Danielle Collins

Emerging role of hydrogen sulfide in colonic physiology and pathophysiology.

&NA; Hydrogen sulfide (H2S) is a toxic gas that is now recognized as an important mediator of many physiological processes. In the colon, H2S is produced both endogenously and by naturally occurring sulfate‐reducing bacteria (SRB). The full arrays of its effects in the gastrointestinal tract are still being elucidated, but they range from motility to carcinogenesis. We examined the evidence relating to H2S as a modulator of colonic function and disease. H2S is implicated in modulation of colonic compliance through its action on smooth muscle. There is also evidence linking H2S to colonic nociception, inflammatory bowel disease (IBD), and colorectal cancer. The exact mechanisms and pathways by which H2S exerts its multitude of effects are not yet fully understood, but its involvement in physiological and pathophysiological conditions of the colon is becoming evident. Elucidating the intricate effects of H2S in the colon and understanding the exact nature of its interactions with the colon makes pharmacological modulation of H2S production and metabolism potential targets for treatment of a multitude of colonic conditions in the future.(Inflamm Bowel Dis 2010)

Microbial and viral pathogens in colorectal cancer.

The heterogenetic and sporadic nature of colorectal cancer has led to many epidemiological associations with causes of this disease. As our understanding of the underlying molecular processes in colorectal-cancer develops, the concept of microbial-epithelial interactions as an oncogenic trigger might provide a plausible hypothesis for the pathogenesis of colorectal cancer. By contrast with other cancers of the gastrointestinal tract (gastric carcinoma, mucosa-associated lymphoid-tissue lymphoma), a direct causal link between microbial infection (bacteria and viruses) and colorectal carcinoma has not been established. Studies support the involvement of these organisms in oncogenesis, however, in colorectal cancer, clinical data are lacking. Here, we discuss current evidence (both in vitro and clinical studies), and focus on a putative role for bacterial and viral pathogens as a cause of colorectal cancer.

Laparoscopic lavage for perforated diverticulitis: a population analysis.

BACKGROUND: Laparoscopic lavage has shown promising results in nonfeculent perforated diverticulitis. It is an appealing strategy; it avoids the complications associated with resection. However, there has been some reluctance to widespread uptake because of the scarcity of large-scale studies. OBJECTIVE: This study investigated national trends in management of perforated diverticulitis. DESIGN: This retrospective population study used an Irish national database to identify patients acutely admitted with diverticulitis, as defined by the International Classification of Diseases. Demographics, procedures, comorbidities, and outcomes were obtained for the years 1995 to 2008. SETTINGS: The study was conducted in Ireland. PATIENTS: Patients with International Classification of Diseases codes corresponding to diverticulitis who underwent operative intervention were included. MAIN OUTCOME MEASURES: The primary outcome was mortality, and secondary outcomes were length of stay and postoperative complications. RESULTS: Two thousand four hundred fifty-five patients underwent surgery for diverticulitis, of whom 427 underwent laparoscopic lavage. Patients selected for laparoscopic lavage had lower mortality (4.0% vs 10.4%, p < 0.001), complications (14.1% vs 25.0%, p < 0.001), and length of stay (10 days vs 20 days, p < 0.001) than those requiring laparotomy/resection. Patients older than 65 years were more likely to die (OR 4.1, p < 0.001), as were those with connective tissue disease (OR 7.3, p < 0.05) or chronic kidney disease (OR 8.0, p < 0.001). LIMITATIONS: This retrospective study is limited by the quality of data obtained and is subject to selection bias. Furthermore, the lack of disease stratification means it is not possible to identify the extent of peritonitis; feculent peritonitis has worse outcomes and is not likely to be included in the lavage group. CONCLUSIONS: The number of patients selected for laparoscopic lavage in perforated diverticulitis is increasing, and the outcomes in this study are comparable to other reports. Those patients in whom laparoscopic lavage alone was suitable had lower mortality and morbidity than those in whom resection was considered necessary.

Estrogen and gastrointestinal malignancy

The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.

Review Article: Loss of the Calcium-Sensing Receptor in Colonic Epithelium is a Key Event in the Pathogenesis of Colon Cancer

The calcium-sensing receptor (CaSR) is expressed abundantly in normal colonic epithelium and lost in colon cancer, but its exact role on a molecular level and within the carcinogenesis pathway is yet to be described. Epidemiologic studies show that inadequate dietary calcium predisposes to colon cancer; this may be due to the ability of calcium to bind and upregulate the CaSR. Loss of CaSR expression does not seem to be an early event in carcinogenesis; indeed it is associated with late stage, poorly differentiated, chemo-resistant tumors. Induction of CaSR expression in neoplastic colonocytes arrests tumor progression and deems tumors more sensitive to chemotherapy; hence CaSR may be an important target in colon cancer treatment. The CaSR has a complex role in colon cancer; however, more investigation is required on a molecular level to clarify its exact function in carcinogenesis. This review describes the mechanisms by which the CaSR is currently implicated in colon cancer and identifies areas where further study is needed.

Differential protein abundance and function of UT-B urea transporters in human colon

Facilitative UT-B urea transporters enable the passage of urea across cell membranes. Gastrointestinal urea transporters are thought to play a significant role in the urea nitrogen salvaging process that occurs between mammalian hosts and their gut bacteria. This study investigated the expression of UT-B urea transporters in different segments of human colon. Immunoblot analysis showed that human colon expressed a 35-kDa glycosylated UT-B protein in the colonic mucosa. The 35-kDa UT-B transporter was predominantly located in plasma membrane-enriched samples (P < 0.001; n = 6), and its expression was greater in the ascending colon compared with the descending colon (P < 0.01; n = 3). At the cellular level, UT-B transporters were located throughout colonocytes situated in the upper portion of the colonic crypts. Bidirectional trans-epithelial urea transport was significantly greater in the ascending colon than the descending colon (P < 0.05; n = 6). In addition, the facilitative urea transporter inhibitor 1,3,dimethylurea significantly reduced urea transport in the ascending colon (P < 0.05; n = 6) but had no effect in the descending colon (NS; n = 6). These results illustrate differential protein abundance of functional UT-B protein in different sections of the human colon, strongly correlating to regions that contain the largest populations of intestinal bacteria. This study suggests an important role for UT-B urea transporters in maintaining the symbiotic relationship between humans and their gut bacteria.

Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism

Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non‐genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women.

The mycotoxin patulin increases colonic epithelial permeability in vitro.

The gastrointestinal lumen is directly exposed to dietary contaminants, including patulin, a mycotoxin produced by moulds. Patulin is known to increase permeability across intestinal Caco-2 monolayers. This study aimed to determine the effect of patulin on permeability, ion transport and morphology in isolated rat colonic mucosae. Mucosal sheets were mounted in Ussing chambers and voltage clamped. Apical addition of patulin (100-500 μM) rapidly reduced transepithelial electrical resistance (TEER) and increased permeability to [(14)C] mannitol (2.9-fold). Patulin also inhibited carbachol-induced electrogenic chloride secretion and histological evidence of mucosal damage was observed. To examine potential mechanisms of action of patulin on colonic epithelial cells, high-content analysis of Caco-2 cells was performed and this novel, quantitative fluorescence-based approach confirmed its cytotoxic effects. With regard to time course, the cytotoxicity determined by high content analysis took longer than the almost immediate reduction of electrical resistance in isolated mucosal sheets. These data indicate patulin is not only cytotoxic to enterocytes but also has the capacity to directly alter permeability and ion transport in intact intestinal mucosae. These data corroborate and extend findings in intestinal cell culture monolayers, and further suggest that safety limits on consumption of patulin may be warranted.

Estrogen and its role in gastrointestinal health and disease

IntroductionWhile the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes.MethodsA literature search was conducted using the PubMed database and the search terms were “estrogen,” “estrogen AND gastrointestinal tract,” “estrogen AND colon,” “estrogen AND esophagus,” “estrogen AND small intestine,” “estrogen AND stomach,” “estrogen AND gallbladder,” and “estrogen AND motility.” Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis.ConclusionsEffects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

Clinic Network Collaboration and Patient Tracing to Maximize Retention in HIV Care.

Background Understanding retention and loss to follow up in HIV care, in particular the number of people with unknown outcomes, is critical to maximise the benefits of antiretroviral therapy. Individual-level data are not available for these outcomes in Australia, which has an HIV epidemic predominantly focused amongst men who have sex with men. Methods and Findings A network of the 6 main HIV clinical care sites was established in the state of Victoria, Australia. Individuals who had accessed care at these sites between February 2011 and June 2013 as assessed by HIV viral load testing but not accessed care between June 2013 and February 2014 were considered individuals with potentially unknown outcomes. For this group an intervention combining cross-referencing of clinical data between sites and phone tracing individuals with unknown outcomes was performed. 4966 people were in care in the network and before the intervention estimates of retention ranged from 85.9%–95.8% and the proportion with unknown outcomes ranged from 1.3-5.5%. After the intervention retention increased to 91.4–98.8% and unknown outcomes decreased to 0.1–2.4% (p<.01 for all sites for both outcomes). Most common reasons for disengagement from care were being too busy to attend or feeling well. For those with unknown outcomes prior to the intervention documented active psychiatric illness at last visit was associated with not re-entering care (p = 0.04) Conclusions The network demonstrated low numbers of people with unknown outcomes and high levels of retention in care. Increased levels of retention in care and reductions in unknown outcomes identified after the intervention largely reflected confirmation of clinic transfers while a smaller number were successfully re-engaged in care. Factors associated with disengagement from care were identified. Systems to monitor patient retention, care transfer and minimize disengagement will maximise individual and population-level outcomes for populations with HIV.