Dietary vitamin D improves performance and bone mineralisation, but increases parasite replication and compromises gut health in Eimeria infected broilers

Coccidial infections may reduce fat soluble vitamin status and bone mineralisation in broiler chickens. We hypothesised that broilers infected with Eimeria maxima would benefit from increased dietary supplementation with vitamin D (vitD) or with 25-OH-D3 (25D3). Male Ross 308 chickens were assigned to diets with low (L) or commercial (M) vitD levels (1000 vs 4000 IU/kg) supplemented as D3 or 25D3. At d11 of age birds were inoculated with water (C) or 7000 E. maxima oocysts (I). Pen performance was calculated over the early (d1 - 6), acute (d7 - 10) and recovery periods (d11 - 14) post-infection (pi). At the end of each period 6 birds per treatment were dissected to assess long bone mineralisation, plasma levels of 25D3, calcium and phosphorus, and intestinal histomorphometry. Parasite replication and transcription of cytokines IL-10 and IFN-γ were assessed at d6 pi using quantitative PCR. Performance, bone mineralisation and plasma 25D3 levels were significantly reduced during infection (P < 0.05). M diets or diets with 25D3 raised plasma 25D3, improved performance and aspects of mineralisation (P < 0.05). Offering L diets compromised feed efficiency pi, reduced femur breaking strength and plasma phosphorous levels at d10 pi in I birds (P < 0.05). Contrastingly, offering M diets or diets with 25D3 resulted in higher parasite loads (P < 0.001) and reduced jejunal villi length at d10 pi (P < 0.01), with no effect on IL-10 or IFN-γ transcription. Diets with 4000 IU/kg vitD content or with 25D3 improved performance and mineralisation, irrespective of infection status, whilst 4000 IU/kg levels of vitD further improved feed efficiency and mineralisation in the presence of a coccidial infection

Multimodal Analgesia in Orthopaedic Surgery and Presentation of a Comprehensive Postoperative Pain Protocol: A Review

Rising opioid use in the United States has now been termed an epidemic. Opioid use is associated with considerable morbidity, mortality, and cost to the healthcare system. Orthopaedic surgeons play a key role in the opioid epidemic by prescribing postoperative narcotics. Although our understanding of the quantity of narcotics to prescribe postoperatively for analgesia is progressing, there is still a paucity of data focused on routine postoperative pain protocols. The purpose of this article is to review the current options for both opioid and non-opioid analgesia and put forth a multisubspecialty orthopaedic protocol of postoperative pain. On the basis of study findings and the individual experiences of surgeons within our orthopaedic department, our comprehensive pain protocol includes the following considerations: use of non-steroidal antiinflammatory drugs on an individual basis, limited use of benzodiazepines, use of diazepam in only pediatric patients undergoing major procedures, lower doses of gabapentin after hip and knee arthroplasty, higher doses of gabapentin after spine procedures, general use of oxycodone owing to its accessibility, use of isolated opioids rather than combined forms, and close collaboration with anesthesiologists for determining use of peripheral nerve block. Our resultant comprehensive pain protocol can provide orthopaedic surgeons with a framework to build upon, which will benefit greatly from future studies that examine narcotic use with specific procedures

Brief communication: Strengthening coherence between climate change adaptation and disaster risk reduction

Reducing disaster risks and adapting to climate change are ever more important policy goals in Europe and worldwide. The commitment to the 2030 Agenda for Sustainable Development and complementary multilateral frameworks, including the Sendai Framework for Disaster Risk Reduction 2015–2030 and the Paris Agreement on Climate Change, has galvanized pursuits for policy coherence. The report Climate change adaptation and disaster risk reduction in Europe: enhancing coherence of the knowledge base, policies and practices of the European Environment Agency identified several ways for how coherence and resilience can be built through knowledge sharing, collaboration and investments.</p

Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

The Transcriptome of Human Epicardial, Mediastinal and Subcutaneous Adipose Tissues in Men with Coronary Artery Disease

The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases.Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects.Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD

MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana

In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2+/+ but not from MKP-2−/− mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2−/− macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE2 production. However surprisingly, in MKP-2−/− macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2−/− mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2−/− T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2−/− bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage

Choline transporter gene variation is associated with attention-deficit hyperactivity disorder

The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes