Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice

BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.

Calcium-sensing receptor: A new target for therapy of diarrhea

Management of acute diarrhea remains a global challenge, particularly in resource-limiting countries. Oral rehydration solution (ORS), a passive rehydrating therapy developed approximately 40 years ago, remains the mainstay treatment. Although ORS is effective for hydration, since it does not inhibit enterotoxin-mediated excessive secretion, reduced absorption and compromised barrier function - the primary mechanisms of diarrhea, ORS does not offer a rapid relief of diarrhea symptom. There are a few alternative therapies available, yet the use of these drugs is limited by their expense, lack of availability and/or safety concerns. Novel anti-diarrheal therapeutic approaches, particularly those simple affordable therapies, are needed. This article explores intestinal calcium-sensing receptor (CaSR), a newly uncovered target for therapy of diarrhea. Unlike others, targeting this host antidiarrheal receptor system appears “all-inclusive”: it is anti-secretory, pro-absorptive, anti-motility, and anti-inflammatory. Thus, activating CaSR reverses changes of both secretory and inflammatory diarrheas. Considering its unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators, it is possible that through targeting of CaSR with a combination of specific nutrients, novel oral rehydrating solutions that are inexpensive and practical to use in all countries may be developed.

Diarrhea in neonatal intensive care unit

AIM:To investigate the frequency,etiology,and current management strategies for diarrhea in newborn.METHODS:Retrospective,nationwide study involving 5801 subjects observed in neonatal intensive care units during 3 years.The main anamnesis and demographic characteristics,etiology and characteristics of diarrhea,nutritional and therapeutic management,clinical outcomes were evaluated.RESULTS:Thirty-nine cases of diarrhea(36 acute,3 chronic) were identified.The occurrence rate of diarrhea was 6.72 per 1000 hospitalized newborn.Etiology was defined in 29 of 39 newborn(74.3%):food allergy(20.5%),gastrointestinal infections(17.9%),antibiotic-associated diarrhea(12.8%),congenital defects of ion transport(5.1%),withdrawal syndrome(5.1%),Hirschsprung's disease(2.5%),parenteral diarrhea(2.5%),cystic fibrosis(2.5%),and metabolic disorders(2.5%).Three patients died due to complications related to diarrhea(7.7%).In 19 of 39 patients(48.7%),rehydration was performed exclusively by the enteral route.CONCLUSION:Diarrhea in neonates is a challenging clinical condition due to the possible heterogeneous etiologies and severe outcomes.Specific guidelines are advocated in order to optimize management of diarrhea in this particular setting.

Health Emergency and Disaster Risk Management (Health-EDRM) in Remote Ethnic Minority Areas of Rural China:The Case of a Flood-Prone Village in Sichuan

Remote,rural ethnic-minority communities face greater disaster-related public health risks due to their lack of resources and limited access to health care.The Ethnic Minority Health Project(EMHP) was initiated in 2009 to work with remote,disaster-prone ethnic-minority villages that live in extreme poverty.One of the project's aims is to develop and evaluate bottom-up health risk reduction efforts in emergency and disaster risk management(HealthEDRM).This article shares project updates and describes field intervention results from the Yi ethnic community of Hongyan village in China's Sichuan Province,an area that experiences recurrent floods.It was found that 64% of the village respondents had never considered any form of disaster preparation,even with the recurrent flood risks.Health intervention participants showed sustained knowledge retention and were nine times more likely to know the correct composition of oral rehydration solution(ORS) after the intervention.Participants also retained the improved knowledge on ORS and disaster preparedness kit ownership12 months after the intervention.

Clinical and Experimental Study on Zhixie Buye Mixture (止泻补液合剂) in Treating Infantile Diarrhea Complicated with Dehydration

Objective: To observe the therapeutic effect of Zhixie Buye mixture (止泻补液合剂, ZXBYM) on infantile diarrhea patients with mild or middle degree of dehydration. Methods: Controlled observation method was adopted in the clinical and experimental study. Results: There was no significant difference in the treatment of dehydration between the ZXBYM group and oral rehydration solution (ORS) group (P>0.05), at the same time it was more effective for ZXBYM to eliminate such symptoms as vomiting and abdominal distension (P<0.01). In addition, it was confirmed that the ion concentration of sodium, potassium, chlorine, glucose and osmotic pressure in the mixture was similar to those in ORS. Animal experiment showed that ZXBYM has the effect of rat intestine peristalsis suppression and water absorption promotion in colon. And there was statistical difference in antidiarrhea effect between the mixture and ORS (P<0.01). Conclusion: ZXBYM is an effective mixture in the treatment of diarrhea with dehydration. It has a good prospect for the development and application.