Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

Taxonomic Distinctness of Demersal Fishes of the California Current: Moving Beyond Simple Measures of Diversity for Marine Ecosystem-Based Management

BACKGROUND: Large-scale patterns or trends in species diversity have long interested ecologists. The classic pattern is for diversity (e.g., species richness) to decrease with increasing latitude. Taxonomic distinctness is a diversity measure based on the relatedness of the species within a sample. Here we examined patterns of taxonomic distinctness in relation to latitude (ca. 32-48 degrees N) and depth (ca. 50-1220 m) for demersal fishes on the continental shelf and slope of the US Pacific coast. METHODOLOGY/PRINCIPAL FINDINGS: Both average taxonomic distinctness (AvTD) and variation in taxonomic distinctness (VarTD) changed with latitude and depth. AvTD was highest at approximately 500 m and lowest at around 200 m bottom depth. Latitudinal trends in AvTD were somewhat weaker and were depth-specific. AvTD increased with latitude on the shelf (50-150 m) but tended to decrease with latitude at deeper depths. Variation in taxonomic distinctness (VarTD) was highest around 300 m. As with AvTD, latitudinal trends in VarTD were depth-specific. On the shelf (50-150 m), VarTD increased with latitude, while in deeper areas the patterns were more complex. Closer inspection of the data showed that the number and distribution of species within the class Chondrichthyes were the primary drivers of the overall patterns seen in AvTD and VarTD, while the relatedness and distribution of species in the order Scorpaeniformes appeared to cause the relatively low observed values of AvTD at around 200 m. CONCLUSIONS/SIGNIFICANCE: These trends contrast to some extent the patterns seen in earlier studies for species richness and evenness in demersal fishes along this coast and add to our understanding of diversity of the demersal fishes of the California Current

The formation of human populations in South and Central Asia

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization’s decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Ileal pouch dialysate is cytotoxic to epithelial cell lines, but not to CaCo-2 monolayers.

OBJECTIVE: All patients with ileal pouch-anal anastomosis (IPAA) have some degree of villous atrophy, mucin changes and chronic inflammation. The mechanism underlying these changes is unknown. This study investigates the hypothesis that luminal factor(s) may affect epithelial cells in in-vitro studies. DESIGN: IPAA dialysate from eight patients with prior ulcerative colitis was assessed. METHODS: The effect of the dialysate on epithelial cell (i-407, HT-29 and CaCo-2) proliferation (3H-thymidine incorporation) and cytotoxicity (51-chromium release) was determined. Bile acid(s) at concentrations measured in IPAA dialysate were assessed in isolation and in combination for cytotoxicity against CaCo-2 cells. The effect of dialysate and bile acids on immature and mature CaCo-2 monolayer cytotoxicity, transepithelial electrical resistance (TEER) and histology was investigated. RESULTS: IPAA dialysate is antiproliferative and cytotoxic to the cell lines. At concentrations present in dialysate chenodeoxycholic acid and deoxycholic acid were cytotoxic to CaCo-2 cells. IPAA dialysate was not cytotoxic to mature CaCo-2 cell monolayers. TEER was maintained across monolayers with dialysate but not with control Rheomacrodex (P = 0.02). Bile acids at concentrations present in dialysate were cytotoxic to monolayers. CONCLUSION: Ileal pouch dialysate is cytotoxic to epithelial cells due (in part) to bile acids. Bile acids in isolation are cytotoxic to both CaCo-2 cells and monolayers. Despite the presence of bile acid the dialysate is not cytotoxic to CaCo-2 monolayers and preserves epithelial resistance and histological structure

5-Aminosalicylic acid inhibits the impaired epithelial barrier function induced by gamma interferon.

Gamma interferon (IFN gamma) impairs epithelial barrier function and induces HLA-DR expression on colonic cancer cell lines. Salicylates have been shown to reduce IFN gamma induced HLA-DR expression. The effect of 5-aminosalicylic acid (5-ASA) on IFN gamma induced changes in transepithelial resistance and permeability was investigated in HT29 clone 19A and Caco 2 monolayers. Monolayers were incubated with different concentrations of IFN gamma (100, 500, 1000, and 3000 U/ml) and 5-ASA. IFN gamma induced class II expression in a time and dose dependent manner in HT29:19A but not Caco 2 cells. HT29:19A monolayers incubated with both IFN gamma and 5-ASA showed lower HLA-DR expression compared with monolayers incubated with IFN gamma alone. Electrical resistance and 14C-mannitol flux across HT29:19A monolayers were significantly changed by IFN gamma. Addition of both IFN gamma and 5-ASA to the basolateral surface of the monolayers significantly reduced paracellular permeability compared with addition of IFN gamma alone. These data show that IFN gamma is able to induce HLA-DR expression and to impair the barrier function of HT29:19A monolayers, and that 5-ASA reduces IFN gamma induced HLA-DR expression and inhibits the effects of IFN gamma on epithelial barrier function

Cyclosporin A retention enemas in refractory distal ulcerative colitis and 'pouchitis'.

The aim of this study was to evaluate the use of cyclosporin enemas in patients with distal ulcerative colitis and 'pouchitis' resistant to all conventional medical therapy. In an trial 12 patients with distal ulcerative colitis unresponsive to treatment with topical and oral corticosteroids, 5-aminosalicylic acid, and oral immunosuppressive therapy together with 1 patient with 'pouchitis' unresponsive to repeated courses of antibiotics, topical corticosteroids, and oral mesalazine received 250 mg cyclosporin administered daily as a retention enema. Changes in symptoms and the sigmoidoscopic/histologic appearances of the rectal mucosa were assessed at monthly intervals. Seven of 12 patients with ulcerative colitis improved. There was a strong correlation between clinical and histologic improvement (p < 0.005). Four of 12 patients showed no response. Three of these required colectomy, two of whom had more extensive disease than had previously been documented. The patient with pouchitis showed improvement in symptoms and 'pouchoscopy' appearance but not in histologic score. Cyclosporin blood concentrations were very low and side effects negligible. Cyclosporin A retention enemas are safe and may be useful in the treatment of severe refractory distal ulcerative colitis. A controlled trial would now seem warranted

Nicotine exposure alters in vivo human responses to endotoxin

The alpha 7 nicotinic receptor is reportedly a key element in the cholinergic anti-inflammatory pathway. Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2·5–6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype