Water and solute absorption from hypotonic glucose-electrolyte solutions in human jejunum.

While oral rehydration therapy with glucose-electrolyte solutions is highly effective, the optimal formulation has not yet been defined. Recent clinical studies suggest that stool volume, and thus water losses, may be reduced if glucose is replaced by a polymeric substrate which reduces osmolality. It is possible that the efficacy of glucose monomer based oral rehydration solutions (ORS) will also improve if osmolality is decreased. Using jejunal triple lumen perfusion in healthy adult volunteers net water and solute absorption were studied from three hypotonic solutions with different sodium concentrations (46, 60, 75 mmol/l) but identical glucose concentrations (90 mmol/l), thus allowing osmolality to rise (210, 240, and 270 mOsm/kg, respectively). Results from these solutions (ORS 45:210, ORS 60:240, and ORS 75:270) were compared with the World Health Organisation oral rehydration solution (WHO-ORS). Greatest water absorption was seen with ORS 60:240 (p less than 0.01). Sodium absorption from ORS 60:240 and WHO-ORS was similar and greater than sodium absorption from ORS 45:210 (p less than 0.05). Potassium and glucose absorption were greater from ORS 60:240 than from any of the other hypotonic solutions (p less than 0.05) and were equal to absorption from WHO-ORS). These results in a short segment of healthy human jejunum suggest that hypotonic ORS containing monomeric glucose may increase water absorption.     

Absorption of a hypotonic oral rehydration solution in a human model of cholera.

The development of oral rehydration solutions (ORSs) has been one of the important therapeutic advances of this century. The optimal formulation, however, of ORSs for both cholera and other infective diarrhoeas is still debated. Part of the problem in developing ORSs has been the lack of adequate test systems for the assessment of new formulations before clinical trial. We have developed a jejunal perfusion, cholera toxin induced, secretory model in humans and have compared net water and solute absorption from a hypotonic ORS (HYPO-ORS: sodium 60 mmol/l, glucose 90 mmol/l, osmolality 240 mOsm/kg) and the British Pharmacopoeia recommended ORS (UK-ORS: sodium 35 mmol/l, glucose 200 mmol/l, osmolality 310 mOsm/kg) in six healthy volunteers. A plasma electrolyte solution (PES) was also perfused in all subjects to confirm a secretory state. Only HYPO-ORS reversed sodium secretion to absorption (p < 0.01). Both ORSs promoted net water absorption but this was greatest with HYPO-ORS (p < 0.01). Glucose and potassium absorption rates were similar for both ORSs whereas chloride absorption mirrored sodium absorption and was greatest from HYPO-ORS (p < 0.05). These results, in a biologically relevant model of secretory diarrhoea, suggest it may be possible to achieve improved rates of rehydration by the use of hypotonic ORS with mid range sodium concentrations.     

Evaluation of the efficacy of oral rehydration solutions using human whole gut perfusion.

Whole gut perfusion in humans was used to compare the effect on intestinal water and electrolyte transport of the World Health Organisation oral rehydration solution (solution II, composition in mmol/l: glucose 111, sodium 90, bicarbonate 30, potassium 20; 308 mOsm/kg); a hypertonic commercial oral rehydration solution (solution III, glucose 188, sodium 50, bicarbonate 20, potassium 20 mmol/l; 335 mOsm/kg); and three experimental bicarbonate free, hypotonic oral rehydration solutions: solution IV (glucose 111, sodium 60, potassium 20 mmol/l; 260 mOsm/kg), solution V (glucose 80, sodium 60, potassium 20 mmol/l; 219 mOsm/kg), and solution VI (glucose 80, sodium 30, potassium 20 mmol/l; 177 mOsm/kg). Perfusion of the intestine with a standard cleansing solution (solution I, sodium 125, potassium 10, bicarbonate 20, sulphate 40, mannitol 80 mmol/l; 275 mOsm/kg) confirmed published data on minimal water and sodium absorption. Experimental solution VI produced maximum water absorption (mean (SE) +1660.0 (29.8) ml/h) significantly greater than solution II (+1195.3 (79.5) ml/h), III (+534.7 (140.3) ml/h), IV (+1498.0 (42.7) ml/h), and V (+1327.7 (24.4) ml/h; p less than 0.05). Sodium absorption was significantly greater with solution II (+97.4 (7.9) mmol/h) compared to VI (+43.3 (7.8) mmol/h; p less than 0.01) but not compared to IV (+67.2 (13.0) mmol/h). A hypotonic oral rehydration solution such as solution VI may provide optimal replacement treatment for patients with acute diarrhoea.     

Effects of long chain fatty acids on solute absorption: perfusion studies in the human jejunum.

Perfusion studies were performed in healthy volunteers to test the hypothesis that net fluid secretion induced by fatty acids is accompanied by parallel reduction in solute transport. Ricinoleic acid provoked a marked net secretion of fluid and concomitantly inhibited the absorption of all solutes tested; these included glucose, xylose, L-leucine, L-lysine, Folic acid, and 2-mono-olein. Oleic acid also reduced net fluid and solute transport, but was less potent in reducing solute absorption than was ricinoleic acid. When fluid secretion was induced osmotically with mannitol, glucose and xylose absorption was not affected. The mechanism for this generalised effect of fatty acids on solute absorption is uncertain, possibly nonspecific, and might be related to mucosal damage and altered mucosal permeability induced by these agents.     

Gum arabic promotes rat jejunal sodium and water absorption from oral rehydration solutions in two models of diarrhea

BACKGROUND & AIMS: We have shown that addition of gum arabic (GA) to a 90 mmol/L sodium-111 mmol/L glucose oral rehydration solution (ORS) enhances its effectiveness for water and electrolyte absorption in normal rats. The present study extends these observations on GA in ORS to two rat models of diarrheal disease. METHODS: Juvenile rats were either treated for 1 week with magnesium citrate-phenolphthalein to produce chronic osmotic-secretory diarrhea or luminally exposed to 10 mmol/L theophylline to induce jejunal secretion. In both models jejunal perfusion was used to assess absorption. RESULTS: Addition of 2.5 or 5.0 g/L GA to ORS increased roughly twofold absorption of sodium, potassium, and water in the model of chronic osmotic-secretory diarrhea. Rats perfused with GA-supplemented ORS showed an expansion of the basolateral intercellular spaces between villus absorptive epithelial cells and the lamina propria, reflecting enhanced water and sodium absorption. Similarly, addition of 2.5, 5.0, or 10.0 g/L GA to the ORS neutralized theophylline-induced abolition of net sodium and potassium absorption and reversed water and glucose malabsorption. CONCLUSIONS: These experimental studies in models of diarrhea suggest that GA may be a useful additive to ORS for the potentiation of water and electrolyte absorption. (Gastroenterology 1997 Jun;112(6):1979-85)     

First do no harm: making oral rehydration solution safer in a cholera epidemic.

Oral rehydration solution (ORS) is lifesaving therapy for cholera and pediatric diarrhea. During a cholera epidemic in Guinea-Bissau, we evaluated the microbiologic quality of ORS prepared at a hospital and tested a simple intervention using special vessels for disinfecting tap water with bleach and for preparing, storing, and dispensing ORS. Few coliform bacteria and Escherichia coli were recovered from tap water; however, pre-intervention ORS contained numerous bacteria including E. coli and toxigenic Vibrio cholerae O1. In contrast, ORS samples from intervention vessels had few or no coliform bacteria, no E. coli, and no V. cholerae. Mean pre-intervention counts of coliform bacteria (3.4 x 10(7) colony-forming units [cfu]/100 ml) and E. coli (6.2 x 10(3) cfu) decreased significantly during the intervention period to 3.6 x 10(2) cfu and 0 cfu, respectively (P < 0.001). This simple system using bleach disinfectant and special storage vessels prevents bacterial contamination of ORS and reduces the risk of nosocomial transmission of cholera and other enteric pathogens.     

Effect of bicarbonate or base precursor on water and solute absorption from a glucose-electrolyte solution in the human jejunum

A modified perfusion technique was used to examine the effect on water and solute absorption in the healthy human jejunum of replacing bicarbonate (18 mmol/l) by equivalent amounts of different base precursors in a glucose-electrolyte solution. Acetate, citrate and lactate were absorbed from the perfusion solutions. Absorption of these base precursors appeared to have no effect on water uptake, but greater sodium (p less than 0.05) absorption occurred from solutions containing either acetate or lactate compared with the bicarbonate-containing solution. These data suggest that oral rehydration solutions with base precursors other than bicarbonate are as effective as bicarbonate-containing solutions in promoting absorption of water and electrolytes.     

L-arginine in low concentration improves rat intestinal water and sodium absorption from oral rehydration solutions.

BACKGROUND: The nitric oxide (NO) precursor L-arginine has been shown to produce variable effects on intestinal absorptive function, including ion transport. AIMS: To determine whether there is an optimal concentration of L-arginine, promoting proabsorptive effects from oral rehydration solutions (ORS) with 90 or 60 mM sodium. SUBJECTS AND METHODS: In vivo perfusion of rat jejunum with determination of net water absorption, unidirectional fluid exchanges, sodium and calcium transport, and glucose absorption. RESULTS: L-Arginine (1 mM) added to the 90 mM sodium ORS increased intestinal absorption of both sodium and water. Higher concentrations of L-arginine (2 to 10 mM) lacked this stimulatory effect. At 20 mM, L-arginine decreased sodium absorption below baseline. With a 60 mM sodium ORS, 2 mM L-arginine had a maximal fluid and electrolyte proabsorptive effect. At 20 mM L-arginine, net water absorption was indistinguishable from that obtained in the absence of L-arginine, and lower than with 2 mM L-arginine. Sodium absorption remained raised above baseline in perfusions with 10 and 20 mM L-arginine. Morphologically, villi from perfusions with increased absorption showed a large expansion of intercellular and lamina propria intercellular spaces. CONCLUSIONS: Low concentrations of L-arginine seem to stimulate water and electrolyte absorption by the small intestine. This effect is consistent with NO induced vasodilation, may be vaso-constrictive and thereby reverse fluid and electrolyte transport.     

Search for the ideal oral rehydration solution: studies in a model of secretory diarrhoea.

In situ perfusion of whole rat small intestine was used to compare the efficacy of five oral rehydration solutions in promoting water and sodium absorption in normal intestine and secreting intestine after exposure to cholera toxin. Solutions varied in their sodium (35-90 mmol/l) and glucose (111-200 mmol/l) concentrations, molar ratio of glucose:sodium (1.2-5.8), and osmolality (281-331 mOsmol/kg), and contained either bicarbonate (18-30 mmol/l) or citrate (10 mmol/l). In normal intestine all solutions promoted net water absorption. Cholera toxin induced reproducible water secretion but all solutions reversed this to absorption. Water absorption was greatest with solutions containing sodium 60 mmol/l and glucose 111 or 140 mmol/l, and with a glucose:sodium ratio approximately 2, in both normal and secreting intestine. All solutions promoted net glucose absorption in both normal and secreting intestine. Net sodium absorption occurred with solutions containing greater than or equal to 60 mmol/l sodium in normal intestine but sodium secretion occurred from all solutions in secreting intestine. Sodium movement was directly related to the sodium concentration of the solution and sodium secretion occurred despite net water and glucose absorption. We consider that these studies may guide future development of oral rehydration solutions.     

Evaluation of home-made salt-sugar oral rehydration solution in a rural Nigerian population

Standardized local measures for preparing oral rehydration solution (ORS) in Nigeria were re-evaluated under laboratory conditions. Our results confirm those of the standardization team in respect of granulated and cube sugar. However, our mean weight of one salt measure (2.8155 +/- 0.292 g) is about 20% greater than their value. Consequently, correct use of the measures in our study gave solutions of 211-297 mmol-1 total concentration and 60-80 mmol-1, Na+ as against their values of 173-251 mmol 1-1 and 45-70 mmol-1, respectively. This discrepancy is most likely due to differences in salt type. Analysis of home-made solutions prepared by 40 illiterate mothers showed that 60% of them made accurately composed solutions. All the rest made hypertonic solutions. Salt type, spoon size and levelling technique are all possible causes of their error. The tendency to err only on the side of greater rather than lower salt concentration may be culture based or simply due to natural maternal instinct. To combat this trend, health education programmes in Nigeria should emphasize the danger in feeding a hypernatremic solution to a dehydrated child.     

Sodium content of oral rehydration solutions: a reappraisal.

Proper choice of oral rehydration solution, with regard to sodium content, is a conflicting issue to general practitioners and pediatricians. World Health Organization (WHO) recommendations of oral rehydration solution containing 90mmol/1 sodium, have been effective throughout developing countries worldwide. In developed countries, however, such as England, this recommendation seems inappropriate; a recommendation of 50 - 60 mmol/1 sodium with 90 -111mmol/1 glucose is preferred. This combination will eliminate the need for free water recommended by the WHO maintenance therapy. Normonatraemia is maintained, and hyponatraemia and hypernatraemia can both be corrected. Sodium content is adequate in replacing stool loss resulting from viral and bacterial diarrheas. Iatrogenic hyponatraemia and hypernatraemia do not occur as they would with oral rehydration solutions with low (30-35) or high (90mmol/1) sodium concentration. Solutions containing 50-60 mmol/1 sodium is safer in neonates and young infants with immature renal functions, incapable of properly distributing increased sodium leads. Glucose concentration necessary to make oral rehydration with 50 - 60 mmol/1 isotonic, or hypotonic, resembles WHO - ORS, but is half that in 30-35 mmol/1 sodium solutions. In controlled clinical trials, oral rehydration solutions with 50-60 mmol/1 sodium have proven safe, and performance was compatible with WHO-ORS. For both rehydration and correction of acidosis, the solution proved effective. When oral rehydration solution sodium, concentrate is below 90 mmol/1, errors in reconstituting may be common, but offers less risk resulting in dangerous hypernatraemia. An "all purpose" physiological oral rehydration solution would make oral rehydration therapy, more economical, simpler, and safe in developed countries worldwide.     

Antineutrophil cytoplasmic autoantibodies and pathophysiology: new insights from animal models

PURPOSE OF REVIEW: Since the discovery of antineutrophil cytoplasmic autoantibodies (ANCA) and their association with the occurrence of several types of small-vessel vasculitis, a causal relation between the two has been suggested. Various in vitro and in vivo experimental data provide indirect evidence in support of this view. This article comprises a review of the animal models that have been used to investigate the pathogenesis of ANCA-associated vasculitis, and focuses on recent developments in this field. RECENT FINDINGS: Xiao et al. provide definite proof of the pathogenic potential of ANCA in a novel mouse model of myeloperoxidase (MPO)-ANCA-associated vasculitis, in which transfer of splenocytes or IgG from MPO-/- mice immunized with murine MPO, to naive wild-type or Rag2-/- (lacking mature B and T lymphocytes) mice causes a disease remarkably similar to its human counterpart. In addition, preliminary studies by Smyth et al. show that immunization of Wistar Kyoto rats with human MPO induces antihuman MPO antibodies that cross-react with rat MPO, as well as a disease closely resembling human small-vessel vasculitis. Another murine ANCA model is the SCG/Kj mouse. A recent publication by Neumann et al., however, puts an important limitation on the use of this mouse model for the study of ANCA-associated vasculitis, demonstrating multiple immune complex deposits in the spontaneously occurring vascular lesions. SUMMARY Recently developed animal models of MPO-ANCA-associated vasculitis convincingly demonstrate that MPO-ANCA are pathogenic. Whether similar strategies can be used to develop an appropriate model for proteinase 3-ANCA-associated vasculitis remains to be investigated.     

Gastric emptying in children. V. Effect of the replacement of glucose by sucrose in a solution for oral rehydration

A study was carried out on 18 children of both sexes aged 3 to 32 months (median 8 months) and weighing 3440 to 9520 grams (median 5120 grams). Each child was submitted to three consecutive gastric emptying tests at 24 hour intervals, using three solutions of different composition. The children were divided into two groups: Group I: twelve children submitted to the gastric emptying test 10 minutes after the administration of the test meal; Group II: six children submitted to the gastric emptying test 30 minutes after the administration of the test meal. The hydrating solutions used in the study consisted of the basic electrolyte composition recommended by the World Health Organization, and only differed in terms of the amount of sugar added. Solution A contained 20 grams of glucose per liter, solution B, 20 grams of sucrose per liter, and solution C, 40 grams of sucrose per liter. Gastric retention, expressed as a percentage of the volume of the test meal, was similar for solutions A and C and significantly higher than for solution B in Group I. In Group II, gastric retention of solution B also tended to be lower than for solutions A and C, although no statistically significant differences were observed between the three solutions.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of circulating IGF-I: lessons from human and animal models

Insulin-like growth factors (IGF-I and IGF-II) play a crucial role in regulating cell proliferation and differentiation. The IGFs have mitogenic and antiapoptotic effects on normal and transformed cells. These peptide growth factors are produced by virtually all tissues and act in an endocrine, autocrine, and paracrine fashion. The endocrine form of IGF-I originates mostly (75%) from the liver and IGF-binding proteins regulate its bioactivity. Compared to other peptide growth factors, the IGFs are in abundant supply in circulation. The role of this large reservoir of IGFs has been debated for many years. In the last few years substantial progress has been made in understanding the function of the endocrine IGF-I using new animal models. This review will revisit the IGF system with particular attention to the role of circulating IGF-I in growth regulation, metabolism, and cancer.     

Cholestasis: human disease and experimental animal models

Cholestasis may result from a failure in bile secretion in hepatocytes or ductular cells, or from a blockade to the free bile flow. Human cholestasis may be induced by many drugs, being antibiotics the more common. Other types of cholestasis seen in humans are a group of familial cholestatic disorders, obstructive cholestasis, primary biliary cirrhosis, extrahepatic biliary atresia, primary sclerosing cholangitis, cholestasis of pregnancy, oral contraceptive-induced cholestasis, and sepsis-induced cholestasis. Experimental animal models allow the understanding of pathophysiological mechanisms involved and their clinical correlates. The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis. A well known model of extrahepatic biliary obstruction is common bile duct ligation. Drug-induced cholestasis were described using different drugs. On this regard, alpha naphthylisothiocyanate treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. Congenital defficiency of transport proteins also were studied in natural rat models of cholestasis. The experimental animal models allow to define down-regulated alterations of hepatocyte transport proteins, and up-regulated ones acting as compensatory mechanisms. In conclusion, animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms that operate on liver cells.     

Oral health in geroscience: animal models and the aging oral cavity

Age is the single greatest risk factor for many diseases, including oral diseases. Despite this, a majority of preclinical oral health research has not adequately considered the importance of aging in research aimed at the mechanistic understanding of oral disease. Here, we have attempted to provide insights from animal studies in the geroscience field and apply them in the context of oral health research. In particular, we discuss the relationship between the biology of aging and mechanisms of oral disease. We also present a framework for defining and utilizing age-appropriate rodents and present experimental design considerations, such as the number of age-points used and the importance of genetic background. While focused primarily on rodent models, alternative animal models that may be particularly useful for studies of oral health during aging, such as companion dogs and marmoset monkeys, are also discussed. We hope that such information will aid in the design of future preclinical studies of geriatric dental health, thus allowing more reliability for translation of such studies to age-associated oral disease in people.     

Rehydration and maintenance therapy of cholera patients in Jakarta: citrate-based versus bicarbonate-based oral rehydration salt solution

We compared the therapeutic efficacy of a World Health Organization standard bicarbonate-based oral rehydration salt solution (BBORS) with a citrate-based oral rehydration solution (CBORS) in a randomized, double-blind, controlled trial in 130 dehydrated patients with cholera aged three to 82 years. On admission the 70 patients who received CBORS and the 60 who received BBORS were similar except that the serum CO2 content (mmol/liter) was significantly lower in the CBORS group (10.8 +/- 3.6 vs. 12.5 +/- 5.3). The incidence of vomiting postadmission (41% vs. 62%, respectively), the stool output during the first 24 hr (4,252 +/- 3,900 ml vs. 6,025 +/- 4,389 ml, respectively), and the time until the patients' conditions were considered normal (38.9 +/- 14.5 hr vs. 46.3 +/- 22.7 hr, respectively) were all significantly less in the CBORS group. The serum CO2 content increased more rapidly during the first 48 hr in the CBORS group (87% +/- 74% vs. 61% +/- 68% for the BBORS group); 23% of the patients receiving CBORS and 35% of the patients receiving BBORS were considered oral-therapy treatment failures. The results indicate that CBORS was superior to BBORS for rehydration and maintenance therapy of hospitalized cholera patients in Jakarta.