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Liu X, Liu X, Liu Y, Long A, Liu W, Sun S, Lu S, Wu X, Jia X, Jose PA, Wei Q, Jiang X, Zhang H, Yang Z. Intestinal Gastrin/CCKBR Axis Protects against Type 2 Diabetes by Reducing Intestinal Glucose Absorption through the PI3K/Akt/eIF4B Signaling Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410032. [PMID: 39950948 PMCID: PMC11967862 DOI: 10.1002/advs.202410032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/31/2024] [Indexed: 04/05/2025]
Abstract
The Gastrin/CCKBR axis is essential for inhibiting intestinal sodium absorption, but its effects on intestinal glucose metabolism remain elusive. This study aims to determine the role of intestinal Gastrin/CCKBR on glucose absorption in the development of type 2 diabetes (T2D). Intestinal epithelial cell-specific Cckbr knockout mice and control wild-type mice are fed normal diet (ND, 10% fat) or high fat diet (HFD, 60% fat) to study the effect of intestinal Gastrin/CCKBR on blood glucose levels. Gastrin-SiO2 microspheres (20 mg kg-1 d-1) are designed so that gastrin specifically stimulates intestinal CCKBR, without its absorption into the circulation. Mice with silenced intestinal Cckbr has pre-diabetes mellitus (Pre-DM) that rapidly progressed into T2D when fed HFD. Moreover, Gastrin-SiO2 microspheres markedly reduce glucose absorption in duodenum obtained from patients with T2D. In mice with HFD-induced T2D, Gastrin-SiO2 microspheres reduce intestinal glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion. This study shows the important role of intestinal Gastrin/CCKBR in intestinal glucose absorption. Gastrin-SiO2 microspheres may be a promising strategy for the treatment of patients with T2D.
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Affiliation(s)
- Xue Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
- Department of Cardiologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityState Key Laboratory of Transvascular Implantation DevicesHeart Regeneration and Repair Key Laboratory Zhejiang Province310009HangzhouChina
| | - Xing Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Yunpeng Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Anxiong Long
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Wei Liu
- Graduate School of Hebei North UniversityZhangjiakouHebei075031China
| | - Shiyun Sun
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Shuaibing Lu
- Department of Colorectal SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021BeijingChina
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Xianxian Wu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Xiaodi Jia
- Taihe County People's HospitalThe Taihe Hospital of Wannan Medical College21 Jiankang RoadTaihe CountyAnhui Province236600China
| | - Pedro A Jose
- Department of Pharmacology and PhysiologyThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
- Department of MedicineDivision of Kidney Diseases & HypertensionThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
| | - Qiang Wei
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Xiaoliang Jiang
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Haizeng Zhang
- Department of Colorectal SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021BeijingChina
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Zhiwei Yang
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
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Lecker SH, Greenberg KI. Metabolic Alkalosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:523-528. [PMID: 39577886 DOI: 10.1053/j.akdh.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/23/2024] [Accepted: 08/02/2024] [Indexed: 11/24/2024]
Abstract
Metabolic alkalosis is one of the four cardinal acid-base disorders and perhaps the least well understood by students. Taking a mechanistic approach to etiologies and management can be very helpful in such cases. Particularly, one should focus on the factors that generate the alkalosis (source of fluid loss and composition, less commonly alkali administration) and the factors (extracellular fluid volume status, hormonal systems) that maintain the abnormality.
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Affiliation(s)
- Stewart H Lecker
- Beth Israel Deaconess Medical Center, Division of Nephrology, Harvard Medical School, Boston, MA.
| | - Keiko I Greenberg
- MedStar Georgetown University Hospital, Division of Nephrology, Washington, DC
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Bouyer PG, Salameh AI, Zhou Y, Kolba TN, Boron WF. Effects of extracellular metabolic acidosis and out-of-equilibrium CO 2/HCO 3 - solutions on intracellular pH in cultured rat hippocampal neurons. Front Physiol 2024; 15:1434359. [PMID: 39444753 PMCID: PMC11496273 DOI: 10.3389/fphys.2024.1434359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/28/2024] [Indexed: 10/25/2024] Open
Abstract
Metabolic acidosis (MAc)-an extracellular pH (pHo) decrease caused by a [HCO3 -]o decrease at constant [CO2]o-usually causes intracellular pH (pHi) to fall. Here we determine the extent to which the pHi decrease depends on the pHo decrease vs the concomitant [HCO3 -]o decrease. We use rapid-mixing to generate out-of-equilibrium CO2/HCO3 - solutions in which we stabilize [CO2]o and [HCO3 -]o while decreasing pHo (pure acidosis, pAc), or stabilize [CO2]o and pHo while decreasing [HCO3 -]o (pure metabolic/down, pMet↓). Using the fluorescent dye 2',7'-bis-2-carboxyethyl)-5(and-6)carboxyfluorescein (BCECF) to monitor pHi in rat hippocampal neurons in primary culture, we find that-in naïve neurons-the pHi decrease caused by MAc is virtually the sum of those caused by pAc (∼70%) + pMet↓ (∼30%). However, if we impose a first challenge (MAc1, pAc1, or pMet↓1), allow the neurons to recover, and then impose a second challenge (MAc2, pAc2, or pMet↓2), we find that pAc/pMet↓ additivity breaks down. In a twin-challenge protocol in which challenge #2 is MAc, the pHo and [HCO3 -]o decreases during challenge #1 must be coincident in order to mimic the effects of MAc1 on MAc2. Conversely, if challenge #1 is MAc, then the pHo and [HCO3 -]o decreases during challenge #2 must be coincident in order for MAc1 to produce its physiological effects during the challenge #2 period. We conclude that the history of challenge #1 (MAc1, pAc1, or pMet↓1)-presumably as detected by one or more acid-base sensors-has a major impact on the pHi response during challenge #2 (MAc2, pAc2, or pMet↓2).
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Affiliation(s)
- Patrice G. Bouyer
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Biology, Valparaiso University, Valparaiso, IN, United States
| | - Ahlam I. Salameh
- Preclinical Sciences Division, Kent State University College of Podiatric Medicine, Independence, OH, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Yuehan Zhou
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Tiffany N. Kolba
- Department of Mathematics & Statistics, Valparaiso University, Valparaiso, IN, United States
| | - Walter F. Boron
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
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TSUKANO K, YAMAKAWA S, SUZUKI K. Blood chloride abnormalities in diarrheic neonatal calves with metabolic acidosis. J Vet Med Sci 2024; 86:721-726. [PMID: 38797680 PMCID: PMC11251811 DOI: 10.1292/jvms.24-0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/12/2024] [Indexed: 05/29/2024] Open
Abstract
The present study investigated the prevalence of blood chloride (Cl) abnormalities in diarrheic neonatal calves with metabolic acidosis and attempted to identify the most relevant electrolyte abnormality to these abnormalities. A retrospective analysis was conducted on the medical records of 157 diarrheic neonatal calves aged 10.3 ± 4.2 days old with metabolic acidosis. Hypochloremia, normochloremia, and hyperchloremia were observed in 8.9% (14/157), 43.3% (68/157), and 47.8% (68/157), respectively, of diarrheic calves with metabolic acidosis. This distribution remained similar regardless of age (under 8 days or 8 days and older). Furthermore, a multiple logistic regression analysis showed that variations in values for blood sodium [Na (regression coefficients 0.877; 95% confidence interval (CI) 13.977-134.195; P<0.01)], pH (regression coefficients -10.719; 95% CI -19.076- -2.362; P<0.05), and bicarbonate [HCO3- (regression coefficients -0.555; 95% CI -0.820- -0.290; P<0.01)] were associated with blood Cl abnormalities. The present results revealed that blood Na concentrations were more strongly associated with blood Cl concentrations than blood pH and HCO3- values. In the present study, diarrheic calves with hyperchloremia were characterized by normonatremia and extremely severe metabolic acidosis.
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Affiliation(s)
- Kenji TSUKANO
- Aomori Agricultural Mutual Aid Association, Aomori, Japan
| | - Shohei YAMAKAWA
- Hokkaido Agricultural Mutual Aid Association, Hokkaido, Japan
| | - Kazuyuki SUZUKI
- School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan
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Kunchur MG, Mauch TJ, Parkanzky M, Rahilly LJ. A review of renal tubular acidosis. J Vet Emerg Crit Care (San Antonio) 2024; 34:325-355. [PMID: 39023331 DOI: 10.1111/vec.13407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 10/14/2022] [Accepted: 11/11/2022] [Indexed: 07/20/2024]
Abstract
OBJECTIVE To review the current scientific literature on renal tubular acidosis (RTA) in people and small animals, focusing on diseases in veterinary medicine that result in secondary RTA. DATA SOURCES Scientific reviews and original research publications on people and small animals focusing on RTA. SUMMARY RTA is characterized by defective renal acid-base regulation that results in normal anion gap hyperchloremic metabolic acidosis. Renal acid-base regulation includes the reabsorption and regeneration of bicarbonate in the renal proximal tubule and collecting ducts and the process of ammoniagenesis. RTA occurs as a primary genetic disorder or secondary to disease conditions. Based on pathophysiology, RTA is classified as distal or type 1 RTA, proximal or type 2 RTA, type 3 RTA or carbonic anhydrase II mutation, and type 4 or hyperkalemic RTA. Fanconi syndrome comprises proximal RTA with additional defects in proximal tubular function. Extensive research elucidating the genetic basis of RTA in people exists. RTA is a genetic disorder in the Basenji breed of dogs, where the mutation is known. Secondary RTA in human and veterinary medicine is the sequela of diseases that include immune-mediated, toxic, and infectious causes. Diagnosis and characterization of RTA include the measurement of urine pH and the evaluation of renal handling of substances that should affect acid or bicarbonate excretion. CONCLUSIONS Commonality exists between human and veterinary medicine among the types of RTA. Many genetic defects causing primary RTA are identified in people, but those in companion animals other than in the Basenji are unknown. Critically ill veterinary patients are often admitted to the ICU for diseases associated with secondary RTA, or they may develop RTA while hospitalized. Recognition and treatment of RTA may reverse tubular dysfunction and promote recovery by correcting metabolic acidosis.
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Affiliation(s)
| | - Teri Jo Mauch
- University of Nebraska Medical Center and Children's Hospital, Omaha, Nebraska, USA
- University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | | | - Louisa J Rahilly
- Cape Cod Veterinary Specialists, Buzzards Bay, Massachusetts, USA
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Tzamaloukas AH. Editorial: Dysnatremias and related disorders. Front Med (Lausanne) 2024; 11:1411974. [PMID: 38919944 PMCID: PMC11196840 DOI: 10.3389/fmed.2024.1411974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/28/2024] [Indexed: 06/27/2024] Open
Affiliation(s)
- Antonios H. Tzamaloukas
- Research Service, Raymond. G. Murphy Veterans Affairs Medical Center, Albuquerque, NM, United States
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
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Foerster RH, Lamprecht G, Rischmüller K, Berlin P, Rousing AQ, Sørensen MV, Leipziger J, Berg P. Urinary acid-base excretion deciphers high acid load from colonic bicarbonate loss in intestinal failure patients with ileocolonic anastomosis - Guidance for composition of parenteral support. Clin Nutr 2024; 43:1043-1050. [PMID: 38554476 DOI: 10.1016/j.clnu.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 04/01/2024]
Abstract
BACKGROUND & AIMS Acid-base disturbances are common in short bowel (SB) patients due to increased intestinal bicarbonate loss. However, the resulting systemic acid load has not been quantified. Base excess is used to monitor metabolic acid-base disturbances but inadequately reflects the acid load. Our aim was to investigate the systemic acid/base load in SB-patients to obtain quantitative estimates to guide the composition of parenteral support. METHODS We calculated total acid load in SB patients by summing 24-h urinary net acid excretion (NAE) and the provision of base equivalents in parenteral support. We then compared differences among anatomical SB-types: jejunostomy (SB-J), jejunocolostomy (SB-JC), and jejunoileostomy (SB-JIC). 47 urine samples from 34 SB patients were analyzed for bicarbonate (HCO3-), ammonium (NH4+), and titratable acid (TA) concentrations. NAE was calculated as (TA + NH4+) - HCO3-. Mixed-effects repeated-measures models were used to statistically examine differences between SB-types and associations with parenteral nutrition and NAE. A healthy cohort served as control. RESULTS In comparison to SB-J, SB-JC patients had a 4.1 mmoL/l lower base excess (95% CI: -6.3 to -1.8) and an 84.5 mmol/day higher total acid load (CI: 41.3 to 127.7). There were no significant differences between SB-JIC and SB-J regarding base excess, NAE, or total acid load. Higher amounts of infused acetate, sodium, and chloride, but not the acetate/chloride ratio, were associated with lower NAE and higher base excess. CONCLUSIONS Due to increased colonic bicarbonate loss, patients with SB-JC have a ∼4.4-fold higher acid load than healthy controls. The ion transport mechanisms mediating this bicarbonate loss from the remaining colon need further experimental investigation. NAE could be a useful tool to adjust base infusion in SB.
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Affiliation(s)
- Robert H Foerster
- Rostock University Medical Center, Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock, Germany
| | - Georg Lamprecht
- Rostock University Medical Center, Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock, Germany.
| | - Karen Rischmüller
- Rostock University Medical Center, Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock, Germany
| | - Peggy Berlin
- Rostock University Medical Center, Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock, Germany
| | - Amalie Q Rousing
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
| | - Mads V Sørensen
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
| | - Jens Leipziger
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
| | - Peder Berg
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
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Salcedo-Betancourt JD, Moe OW. The Effects of Acid on Calcium and Phosphate Metabolism. Int J Mol Sci 2024; 25:2081. [PMID: 38396761 PMCID: PMC10889523 DOI: 10.3390/ijms25042081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation. The renal handling of calcium, phosphate and citrate is also affected, with resultant hypercalciuria, hyperphosphaturia and hypocitraturia.
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Affiliation(s)
- Juan D. Salcedo-Betancourt
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Orson W. Moe
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Niles SE, Blazy P, Cheuvront SN, Kenefick RW, Vidyasagar S, Smith AB, Fawkes N, Denman W. Effectiveness of an amino acid beverage formulation in diarrhea-predominant irritable bowel syndrome: A pragmatic real-world study. World J Gastrointest Pharmacol Ther 2023; 14:39-49. [PMID: 38174291 PMCID: PMC10758599 DOI: 10.4292/wjgpt.v14.i5.39] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/16/2023] [Accepted: 11/15/2023] [Indexed: 12/12/2023] Open
Abstract
BACKGROUND Amino-acid based medical foods have shown promise in alleviating symptoms of drug induced gastrointestinal side effects; particularly, diarrhea-predominant symptoms. Irritable bowel syndrome (IBS) is a gastrointestinal disorder that affects up to 9% of people globally, with diarrhea predominant IBS (IBS-D) being the most prevalent subtype. Further trials are needed to explore potential added benefits when integrated into standard care for IBS-D. AIM To assess the effectiveness of an amino acid-based medical food as an adjunct to standard of care for adults with IBS-D. METHODS This is a pragmatic, real world, open label, single arm study comparing a 2-week baseline assessment to a 2-week intervention period. One hundred adults, aged 18 to 65 years, with IBS-D, according to Rome IV criteria, were enrolled after completing a 2-week baseline assessment period and received a 2-week supply of an amino acid based medical food which was consumed at home twice daily on top of their standard of care. The primary outcome was an assessment of tolerability after 2-weeks of consumption, while secondary outcomes included changes in stool consistency (Bristol Stool Form Scale), severity of abdominal pain & discomfort, symptoms of urgency, Global Improvement Survey (GIS), and the IBS severity scoring system (IBS-SSS). RESULTS The test product was well-tolerated as each participant successfully completed the full 14-day trial, and there were no instances of dropouts or discontinuation of the study product reported. Forty percent of participants achieved a 50% or more reduction in the number of days with type 6-7 bowel movements (IBS-D stool consistency responders). Fifty-three percent of participants achieved a clinically meaningful reduction of 30% in mean weekly pain scores, and 55% experienced the same for mean weekly discomfort scores (IBS-D pain and discomfort responders). Participants experienced a mean -109.4 (95% confidence interval: -130.1, -88.8) point reduction on the IBS-SSS and 52% experienced a minimally clinically important difference of > 95 points. An IBS-SSS category shift from severe to moderate or mild occurred in 69% of participants. For functional symptoms, 76% of participants reported symptom relief on the GIS. CONCLUSION The amino acid-based medical food was well-tolerated, when added to the standard of care, and demonstrated improvements in both overall IBS symptom severity and IBS-D symptoms within just 2 wk.
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Affiliation(s)
- Samantha E Niles
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - Phil Blazy
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - Samuel N Cheuvront
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - Robert W Kenefick
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - Sadasivan Vidyasagar
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
- Department of Radiation Oncology, University of Florida, Gainesville, FL 32611, United States
| | - Adam B Smith
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - Neil Fawkes
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
| | - William Denman
- Department of Research and Development, Entrinsic Bioscience, Norwood, MA 02062, United States
- Department of Anesthesiology, Massachusetts General Hospital, Boston, MA 02114, United States
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Liu Z, Xiang L, Tian M, Wang H, Zhao X, Liu K, Yu J, Liu T, Liu S, Mu X, Yang B, Zhang S, Luo J. A Counterion-Free Strategy for Chronic Metabolic Acidosis Based on an Orally Administered Gut-Restricted Inorganic Adsorbent. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2305992. [PMID: 37921507 DOI: 10.1002/adma.202305992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/23/2023] [Indexed: 11/04/2023]
Abstract
Chronic metabolic acidosis, arising as a complication of chronic kidney disease (CKD), not only reduces patients' quality of life but also aggravates renal impairment. The only available therapeutic modality, involving intravenous infusion of NaHCO3 , engenders undesirable sodium retention, thereby increasing hemodynamic load and seriously exacerbating the primary disease. This deleterious cascade extends to the development of cardiovascular diseases. Herein, an orally administered, gut-restricted inorganic adsorbent that can effectively alleviate chronic metabolic acidosis without causing any electrolytic derangement or superfluous cardiovascular strain is developed. The genesis of ABC-350 entails the engineering of bismuth subcarbonate via annealing, thereby yielding a partially β-Bi2 O3 -doped (BiO)2 CO3 biphasic crystalline structure framework enriched with atomic vacancies. ABC-350 can selectively remove chloride ions and protons from the gastrointestinal tract, mimicking the physiological response to gastric acid removal and resulting in increased serum bicarbonate. Owing to its gut-restricted nature, ABC-350 exhibits commendable biosafety, averting undue systemic exposure. In two rat models of metabolic acidosis, ABC-350 emerges not only as a potent mitigator of acidosis but also effects discernible amelioration concerning proximal tubular morphology, interstitial fibrosis, and the incendiary cascades incited by metabolic acidosis. ABC-350, as the translationally relevant material, provides a promising strategy for the treatment of metabolic acidosis.
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Affiliation(s)
- Zhen Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Liang Xiang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Meng Tian
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Haoyu Wang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xin Zhao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Kangfei Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jia Yu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Tianzhi Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shangpeng Liu
- School of Materials Science and Engineering, Tongji University, Shanghai, 201384, China
| | - Xin Mu
- School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Bingxue Yang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shiyi Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jie Luo
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
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Wuttiputhanun T, Townamchai N, Eiam‐Ong S, Takkavatakarn K. Metabolic alkalosis masked presentation of diabetic ketoacidosis: A case report. Clin Case Rep 2023; 11:e8250. [PMID: 38033688 PMCID: PMC10682229 DOI: 10.1002/ccr3.8250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/09/2023] [Accepted: 11/11/2023] [Indexed: 12/02/2023] Open
Abstract
Managing mixed acid-base disorders can be diagnostically challenging, particularly when metabolic acidosis and metabolic alkalosis occur simultaneously. When dealing with metabolic alkalosis, a comprehensive approach involves taking a detailed medical history, assessing volume status, and performing urine chloride analysis. Routine calculation of the anion gap is important to identify masked wide anion gap metabolic acidosis. We report a case of a 32-year-old female with type 1 diabetes mellitus, presented with intractable vomiting for 2 days with hyperglycemia, hypokalemia, and metabolic alkalosis, along with a wide anion gap. She was diagnosed with "diabetic ketoalkalosis" due to diabetic ketoacidosis combined with vomiting-induced metabolic alkalosis. She became clinically stable after resuscitation with normal saline, intravenous potassium, and intravenous insulin.
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Affiliation(s)
- Thunyatorn Wuttiputhanun
- Division of Nephrology, Department of MedicineKing Chulalongkorn Memorial Hospital and Chulalongkorn UniversityBangkokThailand
| | - Natavudh Townamchai
- Division of Nephrology, Department of MedicineKing Chulalongkorn Memorial Hospital and Chulalongkorn UniversityBangkokThailand
| | - Somchai Eiam‐Ong
- Division of Nephrology, Department of MedicineKing Chulalongkorn Memorial Hospital and Chulalongkorn UniversityBangkokThailand
| | - Kullaya Takkavatakarn
- Division of Nephrology, Department of MedicineKing Chulalongkorn Memorial Hospital and Chulalongkorn UniversityBangkokThailand
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12
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Lozano BA, Yankin I, Perry S, Rutter CR. Acid-base and electrolyte evaluation in dogs with upper GI obstruction: 115 dogs (2015-2021). J Small Anim Pract 2023; 64:696-703. [PMID: 37565533 DOI: 10.1111/jsap.13656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 06/10/2023] [Accepted: 06/29/2023] [Indexed: 08/12/2023]
Abstract
OBJECTIVES Metabolic alkalosis, although uncommon in small animals, has been previously associated with gastrointestinal obstructions. Depending on the population and disease process evaluated, previous prevalence of metabolic alkalosis is reported as ranging from 2% to 45% in canine patients. The objective of this study was to determine the prevalence of metabolic alkalosis and other acid-base and electrolyte disorders in a cohort of dogs with a confirmed upper gastrointestinal obstruction. MATERIALS AND METHODS Electronic medical records were reviewed to identify dogs who presented for vomiting with evidence of an upper gastrointestinal obstruction from January 2015 to October 2021. Patients were enrolled only if a preoperative venous blood gas was obtained and analysed in house. Traditional acid-base analysis was utilised to determine an acid-base status before relieving the obstruction. When available, post-operative venous acid-base status was determined within 24 hours after surgery, and compared to preoperative results. RESULTS A total of 115 dogs were included in the study. Twenty-five out of 115 (22%) dogs displayed either a simple metabolic alkalosis or a mixed acid-base disturbance before surgery. Twenty-seven out of 115 dogs (37%) had a normal acid-base status at entry. Seventy-one dogs had pre- and post-operative venous blood gas results available. Metabolic alkalosis was resolved in nearly all patients post-operatively, with no patients displaying a simple metabolic alkalosis. A mixed metabolic acidosis and respiratory alkalosis was the most common condition post-operatively, found in 25 of 71 (35%) dogs. Severe derangements of electrolytes were infrequent preoperatively (3/115; 2.6%). A majority of patients in this study exhibited hypokalaemia (64.4%), hypochloraemia (72.8%) and hyponatraemia (77.4%) on preoperative venous blood gases. Venous pH, Pv CO2 , bicarbonate and base excess were significantly higher preoperatively when compared to the post-operative results. CLINICAL SIGNIFICANCE This study found the prevalence of pre-operative metabolic alkalosis in dogs with a documented upper gastrointestinal obstruction to be lower than previously reported. Surgical or endoscopic alleviation of the upper gastrointestinal obstruction resulted in resolution of metabolic alkalosis in nearly all patients.
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Affiliation(s)
- B A Lozano
- Texas A&M University, Veterinary Medical Teaching Hospital, 408 Raymond Stotzer Pkwy, College Station, TX, 77845, USA
| | - I Yankin
- Texas A&M University, Veterinary Medical Teaching Hospital, 408 Raymond Stotzer Pkwy, College Station, TX, 77845, USA
| | - S Perry
- Texas A&M University, Veterinary Medical Teaching Hospital, 408 Raymond Stotzer Pkwy, College Station, TX, 77845, USA
| | - C R Rutter
- Texas A&M University, Veterinary Medical Teaching Hospital, 408 Raymond Stotzer Pkwy, College Station, TX, 77845, USA
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13
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Viering DH, Vermeltfoort L, Bindels RJ, Deinum J, de Baaij JH. Electrolyte Disorders in Mitochondrial Cytopathies: A Systematic Review. J Am Soc Nephrol 2023; 34:1875-1888. [PMID: 37678265 PMCID: PMC10631606 DOI: 10.1681/asn.0000000000000224] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023] Open
Abstract
SIGNIFICANCE STATEMENT Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies. BACKGROUND Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies. METHODS We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies. RESULTS Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes. CONCLUSIONS Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.
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Affiliation(s)
- Daan H.H.M. Viering
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lars Vermeltfoort
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - René J.M. Bindels
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jaap Deinum
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H.F. de Baaij
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
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14
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Wagner B, Malhotra D, Schmidt D, Raj DS, Khitan ZJ, Shapiro JI, Tzamaloukas AH. Hypertonic Saline Infusion for Hyponatremia: Limitations of the Adrogué-Madias and Other Formulas. KIDNEY360 2023; 4:e555-e561. [PMID: 36758190 PMCID: PMC10278828 DOI: 10.34067/kid.0000000000000075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/10/2023] [Indexed: 02/11/2023]
Abstract
Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of the volume of infused hypertonic saline ( VInf ) should address prevention of overcorrection or undercorrection. Several formulas computing this VInf have been proposed. The limitations common to these formulas consist of (1) failure to include potential determinants of change in serum sodium concentration ([ Na ]) including exchanges between osmotically active and inactive sodium compartments, changes in hydrogen binding of body water to hydrophilic compounds, and genetic influences and (2) inaccurate estimates of baseline body water entered in any formula and of gains or losses of water, sodium, and potassium during treatment entered in formulas that account for such gains or losses. In addition, computing VInf from the Adrogué-Madias formula by a calculation assuming a linear relation between VInf and increase in [ Na ] is a source of errors because the relation between these two variables was proven to be curvilinear. However, these errors were shown to be negligible by a comparison of estimates of VInf by the Adrogué-Madias formula and by a formula using the same determinants of the change in [ Na ] and the curvilinear relation between this change and VInf . Regardless of the method used to correct hyponatremia, monitoring [ Na ] and changes in external balances of water, sodium, and potassium during treatment remain imperative.
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Affiliation(s)
- Brent Wagner
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, New Mexico
- Research Service, Raymond G. Murphy Veterans Affairs Medical Center, Albuquerque, New Mexico
- Kidney Institute of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Deepak Malhotra
- Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio
| | - Darren Schmidt
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Dominic S. Raj
- Division of Nephrology, George Washington University School of Medicine, Washington, DC
| | - Zeid J. Khitan
- Division of Nephrology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Joseph I. Shapiro
- Division of Nephrology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Antonios H. Tzamaloukas
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, New Mexico
- Research Service, Raymond G. Murphy Veterans Affairs Medical Center, Albuquerque, New Mexico
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15
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Tseng T, Seagroves A, Tanawattanacharoen VK, Liang MC, Koppin CM, Keenan M, Davidowitz E, Nguyen E, Chand S, Geffner ME, Chang TP, Kim MS. Electrolyte abnormalities and stress dosing predict illness-related hospitalizations among infants and toddlers with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2023; 98:536-542. [PMID: 36593179 PMCID: PMC10006318 DOI: 10.1111/cen.14876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Infants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for morbidity/mortality arising from life-threatening adrenal crisis. Management of acute illnesses in CAH requires an understanding of factors leading to emergency department (ED) visits and hospitalizations in the first few years of life. We, therefore, examined adrenal crisis at prehospital and ED stages of illness in young children with CAH as they related to medical outcomes. PATIENTS AND DESIGN Retrospective cohort study of 39 children with CAH due to 21-hydroxylase deficiency (0-4 years of age) and 27 age-matched controls. MEASUREMENTS ED visit, acute illness symptoms (fever, vomiting, diarrhoea) and other characteristics (hospitalizations, administration of stress-dose hydrocortisone, electrolyte abnormalities). RESULTS CAH infants and toddlers had significantly higher rates of ED visits (0.50 [0.25-0.88] per person-year) than controls (0 [0-0] per person-year; p < .001). Moreover, CAH children under 6 months old had significantly higher rates of ED visits compared with older ages. Only 50% (51/102) of illness-related ED visits in CAH children were preceded by the administration of either oral (46/51) or intramuscular (11/51) stress dosing by parents. A total of 10.8% of ED visits resulted in hospital admission. Controlling for age and 17-hydroxyprogesterone at diagnosis, electrolyte abnormalities and administration of parenteral hydrocortisone in the ED significantly predicted hospital admission. Receiving a hydrocortisone injection before the ED was a significant predictor of having electrolyte abnormalities. CONCLUSIONS Infants and toddlers with classical CAH are at high risk for acute illness and hospitalizations and often do not receive adequate stress dosing before the ED.
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Affiliation(s)
- Teresa Tseng
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Amy Seagroves
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Veeraya K Tanawattanacharoen
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Mark C Liang
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Christina M Koppin
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Madison Keenan
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Elana Davidowitz
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Eugene Nguyen
- Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Sanjay Chand
- Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Mitchell E Geffner
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
- The Saban Research Institute, Los Angeles, California, USA
- Division of Emergency Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Todd P Chang
- Keck School of Medicine of University of Southern California, Los Angeles, California, USA
- The Saban Research Institute, Los Angeles, California, USA
- Division of Emergency Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Mimi S Kim
- Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California, USA
- The Saban Research Institute, Los Angeles, California, USA
- Division of Emergency Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA
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16
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Wan ER, Iancu D, Ashton E, Siew K, Mohidin B, Sung CC, Nagano C, Bockenhauer D, Lin SH, Nozu K, Walsh SB. Machine Learning to Identify Genetic Salt-Losing Tubulopathies in Hypokalemic Patients. Kidney Int Rep 2023; 8:556-565. [PMID: 36938092 PMCID: PMC10014379 DOI: 10.1016/j.ekir.2022.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/25/2022] Open
Abstract
Introduction Clinically distinguishing patients with the inherited salt-losing tubulopathies (SLTs), Gitelman or Bartter syndrome (GS or BS) from other causes of hypokalemia (LK) patients is difficult, and genotyping is costly. We decided to identify clinical characteristics that differentiate SLTs from LK. Methods A total of 66 hypokalemic patients with possible SLTs were recruited to a prospective observational cohort study at the University College London Renal Tubular Clinic, London. All patients were genotyped for pathogenic variants in genes which cause SLTs; 39 patients had pathogenic variants in genes causing SLTs. We obtained similar data sets from cohorts in Taipei and Kobe, as follows: the combined data set comprised 419 patients; 291 had genetically confirmed SLT. London and Taipei data sets were combined to train machine learning (ML) algorithms, which were then tested on the Kobe data set. Results Single biochemical variables (e.g., plasma renin) were significantly, but inconsistently, different between SLTs and LK in all cohorts. A decision table algorithm using serum bicarbonate and urinary sodium excretion (FENa) achieved a classification accuracy of 74%. This was superior to all the single biochemical variables identified previously. Conclusion ML algorithms can differentiate true SLT in the context of a specialist clinic with some accuracy. However, based on routine biochemistry, the accuracy is insufficient to make genotyping redundant.
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Affiliation(s)
- Elizabeth R. Wan
- Department of Renal Medicine, University College London, London, UK
| | - Daniela Iancu
- Department of Renal Medicine, University College London, London, UK
| | - Emma Ashton
- North East Thames Regional Genetics Service Laboratories, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK
| | - Keith Siew
- Department of Renal Medicine, University College London, London, UK
| | - Barian Mohidin
- Department of Renal Medicine, University College London, London, UK
| | - Chih-Chien Sung
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Detlef Bockenhauer
- Department of Renal Medicine, University College London, London, UK
- Department of Pediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK
| | - Shih-Hua Lin
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Stephen B. Walsh
- Department of Renal Medicine, University College London, London, UK
- Correspondence: Stephen B. Walsh, Department of Renal Medicine, University College London, 1st Floor Medical School, Royal Free Hospital, Rowland Hill Street, Hampstead, London, NW3 2PF, UK.
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17
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Peden DL, Funnell MP, Reynolds KM, Kenefick RW, Cheuvront SN, Mears SA, James LJ. Post-exercise rehydration: Comparing the efficacy of three commercial oral rehydration solutions. Front Sports Act Living 2023; 5:1158167. [PMID: 37181252 PMCID: PMC10174327 DOI: 10.3389/fspor.2023.1158167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/04/2023] [Indexed: 05/16/2023] Open
Abstract
Introduction This study compared the efficacy of three commercial oral rehydration solutions (ORS) for restoring fluid and electrolyte balance, after exercise-induced dehydration. Method Healthy, active participants (N = 20; ♀ = 3; age ∼27 y, V˙O2peak ∼52 ml/kg/min) completed three randomised, counterbalanced trials whereby intermittent exercise in the heat (∼36°C, ∼50% humidity) induced ∼2.5% dehydration. Subsequently, participants rehydrated (125% fluid loss in four equal aliquots at 0, 1, 2, 3 h) with a glucose-based (G-ORS), sugar-free (Z-ORS) or amino acid-based sugar-free (AA-ORS) ORS of varying electrolyte composition. Urine output was measured hourly and capillary blood samples collected pre-exercise, 0, 2 and 5 h post-exercise. Sodium, potassium, and chloride concentrations in urine, sweat, and blood were determined. Results Net fluid balance peaked at 4 h and was greater in AA-ORS (141 ± 155 ml) and G-ORS (101 ± 195 ml) than Z-ORS (-47 ± 208 ml; P ≤ 0.010). Only AA-ORS achieved positive sodium and chloride balance post-exercise, which were greater for AA-ORS than G-ORS and Z-ORS (P ≤ 0.006), as well as for G-ORS than Z-ORS (P ≤ 0.007) from 1 to 5 h. Conclusion when provided in a volume equivalent to 125% of exercise-induced fluid loss, AA-ORS produced comparable/superior fluid balance and superior sodium/chloride balance responses to popular glucose-based and sugar-free ORS.
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Affiliation(s)
- Donald L. Peden
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Mark P. Funnell
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Kirsty M. Reynolds
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | | | - Samuel N. Cheuvront
- Entrinsic Bioscience, LLC, Norwood, MA, United States
- Sports Science Synergy, LLC, Franklin, MA, United States
| | - Stephen A. Mears
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
| | - Lewis J. James
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
- Correspondence: Lewis J. James
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18
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Muacevic A, Adler JR, Naito Y, Sano C, Ohta R. Acute Exacerbation of Hypereosinophilic Syndrome Complicated With Dermatitis, Enteritis, and Myositis: A Case Report. Cureus 2023; 15:e34090. [PMID: 36843679 PMCID: PMC9946152 DOI: 10.7759/cureus.34090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2023] [Indexed: 01/24/2023] Open
Abstract
Hypereosinophilic syndrome is a disease that presents with a variety of symptoms caused by an abnormal rise in eosinophils in the blood and infiltration into various organs. Typical symptoms include skin symptoms and diarrhea. Diagnosis may be difficult because of the self-limiting phases of the disease with various symptoms. In addition, diagnosis may be delayed by the presence of rare concomitant symptoms, such as muscle pain and numbness. Here, we report the case of a 67-year-old patient with asymptomatic hypereosinophilia with chronic diarrhea, acute-onset weakness, and myalgia. We diagnosed eosinophilic gastroenteropathy, chronic urticaria, and eosinophilic myositis through multiple biopsies of the skin and colon. This case shows that chronic hypereosinophilic syndrome can be exacerbated transiently with acute symptoms and that prompt examination and treatment of hypereosinophilic syndrome based on the involved organs is recommended in a background of eosinophilia.
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19
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Do C, Evans GJ, DeAguero J, Escobar GP, Lin HC, Wagner B. Dysnatremia in Gastrointestinal Disorders. Front Med (Lausanne) 2022; 9:892265. [PMID: 35646996 PMCID: PMC9136014 DOI: 10.3389/fmed.2022.892265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/22/2022] [Indexed: 01/19/2023] Open
Abstract
The primary solute of the milieu intérieur is sodium and accompanying anions. The solvent is water. The kidneys acutely regulate homeostasis in filtration, secretion, and resorption of electrolytes, non-electrolytes, and minerals while balancing water retention and clearance. The gastrointestinal absorptive and secretory functions enable food digestion and water absorption needed to sustain life. Gastrointestinal perturbations including vomiting and diarrhea can lead to significant volume and electrolyte losses, overwhelming the renal homeostatic compensatory mechanisms. Dysnatremia, potassium and acid-base disturbances can result from gastrointestinal pathophysiologic processes. Understanding the renal and gastrointestinal contributions to homeostatis are important for the clinical evaluation of perturbed volume disturbances.
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Affiliation(s)
- Catherine Do
- Division of Nephrology, Department of Medicine, Kidney Institute of New Mexico, University of New Mexico Health Science Center, Albuquerque, NM, United States,New Mexico Veterans Administration Health Care System, Albuquerque, NM, United States,University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Gretta J. Evans
- University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Joshua DeAguero
- Division of Nephrology, Department of Medicine, Kidney Institute of New Mexico, University of New Mexico Health Science Center, Albuquerque, NM, United States,University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - G. Patricia Escobar
- Division of Nephrology, Department of Medicine, Kidney Institute of New Mexico, University of New Mexico Health Science Center, Albuquerque, NM, United States,University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Henry C. Lin
- New Mexico Veterans Administration Health Care System, Albuquerque, NM, United States
| | - Brent Wagner
- Division of Nephrology, Department of Medicine, Kidney Institute of New Mexico, University of New Mexico Health Science Center, Albuquerque, NM, United States,New Mexico Veterans Administration Health Care System, Albuquerque, NM, United States,University of New Mexico Health Sciences Center, Albuquerque, NM, United States,*Correspondence: Brent Wagner
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20
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Buzakuk B, van der Voort J. Metabolic mayhem. The advantage of keeping your nose both in the books and in the nappy! Arch Dis Child Educ Pract Ed 2022; 107:150-155. [PMID: 34131008 DOI: 10.1136/archdischild-2019-318477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/21/2021] [Indexed: 11/03/2022]
Abstract
This case presentation takes you on a journey of diagnostic hurdles, covering a common neonatal presentation: abdominal distention with failure to pass meconium, followed by a presentation in infancy with metabolic, renal and electrolyte abnormalities. The article provides a systematic approach to the different clinical problems, allowing interpretation of results, making differential diagnoses and deciding on investigations and management.
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Affiliation(s)
- Buthaina Buzakuk
- Paediatrics and Paediatric Gastroenterology, Swansea Bay University Health Board, Swansea, Neath Port Talbot, UK
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21
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Kramarov S, Yevtushenko V, Yevtushenko О, Maevska Y, Babak V. The problem of dehydration in pediatrics. CHILD`S HEALTH 2022; 16:296-303. [DOI: 10.22141/2224-0551.16.4.2021.236909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Dehydration syndrome often complicates the course of various diseases in children. The article covers the main pathological conditions that are accompanied by fluid loss, such as infectious diarrhea, cyclic vomiting syndrome, non-diabetic ketosis and ketoacidosis. The pathophysiological mechanisms that lead to water and electrolyte loss are described, as well as methods for correcting dehydration in pediatrics. We presented the results of a clinical study of Reogel, which was used for oral rehydration in children with acute infectious diarrhea receiving inpatient treatment. According to the results of this observation, we did not find a significant difference in the duration of the main clinical symptoms of the disease, such as diarrhea, vomiting and dehydration symptoms, as well as the frequency and duration of parenteral rehydration between groups of children receiving Reogel and standard oral rehydration. The results of this study give grounds to consider Reogel as an alternative to traditional oral rehydration in children with infectious diarrhea, accompanied by mild and moderate dehydration.
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22
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Whittamore JM, Hatch M. Oxalate Flux Across the Intestine: Contributions from Membrane Transporters. Compr Physiol 2021; 12:2835-2875. [PMID: 34964122 DOI: 10.1002/cphy.c210013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.
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Affiliation(s)
- Jonathan M Whittamore
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Marguerite Hatch
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
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23
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Sangnes DA, Dimcevski G, Frey J, Søfteland E. Diabetic diarrhoea: A study on gastrointestinal motility, pH levels and autonomic function. J Intern Med 2021; 290:1206-1218. [PMID: 34089624 DOI: 10.1111/joim.13340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chronic diarrhoea is a common, but poorly investigated diabetes complication. Autonomic neuropathy is a leading pathophysiological theory founded on old, small studies. Studies of gastrointestinal motility and pH levels are lacking. OBJECTIVES Using new diagnostic methods, we aimed to find out if diabetic diarrhoea was associated with alterations in gastrointestinal motility, pH levels and autonomic function. METHODS Fifty-seven patients (42 women, 46 with type 1 diabetes) were prospectively included. Symptoms were evaluated with the gastrointestinal symptom rating scale, defining ≥4 points as cases with diarrhoea. Patients scoring <4 were used as controls. We used the wireless motility capsule to measure gastrointestinal transit times, pH levels and contractility parameters. Autonomic function was assessed by measuring heart rate variability, baroreflex sensitivity and orthostatic hypotension. RESULTS Seventeen patients (30%) had diarrhoea. Compared with controls, cases had slower gastric emptying (21:46 vs. 4:14, h:min, p = 0.03) and faster colonic transit (18:37 vs. 54:25, p < 0.001). Cases had increased intraluminal pH in the antrum (2.4 vs. 1.2, p = 0.009), caecum (7.3 vs. 6.4, p = 0.008) and entire colon (7.1 vs. 6.7, p = 0.05). They also had a decreased pH difference across the pylorus (3.3 vs. 4.9, p = 0.004) and ileocaecal junction (0.6 vs 1.0, p = 0.009). The groups did not differ in autonomic function, but diastolic blood pressure drop correlated rs = -0.34 (p = 0.04) with colonic transit time. CONCLUSIONS Patients with diabetic diarrhoea had altered gastrointestinal transit and intraluminal pH levels, but minimal changes in autonomic function. Our results suggest that tests of gastrointestinal function are clinically useful in diabetic diarrhoea.
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Affiliation(s)
- Dag A Sangnes
- Department of Medicine, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Jakub Frey
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eirik Søfteland
- Department of Medicine, Haukeland University Hospital, Bergen, Norway.,Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
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24
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Grubb SM, Riddle M. Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure. Mil Med 2021; 186:e1246-e1249. [PMID: 33252133 DOI: 10.1093/milmed/usaa530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/10/2020] [Accepted: 11/20/2020] [Indexed: 11/14/2022] Open
Abstract
Cholera is a well known cause of significant disease, particularly in resource-poor nations, but it is very rare in developed countries. The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. In the following case, a 60-year-old man with no recent travel history presented to the emergency department with muscle cramping, abdominal pain, and gastrointestinal distress. It was later confirmed that he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. After a complicated hospital course, he fortunately made a complete recovery. This case demonstrates that common complaints may result in uncommon diagnoses. It is important to pay attention to the clinical situation and intervene accordingly.
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Affiliation(s)
- Seth M Grubb
- Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA
| | - Mark Riddle
- Department of Emergency Medicine, Carl R. Darnall Army Medical Center, Fort Hood, TX 78628, USA
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25
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Suarez J, Knape K, Carey J. Evaluation of animal feed grade sodium bisulfate supplementation on performance, intestinal morphology and vitamin D status of broilers challenged with coccidiosis vaccine. J APPL POULTRY RES 2021. [DOI: 10.1016/j.japr.2021.100171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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26
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Nechipurenko YD, Semyonov DA, Lavrinenko IA, Lagutkin DA, Generalov EA, Zaitceva AY, Matveeva OV, Yegorov YE. The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19. BIOLOGY 2021; 10:852. [PMID: 34571729 PMCID: PMC8469745 DOI: 10.3390/biology10090852] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/23/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022]
Abstract
COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest that the pathogenesis of severe forms of COVID-19 can be associated with acidosis. This review article discusses several mechanisms potentially linking the damaging effects of COVID-19 with acidosis and shows the existence of a vicious cycle between the development of hypoxia and acidosis in COVID-19 patients. At the early stages of the disease, inflammation, difficulty in gas exchange in the lungs and thrombosis collectively contribute to the onset of acidosis. In accordance with the Verigo-Bohr effect, a decrease in blood pH leads to a decrease in oxygen saturation, which contributes to the exacerbation of acidosis and results in a deterioration of the patient's condition. A decrease in pH can also cause conformational changes in the S-protein of the virus and thus lead to a decrease in the affinity and avidity of protective antibodies. Hypoxia and acidosis lead to dysregulation of the immune system and multidirectional pro- and anti-inflammatory reactions, resulting in the development of a "cytokine storm". In this review, we highlight the potential importance of supporting normal blood pH as an approach to COVID-19 therapy.
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Affiliation(s)
- Yury D. Nechipurenko
- Laboratory DNA-Protein Recognition, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Denis A. Semyonov
- Institute of Molecular Medicine and Pathobiochemistry, Voyno-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk 660022, Russia;
- Institute of Biophysics Siberian Branch of Russian Academy of Sciences, Krasnoyarsk 660036, Russia
| | - Igor A. Lavrinenko
- Department of Human and Animal Physiology, Faculty of Medicine and Biology, Voronezh State University, Voronezh 394018, Russia;
| | - Denis A. Lagutkin
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia;
| | - Evgenii A. Generalov
- Department of Biophysics, Faculty of Physics, Lomonosov Moscow State University, Moscow 119991, Russia;
| | - Anna Y. Zaitceva
- Laboratory of Medical Analytical Methods and Devices, Institute for Analytical Instrumentation of the Russian Academy of Sciences, St. Petersburg 198095, Russia;
| | | | - Yegor E. Yegorov
- Laboratory of Cellular Bases for the Development of Malignant Diseases, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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27
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The Hormetic Effect of Metformin: "Less Is More"? Int J Mol Sci 2021; 22:ijms22126297. [PMID: 34208371 PMCID: PMC8231127 DOI: 10.3390/ijms22126297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.
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28
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Kamel KS, Halperin ML. Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders. Kidney Int Rep 2021; 6:1211-1224. [PMID: 34013099 PMCID: PMC8116912 DOI: 10.1016/j.ekir.2021.02.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 02/01/2021] [Indexed: 01/16/2023] Open
Abstract
We discuss the use of urine electrolytes and urine osmolality in the clinical diagnosis of patients with fluid, electrolytes, and acid-base disorders, emphasizing their physiological basis, their utility, and the caveats and limitations in their use. While our focus is on information obtained from measurements in the urine, clinical diagnosis in these patients must integrate information obtained from the history, the physical examination, and other laboratory data.
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Affiliation(s)
- Kamel S. Kamel
- Renal Division, St. Michael’s Hospital and The University of Toronto, Toronto, Ontario, Canada
- Keenan Research Center in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Mitchell L. Halperin
- Renal Division, St. Michael’s Hospital and The University of Toronto, Toronto, Ontario, Canada
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29
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Cheuvront SN, Kenefick RW, Luque L, Mitchell KM, Vidyasagar S. Are oral rehydration solutions optimized for treating diarrhea? Nutr Health 2021; 27:461-465. [PMID: 33583247 DOI: 10.1177/0260106021991641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND A historical turning point occurred in the treatment of diarrhea when it was discovered that glucose could enhance intestinal sodium and water absorption. Adding glucose to salt water (oral rehydration solution, ORS) more efficiently replaced intestinal water and salt losses. AIM Provide a novel hypothesis to explain why mainstream use of ORS has been strongly recommended, but weakly adopted. METHODS Traditional (absorptive) and novel (secretory) physiological functions of glucose in an ORS were reviewed. RESULTS Small amounts of glucose can stimulate both intestinal absorption and secretion. Glucose can exacerbate a net secretory state and may aggravate pathogen-induced diarrhea, particularly for pathogens that affect glucose transport. CONCLUSION A hypothesis is made to explain why glucose-based ORS does not appreciably reduce diarrheal stool volume and why modern food science initiatives should focus on ORS formulations that replace water and electrolytes while also reducing stool volume and duration of diarrhea.
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30
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Smith NW, Shorten PR, Altermann E, Roy NC, McNabb WC. Examination of hydrogen cross-feeders using a colonic microbiota model. BMC Bioinformatics 2021; 22:3. [PMID: 33407079 PMCID: PMC7789523 DOI: 10.1186/s12859-020-03923-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/07/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hydrogen cross-feeding microbes form a functionally important subset of the human colonic microbiota. The three major hydrogenotrophic functional groups of the colon: sulphate-reducing bacteria (SRB), methanogens and reductive acetogens, have been linked to wide ranging impacts on host physiology, health and wellbeing. Results An existing mathematical model for microbial community growth and metabolism was combined with models for each of the three hydrogenotrophic functional groups. The model was further developed for application to the colonic environment via inclusion of responsive pH, host metabolite absorption and the inclusion of host mucins. Predictions of the model, using two existing metabolic parameter sets, were compared to experimental faecal culture datasets. Model accuracy varied between experiments and measured variables and was most successful in predicting the growth of high relative abundance functional groups, such as the Bacteroides, and short chain fatty acid (SCFA) production. Two versions of the colonic model were developed: one representing the colon with sequential compartments and one utilising a continuous spatial representation. When applied to the colonic environment, the model predicted pH dynamics within the ranges measured in vivo and SCFA ratios comparable to those in the literature. The continuous version of the model simulated relative abundances of microbial functional groups comparable to measured values, but predictions were sensitive to the metabolic parameter values used for each functional group. Sulphate availability was found to strongly influence hydrogenotroph activity in the continuous version of the model, correlating positively with SRB and sulphide concentration and negatively with methanogen concentration, but had no effect in the compartmentalised model version. Conclusions Although the model predictions compared well to only some experimental measurements, the important features of the colon environment included make it a novel and useful contribution to modelling the colonic microbiota.
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Affiliation(s)
- Nick W Smith
- School of Food and Advanced Technology, Massey University, Palmerston North, New Zealand.,Riddet Institute, Massey University, Private Bag 11222, Palmerston North, 4442, New Zealand.,AgResearch, Ruakura Research Centre, Private Bag 3123, Hamilton, 3240, New Zealand
| | - Paul R Shorten
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North, 4442, New Zealand. .,AgResearch, Ruakura Research Centre, Private Bag 3123, Hamilton, 3240, New Zealand.
| | - Eric Altermann
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North, 4442, New Zealand.,AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston North, 4442, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Nicole C Roy
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North, 4442, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand.,Department of Human Nutrition, University of Otago, Dunedin, New Zealand.,Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Warren C McNabb
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North, 4442, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
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31
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Pitchumoni CS. Gastrointestinal Physiology and Aging. GERIATRIC GASTROENTEROLOGY 2021:155-200. [DOI: 10.1007/978-3-030-30192-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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32
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Quade BN, Parker MD, Occhipinti R. The therapeutic importance of acid-base balance. Biochem Pharmacol 2021; 183:114278. [PMID: 33039418 PMCID: PMC7544731 DOI: 10.1016/j.bcp.2020.114278] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.
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Affiliation(s)
- Bianca N Quade
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA
| | - Mark D Parker
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA; Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; State University of New York Eye Institute, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Rossana Occhipinti
- Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
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33
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Klaerner G, Shao J, Biyani K, Kade M, Kierstead P, Gbur R, Tabakman S, Nguyen S, Buysse J. Mechanism of Action of Veverimer: A Novel, Orally Administered, Nonabsorbed, Counterion-Free, Hydrochloric Acid Binder under Development for the Treatment of Metabolic Acidosis in Chronic Kidney Disease. J Pharmacol Exp Ther 2020; 375:439-450. [PMID: 33033169 DOI: 10.1124/jpet.120.000190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
Current management of metabolic acidosis in patients with chronic kidney disease (CKD) relies on dietary intervention to reduce daily endogenous acid production or neutralization of retained acid with oral alkali (sodium bicarbonate, sodium citrate). Veverimer is being developed as a novel oral treatment for metabolic acidosis through removal of intestinal acid, resulting in an increase in serum bicarbonate. Veverimer is a free-amine polymer that combines high capacity and selectivity to bind and remove hydrochloric acid (HCl) from the gastrointestinal (GI) tract. In vitro studies demonstrated that veverimer had a binding capacity of 10.7 ± 0.4 mmol HCl per gram of polymer with significant binding capacity (>5 mmol/g) across the range of pH values found in the human GI tract (1.5-7). Upon protonation, veverimer bound chloride with high specificity but showed little or no binding of phosphate, citrate, or taurocholate (<1.5 mmol/g), which are all anions commonly found in the human GI tract. Administration of veverimer to rats with adenine-induced CKD and metabolic acidosis resulted in a significant increase in fecal chloride excretion and a dose-dependent increase in serum bicarbonate to within the normal range compared with untreated controls. Absorption, distribution, metabolism, and excretion studies in rats and dogs dosed with 14C-labeled veverimer showed that the polymer was not absorbed from the GI tract and was quantitatively eliminated in the feces. Acid removal by veverimer, an orally administered, nonabsorbed polymer, may provide a potential new treatment for metabolic acidosis in patients with CKD. SIGNIFICANCE STATEMENT: Metabolic acidosis is a complication of chronic kidney disease (CKD) as well as a cause of CKD progression. Veverimer is a high-capacity, selective, nonabsorbed, hydrochloric acid-binding polymer being developed as a treatment for metabolic acidosis. Veverimer binds and removes hydrochloric acid from the gastrointestinal tract, resulting in increased serum bicarbonate and the correction of metabolic acidosis. Veverimer is not an ion-exchange resin and does not deliver sodium or other counterions, and so it may be appropriate for patients with CKD with and without sodium-sensitive comorbidities.
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Affiliation(s)
- Gerrit Klaerner
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Jun Shao
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Kalpesh Biyani
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Matthew Kade
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Paul Kierstead
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Randi Gbur
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Scott Tabakman
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Son Nguyen
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Jerry Buysse
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
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Shan W, Hu Y, Ding J, Yang X, Lou J, Du Q, Liao Q, Luo L, Xu J, Xie R. Advances in Ca 2+ modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review). Exp Ther Med 2020; 20:8. [PMID: 32934673 PMCID: PMC7471861 DOI: 10.3892/etm.2020.9136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 05/22/2020] [Indexed: 11/29/2022] Open
Abstract
Intracellular calcium (Ca2+) is a critical cell signaling component in gastrointestinal (GI) physiology. Cytosolic calcium ([Ca2+]cyt), as a secondary messenger, controls GI epithelial fluid and ion transport, mucus and neuropeptide secretion, as well as synaptic transmission and motility. The key roles of Ca2+ signaling in other types of secretory cell (including those in the airways and salivary glands) are well known. However, its action in GI epithelial secretion and the underlying molecular mechanisms have remained to be fully elucidated. The present review focused on the role of [Ca2+]cyt in GI epithelial anion secretion. Ca2+ signaling regulates the activities of ion channels and transporters involved in GI epithelial ion and fluid transport, including Cl- channels, Ca2+-activated K+ channels, cystic fibrosis (CF) transmembrane conductance regulator and anion/HCO3- exchangers. Previous studies by the current researchers have focused on this field over several years, providing solid evidence that Ca2+ signaling has an important role in the regulation of GI epithelial anion secretion and uncovering underlying molecular mechanisms. The present review is largely based on previous studies by the current researchers and provides an overview of the currently known molecular mechanisms of GI epithelial anion secretion with an emphasis on Ca2+-mediated ion secretion and its dysregulation in GI disorders. In addition, previous studies by the current researchers demonstrated that different regulatory mechanisms are in place for GI epithelial HCO3- and Cl- secretion. An increased understanding of the roles of Ca2+ signaling and its targets in GI anion secretion may lead to the development of novel strategies to inhibit GI diseases, including the enhancement of fluid secretion in CF and protection of the GI mucosa in ulcer diseases.
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Affiliation(s)
- Weixi Shan
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yanxia Hu
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jianhong Ding
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xiaoxu Yang
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jun Lou
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qian Du
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qiushi Liao
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Lihong Luo
- Department of Oncology and Geriatrics, Traditional Chinese Medicine Hospital of Chishui City, Guizhou 564700, P.R. China
| | - Jingyu Xu
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Rui Xie
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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Sodium bisulfate feed additive aids broilers in growth and intestinal health during a coccidiosis challenge. Poult Sci 2020; 99:5324-5330. [PMID: 33142448 PMCID: PMC7647734 DOI: 10.1016/j.psj.2020.07.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 06/19/2020] [Accepted: 07/22/2020] [Indexed: 12/13/2022] Open
Abstract
Sodium bisulfate (SB) was evaluated on its ability to improve broiler growth and intestinal structure with(out) a coccidia challenge. One thousand two hundred Cobb500 day-old males were randomly assigned within 4 experimental groups with a 2 × 2 factorial design, with (out) SB in the diet and with(out) a day 0 coccidia challenge using a 10× dose of a commercial vaccine. At day 7, oocysts per gram of feces were determined. At day 0, 14, 28, and 41, BW and feed consumption were measured. At day 21, 20 birds per treatment were subjectively scored for coccidia lesions, and jejunal histologic samples were collected for villi measurements. Twenty additional birds were given fluorescein isothiocyanate-dextran to determine gut permeability. At day 41, 10 birds per treatment had histologic samples collected. Statistical analysis was conducted in JMP Pro 14 using GLM procedure to compare disease state and diet. Means were separated using Dunnett's test (P ≤ 0.05) with the nonchallenged standard diet treatment that is considered the control. All parameters measured indicated an effect due to the coccidia inoculation. Therefore, effects of diet on (non)challenged treatments were determined using a Student t test (P ≤ 0.05). Limited differences due to diet were seen for the nonchallenged production data. Sodium bisulfate had a thinner villi base width (P = 0.04) on day 21 and greater villi height (P = 0.03), smaller base width (P = 0.04), thicker muscularis (P = 0.03), and lower crypt: height ratio (P = 0.01) on day 41. Challenged SB had similar gut permeability to the nonchallenged control (P = 0.94) on day 21. There was no difference in flock uniformity, feed intake, oocysts per gram of feces, or lesion scores between challenged treatments. Challenged SB had greater BW on day 14 (P < 0.0001), 28 (P < 0.0001), and 41 (P = 0.02). Feed conversion ratio from day 0 to 14 was also lower (P = 0.0002). Challenged SB had smaller crypts (P = 0.02) and therefore a smaller crypt: height ratio (P = 0.03) on day 21. Challenged control had a larger apical width (P = 0.03) and thicker muscularis (P = 0.04) on day 41. Overall, the addition of SB during coccidial enteropathy aided in BW, feed conversion ratio, and villi health with no observed effects on parasite cycling.
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Shin DH, Kim M, Kim Y, Jun I, Jung J, Nam JH, Cheng MH, Lee MG. Bicarbonate permeation through anion channels: its role in health and disease. Pflugers Arch 2020; 472:1003-1018. [PMID: 32621085 DOI: 10.1007/s00424-020-02425-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 12/31/2022]
Abstract
Many anion channels, frequently referred as Cl- channels, are permeable to different anions in addition to Cl-. As the second-most abundant anion in the human body, HCO3- permeation via anion channels has many important physiological roles. In addition to its classical role as an intracellular pH regulator, HCO3- also controls the activity and stability of dissolved proteins in bodily fluids such as saliva, pancreatic juice, intestinal fluid, and airway surface liquid. Moreover, HCO3- permeation through these channels affects membrane potentials that are the driving forces for transmembrane transport of solutes and water in epithelia and affect neuronal excitability in nervous tissue. Consequently, aberrant HCO3- transport via anion channels causes a number of human diseases in respiratory, gastrointestinal, genitourinary, and neuronal systems. Notably, recent studies have shown that the HCO3- permeabilities of several anion channels are not fixed and can be altered by cellular stimuli, findings which may have both physiological and pathophysiological significance. In this review, we summarize recent progress in understanding the molecular mechanisms and the physiological roles of HCO3- permeation through anion channels. We hope that the present discussions can stimulate further research into this very important topic, which will provide the basis for human disorders associated with aberrant HCO3- transport.
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Affiliation(s)
- Dong Hoon Shin
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Minjae Kim
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Yonjung Kim
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Ikhyun Jun
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
- The Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Jinsei Jung
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Joo Hyun Nam
- Department of Physiology, Dongguk University College of Medicine, 123 Dongdae-ro, Kyungju, 780-714, Republic of Korea
| | - Mary Hongying Cheng
- Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Min Goo Lee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea.
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Coffman KE, Mitchell KM, Salgado RM, Miller GD, Kenefick RW, Cheuvront SN. Potential for dehydration to impact the athlete biological passport. Drug Test Anal 2020; 12:1206-1211. [DOI: 10.1002/dta.2811] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 01/06/2023]
Affiliation(s)
- Kirsten E. Coffman
- Thermal and Mountain Medicine Division U.S. Army Research Institute of Environmental Medicine Natick MA 01760 US
| | - Katherine M. Mitchell
- Thermal and Mountain Medicine Division U.S. Army Research Institute of Environmental Medicine Natick MA 01760 US
| | - Roy M. Salgado
- Thermal and Mountain Medicine Division U.S. Army Research Institute of Environmental Medicine Natick MA 01760 US
| | - Geoffrey D. Miller
- Sports Medicine Research and Testing Laboratory Salt Lake City UT 84095 US
| | - Robert W. Kenefick
- Thermal and Mountain Medicine Division U.S. Army Research Institute of Environmental Medicine Natick MA 01760 US
| | - Samuel N. Cheuvront
- Biophysics and Biomedical Modeling Division U.S. Army Research Institute of Environmental Medicine Natick MA 01760 US
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Seifter JL. Body Fluid Compartments, Cell Membrane Ion Transport, Electrolyte Concentrations, and Acid-Base Balance. Semin Nephrol 2020; 39:368-379. [PMID: 31300092 DOI: 10.1016/j.semnephrol.2019.04.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Measurements made in the blood, part of the extracellular compartment, are used in the clinical assessment of acid-base disorders; however, intracellular events determine much of the metabolic importance of these disorders. Intracellular and interstitial compartment acid-base balance is complex and varies in different tissues. This review considers the determination of extracellular pH in the context of ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. A further consideration is the role of these membrane transporters in the generation of acid-base disorders and the associated disruption of electrolyte balance. This review suggests a process of internal and external balance for pH regulation similar to that of potassium, and considers the role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders. Electroneutrality of electrolytes in the extracellular fluid is a fundamental feature of reciprocal changes in Cl- or non-Cl- anions and HCO3-. Normal mechanisms for protecting cell pH and producing normal gastrointestinal and renal secretions in healthy states also may result in disease when abnormal. In a similar manner, organic anions such as ketoacid anions and lactate, normally transported as fuels between organs, result in acid-base disturbances in disease. Understanding the genomic basis of these transporters may contribute to specific treatments.
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FitzHenry F, Eden SK, Denton J, Cao H, Cao A, Reeves R, Chen G, Gobbel G, Wells N, Matheny ME. Prevalence and Risk Factors for Opioid-Induced Constipation in an Older National Veteran Cohort. Pain Res Manag 2020; 2020:5165682. [PMID: 32318129 PMCID: PMC7149448 DOI: 10.1155/2020/5165682] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/27/2020] [Accepted: 02/18/2020] [Indexed: 12/22/2022]
Abstract
Objectives This research describes the prevalence and covariates associated with opioid-induced constipation (OIC) in an observational cohort study utilizing a national veteran cohort and integrated data from the Center for Medicare and Medicaid Services (CMS). Methods A cohort of 152,904 veterans with encounters between 1 January 2008 and 30 November 2010, an exposure to opioids of 30 days or more, and no exposure in the prior year was developed to establish existing conditions and medications at the start of the opioid exposure and determining outcomes through the end of exposure. OIC was identified through additions/changes in laxative prescriptions, all-cause constipation identification through diagnosis, or constipation related procedures in the presence of opioid exposure. The association of time to constipation with opioid use was analyzed using Cox proportional hazard regression adjusted for patient characteristics, concomitant medications, laboratory tests, and comorbidities. Results The prevalence of OIC was 12.6%. Twelve positively associated covariates were identified with the largest associations for prior constipation and prevalent laxative (any laxative that continued into the first day of opioid exposure). Among the 17 negatively associated covariates, the largest associations were for erythromycins, androgens/anabolics, and unknown race. Conclusions There were several novel covariates found that are seen in the all-cause chronic constipation literature but have not been reported for opioid-induced constipation. Some are modifiable covariates, particularly medication coadministration, which may assist clinicians and researchers in risk stratification efforts when initiating opioid medications. The integration of CMS data supports the robustness of the analysis and may be of interest in the elderly population warranting future examination.
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Affiliation(s)
- Fern FitzHenry
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Svetlana K. Eden
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Jason Denton
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Hui Cao
- AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA
| | - Aize Cao
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Ruth Reeves
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Guanhua Chen
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
- University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Glenn Gobbel
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Nancy Wells
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
| | - Michael E. Matheny
- Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA
- Vanderbilt University, Nashville, TN, USA
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40
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Masuyama S, Nagatoya K, Kawaoka T, Kawanishi S, Nomi H, Warada A, Tokuyama A, Haga R, Mori D, Yamauchi A. Metabolic alkalosis due to short bowel syndrome in a hemodialysis patient. CEN Case Rep 2020; 9:162-164. [DOI: 10.1007/s13730-020-00445-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 01/07/2020] [Indexed: 11/25/2022] Open
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41
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Wakeman M, Archer DT. Metformin and Micronutrient Status in Type 2 Diabetes: Does Polypharmacy Involving Acid-Suppressing Medications Affect Vitamin B12 Levels? Diabetes Metab Syndr Obes 2020; 13:2093-2108. [PMID: 32606868 PMCID: PMC7308123 DOI: 10.2147/dmso.s237454] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
Metformin is the first-choice drug in uncomplicated type 2 diabetes (T2DM) and is effective in improving glycaemic control. It is the most widely prescribed oral antidiabetic medicine and has a good safety profile. However, there is an abundance of evidence that metformin use is associated with decreased Vitamin B12 status, though the clinical implications of this in terms of increased risk of diabetic peripheral neuropathy are debated. There is growing evidence that other B vitamins, vitamin D and magnesium may also be impacted by metformin use in addition to alterations to the composition of the microbiome, depending on the dose and duration of therapy. Patients using metformin for prolonged periods may, therefore, need initial screening with intermittent follow-up, particularly since vitamin B12 deficiency has similar symptoms to diabetic neuropathy which itself affects 40-50% of patients with T2DM at some stage. Among patients with T2DM, 40% are reported to experience symptomatic gastroesophageal reflux disease (GORD), of whom 70% use oral antidiabetic medications. The most common medications used to treat GORD are proton pump inhibitors (PPIs) and antagonists of histamine selective H2 receptors (H2RAs), both of which independently affect vitamin B12 and magnesium status. Research indicates that co-prescribing metformin with either PPIs or H2RAs can have further deleterious effects on vitamin B12 status. Vitamin B12 deficiency related to metformin and polypharmacy is likely to contribute to the symptoms of diabetic neuropathy which may frequently be under-recognised. This review explores current knowledge surrounding these issues and suggests treatment strategies such as supplementation.
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Affiliation(s)
- Michael Wakeman
- Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1, UK
- Correspondence: Michael Wakeman Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1 3SD, UKTel +44 191 5153381 Email
| | - David T Archer
- Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1, UK
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42
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Smith NW, Shorten PR, Altermann E, Roy NC, McNabb WC. A Mathematical Model for the Hydrogenotrophic Metabolism of Sulphate-Reducing Bacteria. Front Microbiol 2019; 10:1652. [PMID: 31379794 PMCID: PMC6653664 DOI: 10.3389/fmicb.2019.01652] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/03/2019] [Indexed: 12/13/2022] Open
Abstract
Sulphate-reducing bacteria (SRB) are studied across a range of scientific fields due to their characteristic ability to metabolise sulphate and produce hydrogen sulphide, which can lead to significant consequences for human activities. Importantly, they are members of the human gastrointestinal microbial population, contributing to the metabolism of dietary and host secreted molecules found in this environment. The role of the microbiota in host digestion is well studied, but the full role of SRB in this process has not been established. Moreover, from a human health perspective, SRB have been implicated in a number of functional gastrointestinal disorders such as Irritable Bowel Syndrome and the development of colorectal cancer. To assist with the study of SRB, we present a mathematical model for the growth and metabolism of the well-studied SRB, Desulfovibrio vulgaris in a closed system. Previous attempts to model SRB have resulted in complex or highly specific models that are not easily adapted to the study of SRB in different environments, such as the gastrointestinal tract. We propose a simpler, Monod-based model that allows for easy alteration of both key parameter values and the governing equations to enable model adaptation. To prevent any incorrect assumptions about the nature of SRB metabolic pathways, we structure the model to consider only the concentrations of initial and final metabolites in a pathway, which circumvents the current uncertainty around hydrogen cycling by SRB. We parameterise our model using experiments with varied initial substrate conditions, obtaining parameter values that compare well with experimental estimates in the literature. We then validate our model against four independent experiments involving D. vulgaris with further variations to substrate availability. Further use of the model will be possible in a number of settings, notably as part of larger models studying the metabolic interactions between SRB and other hydrogenotrophic microbes in the human gastrointestinal tract and how this relates to functional disorders.
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Affiliation(s)
- Nick W Smith
- AgResearch, Ruakura Research Centre, Hamilton, New Zealand.,AgResearch, Grasslands Research Centre, Palmerston North, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,School of Food and Advanced Technology, Massey University, Palmerston North, New Zealand
| | - Paul R Shorten
- AgResearch, Ruakura Research Centre, Hamilton, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand
| | - Eric Altermann
- AgResearch, Grasslands Research Centre, Palmerston North, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand
| | - Nicole C Roy
- AgResearch, Grasslands Research Centre, Palmerston North, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, The University of Auckland, Auckland, New Zealand
| | - Warren C McNabb
- Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, The University of Auckland, Auckland, New Zealand
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Mehler PS, O'Melia A, Brown C, Gibson D, Hollis J, Westmoreland P. Medical complications of bulimia nervosa. Br J Hosp Med (Lond) 2019; 78:672-677. [PMID: 29240508 DOI: 10.12968/hmed.2017.78.12.672] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Bulimia nervosa is a psychiatric disorder with many different medical sequelae. This article reviews the principal medical complications associated with bulimia nervosa, and emphasizes the importance of a timely approach to diagnosis and management.
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Affiliation(s)
- Philip S Mehler
- Founder and Executive Medical Director ACUTE at Denver Health, Chief Medical Officer, Eating Recovery Center of Denver, Denver, CO 80204, USA
| | - Anne O'Melia
- Psychiatrist, Eating Recovery Center of Denver, Denver, CO, USA
| | - Carrie Brown
- Hospitalist, Denver Health and Hospital Authority, Denver, CO, USA
| | - Dennis Gibson
- Hospitalist, Denver Health and Hospital Authority, Denver, CO, USA
| | - Jeff Hollis
- Hospitalist, Denver Health and Hospital Authority, Denver, CO, USA
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44
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Rao MC. Physiology of Electrolyte Transport in the Gut: Implications for Disease. Compr Physiol 2019; 9:947-1023. [PMID: 31187895 DOI: 10.1002/cphy.c180011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR-CAS technology, stem cell-derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na+ /K+ ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl- channels and the basolateral Na+ -K+ -2Cl- cotransporter, NKCC1 and K+ channels. Absorption chiefly involves apical membrane Na+ /H+ exchangers and Cl- /HCO3 - exchangers in the small intestine and proximal colon and Na+ channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947-1023, 2019.
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Affiliation(s)
- Mrinalini C Rao
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
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45
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cAMP Stimulates SLC26A3 Activity in Human Colon by a CFTR-Dependent Mechanism That Does Not Require CFTR Activity. Cell Mol Gastroenterol Hepatol 2019; 7:641-653. [PMID: 30659943 PMCID: PMC6438990 DOI: 10.1016/j.jcmgh.2019.01.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 01/07/2019] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS SLC26A3 (DRA) is an electroneutral Cl-/HCO3- exchanger that is present in the apical domain of multiple intestinal segments. An area that has continued to be poorly understood is related to DRA regulation in acute adenosine 3',5'-cyclic monophosphate (cAMP)-related diarrheas, in which DRA appears to be both inhibited as part of NaCl absorption and stimulated to contribute to increased HCO3- secretion. Different cell models expressing DRA have shown that cAMP inhibits, stimulates, or does not affect its activity. METHODS This study re-evaluated cAMP regulation of DRA using new tools, including a successful knockout cell model, a specific DRA inhibitor (DRAinh-A250), specific antibodies, and a transport assay that did not rely on nonspecific inhibitors. The studies compared DRA regulation in colonoids made from normal human colon with regulation in the colon cancer cell line, Caco-2. RESULTS DRA is an apical protein in human proximal colon, differentiated colonoid monolayers, and Caco-2 cells. It is glycosylated and appears as 2 bands. cAMP (forskolin) acutely stimulated DRA activity in human colonoids and Caco-2 cells. In these cells, DRA is the predominant apical Cl-/HCO3- exchanger and is inhibited by DRAinh-A250 with a median inhibitory concentration of 0.5 and 0.2 μmol/L, respectively. However, there was no effect of cAMP in HEK293/DRA cells that lacked a cystic fibrosis transmembrane conductance regulator (CFTR). When CFTR was expressed in HEK293/DRA cells, cAMP also stimulated DRA activity. In all cases, cAMP stimulation of DRA was not inhibited by CFTRinh-172. CONCLUSIONS DRA is acutely stimulated by cAMP by a process that is CFTR-dependent, but appears to be one of multiple regulatory effects of CFTR that does not require CFTR activity.
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46
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Seifter JL, Chang HY. Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments. Physiology (Bethesda) 2018; 32:367-379. [PMID: 28814497 DOI: 10.1152/physiol.00007.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 07/05/2017] [Accepted: 07/06/2017] [Indexed: 01/18/2023] Open
Abstract
Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl- or non Cl- anions and [Formula: see text].
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47
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Whittamore JM, Hatch M. Oxalate transport by the mouse intestine in vitro is not affected by chronic challenges to systemic acid-base homeostasis. Urolithiasis 2018; 47:243-254. [PMID: 29947993 DOI: 10.1007/s00240-018-1067-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/10/2018] [Indexed: 12/15/2022]
Abstract
In rats, we recently showed how a chronic metabolic acidosis simultaneously reduced urinary oxalate excretion and promoted oxalate secretion by the distal colon leading to the proposition that acid-base disturbances may trigger changes to renal and intestinal oxalate handling. The present study sought to reproduce and extend these observations using the mouse model, where the availability of targeted gene knockouts (KOs) would offer future opportunities to reveal some of the underlying transporters and mechanisms involved. Mice were provided with a sustained load of acid (NH4Cl), base (NaHCO3) or the carbonic anhydrase inhibitor acetazolamide (ATZ) for 7 days after which time the impacts on urinary oxalate excretion and its transport by the intestine were evaluated. Mice consuming NH4Cl developed a metabolic acidosis but urinary oxalate was only reduced 46% and not statistically different from the control group, while provision of NaHCO3 provoked a significant 2.6-fold increase in oxalate excretion. For mice receiving ATZ, the rate of urinary oxalate excretion did not change significantly. Critically, none of these treatments altered the fluxes of oxalate (or chloride) across the distal ileum, cecum or distal colon. Hence, we were unable to produce the same effects of a metabolic acidosis in mice that we had previously found in rats, failing to find any evidence of the 'gut-kidney axis' influencing oxalate handling in response to various acid-base challenges. Despite the potential advantages offered by KO mice, this model species is not suitable for exploring how acid-base status regulates oxalate handling between the kidney and intestine.
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Affiliation(s)
- Jonathan M Whittamore
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, PO Box 100275, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.
| | - Marguerite Hatch
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, PO Box 100275, 1600 SW Archer Rd, Gainesville, FL, 32610, USA
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Butler T. Treatment of severe cholera: a review of strategies to reduce stool output and volumes of rehydration fluid. Trans R Soc Trop Med Hyg 2018; 111:204-210. [PMID: 28957470 DOI: 10.1093/trstmh/trx041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 07/27/2017] [Indexed: 11/14/2022] Open
Abstract
Background Severe cholera is a life-threatening illness of hypovolemic shock and metabolic acidosis due to rapid and profuse diarrheal fluid loss. Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis. After this initial rehydration, for the next 2 days ongoing stool losses are replaced with oral rehydration solution (ORS), which contains sodium chloride, potassium and alkali together with glucose or rice powder as a source of glucose to serve as a carrier for sodium. Results In actual field trials, antibiotics are given to reduce fluid requirements, but large volumes averaging about 7 liters of i.v. fluid followed by about 14 liters of ORS have been given to adult patients. Disturbing trends during therapy have included overhydration, hyponatremia and polyuria. Conclusions It is suggested that stool output and fluid requirements could be reduced, if borne out in future research, by avoiding overhydration by restricting ORS intake to match stool output and promoting intestinal reabsorption of luminal fluid by early introduction of glucose without salts into the intestine, more gradual correction of dehydration, giving mineralocorticoid and vasopressin, and infusing glucose or short-chain fatty acids into the proximal colon.
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Affiliation(s)
- Thomas Butler
- Ross University School of Medicine, Portsmouth, Dominica, West Indies
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49
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Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke. JOURNAL OF SPORTS MEDICINE 2018; 2018:5724575. [PMID: 29850597 PMCID: PMC5926483 DOI: 10.1155/2018/5724575] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 01/03/2018] [Indexed: 12/14/2022]
Abstract
Exertional heatstroke (EHS) is a medical emergency that cannot be predicted, requires immediate whole-body cooling to reduce elevated internal body temperature, and is influenced by numerous host and environmental factors. Widely accepted predisposing factors (PDF) include prolonged or intense exercise, lack of heat acclimatization, sleep deprivation, dehydration, diet, alcohol abuse, drug use, chronic inflammation, febrile illness, older age, and nonsteroidal anti-inflammatory drug use. The present review links these factors to the human intestinal microbiota (IM) and diet, which previously have not been appreciated as PDF. This review also describes plausible mechanisms by which these PDF lead to EHS: endotoxemia resulting from elevated plasma lipopolysaccharide (i.e., a structural component of the outer membrane of Gram-negative bacteria) and tissue injury from oxygen free radicals. We propose that recognizing the lifestyle and host factors which are influenced by intestine-microbial interactions, and modifying habitual dietary patterns to alter the IM ecosystem, will encourage efficient immune function, optimize the intestinal epithelial barrier, and reduce EHS morbidity and mortality.
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50
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Cheuvront SN, Kenefick RW, Charkoudian N, Mitchell KM, Luippold AJ, Bradbury KE, Vidyasagar S. Efficacy of Glucose or Amino Acid-Based Commercial Beverages in Meeting Oral Rehydration Therapy Goals After Acute Hypertonic and Isotonic Dehydration. JPEN J Parenter Enteral Nutr 2018; 42:1185-1193. [DOI: 10.1002/jpen.1142] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/30/2017] [Indexed: 01/04/2023]
Affiliation(s)
| | | | - Nisha Charkoudian
- U.S. Army Research Institute of Environmental Medicine; Natick MA USA
| | | | - Adam J. Luippold
- U.S. Army Research Institute of Environmental Medicine; Natick MA USA
| | | | - Sadasivan Vidyasagar
- Department of Radiation Oncology; University of Florida Health Cancer Center; Cancer and Genetics Research; Gainesville FL USA
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