Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease.     

Potent triazolyl-proline-based inhibitors of HCV NS3 protease

The design and synthesis of tripeptide-based inhibitors of the HCV NS3 protease containing a novel P2-triazole is described. Replacement of the P2 quinoline with a triazole moiety provided a versatile handle which could be expediently modified to generate a diverse series of inhibitors. Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity.     

High body mass alters colonic sensory-motor function and transit in humans

There is increased prevalence of abdominal pain and diarrhea and decreased gastric sensation with increased body mass index (BMI). Our hypothesis is that increased BMI is associated with increased colonic motility and sensation. The study aim was to assess effect of BMI on colonic sensory and motor functions and transit. We used a database of colonic tone, compliance, and perception of distensions measured by intracolonic, barostat-controlled balloon, and gastrointestinal transit was measured by validated scintigraphy in healthy obese and nonobese subjects. Regression analysis was applied to assess the association of BMI with colonic sensory and motor functions. We included adjustments for sex differences, age, height, balloon volumes during distension, and psychological stress. Among 165 participants (87 women, 78 men), increased BMI was associated with decreased colonic compliance (P < 0.006, adjusted), decreased pain rating during distensions (P = 0.02, adjusted), and a higher threshold for pain (P = 0.042, adjusted). Sensation for gas, colonic tone, and contraction after meal ingestion were not significantly associated with BMI. Transit was assessed in 72 participants (41 women, 31 men); colonic transit was faster with BMI >30 kg/m(2) (P = 0.003 unadjusted, P = 0.08 adjusted for gender). In conclusion, BMI >25 kg/m(2) is associated with decreased colonic compliance and pain sensation; colonic transit is accelerated particularly with BMI >30 kg/m(2) in women. These data suggest that colonic dysfunction may contribute to diarrhea, but the cause of increased abdominal pain in obesity is not explained by the studies of colonic sensation and requires further study of afferent, spinal, and central mechanisms.     

Nitric oxide synthase type I (nNOS), vascular endothelial growth factor (VEGF) and myoglobin-like expression in skeletal muscle of Antarctic icefishes (Notothenioidei: Channichthyidae)

The Antarctic icefishes Channichthyidae lack haemoglobin and are thought to lack myoglobin (Mb) in their skeletal muscle as well. Due to the absence of both respiratory pigments, icefishes may present a variety of physiological adaptations in their skeletal muscles. In mammals, molecular responses to limiting oxygen availability in the skeletal muscle include, among others, the over expression of nitric oxide synthases (NOS), such as type I (neuronal nNOS) and type III (endothelial eNOS), as well as the vascular endothelial growth factor (VEGF). In this paper, we evaluated by western blot analysis whether the skeletal muscle of haemoglobin-less icefishes expresses in a constitutive manner higher levels of the type I and type III NOS isoforms and VEGF. Our results demonstrate that haemoglobin-less icefish of the family Channichthyidae do indeed present higher expression of the type I NOS isoform compared with red-blooded Antarctic fish species of other families of the same suborder Notothenioidei. In contrast, VEGF was not over-expressed. Moreover, we show that some icefish species, thought previously to lack Mb in oxidative muscles, actually present Mb-like immunoreactivity in their skeletal muscle.     

The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe

BACKGROUND AND AIM: Helicobacter pylori is the major cause of peptic ulcer disease, but the proportion of H. pylori-negative peptic ulcers seems to be increasing in developed countries. We investigated the frequency of H. pylori-negative peptic ulcer without intake of nonsteroidal anti-inflammatory drugs (NSAIDs) in a Mediterranean European country. MATERIALS AND METHODS: We prospectively collected consecutive patients with an endoscopically verified active peptic ulcer over 6 months from different areas of Spain. Helicobacter pylori infection was assessed by rapid urease test and histologic examination (corpus and antral biopsies). A (13)C-urea breath test was performed if H. pylori was not detected with the invasive test. Patients were considered H. pylori-negative if all three tests were negative. NSAID use was determined by structured data collection. RESULTS: Of 754 consecutive peptic ulcer patients, 16 (2.1%) were H. pylori-negative and had not used NSAIDs before the diagnosis. Of the 472 patients who had duodenal ulcers, 95.7% (n = 452) were H. pylori-positive and only 1.69% (n = 8) were negative for both H. pylori infection and NSAID use; 193 patients had benign gastric ulcers and 87% (n = 168) of them were infected by H. pylori (p <.001 vs. duodenal ulcers). NSAID intake was more frequent in gastric ulcer patients (52.8%) than in duodenal ulcer patients (25.4%; p <.001). Consequently, the frequency of H. pylori-negative gastric ulcer in patients not using NSAID was 4.1% (n = 8). CONCLUSION: Peptic ulcer disease is still highly associated with H. pylori infection in southern Europe, and only 1.6% of all duodenal ulcers and 4.1% of all gastric ulcers were not associated with either H. pylori infection or NSAID use.     

Temporal Trends in Metal Concentrations in Soils and Herbage Collected Near a Municipal Waste Incinerator: Human Health Risks

Emissions of metals by municipal solid waste incinerators (MSWIs) are still an issue of concern for the health of residents in the vicinity of these facilities. Since 1991 a MSWI has been operating in Tarragona (Spain). In 1997, a modernization of the flue gas cleaning systems of the MSWI was completed. Since then, periodically soil and herbage samples have been collected near the facility and the concentrations of the following elements determined: As, Be, Cd, Cr, Hg, Mn, Ni, Pb, Tl, and V. In 2002, a 4-year environmental surveillance program was initiated. The mean concentrations of these elements in various surveys performed between 1997 and 2005, as well as the temporal trends are reported. Human health risks, carcinogenic and non-carcinogenic, were also assessed. Risks for adults and children were separately evaluated. Children were chosen because they are one of the most susceptible groups of a population. According to the current results, in principle, no significant health risks for the population living in the neighborhood of the facility can be expected due to metal emissions from the stack. However, a continuous environmental surveillance program is recommended because As levels in soils of Tarragona are slightly higher than the U.S. Environmental Protection Agency's Preliminary Remediation Goals.     

Preparation of Oligonucleotides Containing Non-natural Base Analogues

Abstract

The preparation of a protected derivative of 2-aza- 2′-deoxyinosine carrying a photolabile protecting group is described. The new derivative is useful to prepare oligonucleotides containing 2-azahypoxanthine. The synthesis of oligonucleotides containing 2-fluorohypoxanthine and O⁴-alkylthymine is also described.     

Challenges in the Diagnosis of Iron Deficiency in Children Exposed to High Prevalence of Infections

Background

While WHO guidelines recommend iron supplements to only iron-deficient children in high infection pressure areas, these are rarely implemented. One of the reasons for this is the commonly held view that iron supplementation increases the susceptibility to some infectious diseases including malaria. Secondly, currently used markers to diagnose iron deficiency are also modified by infections. With the objective of improving iron deficiency diagnosis and thus, its management, we evaluated the performance of iron markers in children exposed to high infection pressure.

Methodology/Principal Findings

Iron markers were compared to bone marrow findings in 180 anaemic children attending a rural hospital in southern Mozambique. Eighty percent (144/180) of the children had iron deficiency by bone marrow examination, 88% (155/176) had an inflammatory process, 66% (119/180) had moderate anaemia, 25% (45/180) severe anaemia and 9% (16/180) very severe anaemia. Mean cell haemoglobin concentration had a sensitivity of 51% and specificity of 71% for detecting iron deficiency. Soluble transferrin receptor (sTfR) and soluble transferrin receptor/log ferritin (TfR-F) index (adjusted by C reactive protein) showed the highest areas under the ROC curve (AUC^ROC) (0.75 and 0.76, respectively), and were the most sensitive markers in detecting iron deficiency (83% and 75%, respectively), but with moderate specificities (50% and 56%, respectively).

Conclusions/Significance

Iron deficiency by bone marrow examination was extremely frequent in these children exposed to high prevalence of infections. However, even the best markers of bone marrow iron deficiency did not identify around a quarter of iron-deficient children. Tough not directly extrapolated to the community, these findings urge for more reliable, affordable and easy to measure iron indicators to reduce the burden of iron deficiency anaemia in resource-poor settings where it is most prevalent.     

Biaryl analogues of teriflunomide as potent DHODH inhibitors

The structure–activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.     

Design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases

Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases.