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 calcimimetic 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.

Ca2+ fortified oral rehydration solution is effective in reducing diarrhea morbidity in cholera toxin-pretreated mice.

Diarrhea like cholera remains a leading cause of mortality and morbidity globally. Oral rehydration solution (ORS) that developed in 1970s significantly decreases diarrhea mortality; yet, it does not reduce diarrhea morbidity and its usage has reduced persistently. Patients with diarrhea lose not only monovalent ions Na+, K+, Cl- and HCO3, which are replaced via ORS, but also divalent ions Zn2+ and Ca2+, which are not routinely replaced, particularly for Ca2+. Using several in vitro technologies performed in isolated tissues, we have previously shown that Ca2+, a primary ligand that activates the Ca2+-sensing receptor, can act on intestinal epithelium and enteric nervous system and reverse cholera toxin-induced fluid secretion. In the present study, using the cholera toxin-pretreated C57BL/6 mice as a model, we show that the anti-diarrheal effect of Ca2+ can also occur in vivo. Our results raise a question of whether this divalent ion also needs to be replaced in diarrhea management. Perhaps, an ideal rehydration therapy would be solutions that contain both monovalent ions, which reduce diarrhea mortality, and divalent minerals, which reduce diarrhea morbidity.

Understanding and treatment of cutaneous graft-versus-host-disease.

The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients' quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.

Noninfectious Pulmonary Complications after Hematopoietic Stem Cell Transplantation.

Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications' underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.

Extracellular Calcium Dictates Onset, Severity, and Recovery of Diarrhea in a Child with Immune-Mediated Enteropathy.

Diarrhea causes monovalent and divalent ion losses that can influence clinical outcome. Unlike the losses of monovalent ions, such as Na+, K+, Cl-, and [Formula: see text], which are generally large in quantity (osmoles) and therefore determine the severity of diarrhea, the losses of divalent ions are relatively small in osmoles and are often overlooked during diarrheal treatment. Studies now suggest that despite divalent ions being small in osmoles, their effects are large due to the presence of divalent ion-sensing receptors and their amplifying effects in the gut. As a result, losses of these divalent ions without prompt replacement could also significantly affect the onset, severity, and/or recovery of diarrheal disease. Herein, we report a case of a malnourished child with an immune-mediated enteropathy who developed episodes of "breakthrough" diarrhea with concurrent hypocalcemia while on appropriate immunotherapy. Interestingly, during these periods of diarrhea, stool volume fluctuated with levels of blood Ca2+. When Ca2+ was low, diarrhea occurred; when Ca2+ levels normalized with replacement, diarrhea stopped. Based on this and other observations, a broader question arises as to whether the Ca2+ lost in diarrhea should be replaced promptly in these patients.