Antidepresivos e interacciones farmacológicas con riesgos de toxicidad serotoninérgica.

Serotonin syndrome is a potentially lethal disease caused by excessive serotonin activity at the synapses in the central and peripheral nervous system. Currently, there is an increase in the use of antidepressants in the United States, which has contributed to being one of the most frequent causes of toxicity and overdose, thus increasing the risk of serotonin syndrome. Also, there are several drugs and mechanisms involved, the most common interactions are between monoamine oxidase inhibitor antidepressants, selective serotonin receptor inhibitors, and serotonin and norepinephrine reuptake inhibitors. In general, the mechanisms in place alter the metabolism, release, and activation of serotonin receptors. The clinical manifestations are usually autonomic hyperactivity, mental alterations, and muscular hyperactivity, the degree of symptoms varies from mild, moderate, and severe; most are mild and resolve after withdrawing the medication or serotonergic drug. Meanwhile, severe cases are rare and can be complicated by hemodynamic instability, hyperthermia, rhabdomyolysis, and arrhythmias; Therefore, it requires specific treatment. Compared to other criteria, the most specific and sensitive are the Hunter criteria for serotonergic toxicity, however, this remains in dispute and subject to change in the future. Even so, there are few cases reported or recognized by health personnel. In any case, the objective of this article is to summarize the most recent information about serotonin syndrome, and provide the clinician with the skills to diagnose, treat, and know how to prevent more cases.El síndrome serotoninérgico es una enfermedad potencialmente letal, causada por una actividad excesiva de la serotonina en las sinapsis del sistema nerviosos central y periférico. En la actualidad, hay un aumento en el uso de antidepresivos por los Estados Unidos, lo cual ha contribuido a ser una de las causas más frecuentes de toxicidad y sobredosis, elevando así el riesgo de síndrome serotoninérgico. También, existen varios medicamentos y mecanismos involucrados, las interacciones más comunes son entre antidepresivos inhibidores de la monoaminooxidasa, inhibidores selectivos de receptor de serotonina, e inhibidores de recaptura de serotonina y norepinefrina. En general, los mecanismos alteran el metabolismo, liberación, y activación de receptores de serotonina. Las manifestaciones clínicas suelen ser de hiperactividad autonómica, alteraciones mentales, e hiperactividad muscular, el grado de síntomas varían desde leves, moderadas, y severas; la mayoría son leves y resuelven tras retirar el medicamento o droga serotoninérgica. Mientras tanto, los casos severos son raros y se pueden complicar con inestabilidad hemodinámica, hipertermia, rabdomiólisis, y arritmias; por lo que requiere de tratamiento específico. En comparación a otros criterios, los más específico y sensible son los criterios de Hunter por toxicidad serotoninérgica, sin embargo, esto continua en disputa y sujeto a cambios en el futuro. Aun así, son pocos los casos reportados o reconocidos por el personal de salud. En todo caso, el objetivo de este artículo es resumir la información más reciente acerca de síndrome serotoninérgico, y aportar al clínico las capacidades para diagnosticar, dar tratamiento, y conocimiento para prevenir más casos

Actualización de epidemia por opioides, y fentanilo: consecuencias y soluciones en salud publica.

La actual crisis de opioides, esta reforzada por el consumo y la mayor producción de fentanilo ilícito; su creciente mortalidad se relaciona con el abuso de múltiples sustancias como las benzodiacepinas y el alcohol. Sorprendentemente, el consumo del 95% de opioides global, es por el occidente, que compone un 15% de la población mundial. Incluso, el fentanilo es un opioide sintético, lipofílico de acción corta, con mayor potencia analgésica que la morfina. Además, la adulteración de otras drogas ilícitas con fentanilo y sus análogos, aumentan el riesgo de sobredosis. El metabolismo del fentanilo por el citocromo P450 CYP3A4, resulta en interacciones con otros medicamentos dependientes de esta vía. Mientras, la naloxona es un antagonista del receptor opioide no competitivo, con capacidad de revertir la depresión respiratoria. Al mismo tiempo, como consecuencia aumentan los casos de endocarditis, hepatitis B, hepatitis C, HIV y otras infecciones. Los síntomas agudos de sobredosis se destacan por la depresión de centros respiratorios, y del sistema nervioso central, pupilas mióticas, y pérdida de los reflejos protectores de la vía aérea; el tratamiento consiste en el uso de naloxona y el manejo de las complicaciones. A largo plazo se deben implementar estrategias, con el fin de brindar tratamiento sustituto y de rescate, y reforzar la prevención. En todo caso, la meta de esta revisión es resumir la información más reciente acerca de las crisis de opioides, especialmente fentanilo, y brindar a los clínicos la capacidad de diagnosticar, tratar, la prevención al formar parte de las nuevas estrategias

Band structure, superconductivity and polytypism in AuSn4_4

The orthorhombic compound AuSn4 is compositionally similar to the Dirac node arc semimetal PtSn$_4$. AuSn$_4$ is, contrary to PtSn$_4$, superconducting with a critical temperature of T$_c$ = 2.35 K. Recent measurements present indications for quasi two-dimensional superconducting behavior in AuSn$_4$. Here we present measurements of the superconducting density of states and the band structure of AuSn$_4$ through Scanning Tunneling Microscopy (STM) and Angular Resolved Photoemission Spectroscopy (ARPES). The superconducting gap values in different portions of the Fermi surface are spread around {\Delta}0 = 0.4 meV, which is close to but somewhat larger than $\Delta =$ 1.76kBT$_c$ expected from BCS theory. We observe superconducting features in the tunneling conductance at the surface up to temperatures about 20% larger than bulk Tc. The band structure calculated with Density Functional Theory (DFT) follows well the results of ARPES. The crystal structure presents two possible stackings of Sn layers, giving two nearly degenerate polytypes. This makes AuSn$_4$ a rather unique case with a three dimensional electronic band structure but properties ressembling those of low dimensional layered compounds

Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls

We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD. © 2013 Liu et al

Location analysis for the estrogen receptor-α reveals binding to diverse ERE sequences and widespread binding within repetitive DNA elements

Location analysis for estrogen receptor-α (ERα)-bound cis-regulatory elements was determined in MCF7 cells using chromatin immunoprecipitation (ChIP)-on-chip. Here, we present the estrogen response element (ERE) sequences that were identified at ERα-bound loci and quantify the incidence of ERE sequences under two stringencies of detection: <10% and 10–20% nucleotide deviation from the canonical ERE sequence. We demonstrate that ∼50% of all ERα-bound loci do not have a discernable ERE and show that most ERα-bound EREs are not perfect consensus EREs. Approximately one-third of all ERα-bound ERE sequences reside within repetitive DNA sequences, most commonly of the AluS family. In addition, the 3-bp spacer between the inverted ERE half-sites, rather than being random nucleotides, is C(A/T)G-enriched at bona fide receptor targets. Diverse ERα-bound loci were validated using electrophoretic mobility shift assay and ChIP-polymerase chain reaction (PCR). The functional significance of receptor-bound loci was demonstrated using luciferase reporter assays which proved that repetitive element ERE sequences contribute to enhancer function. ChIP-PCR demonstrated estrogen-dependent recruitment of the coactivator SRC3 to these loci in vivo. Our data demonstrate that ERα binds to widely variant EREs with less sequence specificity than had previously been suspected and that binding at repetitive and nonrepetitive genomic targets is favored by specific trinucleotide spacers

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors

Why helping coworkers does not always make you poor:the contingent role of common and unique position within the sales team

In recent years, many companies have implemented sales teams as a way of streamlining accountability and promoting the development of sales expertise. The success of such work groups largely depends on experienced members' willingness to help coworkers. Previous studies indicate that group structure and individual position along individual attributes (e.g., experience) are important to understand interactions between coworkers. However, sales research on this topic is lacking. Drawing on a motivation-opportunity-ability framework, this study addresses this void by examining the impact of individual salesperson's job experience position within work groups on the motivation to help coworkers and his or her own sales performance. The findings of a multisource, multilevel empirical study reveal interesting effects. The results highlight the important role of job experience position: if a salesperson's level of job experience is common within the sales team, it activates identification as a driver of helping behaviors, which in turn negatively influences own performance. Conversely, if a salesperson's level of job experience is unique, it does not activate identification as a driver of helping, but does positively influence the effect of helping on own performance. The authors discuss implications for theory and practice

Product and process innovation in manufacturing firms: a 30-year bibliometric analysis

Built upon a thirty-year dataset collected from the Web of Science database, the present research aims to offer a comprehensive overview of papers, authors, streams of research, and the most influential journals that discuss product and process innovation in the manufacturing environment. The dataset is composed of 418 papers from more than 150 journals from the period between 1985 and 2015. Homogeneity analysis by means of alternating least squares (HOMALS) and Social Network Analysis (SNA) are used to accomplish the objectives listed above through the keywords given by authors. Initially, the paper highlights and discusses the similarity between the topics debated by the main journals in this field. Subsequently, a wide-range map of topics is presented highlighting five main areas of interests; namely, performance, patent, small firm, product development, and organization. A SNA is also performed in order to validate the results that emerged from HOMALS. Finally, several insights about future research avenues in the manufacturing field are provided

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research