118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

<p>Abstract</p> <p>Background</p> <p>Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.</p> <p>Methods</p> <p>Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983–86 or 1994–95. It also included 214 infants with conotruncal heart defects born during 1983–86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.</p> <p>Results</p> <p>Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: <it>BHMT </it>(rs3733890) OR = 1.8 (1.1–3.1), <it>CBS </it>(rs2851391) OR = 2.0 (1.2–3.1); <it>CBS </it>(rs234713) OR = 2.9 (1.3–6.7); <it>MTHFD1 </it>(rs2236224) OR = 1.7 (1.1–2.7); <it>MTHFD1 </it>(hcv11462908) OR = 0.2 (0–0.9); <it>MTHFD2 </it>(rs702465) OR = 0.6 (0.4–0.9); <it>MTHFD2 </it>(rs7571842) OR = 0.6 (0.4–0.9); <it>MTHFR </it>(rs1801133) OR = 2.0 (1.2–3.1); <it>MTRR </it>(rs162036) OR = 3.0 (1.5–5.9); <it>MTRR </it>(rs10380) OR = 3.4 (1.6–7.1); <it>MTRR </it>(rs1801394) OR = 0.7 (0.5–0.9); <it>MTRR </it>(rs9332) OR = 2.7 (1.3–5.3); <it>TYMS </it>(rs2847149) OR = 2.2 (1.4–3.5); <it>TYMS </it>(rs1001761) OR = 2.4 (1.5–3.8); and <it>TYMS </it>(rs502396) OR = 2.1 (1.3–3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with <it>TYMS</it>, <it>MTHFR</it>, <it>BHMT </it>and <it>MTR </it>for spina bifida.</p> <p>Conclusion</p> <p>Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.</p

Stromal IFN-γR-Signaling Modulates Goblet Cell Function During Salmonella Typhimurium Infection

Enteropathogenic bacteria are a frequent cause of diarrhea worldwide. The mucosal defenses against infection are not completely understood. We have used the streptomycin mouse model for Salmonella Typhimurium diarrhea to analyze the role of interferon gamma receptor (IFN-γR)-signaling in mucosal defense. IFN-γ is known to contribute to acute S. Typhimurium diarrhea. We have compared the acute mucosal inflammation in IFN-γR-/- mice and wild type animals. IFN-γR-/- mice harbored increased pathogen loads in the mucosal epithelium and the lamina propria. Surprisingly, the epithelium of the IFN-γR-/- mice did not show the dramatic “loss” of mucus-filled goblet cell vacuoles, a hallmark of the wild type mucosal infection. Using bone marrow chimeric mice we established that IFN-γR-signaling in stromal cells (e.g. goblet cells, enterocytes) controlled mucus excretion/vacuole loss by goblet cells. In contrast, IFN-γR-signaling in bone marrow-derived cells (e.g. macrophages, DCs, PMNs) was required for restricting pathogen growth in the gut tissue. Thus IFN-γR-signaling influences different mucosal responses to infection, including not only pathogen restriction in the lamina propria, but, as shown here, also goblet cell function

Unfolding Simulations of Holomyoglobin from Four Mammals: Identification of Intermediates and β-Sheet Formation from Partially Unfolded States

Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ~1.48-1.51 nm, helicity ~75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0-3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2-11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce

Achieving the "triple aim" for inborn errors of metabolism: a review of challenges to outcomes research and presentation of a new practice-based evidence framework

Across all areas of health care, decision makers are in pursuit of what Berwick and colleagues have called the “triple aim”: improving patient experiences with care, improving health outcomes, and managing health system impacts. This is challenging in a rare disease context, as exemplified by inborn errors of metabolism. There is a need for evaluative outcomes research to support effective and appropriate care for inborn errors of metabolism. We suggest that such research should consider interventions at both the level of the health system (e.g., early detection through newborn screening, programs to provide access to treatments) and the level of individual patient care (e.g., orphan drugs, medical foods). We have developed a practice- based evidence framework to guide outcomes research for inborn errors of metabolism. Focusing on outcomes across the triple aim, this framework integrates three priority themes: tailoring care in the context of clinical heterogeneity; a shift from “urgent care” to “opportunity for improvement”; and the need to evaluate the comparative effectiveness of emerging and established therapies. Guided by the framework, a new Canadian research network has been established to generate knowledge that will inform the design and delivery of health services for patients with inborn errors of metabolism and other rare diseases.This work was supported by a CIHR Emerging Team Grant (“Emerging team in rare diseases: acheiving the ‘triple aim’ for inborn errors of metabolism,” B.K. Potter, P. Chakraborty, and colleagues, 2012– 2017, grant no. TR3–119195). Current investigators and collaborators in the Canadian Inherited Metabolic Diseases Research Network are: B.K. Potter, P. Chakraborty, J. Kronick, D. Coyle, K. Wilson, M. Brownell, R. Casey, A. Chan, S. Dyack, L. Dodds, A. Feigenbaum, D. Fell, M. Geraghty, C. Greenberg, S. Grosse, A. Guttmann, A. Khan, J. Little, B. Maranda, J. MacKenzie, A. Mhanni, F. Miller, G. Mitchell, J. Mitchell, M. Nakhla, M. Potter, C. Prasad, K. Siriwardena, K.N. Speechley, S. Stocker, L. Turner, H. Vallance, and B.J. Wilson. Members of our external advisory board are D. Bidulka, T. Caulfield, J.T.R. Clarke, C. Doiron, K. El Emam, J. Evans, A. Kemper, W. McCormack, and A. Stephenson Julian. J. Little is supported by a Canada Research Chair in Human Genome Epidemiology. K. Wilson is supported by a Canada Research Chair in Public Health Policy

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells