiation was delayed, possibly linked with the delayed expression of at`h5 and crx also observed in morphants. Shh, a regulator of ath5, was normally expressed in morphant. Overexpression of nkx5-3 lead to an anophthalmia, suggesting a role at the early organogenesis of the eye. All the phenotypes observed in morphants and embryos overexpressing nkx5-3 suggest a potential involvement of the FGF and hedgehog signaling pathways.

Flowering date of taxonomic families predicts phenological sensitivity to temperature: Implications for forecasting the effects of climate change on unstudied taxa.

PREMISE OF THE STUDY: Numerous long-term studies in seasonal habitats have tracked interannual variation in first flowering date (FFD) in relation to climate, documenting the effect of warming on the FFD of many species. Despite these efforts, long-term phenological observations are still lacking for many species. If we could forecast responses based on taxonomic affinity, however, then we could leverage existing data to predict the climate-related phenological shifts of many taxa not yet studied. METHODS: We examined phenological time series of 1226 species occurrences (1031 unique species in 119 families) across seven sites in North America and England to determine whether family membership (or family mean FFD) predicts the sensitivity of FFD to standardized interannual changes in temperature and precipitation during seasonal periods before flowering and whether families differ significantly in the direction of their phenological shifts. KEY RESULTS: Patterns observed among species within and across sites are mirrored among family means across sites; early-flowering families advance their FFD in response to warming more than late-flowering families. By contrast, we found no consistent relationships among taxa between mean FFD and sensitivity to precipitation as measured here. CONCLUSIONS: Family membership can be used to identify taxa of high and low sensitivity to temperature within the seasonal, temperate zone plant communities analyzed here. The high sensitivity of early-flowering families (and the absence of early-flowering families not sensitive to temperature) may reflect plasticity in flowering time, which may be adaptive in environments where early-season conditions are highly variable among years.

The characterization of retinal phenotype in a family with C1QTNF5-related late-onset retinal degeneration.

PURPOSE: To describe the clinical, spectral-domain optical coherence tomography and electrophysiological features of C1QTNF5-associated late-onset retinal degeneration in a molecularly confirmed pedigree. METHODS: Five members of a family participated, and affected individuals (n = 4) underwent detailed ophthalmologic evaluation including fundus autofluorescence and spectral-domain optical coherence tomography imaging and electroretinography. Electrooculography was performed in three individuals. RESULTS: The visual acuity was initially normal and worsened with time. Anterior segment abnormalities included peripupillary iris atrophy and long anterior insertion of zonules. Peripapillary atrophy, drusenoid deposition, and scalloped sectorial chorioretinal atrophy were observed in all older individuals (n = 3). Fundus autofluorescence demonstrated hypofluorescent areas corresponding to regions of chorioretinal atrophy. The spectral-domain optical coherence tomography demonstrated multiple areas of retinal pigment epithelium-Bruch membrane separation with intervening homogeneous deposition that corresponded to the drusenoid lesions and areas of chorioretinal atrophy. Electrooculography was normal in one individual and showed abnormally low dark trough measures in older individuals (n = 2). Electroretinography was normal in early stages (n = 1), but showed marked abnormalities in the rod system (n = 3), which was predominantly inner retinal (n = 2) in late stages. CONCLUSION: Late-onset retinal degeneration is a progressive degeneration, and anterior segment abnormalities present early. The widespread sub-retinal pigment epithelium deposition seen on spectral-domain optical coherence tomography in older individuals appears to be a characteristic in late stages. Electrooculography demonstrates abnormalities only in late stages of the disease.

Perception et communication du risque: du diabète à la maladie cardiovasculaire [Risk perception and communication: from diabetes to cardiovascular diseases].

Evidence-based medicine has enabled to approach disease in a more rational and scientific way. Clinical research has identified behaviours and risk factors that could cause disease often "silent" at the beginning, such as diabetes. Despite the clear impact of these evidences on public health, it seems that the individual risk perception level remains weak. To mention as well, the health professionals very often have a different views, which makes it difficult to communicate the risk with patients. In this article we describe the principles of risk perception, the diabetes related risk perception concerning cardiovascular complications, and suggest some practical strategies and tools which could improve risk communication in the everyday practice.