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Background Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. Methods We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. Results IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. Conclusions These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders.

Many Industrial Design professionals in Spain have difficulties when it comes to getting a job related to their field. They also have difficulties incorporating into the labor market as what they have learnt as students does not correspond with the demands of the labour market as far as industrial designers are concerned. By using a nationally representative survey sample of 195 professionals and 36 companies, this paper analyzes competencies, skills and knowledge acquired in Industrial Design Engineering and Product Development Degree, as well as the requirements of the labor market in order to check if this degree has correctly been adapted to the spanish workplace. Results shows the acquired skills’ level is not bad, as a general rule, but this does not mean the labor market needs are fulfilled. There are even more differences between what has been learnt and what is demanded. There is too much content as far as variety is concerned that is generally not demanded by companies. Other demanded knowledge and skills are not taught at all or in a scarce and an insufficient way. This research invite engineering educators and businesses to collaborate redefining skills, competencies and knowledge correctly by transforming the degree’s academic plans.

Foot bones have been shown to be sexually dimorphic and they are frequently used for sex estimation. In this study, we estimated the sex based on the calcaneus and the talus of a modern North American population obtained from the Hamann-Todd Osteological Collection, housed at the Cleveland Museum of Natural History (Ohio, USA). A total of 164 calcanei (84 males and 80 females) and 162 tali (83 males and 79 females) were studied. Several univariate discriminant functions were obtained, with accuracy ranging from 70.2 to 90.2%. The best variable for sex estimation in this sample is the talar length. Multivariate discriminant functions were also obtained. The accuracy (83.3 to 96.4%) was generally higher than that obtained with the univariate discriminant functions. The best multivariate equation is the one that uses all the variables measured in the talus. Discriminant functions previously reported in other studies were tested on the Hamann-Todd collection to verify their validity outside the population for which they were made. In addition, together with the equations reported here, they were applied on data from fossil remains belonging to three different groups (Homo neanderthalensis, hominins from the Sima de los Huesos, and anatomically modern Homo sapiens) in order to find some discriminant functions that allow for a valid determination of sex in this type of fossil populations. Several equations yielded good correct allocation percentages in fossil populations thus facilitating the estimation of sex for 16 fossil specimens of previously unknown sex.

Disturbed intestinal epithelial barrier and mucosal micro-inflammation characterize irritable bowel syndrome (IBS). Despite intensive research demonstrating ovarian hormones modulation of IBS severity, there is still limited knowledge on the mechanisms underlying female predominance in this disorder. Our aim was to identify molecular pathways involved in epithelial barrier dysfunction and female predominance in diarrhea-predominant IBS (IBS-D) patients. Total RNA and protein were obtained from jejunal mucosal biopsies from healthy controls and IBS-D patients meeting the Rome III criteria. IBS severity was recorded based on validated questionnaires. Gene and protein expression profiles were obtained and data integrated to explore biological and molecular functions. Results were validated by western blot. Tight junction signaling, mitochondrial dysfunction, regulation of actin-based motility by Rho, and cytoskeleton signaling were differentially expressed in IBS-D. Decreased TESK1-dependent cofilin 1 phosphorylation (pCFL1) was confirmed in IBS-D, which negatively correlated with bowel movements only in female participants. In conclusion, deregulation of cytoskeleton dynamics through TESK1/CFL1 pathway underlies epithelial intestinal dysfunction in the small bowel mucosa of IBS-D, particularly in female patients. Further understanding of the mechanisms involving sex-mediated regulation of mucosal epithelial integrity may have significant preventive, diagnostic, and therapeutic implications for IBS.

The results of using HbA1C-based criteria for diagnosis of type 2 diabetes and prediabetes have been reported to differ from those obtained using fasting plasma glucose (FPG) or an oral glucose tolerance test (OGTT). We aimed to determine whether these discrepancies might be due to the influence of the glycation gap.For 430 patients without previously diagnosed diabetes for whom an OGTT had been requested in normal clinical practice, FPG, fructosamine and HbA1C were measured at the time of the test and again 1 month later. Glycaemia/diabetes status was classified as normoglycaemia, prediabetes or diabetes using both HbA1C-based and FPG/OGTT-based criteria, and their glycation gaps GG were calculated.The specificity of an HbA1C level of 6.5 % (48 mmol/mol) for diagnosis of FPG/OGTT-defined type 2 diabetes was 99 %, but its sensitivity was less than 37 %. HbA1C-diabetic patients had higher average blood glucose levels than FPG/OGTT-diabetic patients. With either set of criteria, high-GG patients were disproportionately numerous among those classified as diabetic and were disproportionately infrequent among those classified as normoglycaemic, but the effect was greater for the HbA1C criteria.The differences between HbA1C-based and FPG/OGTT-based diagnoses are largely due to the influence of the glycation gap, which may also influence the early stages of FPG/OGTT-defined diabetes.

The heterogeneity of patients meeting American College of Rheumatology (ACR) criteria for a diagnosis of fibromyalgia (FM) challenges our ability to understand the underlying pathogenesis and to optimize treatment of this enigmatic disorder. Our goal was to discern clinically relevant subgroups across multiple psychological and biomedical domains to better characterize the phenomenology of FM. Women meeting 1990 ACR criteria for FM (N = 107) underwent psychological (childhood trauma, mood, anxiety, and stress) and biomedical (neuroendocrine, immune, and metabolic) testing. Cluster analysis identified four distinct subgroups. Subgroups I, II, and III exhibited profiles that included high psychological distress. Subgroup I was further distinguished by a history of childhood maltreatment and hypocortisolism, and these women reported the most pain and disability. Subgroup II evinced more physiological dysregulation and also reported high levels of pain, fatigue, and disability. Subgroup III was characterized by normal biomarkers and reported intermediate pain severity with higher global functioning. Subgroup IV was distinguished by their psychological well-being, reporting less disability and pain. Our findings underscore the heterogeneity of both psychological and physiological features among FM patients presenting with nearly identical tender point counts. This subgroup categorization is compatible with hypothesized pathogenetic mechanisms of early trauma, stress system dysregulation, and pro-inflammatory bias, each prominent in some but not all FM patients. Appreciation of distinct FM subgroup features is invaluable for selecting the most appropriate treatment modalities.

9 páginas, 4 figuras, 1 tabla.-- El pdf del artículo es la versión pre-print.-- et al., The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement., This study was supported by Ministério da Saúde (Project N8 15/2007) and Liga Portuguesa Contra o Cancro. IPATIMUP was funded by Fundaçáo para a Ciência e Tecnologia, through POCI (Programa Operacional Ciència e Inovaçáo 2010). MT and WDF are supported by the Susan G. Komen Foundation for the Cure, the Jewish General Hospital Weekend to End Breast Cancer and the Fonds de la Recherche en Santé du Québec. EAV and MD are supported by grants PI061102 (Ministerio de Ciencia e Innovación) and 200820I135 (CSIC).

PIK3CA mutations at 9 and 20 exons were studied in a series of 56 selected aggressive breast carcinomas (BC): 27 with Her-2 over-expression and negativity for estrogen receptors (ER) and progesterone receptors (PR), and 29 "triple negative" BC (negative for ER, PR and Her-2). Also, immunohistochemical studies of p53, ki-67, Her-1 (EGFR), pIGF-1R, PTEN, p110alpha, and pAkt were performed. Six mutations in exon 20 PIK3CA were identified among the 27 Her-2 positive BC, whereas only one exon 9 PIK3CA mutation was detected in a triple negative tumor (p = 0.035). Furthermore, PIK3CA mutations were associated with p110alpha over-expression (p = 0.001). Overall survival was shorter in cases with PIK3CA mutations (p = 0.015 in all series; and p = 0.041 for Her-2+ tumors), although multivariate analyses did not show statistical differences. No statistical significance was related with disease-free survival. Exon 20 PIK3CA mutations are relatively frequent in Her-2+ tumors and shorten survival, whereas neither exons 9 and 20 mutations seem related with "triple negative" breast carcinomas.

Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30-60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10-12 and exons 15-16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15-16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases.

Single-species toxicity tests are currently used as main tools for assessing effects in ecological risk assessments. Nevertheless, in higher-tier evaluations, alternative ecotoxicological methods can be required. Alternative methods should cover more realistic exposure conditions and/or additional species or endpoints. Water/sediment systems can be considered for covering additional exposure routes. A typical feature of water/sediment systems is the modification of exposure levels with time. The simultaneous exposure of different species within the same system can cover differences in sensitivity and relevance of exposure routes. The aim of this study was to develop a water/sediment test that could detect relevant effects on two selected species and explore the relevance of sediment and waterborne exposure routes. This alternative method may provide relevant information facilitating the design of microcosm and mesocosm studies. A multi-species water/sediment system was designed using two invertebrates: Chironomus prasinus a benthic detritivore invertebrate and Daphnia magna a pelagic filtering invertebrate was designed. Seven static water/sediments systems were built up: two controls and five treatments where sediments were spiked with NaPCP at nominal concentrations of 1.25, 2.5, 5, 10 and 20 mg/kg, respectively. Each system contained caged and free (unrestrained) Daphnia magna organisms to consider differences in the exposure route (through sediment and/or water column) and Chironomus prasinus organisms. Fate and partitioning of PCP within the water/sediment compartments were assessed. Acute (lethality) and chronic effects (reproduction) for Daphnia magna were monitored after 48 h and 16 days of exposure, respectively. Adult emergence and oviposition success of Chironomus prasinus were monitored at the end of test (16 days). Mortality and reproduction inhibition of Daphnia magna occurred at the two higher doses, corresponding to maximum measured PCP water concentrations of 1.95 and 0.746 mg/l, respectively. Chironomus prasinus was less sensitive to PCP than Daphnia magna. Concentrations inhibiting reproduction and provoking almost 100% adult mortality in D. magna only reduced slightly the emergence and reproduction of chironomids. The experimental design focussed on suitability of the system for assessing simultaneously assessing effects on D. magna and C. prasinus instead of calculations of toxicity endpoints for PCP. The results indicate that this experimental design can be useful to the field of sediment/aquatic toxicity testing, particularly through the comparison with single- species results. Assessment of relative contribution of two exposure routes for Daphnia magna and complementary chronic endpoints derived from two different species can be achieved. Another advantage is that differences in reproduction strategies of selected species (sexual vs. parthenogenetic) should permit one to detect mechanisms of action associated to with endocrine disrupters. The feasibility of a two-species test built-up in an artificial sediment/water system has been demonstrated. This experimental design represents a cost/effective test which can assess effects through water and sediment pathways and incorporates several relevant chronic endpoints in a single assay. By building on the experience gained, improvements for further test designs are discussed. Test validation with a set of model chemicals will contribute to address the effectiveness of the test developed as comparing compared to single- species tests.

International audience; Porcine epidemic diarrhea virus (PEDV) spread rapidly after being diagnosed in the USA in April 2013. In this study we assessed whether PEDV could become airborne and if so, whether the virus was infectious. Air samples were collected both from a room containing experimentally infected pigs and at various distances from the outside of swine farms experiencing acute PEDV outbreaks. Results indicated presence of infectious PEDV in the air from experimentally infected pigs and genetic material of PEDV was detected up to 10 miles downwind from naturally infected farms. Airborne transmission should be considered as a potential route for PEDV dissemination.

Microglandular adenosis is a very uncommon benign proliferative disorder of the breast that may mimic tubular carcinoma radiologically and pathologically. We describe the radiological features of this rare condition in a patient with BRCA 1 mutation. To our knowledge, this is the first case of microglandular adenosis reported in the radiology literature. The relationship between microglandular adenosis and malignancy and the association between BRCA 1 and proliferative benign disorders are also discussed.