Copy number variation in bipolar disorder.

Large (>100 kb), rare (500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4))

Avaliação da resistência ao cisalhamento da união entre duas ligas a base de CoCr e uma cerâmica

INTRODUCTION: Based on the importance of the integrity of the metal/ceramic interface, the purpose of this work was to evaluate the shear bond strength of the metal-ceramic union of two Co-Cr alloys (Wirobond C, Bego; Remanium 2000, Dentaurum) combined with Omega 900 ceramic (Vita Zahnfabrik). MATERIAL and METHOD: Eleven cylindrical matrixes were made for each alloy, and the metallic portion was obtained with the lost wax casting technique with standardized waxing of 4mm of height and of 4mm of diameter. The ceramic was applied according to the manufacturer’s recommendations with the aid of a teflon matrix that allowed its dimension to be standardized in the same size as the metallic portion. The specimens were submitted to the shear bond test in an universal testing machine (EMIC), with the aid of a device developed for such intention, and constant speed of 0.5mm/min. RESULTS and CONCLUSIONS: The mean resistance was 48.387MPa for Wirobond C alloy, with standard deviation of 17.718, and 55.956MPa for Remanium 2000, with standard deviation of 17.198. No statistically significant difference was observed between the shear strength of the two metal-ceramic alloys. ______________________________________________________________________________________________________________ RESUMOINTRODUÇÃO: Baseados na importância da integridade da interface metal-cerâmica, este trabalho tem como objetivo avaliar a resistência ao cisalhamento da união metal-cerâmica de duas ligas de Co-Cr (Wirobond C, Bego; Remanium 2000, Dentaurum) combinadas com a cerâmica Omega 900 (Vita Zahnfabrik). MATERIAIS E MÉTODOS: Foram confeccionados 11 corpos-de-prova cilíndricos para cada liga utilizada, sendo que a porção metálica foi obtida por fundição pela técnica da cera perdida, através de enceramentos padronizados com 4mm de altura por 4mm de diâmetro. A aplicação da cerâmica foi realizada segundo recomendações do fabricante, com auxílio de uma matriz de teflon que permitia sua padronização com as mesmas dimensões da porção metálica. Os corpos-de-prova foram submetidos ao ensaio de resistência ao cisalhamento em máquina de ensaios universal (EMIC), com auxílio de dispositivo desenvolvido para tal propósito, sob velocidade constante de 0,5mm/ min. RESULTADOS E CONCLUSÕES: As médias de resistência obtidas foram 48,387 MPa para a liga Wirobond C, com desvio padrão de 17,718, e 55,956 MPa para a Remanium 2000, com desvio padrão de 17,198. Após análise de variância foi possível observar que não há diferença estatisticamente significante entre os valores de resistência ao cisalhamento das duas ligas metalocerâmicas

Untangling knowledge creation and knowledge integration in enterprise wikis

A central challenge organizations face is how to build, store, and maintain knowledge over time. Enterprise wikis are community-based knowledge systems situated in an organizational context. These systems have the potential to play an important role in managing knowledge within organizations, but the motivating factors that drive individuals to contribute their knowledge to these systems is not very well understood. We theorize that enterprise wiki initiatives require two separate and distinct types of knowledge-sharing behaviors to succeed: knowledge creation (KC) and knowledge integration (KI). We examine a Wiki initiative at a major German bank to untangle the motivating factors behind KC and KI. Our results suggest KC and KI are indeed two distinct behaviors, reconcile inconsistent findings from past studies on the role of motivational factors for knowledge sharing to establish shared electronic knowledge resources in organizations, and identify factors that can be leveraged to tilt behaviors in favor of KC or KI

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

360-Degree Complex Primary Reconstruction Using Porous Tantalum Cages for Adult Degenerative Spinal Deformity

Study Design: Retrospective cohort study. Objective: To assess both implant performance and the amount of correction that can be achieved using multilevel anterior lumbar interbody fusion (ALIF). Methods: Retrospective cohort study (n = 178) performed over a 4-year period. Surgical variables examined included blood loss, operative time, perioperative complications, and secondary/revision procedures. Follow-up radiographic assessment was performed to record implant-related problems. Radiographic parameters were examined pre- and postoperatively. Health-related quality of life (HRQOL) outcome measures were collected preoperatively and at 6 weeks, 6 months, 1 year, and 2 years postoperatively. Descriptive and comparative statistical analysis, using paired-sample t test and repeated-measures analysis of variance (rANOVA), was performed. Results: Lumbar lordosis increased from 42° ± 17° preoperatively to 55° ± 11° postoperatively (P < .001). The visual analog scale back pain mean score improved from 8.3 ± 1.5 preoperatively to 2.6 ± 2.4 at 2 years (P < .001). The mean Oswestry Disability Index improved from 69.5 ± 21.5 preoperatively to 19.9 ± 15.2 at 2 years (P < .001). The EQ-5D mean score improved from 0.2 ± 0.2 preoperatively to 0.8 ± 0.1 at 2 years (P = .02). There were no neurological, vascular, or visceral approach-related injuries reported. No rod breakages and no symptomatic nonunions occurred. There was one revision procedure performed for fracture. Conclusions: The use of porous tantalum cages as part of a 360-degree fusion to treat adult degenerative spinal deformity has been demonstrated to be a safe and effective strategy, leading to good clinical, functional, and radiographic outcomes in the short term

Review: The increasing importance of carbon nanotubes and nanostructured conducting polymers in biosensors

The growing need for analytical devices requiring smaller sample volumes, decreased power consumption and improved performance have been driving forces behind the rapid growth in nanomaterials research. Due to their dimensions, nanostructured materials display unique properties not traditionally observed in bulk materials. Characteristics such as increased surface area along with enhanced electrical/optical properties make them suitable for numerous applications such as nanoelectronics, photovoltaics and chemical/biological sensing. In this review we examine the potential that exists to use nanostructured materials for biosensor devices. By incorporating nanomaterials, it is possible to achieve enhanced sensitivity, improved response time and smaller size. Here we report some of the success that has been achieved in this area. Many nanoparticle and nanofibre geometries are particularly relevant, but in this paper we specifically focus on organic nanostructures, reviewing conducting polymer nanostructures and carbon nanotubes

Vaccine responses in newborns.

Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection

Impact of early life exposures to geohelminth infections on the development of vaccine immunity, allergic sensitization, and allergic inflammatory diseases in children living in tropical Ecuador: the ECUAVIDA birth cohort study.

Background Geohelminth infections are highly prevalent infectious diseases of childhood in many regions of the Tropics, and are associated with significant morbidity especially among pre-school and school-age children. There is growing concern that geohelminth infections, particularly exposures occurring during early life in utero through maternal infections or during infancy, may affect vaccine immunogenicity in populations among whom these infections are endemic. Further, the low prevalence of allergic disease in the rural Tropics has been attributed to the immune modulatory effects of these infections and there is concern that widespread use of anthelmintic treatment in high-risk groups may be associated with an increase in the prevalence of allergic diseases. Because the most widely used vaccines are administered during the first year of life and the antecedents of allergic disease are considered to occur in early childhood, the present study has been designed to investigate the impact of early exposures to geohelminths on the development of protective immunity to vaccines, allergic sensitization, and allergic disease. Methods/Design A cohort of 2,403 neonates followed up to 8 years of age. Primary exposures are infections with geohelminth parasites during the last trimester of pregnancy and the first 2 years of life. Primary study outcomes are the development of protective immunity to common childhood vaccines (i.e. rotavirus, Haemophilus influenzae type B, Hepatitis B, tetanus toxoid, and oral poliovirus type 3) during the first 5 years of life, the development of eczema by 3 years of age, the development of allergen skin test reactivity at 5 years of age, and the development of asthma at 5 and 8 years of age. Potential immunological mechanisms by which geohelminth infections may affect the study outcomes will be investigated also. Discussion The study will provide information on the potential effects of early exposures to geohelminths (during pregnancy and the first 2 years of life) on the development of vaccine immunity and allergy. The data will inform an ongoing debate of potential effects of geohelminths on child health and will contribute to policy decisions on new interventions designed to improve vaccine immunogenicity and protect against the development of allergic diseases