The role of nitric oxide in the gastrointestinal tract

Nitric oxide (NO) is an important second messenger involved in the regulation of a multitude of mechanisms in the body, such as neurotransmission, smooth muscle contractility, host defense and immune regulation. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic disorders affecting the gastrointestinal (GI) tract with unknown etiology. These diseases are characterized by increased NO levels in the gut lumen, aberrant leukocyte recruitment to the inflamed tissue and changed motility pattern of the intestines. This thesis aimed to investigate NO’s involvement in inflammatory reactions as well as its regulatory role on motility in the GI tract by studying NO-related gene expression in IBD, α2 integrin antibody treatment in comparison to conventional IBD drugs in experimental colitis, neuropeptide S (NPS) effects on motility, contractility and inflammation, as well as NO’s regulation of the migrating motor complex (MMC) in relation to muscarinic and 5-HT3 receptor blockade. Cluster analysis of NO-related gene expression in CD and UC revealed common pathophysiological processes, with hypoxia-inducible factor 1 (HIF-1) as a central regulator of inflammation, angiogenesis and tissue fibrosis. Moreover, interaction analysis pinpointed the association of upregulated expression of IL-8 and ICAM-1 in both diseases, highlighting an exaggerated leukocyte infiltration in the pathophysiology of CD and UC. In comparison to conventional IBD drugs, treatment with a function-blocking anti-α2 antibody by rectal administration showed alleviation of signs of colitis, such as reduced body weight loss, rectal bleeding, inflammation score and inflammatory biomarker expression including inducible NO synthase (iNOS). Although treatment with methotrexate also showed several signs of ameliorated colitis, these effects were not accompanied by a broad reduction in inflammatory marker expression. This study provides evidence for therapeutic use of integrin α2β1 as a novel drug target for treatment of IBD. Infusion with NPS prolonged the MMC cycle length and the phase III duration in upper small intestine. Contractility studies on excised human muscle strips revealed a dampening of the amplitude, with NPS acting directly on small intestine circular muscle, while this effect seems mediated by prejunctional receptors in colon. These effects of NPS on motility and contractility are in agreement with the changes seen during inflammatory reactions in the intestine. Moreover, NPS induced the expression of inflammatory markers iNOS, IL-1β and CXCL1, further supporting a role of NPS in NO-dependent induction of inflammation in the GI tract. Studies with the NOS inhibitor L-NMMA suggested marked effects of NO on motility. L-NMMA, shown to inhibit NO, initiated phase III MMC activity, while additional muscarinic and 5-HT3 receptor blockades revealed that the transition from phase I to phase II activity seem regulated as a balance between inhibitory nitrergic and excitatory cholinergic and serotonergic pathways. These results demonstrate increased iNOS expression during inflammatory reactions in the GI tract, with the resulting increase of NO as a pathophysiological inhibitor of motility seen in inflammatory disorders of the GI tract

Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson\u27s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells

Применение программного комплекса ANSYS CFX для моделирования движения газового потока ротационной печи

Материалы XIII Междунар. науч.-техн. конф. студентов, магистрантов и молодых ученых, Гомель, 25–26 апр. 2013 г

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Measurement properties of tools used to assess depression in adults with and without Autism Spectrum Conditions: a systematic review

Depression is the most commonly experienced mental health condition in adults with Autism Spectrum Conditions (ASC). However, it is unclear what tools are currently being used to assess depression in ASC, or whether tools need to be adapted for this group. This systematic review therefore aimed to identify tools used to assess depression in adults with and without ASC, and then evaluate these tools for their appropriateness and measurement properties. Medline, PsychINFO and Web of Knowledge were searched for studies of depression in: a) adults with ASC, without co-morbid intellectual disability; and b) adults from the general population without co-morbid conditions. Articles examining the measurement properties of these tools were then searched for using a methodological filter in PubMed, and the quality of the evidence was evaluated using the COSMIN checklist. Twelve articles were identified which utilised three tools to assess depression in adults with ASC, but only one article which assessed the measurement properties of one of these tools was identified and thus evaluated. Sixty-five articles were identified which utilised five tools to assess depression in general population adults, and 14 articles had assessed the measurement properties of these tools. Overall, two tools were found to be robust in their measurement properties in the general population – the Beck Depression Inventory (BDI-II), and the Patient Health Questionnaire (PHQ-9). Crucially only one study was identified from the COSMIN search, which showed weak evidence in support of the measurement properties of the BDI-II in an ASC sample. Implications for effective measurement of depression in ASC are discussed

Facebook som kommunikationskanal : En studie om hur Rädda Barnen uppfattas av sin målgrupp via fenomenet Facebook

Vi har förstått under åren att sociala medier har kommit att betyda mycket för privatpersoner och företag och även att sociala medier är i ständig förändring. På ett eller annat sätt handlar det om att marknadsföra sig själv. Sociala medier har blivit en ny ”reklam-kanal”, men det innebär inte för den sakens skull att det alltid är bra reklam. Företag måste ha uppsatta mål och strategier för att kunna nå det som de söker, vare sig det handlar om målgrupp, nya kunder eller att sälja en produkt