Diversity of the mammalian sodium/proton exchanger SLC9 gene family

Sodium/proton antiporters or exchangers (NHE) are integral membrane proteins present in most, if not all, living organisms. In mammals, these transporters chiefly catalyze the electroneutral exchange of Na(+) and H(+) down their respective concentration gradients and are crucial for numerous physiological processes, ranging from the fine control of intracellular pH and cell volume to systemic electrolyte, acid-base and fluid volume homeostasis. NHE activity also facilitates the progression of other cellular events such as adhesion, migration, and proliferation. Thus far, eight distinct NHE genes (NHE1/SLC9A1-NHE8/SLC9A8) and several pseudogenes have been identified in the human genome. The functional genes encode proteins of varying primary sequence identity (25-70%), but share a common predicted secondary structure comprising 12 conserved membrane-spanning segments at the amino-terminus and a more divergent, cytoplasmically-oriented, carboxy-terminus. They show considerable heterogeneity in their patterns of tissue/cell expression and membrane localization. Functional studies have revealed further differences in their kinetic properties, sensitivity to pharmacological antagonists, and regulation by diverse hormonal and mechanical stimuli. Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion. Further characterization of their functional properties should lead to a better understanding of their unique contributions to human health and disease.     

Paradoxical stimulation of food intake by larger loads of glucose,fructose and mannose: Evidence for a positive feedback effect

The phenomenon of paradoxical stimulation of food intake by larger alimentary loads of isotonic glucose was studied with regard to a variety of experimental and nutritional conditions. Thus, paradoxical feeding response was induced not only by the infusions of glucose but also of the other insulinogenic sugars—fructose and mannose. Stimulation of food intake was further observed following the administration of larger volumes of isotonic glucose solutions via the duodenal and intraperitoneal infusion routes in free feeding as well as in 12 hr food-deprived animals. This paradoxical alimentary response was not eliminated or reduced by repeating these infusions daily over a longer period of time; in fact, food in the first postinfusions hour and, unexpectedly, also the total daily food intakes, showed a gradually increasing trend with daily repetitions. Drinking of isotonic glucose for 1 hr in 12 hr water-deprived animals did not suppress the subsequent intake of regular food despite the substantial amount of glucose drunk (94.1 ml vs 76.5 ml of water in controls during the same time period). The conbination of glucose drinking with subsequent food intake resulted in a significant caloric imbalance during the first hour which was not fully compensated within the 24 hr. These findings indicate that larger loads of insulinogenic sugar loads are capable of triggering an antiregulatory positive feedback alimentary response which can induce caloric imbalance and thus adversely affects the short-term maintenance of energy balance.     

A comprehensive simulator of the human respiratory system: Validation with experimental and simulated data

A comprehensive model of oxygen (O₂) and carbon dioxide (CO₂) exchange, transport, and storage in the adult human is presented, and its ability to provide realistic responses under different physiological conditions is evaluated. The model comprises three compartments (i.e., lung, body tissue, and brain tissue) and incorporates a controller that adjusts alveolar ventilation and cardiac output dynamically integrating stimuli coming from peripheral and central chemoreceptors. A new realistic CO₂ dissociation curve based on a two-buffer model of acid-base chemical regulation is included. In addition, the model explicitly considers relevant physiological factors such as buffer base, the nonlinear interaction between the O₂ and CO₂ chemoreceptor responses, pulmonary shunt, dead space, variable time delays, and Bohr and Haldane effects. Model simulations provide results consistent with both dynamic and steady-state responses measured in subjects undergoing inhalation of high CO₂ (hypercapnia) or low O₂ (hypoxia) and subsequent recovery. An analysis of the results indicates that the proposed model fits the experimental data of ventilation and gas partial pressures as some meaningful simulators now available and in a very large range of gas intake fractions. Moreover, it also provides values of blood concentrations of CO₂, HCO⁻ ₃, and hydrogen ions in good agreement with more complex simulators characterized by an implicit formulation of the CO₂ dissociation curve. In the experimental conditions analyzed, the model seems to represent a single theoretical framework able to appropriately describe the different phenomena involved in the control of respiration.     

Differentiation of renal intercalated cells in fetal and postnatal rats

Summary An ultrastructural study was conducted on the kidneys from rat fetuses and pups from ages ranging from birth to 8 weeks to identify the time of appearance of each of the two intercalated cell types. With transmission electron microscopy, A-intercalated cells were recognized by their large apical microvilli and microplicae as well as by the numerous subapical vesicles. Their identification was confirmed by the presence of typical studs at the cytoplasmic face of the apical plasma membrane. By scanning electron microscopy the cells were recognized by their typical microplicae at the apical surface. In 19-day-old fetuses and newborns, A-intercalated cells were numerous in the epithelium lining the renal pelvis and inner medullary intercalated ducts. Two weeks after birth they disappeared from these regions but became numerous at the outer medullary collecting ducts and also at the cortical collecting ducts although to a lesser degree. B-intercalated cells were recognized by the scarcity of microvilli, the absence of microplicae, and the large number of basal infoldings. Their identification was confirmed by the presence of studs at the cytoplasmic face of the basolateral membrane. B-cells started to appear 3 weeks after birth and increased thereafter. We speculate that the particular stages at which the two cell types differentiate might be related to changes in acid-base status.     

The role of E-cadherin in low-grade ductal breast tumourigenesis

Grade I invasive ductal breast carcinomas have a specific pattern of genetic aberrations, namely gain of 1q and loss of 16q. This pattern is very similar to the changes seen in invasive lobular breast carcinomas (ILCs). The gene on 16q involved in ILC is known to be E-cadherin (CDH1). This study has investigated whether the same gene is responsible for grade I invasive ductal carcinoma (IDC), using allele imbalance analysis, mutation screening, and immunohistochemistry (IHC). The data suggest that despite the shared pattern of genetic aberrations seen in grade I IDC and ILC, CDH1 is not the target gene in low-grade ductal tumourigenesis.     

Relationship between plasma pH and pancreatic HCO3- secretion at different intravenous secretin infusion rates

The relationship between pancreatic HCO₃^- secretion and plasma pH during acute systemic acid-base changes was investigated in 6 anesthetized, artificially ventilated pigs (20–25 kg) at 2 different, i.v. secretin infusion rates. At 0.45 C.U./kg b.wt. h^-1 secretin infusion and plasma pH 7.40±0.01 pancreatic HCO₃^- secretion averaged 61±12 μmol/min. Stepwise lowering of plasma pH through i.v. infusion of HCI and CO₂ administration to inspired air proportionately reduced secretion rate; estimated zero HCO₃^- secretion occurring at plasma pH 7.01. Subsequent i.v. secretin infusion at 2.70 C.U./kg b.wt. h^-1 increased HCO₃^- secretion to 249±42 μmol/min at plasma pH 7.33+0.04; stepwise lowering of plasma pH proportionately reduced HCO₃^- secretion to estimated zero at plasma pH 6.71. A reduction of plasma pH by 0.1 pH unit reduced HCO₃^- secretion during low and high rate of i.v. secretin infusion by 18±3 μmol/min and 35±8 μmol/min, respectively. Secretin infusion rate did not affect pancreatic chloride excretion. These findings support the view that secretin increases HCO₃^- secretion, and hence proton transport to the interstitial fluid, by augmenting the proton motive force developed by HCO₃^- secreting cells.     

Effect of anterior prepyriform and medial amygdaloid lesions on acquisition of taste-avoidance and response to dietary amino acid imbalance

Rats with bilateral lesions of the anterior prepyriform cortex or medial amygdala demonstrate attenuated behavioral sensitivity to a dietary threonine-imbalance. While rats with medial amygdaloid lesions demonstrate an attenuated ability to acquire taste-avoidances, such a deficit is not found in rats with lesions of the anterior prepyriform cortex. The effect of anterior prepyriform and medial amygdaloid lesions on behavioral sensitivity to dietary amino acid imbalances is discussed in terms of the probable roles played by these areas in amino acid intake control.     

The Anion Gap is a Predictive Clinical Marker for Death in Patients with Acute Pesticide Intoxication

Pesticide formulation includes solvents (methanol and xylene) and antifreeze (ethylene glycol) whose metabolites are anions such as formic acid, hippuric acid, and oxalate. However, the effect of the anion gap on clinical outcome in acute pesticide intoxication requires clarification. In this prospective study, we compared the anion gap and other parameters between surviving versus deceased patients with acute pesticide intoxication. The following parameters were assessed in 1,058 patients with acute pesticide intoxication: blood chemistry (blood urea nitrogen, creatinine, glucose, lactic acid, liver enzymes, albumin, globulin, and urate), urinalysis (ketone bodies), arterial blood gas analysis, electrolytes (Na⁺, K⁺, Cl^- HCO₃^-, Ca⁺⁺), pesticide field of use, class, and ingestion amount, clinical outcome (death rate, length of hospital stay, length of intensive care unit stay, and seriousness of toxic symptoms), and the calculated anion gap. Among the 481 patients with a high anion gap, 52.2% had a blood pH in the physiologic range, 35.8% had metabolic acidosis, and 12.1% had acidemia. Age, anion gap, pesticide field of use, pesticide class, seriousness of symptoms (all P < 0.001), and time lag after ingestion (P = 0.048) were significant risk factors for death in univariate analyses. Among these, age, anion gap, and pesticide class were significant risk factors for death in a multiple logistic regression analysis (P < 0.001). In conclusions, high anion gap is a significant risk factor for death, regardless of the accompanying acid-base balance status in patients with acute pesticide intoxication.     

Are we being drowned by overhydration advice on the Internet?

Objective: Because inappropriate recommendations about hydration during exercise appear widespread and potentially dangerous, we assessed the quality of a sampling of information currently available to the public on the Internet.

Methods: Internet searches using the Google search engine were conducted using the terms “hydration,” “hydration guidelines,” “drinking fluids” and “drinking guidelines” combined with “and exercise.” From the first 50 websites for each search phrase, duplicates were removed yielding 141 unique websites that were categorized by source and examined for specific hydration related information and recommendations.

Results: Correct endorsement was as follows (reported as percent endorsing the concept relative to the number of websites addressing the issue): some weight loss should be expected during exercise (69.5% of 95), fluid consumption during exercise should be based upon thirst (7.3% of 110), electrolyte intake is not generally necessary during exercise (10.4% of 106), dehydration is not generally a cause of heat illness (3.4% of 58) or exercise-associated muscle cramping (2.4% of 42), exercise-associated muscle cramping is not generally related to electrolyte loss (0.0% of 16), and overhydration is a risk for hyponatremia (100.0% of 61). Comparison of website information from medical or scientific sources with that from other sources revealed no differences (p = 0.4 to 1.0) in the frequency of correct endorsement of the examined criteria.

Conclusion: Prevalent misinformation on the Internet about hydration needs during exercise and the contribution of hydration status to the development of heat illness and muscle cramping fosters overhydration. In general, those websites that should be most trusted by the public were no better than other websites at providing accurate information, and the potential risk of hyponatremia from overhydration was noted by less than half the websites. Since deaths from exercise-associated hyponatremia should be preventable through avoidance of overhydration, dissemination of a more appropriate hydration message is important.     

Does oral buffered sodium supplementation reduce nausea and vomiting during an ultramarathon?

This work examines whether nausea or vomiting during an ultramarathon are due to a fluid or electrolyte imbalance, and if these symptoms can be reduced through the use of buffered sodium supplements. Starters (n = 376) of a 161.3-km ultramarathon underwent body weight measurements, 74.5% completed a post-race questionnaire, and 53.0% also underwent a post-race blood draw. The incidence of nausea or vomiting progressively increased during the race, and affected 60% of runners overall. Weight change and rate of sodium intake in supplements or in buffered sodium supplements did not differ between those with and without nausea or vomiting. Post-race serum sodium concentration also did not differ between those with and without symptoms in the last race segment. We conclude that weight change, the rate of sodium intake in supplements or in buffered sodium supplements, and serum sodium concentration are not related to symptoms of nausea or vomiting during a 161-km ultramarathon.