Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, represent- ing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated posi- tions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular path- ways associated with aetiological variation in complex disease

Evaluation of a strict protocol approach in managing women with severe disease due to abortion

No  Abstract

Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota

Background: The soil-transmitted helminth (STH), Trichuris trichiura colonises the human large intestine where it may modify inflammatory responses, an effect possibly mediated through alterations in the intestinal microbiota. We hypothesised that patent T. trichiura infections would be associated with altered faecal microbiota and that anthelmintic treatment would induce a microbiota resembling more closely that observed in uninfected individuals. Materials and Methods: School children in Ecuador were screened for STH infections and allocated to 3 groups: uninfected, T. trichiura only, and mixed infections with T. trichiura and Ascaris lumbricoides. A sample of uninfected children and those with T. trichiura infections only were given anthelmintic treatment. Bacterial community profiles in faecal samples were studied by 454 pyrosequencing of 16 S rRNA genes. Results: Microbiota analyses of faeces were done for 97 children: 30 were uninfected, 17 were infected with T. trichiura, and 50 with T. trichiura and A. lumbricoides. Post-treatment samples were analyzed for 14 children initially infected with T. trichiura alone and for 21 uninfected children. Treatment resulted in 100% cure of STH infections. Comparisons of the microbiota at different taxonomic levels showed no statistically significant differences in composition between uninfected children and those with T. trichiura infections. We observed a decreased proportional abundance of a few bacterial genera from the Clostridia class of Firmicutes and a reduced bacterial diversity among children with mixed infections compared to the other two groups, indicating a possible specific effect of A. lumbricoides infection. Anthelmintic treatment of children with T. trichiura did not alter faecal microbiota composition. Discussion: Our data indicate that patent human infections with T. trichiura may have no effect on faecal microbiota but that A. lumbricoides colonisation might be associated with a disturbed microbiota. Our results also catalogue the microbiota of rural Ecuadorians and indicate differences with individuals from more urban industrialised societies

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Identidad étnica y redes personales entre jóvenes de Sarajevo

After fieldwork conducted among young people in Sarajevo, we found a relation between the discourses sustained by them and the ethnic categories they use to classify people and to identify themselves. Also we have found that people self-affiliated as "Bosnians" play an important role in the network of multiethnic relationships, in which strong ties, surprisingly, are still very important. Finally we found a relationship between the composition of personal networks and the ethnic discourses that are maintained.Después de un trabajo de campo realizado con un grupo de jóvenes en Sarajevo, hemos constatado la existencia de una relación entre los discursos que sostienen y las categorías étnicas que utilizan tanto para clasificar a los demás como para auto-identificarse. Asimismo hemos encontrado que los jóvenes que se autodenominan "Bosnios" juegan un rol importante en la red de relaciones multiétnicas, en la que los lazos fuertes, sorprendentemente, son muy importantes. Finalmente hemos hallado una relación entre la composición de las redes personales y los discursos étnicos que se sostienen. Vivimos, o creemos vivir, en múltiples "comunidades", imaginadas o no. Al mismo tiempo, el individuo y no el lugar, la familia o el grupo, se sitúa en el centro de la vida social y de las comunicaciones (Cf. Wellman, 2001). En este contexto, inducido por el avance del capitalismo flexible (Castells, 1996), pensamos que para entender adecuadamente la identidad o identidades postuladas por los individuos es necesario estudiar las redes personales y su dinámica. Desde esta perspectiva no podemos hablar de "etnias" o "multietnicidad" sin más precisiones, pues son conceptos basados en una concepción esencialista y estática de la identidad individual. El concepto de "sociedad multiétnica" es utilizado de una manera engañosamente progresista y objetiva, pues lo que en realidad legitima es la existencia de diferencias esenciales entre personas, alejando en lugar de acercar. Sin embargo, somos plenamente conscientes que los discursos esencialistas de la identidad étnica son omnipresentes, con enormes efectos políticos e individuales. Que planteemos que la concepción esencialista de la identidad sea inapropiada desde un punto de vista académico, no significa que ésta no se utilice políticamente y por lo tanto tenga consecuencias formidables en las relaciones sociales. Precisamente el estudio de las redes personales nos permite situarnos en una perspectiva que no utiliza con pretensiones analíticas conceptos "folk", como son los de "etnia", "pueblo" o "nación", sino que los sitúa en el terreno de los discursos sustentados por los actores (y los estados y medios de comunicación) y nos permite contextualizarlos mediante conceptos etic, es decir, impuestos por los investigadores. Sólo así podemos superar las tautologías que abundan en los discursos étnicos

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Intensive removal of signal crayfish (Pacifastacus leniusculus) from rivers increases numbers and taxon richness of macroinvertebrate species

Invasive species are a major cause of species extinction in freshwater ecosystems, and crayfish species are particularly pervasive. The invasive American signal crayfish Pacifastacus leniusculus has impacts over a range of trophic levels, but particularly on benthic aquatic macroinvertebrates. Our study examined the effect on the macroinvertebrate community of removal trapping of signal crayfish from UK rivers. Crayfish were intensively trapped and removed from two tributaries of the River Thames to test the hypothesis that lowering signal crayfish densities would result in increases in macroinvertebrate numbers and taxon richness. We removed 6181 crayfish over four sessions, resulting in crayfish densities that decreased toward the center of the removal sections. Conversely in control sections (where crayfish were trapped and returned), crayfish density increased toward the center of the section. Macroinvertebrate numbers and taxon richness were inversely correlated with crayfish densities. Multivariate analysis of the abundance of each taxon yielded similar results and indicated that crayfish removals had positive impacts on macroinvertebrate numbers and taxon richness but did not alter the composition of the wider macroinvertebrate community. Synthesis and applications: Our results demonstrate that non‐eradication‐oriented crayfish removal programmes may lead to increases in the total number of macroinvertebrates living in the benthos. This represents the first evidence that removing signal crayfish from riparian systems, at intensities feasible during control attempts or commercial crayfishing, may be beneficial for a range of sympatric aquatic macroinvertebrates

High prevalence of trypanosomes in European badgers detected using ITS-PCR.

BACKGROUND: Wildlife can be important sources and reservoirs for pathogens. Trypanosome infections are common in many mammalian species, and are pathogenic in some. Molecular detection tools were used to measure trypanosome prevalence in a well-studied population of wild European badgers (Meles meles). FINDINGS: A nested ITS-PCR system, that targeted the ribosomal RNA gene locus, has been widely used to detect pathogenic human and animal trypanosomes in domestic animals in Africa and some wildlife hosts. Samples from a long-term DEFRA funded capture-mark-recapture study of wild badgers at Woodchester Park (Gloucestershire, SW England) were investigated for trypanosome prevalence. A total of 82 badger blood samples were examined by nested ITS-PCR. Twenty-nine of the samples were found to be positive for trypanosomes giving a prevalence of 35.4 % (25.9 % - 46.2 %; 95 % CI). Infection was not found to be linked to badger condition, sex or age. Analysis of DNA sequence data showed the badgers to be infected with Trypanosoma (Megatrypanum) pestanai and phylogenetic analysis showed the Woodchester badger trypanosomes and T. pestanai to cluster in the Megatrypanum clade. CONCLUSIONS: The results show that the ITS Nested PCR is an effective tool for diagnosing trypanosome infection in badgers and suggests that it could be widely used in wildlife species with unknown trypanosomes or mixed infections. The relatively high prevalence observed in these badgers raises the possibility that a significant proportion of UK badgers are naturally infected with trypanosomes

Telephone follow-up of patients after radical prostatectomy : a systematic review

Objective: to assess and summarize the best scientific evidence from randomized controlled clinical trials about telephone follow-up of patients after radical prostatectomy, based on information about how the phone calls are made and the clinical and psychological effects for the individuals who received this intervention. Method: the search was undertaken in the electronic databases Medline, Web of Science, Embase, Cinahl, Lilacs and Cochrane. Among the 368 references found, five were selected. Results: two studies tested interventions focused on psychological support and three tested interventions focused on the physical effects of treatment. The psychoeducative intervention to manage the uncertainty about the disease and the treatment revealed statistically significant evidences and reduced the level of uncertainty and anguish it causes. Conclusion: the beneficial effects of telephone follow-up could be determined, as a useful tool for the monitoring of post-prostatectomy patients.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)