An Investigation of Fecal Volatile Organic Metabolites in Irritable Bowel Syndrome

Diagnosing irritable bowel syndrome (IBS) can be a challenge; many clinicians resort to invasive investigations in order to rule out other diseases and reassure their patients. Volatile organic metabolites (VOMs) are emitted from feces; understanding changes in the patterns of these VOMs could aid our understanding of the etiology of the disease and the development of biomarkers, which can assist in the diagnosis of IBS. We report the first comprehensive study of the fecal VOMs patterns in patients with diarrhea-predominant IBS (IBS-D), active Crohn''s disease (CD), ulcerative colitis (UC) and healthy controls. 30 patients with IBS-D, 62 with CD, 48 with UC and 109 healthy controls were studied. Diagnosis of IBS-D was made using the Manning criteria and all patients with CD and UC met endoscopic, histologic and/or radiologic criteria. Fecal VOMs were extracted by solid phase microextraction (SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS). 240 VOMs were identified. Univariate analysis showed that esters of short chain fatty acids, cyclohexanecarboxylic acid and its ester derivatives were associated with IBS-D (p<0.05), while aldehydes were more abundant in IBD (p<0.05). A predictive model, developed by multivariate analysis, separated IBS-D from active CD, UC and healthy controls with a sensitivity of 94%, 96% and 90%; and a specificity of 82%, 80% and 80% respectively (p<0.05). The understanding of the derivation of these VOMs may cast light on the etiology of IBS-D and IBD. These data show that fecal VOMs analyses could contribute to the diagnosis of IBS-D, for which there is no laboratory test, as well as IBD.     

Reproductive demographics,intersex, and altered hormone levels in shortnose sturgeon,Acipenser brevirostrum,from Delaware River,USA

Non‐lethal sampling techniques were used to document the reproductive structure of the shortnose sturgeon (Acipenser brevirostrum) population at a fish aggregation site (near Bordentown, New Jersey) in the Delaware River. A total of 68 fish were captured using gill nets (100 × 1.8 m, 12.7 or 15.2 cm mesh) and examined laparoscopically in May–June, and 61 additional fish captured and examined in November during 2006–2011. Six stages of reproductive development were identified in females and five stages were identified in males, encompassing differentiation through maturity in both sexes. Fish captured in the spring were predominantly immature with a higher proportion of females (1 : 1.2 M : F sex ratio), while mature males predominated in the autumn (5.7 : 1 M : F), indicating that the Bordentown area serves as an overwintering/pre‐spawn aggregation site. Three distinct forms of intersex were noted in gonads of 11.6% of fish examined: ovo‐testis, consisting of scattered spermatic cysts in predominantly immature ovary (3.9%); testis‐ova, consisting of ovarian lamellae projecting from a predominantly immature testes (4.7%); and zonal distribution, consisting of multiple, nearly‐homogenous pockets of either testicular or ovarian tissues along the gonad (3%). The hormone profile in fish with ovo‐testis was similar to that of immature males, while the hormone profile in fish with testis‐ova was similar to that of immature females. The relatively high prevalence of intersex raises concerns regarding potential reproductive effects and long‐term impacts on shortnose sturgeon in the Delaware River.     

Brief communication: Evolution of a specific O allele (O1vG542A) supports unique ancestry of Native Americans

In this study, we explore the geographic and temporal distribution of a unique variant of the O blood group allele called O1v^G542A, which has been shown to be shared among Native Americans but is rare in other populations. O1v^G542A was previously reported in Native American populations in Mesoamerica and South America, and has been proposed as an ancestry informative marker. We investigated whether this allele is also found in the Tlingit and Haida, two contemporary indigenous populations from Alaska, and a pre‐Columbian population from California. If O1v^G542A is present in Na‐Dene speakers (i.e., Tlingits), it would indicate that Na‐Dene speaking groups share close ancestry with other Native American groups and support a Beringian origin of the allele, consistent with the Beringian Incubation Model. If O1v^G542A is found in pre‐Columbian populations, it would further support a Beringian origin of the allele, rather than a more recent introduction of the allele into the Americas via gene flow from one or more populations which have admixed with Native Americans over the past five centuries. We identified this allele in one Na‐Dene population at a frequency of 0.11, and one ancient California population at a frequency of 0.20. Our results support a Beringian origin of O1v^G542A, which is distributed today among all Native American groups that have been genotyped in appreciable numbers at this locus. This result is consistent with the hypothesis that Na‐Dene and other Native American populations primarily derive their ancestry from a single source population. Am J Phys Anthropol 151:649–657, 2013. © 2013 Wiley Periodicals, Inc.     

Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK)

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.     

Genetic diversity and spatial genetic structure of African wild dogs (<Emphasis Type="Italic">Lycaon pictus</Emphasis>) in the Greater Limpopo transfrontier conservation area

The Greater Limpopo Transfrontier Conservation Area (GLTFCA) is one of the last refuges for the endangered African wild dog and hosts roughly one-tenth of the global population. Wild dogs in this area are currently threatened by human encroachment, habitat fragmentation and scarcity of suitable connecting habitat between protected areas. We derived genetic data from mitochondrial and nuclear markers to test the following hypotheses: (i) demographic declines in wild dogs have caused a loss of genetic variation, and (ii) Zimbabwean and South African populations in the GLTFCA have diverged due to the effects of isolation and genetic drift. Genetic patterns among five populations, taken with comparisons to known information, illustrate that allelic richness and heterozygosity have been lost over time, presumably due to effects of inbreeding and genetic drift. Genetic structuring has occurred due to low dispersal rates, which was most apparent between Kruger National Park and the Zimbabwean Lowveld. Immediate strategies to improve gene flow should focus on increasing the quality of habitat corridors between reserves in the GLTFCA and securing higher wild dog survival rates in unprotected areas, with human-mediated translocation only undertaken as a last resort.     

BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data

Activation of CD4⁺ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.     

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD)

BackgroundAcute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known.AimTo evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis.ResultsMore than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%.ConclusionIn conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.     

Dengue Outbreak in Mombasa City,Kenya, 2013–2014: Entomologic Investigations

Dengue outbreaks were first reported in East Africa in the late 1970s to early 1980s including the 1982 outbreak on the Kenyan coast. In 2011, dengue outbreaks occurred in Mandera in northern Kenya and subsequently in Mombasa city along the Kenyan coast in 2013–2014. Following laboratory confirmation of dengue fever cases, an entomologic investigation was conducted to establish the mosquito species, and densities, causing the outbreak. Affected parts of the city were identified with the help of public health officials. Adult Ae. aegypti mosquitoes were collected using various tools, processed and screened for dengue virus (DENV) by cell culture and RT-PCR. All containers in every accessible house and compound within affected suburbs were inspected for immatures. A total of 2,065 Ae. aegypti adults were collected and 192 houses and 1,676 containers inspected. An overall house index of 22%, container index, 31.0% (indoor = 19; outdoor = 43) and Breteau index, 270.1, were observed, suggesting that the risk of dengue transmission was high. Overall, jerry cans were the most productive containers (18%), followed by drums (17%), buckets (16%), tires (14%) and tanks (10%). However, each site had specific most-productive container-types such as tanks (17%) in Kizingo; Drums in Nyali (30%) and Changamwe (33%), plastic basins (35%) in Nyali-B and plastic buckets (81%) in Ganjoni. We recommend that for effective control of the dengue vector in Mombasa city, all container types would be targeted. Measures would include proper covering of water storage containers and eliminating discarded containers outdoors through a public participatory environmental clean-up exercise. Providing reliable piped water to all households would minimize the need for water storage and reduce aquatic habitats. Isolation of DENV from male Ae. aegypti mosquitoes is a first observation in Kenya and provides further evidence that transovarial transmission may have a role in DENV circulation and/or maintenance in the environment.