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      Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics

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          Abstract

          Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%; p < 0.001) and intact small intestine (>40%; p = 0.03). We propose that mechanical force drives fluid secretion through the tight junction complex via a “one-way check valve” that can be regulated. This pathway of filtration secretion complements chloride-coupled fluid secretion during high-volume fluid flow. The role of filtration secretion in the genesis of diarrhea in intact animals needs further study. Our findings may explain a potential linkage between intestinal motility and intestinal fluid dynamics.

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          Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.

          Single murine and human intestinal stem cells can be expanded in culture over long time periods as genetically and phenotypically stable epithelial organoids. Increased cAMP levels induce rapid swelling of such organoids by opening the cystic fibrosis transmembrane conductor receptor (CFTR). This response is lost in organoids derived from cystic fibrosis (CF) patients. Here we use the CRISPR/Cas9 genome editing system to correct the CFTR locus by homologous recombination in cultured intestinal stem cells of CF patients. The corrected allele is expressed and fully functional as measured in clonally expanded organoids. This study provides proof of concept for gene correction by homologous recombination in primary adult stem cells derived from patients with a single-gene hereditary defect. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria

              Background Zinc deficiency is commonly prevalent in children in developing countries and plays a role in decreased immunity and increased risk of infection. Preventive zinc supplementation in healthy children can reduce mortality due to common causes like diarrhea, pneumonia and malaria. The main objective was to determine all-cause mortality and cause-specific mortality and morbidity in children under five in developing countries for preventive zinc supplementation. Data sources/ review methods A literature search was carried out on PubMed, the Cochrane Library and the WHO regional databases to identify RCTs on zinc supplementation for greater than 3 months in children less than 5 years of age in developing countries and its effect on mortality was analyzed. Results The effect of preventive zinc supplementation on mortality was given in eight trials, while cause specific mortality data was given in five of these eight trials. Zinc supplementation alone was associated with a statistically insignificant 9% (RR = 0.91; 95% CI: 0.82, 1.01) reduction in all cause mortality in the intervention group as compared to controls using a random effect model. The impact on diarrhea-specific mortality of zinc alone was a non-significant 18% reduction (RR = 0.82; 95% CI: 0.64, 1.05) and 15% for pneumonia-specific mortality (RR = 0.85; 95% CI: 0.65, 1.11). The incidence of diarrhea showed a 13% reduction with preventive zinc supplementation (RR = 0.87; 95% CI: 0.81, 0.94) and a 19% reduction in pneumonia morbidity (RR = 0.81; 95% CI: 0.73, 0.90). Keeping in mind the direction of effect of zinc supplementation in reducing diarrhea and pneumonia related morbidity and mortality; we considered all the outcomes for selection of effectiveness estimate for inclusion in the LiST model. After application of the CHERG rules with consideration to quality of evidence and rule # 6, we used the most conservative estimates as a surrogate for mortality. We, therefore, conclude that zinc supplementation in children is associated with a reduction in diarrhea mortality of 13% and pneumonia mortality of 15% for inclusion in the LiST tool. Preventive zinc supplementation had no effect on malaria specific mortality (RR = 0.90; 95% CI: 0.77, 1.06) or incidence of malaria (RR=0.92; 95 % CI 0.82-1.04) Conclusion Zinc supplementation results in reductions in diarrhea and pneumonia mortality.
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                Author and article information

                Journal
                Med Sci (Basel)
                Med Sci (Basel)
                medsci
                Medical Sciences
                MDPI
                2076-3271
                09 February 2021
                March 2021
                : 9
                : 1
                : 9
                Affiliations
                [1 ]School of Health Studies, University of Memphis, Memphis, TN 38152, USA; thomaslwong@ 123456gmail.com
                [2 ]Babies Taking Flight, Memphis, TN 38117, USA
                [3 ]Department of Acute and Tertiary Care, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA; scott.howard@ 123456resonancehealth.org
                Author notes
                [* ]Correspondence: rkb.btf@ 123456gmail.com ; Tel.: +1-662-418-2666
                Author information
                https://orcid.org/0000-0001-5790-0593
                https://orcid.org/0000-0003-3234-8522
                Article
                medsci-09-00009
                10.3390/medsci9010009
                7931054
                33572202
                998e63a7-b361-466d-8b7b-34eb2528d985
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 December 2020
                : 02 February 2021
                Categories
                Article

                diarrhea,filtration secretion,pressure,tight junction,intestinal motility

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