Superior mesenteric artery is more important than inferior mesenteric artery in maintaining colonic mucosal perfusion and integrity in rats

Mucosal hemodynamics (by reflectance spectrophotometry) and mucosal damage (by histologic examination) following acute colonic ischemia were evaluated in different anatomic locations in the colon of anesthetized rats. The reflectance spectrophotometer provides an index of mucosal hemoglobin concentration (IHB) and an index of oxygen saturation of hemoglobin (ISO₂). The patterns of ischemia without congestion (IHB, ISO₂) during superior mesenteric artery occlusion, and ischemia with congestion (IHB, ISO₂) during portal vein occlusion, previously demonstrated in the stomach and duodenum, are also applicable to the colon. The significant linear correlations between changes (as percent of baseline) in IHB, ISO₂, and hydrogen gas clearance suggest that changes in these indices are adequate indicators of changes in colonic mucosal perfusion. Superior mesenteric artery ligation produced significant reductions in both indices, and an increase in damage in the mucosa of the cecum, transverse colon, splenic flexure, and left colon, but not the rectum. Inferior mesenteric artery ligation produced only slight reduction in these indices and minimal damage only in the mucosa of the splenic flexure. These results support the hypothesis that the superior mesenteric artery is more important than the inferior mesenteric artery in maintaining colonic perfusion and colonic mucosal integrity in the rat.Supported by the American Society for Gastrointestinal Endoscopy Career Development Award (H850208, H870212), Veterans Administration Medical Research Funds; and in part by research grants (0162-01, 0162-02; 0291-01) from the Smokeless Tobacco Research Council, Inc.; and by funds provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco Related Disease Research Program of the University of California.     

Enduring effects of prenatal cocaine exposure on selective attention and reactivity to errors: evidence from an animal model

Adult Long-Evans rats, exposed prenatally to 1 of 4 doses of cocaine (0.0,0.5,1.0, or 3.0 mg/kg iv), were tested on a 3-choice visual attention task with an olfactory distractor presented unpredictably on one third of the trials. The performance of all 3 cocaine-exposed groups was significantly more disrupted than that of controls by the presentation of distractors. Results demonstrate that prenatal cocaine exposure increases susceptibility to distractors, using a task specifically designed to measure this function. In addition, the present study revealed that individuals exposed to cocaine in utero exhibit greater performance disruption after an error than controls, in certain types of tasks. Both areas of dysfunction, impaired selective attention and impaired arousal regulation, have important functional consequences in humans, possibly affecting the school performance and social development of cocaine-exposed children.     

Streptococcus pyogenes infection in mouse skin leads to a time-dependent up-regulation of protein H expression

Streptococcus pyogenes protein H (sph) is an immunoglobulin-binding protein present in the Mga regulon of certain M1 serotype isolates. Although sph is present in many strains, it is frequently not expressed. In this paper we show that protein H was highly expressed after bacteria were injected into the skin of mice and were recovered from the blood, kidney, or spleen at various times postinfection. The percentage of protein H-positive colonies increased with time, reaching 100% in the spleen and kidney within 24 to 72 h postinfection. The up-regulation of sph expression was also observed in a mga mutant.     

The role of vitamin B 12 and its transport globulins in the production of antibodies.

Immunological functions were repeatedly tested in a patient with hereditary deficiency of transcobalamin II (TC II): he was unable to synthesize immunoglobulins and specific antibodies, but was able to do so normally after injection of high doses of vitamin B 12 (1000 mug per week). Lymphocytes (B and T) were present in normal numbers prior to therapy, thus indicating normal differentiation of stem cells. In contrast, clonal expansion, necessary for immunoglobulin production, was possible only after vitamin B 12 administration. These observations, as well as the well known disturbances in haemopoiesis, indicate that vitamin B 12 is indispensable to rapidly replicating tissues, and that a severe deficiency of this vitamin in the cells can result from the absence of TC II.     

<Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> Ats1p interacts with Nap1p,a cytoplasmic protein that controls bud morphogenesis

Saccharomyces cerevisiae ATS1 (-tubulin suppressor 1) was originally identified as a high-copy suppressor of class two -tubulin mutations and was proposed to have a regulatory role in coordinating the microtubule state with the cell cycle. Here, we show that Ats1p interacts with Nap1p, a cytoplasmic protein that regulates the activity of the Cdc28p/Clb2p complex. Loss of Nap1p results in a delayed switch from polar to isotropic bud growth. The delayed switch results in elongated buds. Nap1p and Ats1p interact in two-hybrid and co-immunoprecipitation assays. Both nap1 and ats1 cells have a Clb2p-dependent elongated bud morphology. Deletion of ATS1 partially suppresses the elongated bud morphology and benomyl resistance of nap1 mutants. Our results suggest Ats1p might regulate coordination of the microtubule state with the cell cycle through an interaction with Nap1p.Communicated by S. Hohmann     

Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample.

The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675-13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required.     

Characterization of the Strain-Specific and Common Surface Antigens of Mycoplasma arginini

A combination of quantitative immunoelectrophoresis and sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis was used to determine location and molecular weights of surface membrane antigens of four strains of Mycoplasma arginini. Two major surface antigens were identified for M. arginini by absorption of antiserum with whole cells: one surface antigen was strain specific, electrophoretically fast, and prominently located on the surface, whereas the other surface antigen was common to the four strains and of intermediate electrophoretic mobility. Three of the four strains of M. arginini (G-230, 23243, and 27389) possessed immunologically strain-specific antigens which did not cross-react, whereas the leonis strain lacked an immunologically detectable unique surface antigen. A monospecific antiserum prepared against immune precipitates of the strain-specific antigen of strain G-230 detected three polypeptides of 74,000, 44,000, and 17,000 daltons in SDS-polyacrylamide gels of membrane preparations. All four strains shared the common surface antigen which appeared considerably more hydrophobic than the strain-specific surface antigen because it could only be demonstrated by charge-shift immunoelectrophoretic conditions (addition of deoxycholate to the nonionic detergent). Monospecific antiserum to the common antigen of strain G-230 reacted with all four M. arginini strains, but did not react with two other arginine-utilizing species, and recognized three polypeptides of 40,000, 29,000, and 20,000 daltons in membranes of strain G-230. Whereas the common surface antigen is a likely target for conventional serological reactions used for identification of the species M. arginini, strain-specific antigen cannot fulfill this role but must participate in other surface reactions.     

Criteria for the administration of KI for thyroid blocking of radioiodine

Scientific data are reviewed to evaluate the risks of radioiodine uptake and to compare those risks with the benefits and risks of low milligram doses of stable potassium iodide (KI). The limit of 25 rad to the thyroid due to radioiodine uptake is adopted as the "break-even" point above which 130-mg KI doses should be administered. The biological and radiological kinetics of radioiodine for protracted uptakes were derived from the Medical Internal Radiation Dose Committee (MIRD) model (MIRD75). Resulting calculations yielded estimates of dose commitment rates to the thyroid as a function of thyroidal uptake. The extrapolated value of the 1-hr inhalation curve for 131I with 30% uptake compares well with the established MPCa value and intercepts the origin. The calculated KI-blocking efficiency as a function of time after radioiodine uptake agrees well with previously reported experimental data. The prevention or "blocking" of 25 rad to the thyroid was the criterion used to define critical values of radioiodine in the thyroid. Critical values are functions of isotope, the duration of uptake and the elapsed time between inhalation and assay of thyroid content. The presence of radioiodine in the thyroid in amounts greater than the critical value indicates that more than 25 rad to the thyroid can be averted, and KI should be administered in the absence of contraindications. Critical average concentrations are implicitly defined by the method of calculation used in the derivation. Critical average concentrations are presented as criteria for KI administration when assays of the radioiodine content of the thyroid are unavailable. Illustrative applications of critical values and critical average concentrations are presented in the Appendix.     

A phase 3, randomized,double-blind,parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation

BackgroundTezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes.MethodsEnrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV₁). Key secondary endpoints were relative change in ppFEV₁ and absolute change in CF Questionnaire–Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8.ResultsSixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV₁ or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF.ConclusionsThis Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).