A new minimal mathematical model of the endocrine system of normal rats validated against experimental data

As a common laboratory practice, rats are studied as biological models for understanding human physiology. Even though, with the advent of modern computer sciences, new methodologies appeared in medical sciences like simulation and optimization to simplify and improve the experimental work. With this background, a novel simulation model of the endocrine system of Sprague Dawley rats is presented. It is a simplified mathematical model composed of 3 differential equations and 8 parameters that have been determined and validated with experimental measures of plasma glucose and insulin alone by means of calculus and optimization techniques. The results presented here are a step before the development of a type I diabetic model of Sprague Dawley rats.Sociedad Argentina de Informática e Investigación Operativ

The Acid Test of Fluoride: How pH Modulates Toxicity

Background: It is not known why the ameloblasts responsible for dental enamel formation are uniquely sensitive to fluoride ($F^−$). Herein, we present a novel theory with supporting data to show that the low pH environment of maturating stage ameloblasts enhances their sensitivity to a given dose of $F^−$. Enamel formation is initiated in a neutral pH environment (secretory stage); however, the pH can fall to below 6.0 as most of the mineral precipitates (maturation stage). Low pH can facilitate entry of $F^−$ into cells. Here, we asked if $F^−$ was more toxic at low pH, as measured by increased cell stress and decreased cell function. Methodology/Principal Findings: Treatment of ameloblast-derived LS8 cells with $F^−$ at low pH reduced the threshold dose of $F^−$ required to phosphorylate stress-related proteins, PERK, eIF2α, JNK and c-jun. To assess protein secretion, LS8 cells were stably transduced with a secreted reporter, Gaussia luciferase, and secretion was quantified as a function of $F^−$ dose and pH. Luciferase secretion significantly decreased within 2 hr of $F^−$ treatment at low pH versus neutral pH, indicating increased functional toxicity. Rats given 100 ppm $F^−$ in their drinking water exhibited increased stress-mediated phosphorylation of eIF2α in maturation stage ameloblasts (pH<6.0) as compared to secretory stage ameloblasts (pH∼7.2). Intriguingly, $F^−$-treated rats demonstrated a striking decrease in transcripts expressed during the maturation stage of enamel development (Klk4 and Amtn). In contrast, the expression of secretory stage genes, AmelX, Ambn, Enam and Mmp20, was unaffected. Conclusions: The low pH environment of maturation stage ameloblasts facilitates the uptake of $F^−$, causing increased cell stress that compromises ameloblast function, resulting in dental fluorosis

Effect of disodium monofluorphosphate on plasma and blood viscosity in the rat

Alpha macroglobulins (AM) are plasma proteins whose main function is to inactivate proteinases, protecting the tissues from the action of these enzymes. AM have influence on plasma viscosity (PV) and binds monofluorophosphate (MFP), which disturbs its homeostasis. The aim of this work was to evaluate whether the administration with MFP could modify blood viscosity. AM levels (?mol/l), PV (mPa·s), viscosity of red blood cells suspensions in NaCl 9 g/l (VES) and in autologue plasma (VEP) were measured in fifty-day old rats after a single dose of 80 ?mol MFP or after 30 days of treatment with 80 ?mol of MFP. Relative viscosity (RV) was calculated as the ratio VEP/PV. AM and PV increased significantly after 30 min of an oral dose of MFP. Controls (n=6), AM: 19.65±0.85, PV: 1.39±0.01, treated (n=6), AM: 22.88±0.75 (p less than 0.05), PV: 1.76±0.14 (p less than 0.05). After 30 days of treatment with MFP, AM and PV increased significantly. Controls (n=6), AM: 10.76±1.33, PV: 1.19±0.04, treated (n=6), AM: 17.66±1.27 (p less than 0.05), PV: 1.38±0.03 (p less than 0.05). The treatment with MFP modifies neither the VEP nor the RV. These results would indicate that AM and/or MFP did not interact with erythrocyte membrane and did not modify erythrocyte deformability. © 2008 - IOS Press and the authors. All rights reserved

Effect of disodium monofluorphosphate on plasma and blood viscosity in the rat

Alpha macroglobulins (AM) are plasma proteins whose main function is to inactivate proteinases, protecting the tissues from the action of these enzymes. AM have influence on plasma viscosity (PV) and binds monofluorophosphate (MFP), which disturbs its homeostasis. The aim of this work was to evaluate whether the administration with MFP could modify blood viscosity. AM levels (?mol/l), PV (mPa·s), viscosity of red blood cells suspensions in NaCl 9 g/l (VES) and in autologue plasma (VEP) were measured in fifty-day old rats after a single dose of 80 ?mol MFP or after 30 days of treatment with 80 ?mol of MFP. Relative viscosity (RV) was calculated as the ratio VEP/PV. AM and PV increased significantly after 30 min of an oral dose of MFP. Controls (n=6), AM: 19.65±0.85, PV: 1.39±0.01, treated (n=6), AM: 22.88±0.75 (p less than 0.05), PV: 1.76±0.14 (p less than 0.05). After 30 days of treatment with MFP, AM and PV increased significantly. Controls (n=6), AM: 10.76±1.33, PV: 1.19±0.04, treated (n=6), AM: 17.66±1.27 (p less than 0.05), PV: 1.38±0.03 (p less than 0.05). The treatment with MFP modifies neither the VEP nor the RV. These results would indicate that AM and/or MFP did not interact with erythrocyte membrane and did not modify erythrocyte deformability. © 2008 - IOS Press and the authors. All rights reserved

Physical exercise ameliorates the toxic effect of fluoride on the insulin–glucose system

Daily intake of water with fluoride concentrations >1.5 mg/l produces insulin resistance (IR). On the other hand, physical activity increases insulin sensitivity in the muscle. Therefore, the aim of this study was to evaluate the effect of physical activity on IR in rats treated with sodium fluoride (NaF) in drinking water. Sprague–Dawley rats were divided into three groups (n=10/group): Control (drinking water without NaF), NaF (drinking water with NaF 15 mg/l for 30 days), and Exercise (daily running on a treadmill for 60 min at 2.25 m/min and drinking water with NaF 15 mg/l for 30 days). IR was evaluated with the homeostasis model assessment–IR (HOMA–IR) index using fasting plasma levels of glucose and insulin. IR increased in rats treated with 15 mg/l NaF in drinking water. A decrease in IR was observed in rats that performed physical activity and drank water with 15 mg/l NaF; the Exercise group also showed an increase in the amounts of bone fluoride. The variation in the HOMA–IR values could be the consequence of variation in the sensitivity of tissues to insulin or decrease in plasma fluoride levels due to bone fluoride intake. These findings indicate that the performance of daily physical activity could reduce the negative effects of the chronic ingestion of NaF on glucose homeostasis.Fil: Lombarte, Mercedes. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Ósea; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fina, Brenda Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Ósea; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lupo, Maela. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Ósea; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Buzalaf, Marilia A.. Universidade de Sao Paulo; BrasilFil: Rigalli, Alfredo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Ósea; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin