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.

Comparing the Quality of ChatGPT- and Physician-Generated Responses to Patients' Dermatologic Questions in the Electronic Medical Record.

BACKGROUND: Chat Generated Pre-trained Transformer ('ChatGPT,' Open AI, San Francisco, USA) is a free artificial intelligence (AI)-based natural language processing tool that generates complex responses to inputs from users. OBJECTIVE: To determine whether ChatGPT is able to generate high-quality responses to patient-submitted questions in the patient portal. METHODS: Patient-submitted questions and their corresponding responses from their dermatology physician were extracted from the electronic medical record for analysis. The questions were input into ChatGPT (version 3.5), and the outputs were extracted for analysis, with manual removal of verbiage pertaining to ChatGPT's inability to provide medical advice. Ten blinded reviewers (n=7 physicians, n=3 non-physicians) rated and selected their preference in terms of 'overall quality,' 'readability,' 'accuracy,' 'thoroughness,' and 'level of empathy,' of the physician- and ChatGPT-generated responses. RESULTS: Thirty-one messages and responses were analyzed. The physician-generated response was vastly preferred over the ChatGPT response by both physician and non-physician reviewers and received significantly higher ratings for 'readability' and 'level of empathy.' CONCLUSIONS: The results of this study suggest that physician-generated responses to patients' portal messages are still preferred over ChatGPT, but generative AI tools may still be helpful in generating first drafts of responses and education resources for patients.

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.

Advances in the diagnosis of autoimmune bullous dermatoses.

Autoimmune bullous dermatoses are defined by autoantibodies directed against adhesion proteins in the epidermis or basement membrane zone, resulting in blister formation on the skin and mucosa. Diagnosis depends on lesional biopsy for histopathology and perilesional biopsy for direct immunofluorescence. Additional diagnostic methods include indirect immunofluorescence, enzyme-linked immunosorbent assay, and immunoblot (Western blot), which may be selected in specific clinical scenarios due to improved sensitivity and/or specificity. This contribution reviews the available evidence supporting the use of each method to provide a practical reference for clinicians when diagnosing autoimmune bullous disorders. Techniques and cost are reviewed, and newer diagnostic techniques with potential for clinical application are.

Motor impairments in transient ischemic attack increase the odds of a positive diffusion-weighted imaging: A meta-analysis.

BACKGROUND: Unilateral motor impairment is a key symptom used in the diagnosis of transient ischemic attack (TIA). Diffusion-weighted imaging (DWI) is a promising diagnostic tool for detecting ischemic lesions. While both motor impairments and DWI abnormalities are linked to the diagnosis of TIA, the association between these prognostic factors is not well understood. OBJECTIVE: To examine the association between unilateral motor impairments and the odds of a positive DWI in TIA. Further, to determine whether the time between symptom onset and neuroimaging (delay to scan) influences the odds of a positive DWI. METHODS: We used PRISMA guidelines to conduct a systematic search from 1989 to 2018. We included studies that reported number of individuals with/without unilateral motor symptoms and a positive/negative DWI. RESULTS: Twenty-four studies from North America, Australia, Asia, and Europe were submitted to a meta-analysis. A pooled odds ratio of 1.80 (95% CI, 1.45-2.24, p = 0.00; I2 = 57.38) suggested that the odds of a positive DWI are greater in TIA individuals who experience motor symptoms as compared with those who experience no motor symptoms. Further, increasing the time delay to scan from the symptom onset (>2 days) did not influence the odds of a positive DWI as compared with an earlier scan (≤2 days). CONCLUSIONS: The current meta-analysis provides cumulative evidence from 6710 individuals with TIA that the presence of motor symptoms increases the odds of a positive DWI by two-folds. These findings transform the clinical perception into evidence-based knowledge that motor impairments elevate the risk for brain tissue damage. Unilateral motor impairments in a cerebrovascular event should increase a physician's suspicion of detecting brain infarctions. These findings may influence the clinical management of TIA by generating faster response to motor impairments in TIA and accelerating referral to specialized stroke clinic.

Inability to reduce morbidity of diarrhea by ORS: can we design a better therapy?

Diarrheal disease is a worldwide problem that still causes significant morbidity and mortality among children. Currently, oral rehydration solution (ORS) is the standard of care for acute diarrhea in pediatric patients. Although effective in reducing mortality, ORS does not alleviate diarrheal symptoms, thus reducing caregiver compliance and therapeutic efficacy. This article will briefly review the current problem of pediatric diarrhea and the shortcomings of current therapies; however, the focus of this review is to examine the intestinal calcium-sensing receptor (CaSR). The author summarizes the evidence suggesting that targeting the CaSR will enable clinicians to address all four major pathophysiological mechanisms of diarrheal disease, and substantiates the need for future research regarding this therapy.

Motor Impairments in Transient Ischemic Attack Increase the Odds of a Subsequent Stroke: A Meta-Analysis.

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) increases the risk for a subsequent stroke. Typical symptoms include motor weakness, gait disturbance, and loss of coordination. The association between the presence of motor impairments during a TIA and the chances of a subsequent stroke has not been examined. In the current meta-analysis, we examine whether the odds of a stroke are greater in TIA individuals who experience motor impairments as compared with those who do not experience motor impairments. METHODS: We conducted a systematic search of electronic databases as well as manual searches of the reference lists of retrieved articles. The meta-analysis included studies that reported an odds ratio relating motor impairments to a subsequent stroke, or the number of individuals with or without motor impairments who experienced a subsequent stroke. We examined these studies using rigorous meta-analysis techniques including random effects model, forest and funnel plots, I2, publication bias, and fail-safe analysis. RESULTS: Twenty-four studies with 15,129 participants from North America, Australia, Asia, and Europe qualified for inclusion. An odds ratio of 2.11 (95% CI, 1.67-2.65, p = 0.000) suggested that the chances of a subsequent stroke are increased by twofolds in individuals who experience motor impairments during a TIA compared with those individuals who have no motor impairments. CONCLUSION: The presence of motor impairments during TIA is a significantly high-risk clinical characteristic for a subsequent stroke. The current evidence for motor impairments following TIA relies exclusively on the clinical reports of unilateral motor weakness. A comprehensive examination of motor impairments in TIA will enhance TIA prognosis and restoration of residual motor impairments.