Effects of PYY[3-36] in rodent models of diabetes and obesity.

BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration. OBJECTIVE: To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[3-36] acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day). CONCLUSION: Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[3-36].

Aflatoxin M1 contamination in commercial samples of milk and dairy products in Kuwait.

As part of the programme on monitoring of environmental contaminants in food stuff in Kuwait, 54 samples of fresh full cream and skimmed milk, powdered milk, yoghurt, and infant formula were analysed for aflatoxin M1 (AFM1) by HPLC following sample clean up using immuno-affinity columns. Of samples, 28% were contaminated with AFM1 with 6% being above the maximum permissible limit of 0.2 microgl(-1). Three fresh cow milk samples collected from a private local producer showed the highest level of 0.21 microg l(-1) AFM1. There was no contamination with AFM1 in powdered milk and infant formulas. These results show the necessity of a survey involving a larger number of milk and its products and suggest that presently the contamination of milk and milk products with AFM1 does not appear to be a serious health problem in Kuwait. Nevertheless, a continuous surveillance programme may be warranted to monitor regularly the occurrence of aflatoxins in the animal feeds responsible for current limited contamination and to note rapidly and worsening in the situation that may depend on market changes or on unfavourable climatic developments.

A new monoclonal antibody ELISA for detection and characterization of C-telopeptide fragments of type I collagen in urine.

Clinical studies have shown that measurements of urine concentration of degradation products of C-terminal telopeptides of type I collagen provide a selective marker to assess bone resorption. Assays for C-telopeptide fragments have been described using antibodies generated against an eight amino acid synthetic peptide EKAHDGGR. In this study, we describe development of a rat monoclonal antibody against a synthetic linear peptide, DFSFLPQPPQEKAHDGGR, which we isolated and characterized from Paget's urine by chromatographic methods. An ELISA procedure was developed to evaluate the efficacy of this monoclonal to measure bone resorption and characterize urinary degradation products of C-terminal type I collagen. The measuring range of ELISA was 10-1,000 ng/ml with a detection limit of 10 ng/ml. Averaged intraassay and interassay CVs were <7% (n = 8) and <11% (n = 3), respectively. Mean spike and dilution recoveries range between 90 and 116%. In assessing the clinical performance, we observed approximately 48% higher values for postmenopausal patients (n = 20) compared with premenopausal women (n= 19), Z score = 2.7 (P = 0.0091). The discriminatory power to assess subtle changes in bone turnover between pre- and postmenopausal women compares well with the commercially available markers of bone resorption. Comparison of C-telopeptide concentration in a population including normal and osteoporotic patients (n = 74) shows a strong correlation with DPYR r = 0.95 (P < 0.001). In addition, in postmenopausal osteoporotic patients, a 44% (P < 0.05) decrease in C-telopeptide concentration was observed after 3 months of treatment with Alendronate, as compared with basal values. The antibody developed in this study displays a slightly different epitope than that reported previously using eight amino acid residues EKAHDGGR. In addition, isolation and characterization of circulating forms of C-telopeptide from healthy children by immunoaffinity purification revealed the presence of two novel urinary fragments corresponding to amino acid sequence EKAHDGGR and EKAHDG, in addition to the previously known two fragments composed of two alpha-1 chains linked together by a pyridinium crosslinks. The origin of the fragment EKAHDG could not be explained by the known mechanisms involved in collagen degradation, indicating that it could be a product of renal handling of C-telopeptide fragments generated from bone. The preliminary clinical data suggest that the new assay may be useful for further investigation of the clinical importance of measurement of these type I collagen degradation products.

Suspension model for blood flow through stenotic arteries with a cell-free plasma layer.

The effects of the red cell concentration, the shape of the stenosis and a peripheral layer on blood flow characteristics due to the presence of a mild stenosis, are investigated. To account for the red cell concentration and the peripheral layer, blood is represented by a two-fluid model of particle-fluid suspension, and to estimate the effect of the stenosis shape, a suitable geometry has been considered such that the axial shape of the stenosis can be changed easily just by varying a parameter (referred to as the shape parameter). It is shown that the flow resistance increases with the cell concentration but decreases with increasing shape parameter. The existence of the peripheral layer causes significant reduction in the flow resistance. The wall shear stress distribution in the stenotic region and its magnitude at the maximum height of the stenosis (i.e., at stenosis throat) possess the variations similar to the resistance to flow with respect to any parameter except the shape parameter. The latter is independent of the shape whereas the former decreases in the converging zone as the shape parameter increases while it increases in the diverging zone in a similar situation. To discuss the physiological relevance, the analytical results are used to estimate the blood flow characteristics for different diseases using the experimental data and the present theoretical approach.

Two-phase model of blood flow through stenosed tubes in the presence of a peripheral layer: applications.

The effects of red cell concentration and the peripheral layer on blood flow characteristics due to the presence of a mild stenosis, are studied. It is shown that the magnitudes of the flow characteristics significantly increase with cell concentration and the peripheral layer causes marked reduction in the magnitudes of the flow characteristics. Physiological relevance and the influence of various parameters are discussed.

Particle-fluid suspension model of blood flow through stenotic vessels with applications.

The present study deals with the problem of blood flow through stenotic vessels when blood is represented by a particle-fluid suspension model, i.e. a suspension of red blood cells in plasma. The expression for the dimensionless resistance to flow, the wall shear stress, and the shearing stress on the wall at the maximum height of the stenosis are derived. The results obtained in the analysis are discussed in brief, both qualitatively and quantitatively by comparison with other theories. It is observed that the magnitudes of the blood flow characteristics significantly increase with an increase in the red cell concentration. The importance of the decreasing vessel diameter is also pointed out. Finally, to observe the biological relevance of the analysis, the results obtained are used to compute the blood flow characteristics for normal and diseased blood using the experimental data from published literature and results are compared with those computed using the present theoretical approach.

Particulate suspension model for blood flow under external body acceleration.

A mathematical model has been developed to investigate the influence of externally imposed periodic body acceleration on blood flow in aorta and arteriole. The rheological properties of blood has been represented by regarding the blood as a two-phase Newtonian fluid, that is, a suspension of cells in plasma. An exact analytical solution of coupled differential equations, describing the flow of a particle-fluid suspension, is obtained using the Laplace transforms technique. The effects of body acceleration and blood cells concentration on velocity, flow rate, acceleration and shear rates are computed and displayed graphically.

Two-layered model of Casson fluid flow through stenotic blood vessels: applications to the cardiovascular system.

The effects of peripheral layer viscosity on physiological characteristics of blood flow through the artery with mild stenosis have been investigated. Blood has been represented by a two-fluid model, consisting of a core region of suspension of all the erythrocytes assumed to be a Casson fluid and a peripheral layer of plasma as a Newtonian fluid. The study is based on theoretical considerations and numerical evaluations and is restricted to the flow of blood through small arteries (130-1000 microns in diameter). It has been found that the resistance to flow and the wall shear stress decrease as the peripheral layer viscosity decreases. These characteristics are found to be decreasing as peripheral layer thickness increases. The numerical results show that the existence of the peripheral layer is helpful in functioning of the diseased arterial system. The analysis has been applied to calculate the resistance to flow and wall shear stress in different blood vessels.

Peristaltic transport of a particle-fluid suspension.

Peristaltic pumping by a sinusoidal traveling wave in the walls of a two-dimensional channel filled with a viscous incompressible fluid in which are distributed identical rigid spherical particles, is investigated theoretically. A perturbation solution is obtained which satisfies the momentum equations for the case in which amplitude ratio (wave amplitude/channel half width) is small. The results show that the fluid phase mean axial velocity decreases with increase in the particle concentration. The phenomenon of reflux (the mean flow reversal) is discussed. A reversal of velocity in the neighborhood of the centerline occurs when the pressure gradient is greater than that of the critical reflux condition. It is found that the critical reflux pressure is lower for the particle-fluid suspension than for the particle-free fluid. It is further observed that the mean flow reversal is strongly dependent on the particle concentration and the presence of particles in the fluid favors the reversal flow. A motivation of the present analysis has been the hope that such a theory of two-phase flow process is very useful in understanding the role of peristaltic muscular contraction in transporting bio-fluid behaving like a particle-fluid mixture. Also the theory is important to the engineering applications of pumping solid-fluid mixtures by peristalsis.

Interaction of peristaltic flow with pulsatile flow in a circular cylindrical tube.

The effect of pulsatile flow on peristaltic transport in a circular cylindrical tube is analysed. The flow of a Newtonian viscous incompressible fluid in a flexible circular cylindrical tube on which an axisymmetric travelling sinusoidal wave is imposed, is considered. The initial flow in the tube is induced by an arbitrary periodic pressure gradient. A perturbation solution with amplitude ratio (wave amplitude/tube radius) as a parameter is obtained when the frequency of the travelling wave and that of the imposed pressure gradient are equal. The interaction effects of periodic wall induced flow and periodic pressure imposed flow are visualized through the presence of substantially different components of steady and higher harmonic oscillating flow in the first order flow solution. Numerical results show a strong variation of steady state velocity profiles with boundary wave number and Reynolds number and a strong phase shift behaviour of the flow in the radial direction.

Peristaltic transport of a non-Newtonian fluid: applications to the vas deferens and small intestine.

The problem of peristaltic transport of a non-Newtonian (Power law) fluid in a uniform and non-uniform tube has been investigated under zero Reynolds number and long wavelength approximation. A comparison of the results with those of Newtonian fluid model shows that the magnitude of pressure rise, under a given set of conditions, is smaller in the case of non-Newtonian fluid, when the flow behavior index n less than 1, at zero flow rate. Further, the pressure rise decreases as n decreases from 1, at zero flow rate, is independent of n at a certain value of flow rate, and increases if flow rate exceeds further. Also, at a given flow rate, an increase in the wavelength leads to a decrease in pressure rise and increase in the influence of non-Newtonian behavior. Pressure rise, in the case of non-uniform geometry, is found much smaller than the corresponding value in the case of uniform geometry. Finally, the analysis has been applied and compared with observed flow rates in the vas deferens in rhesus monkeys and in the small intestine.

Peristaltic transport of blood: Casson model--II.

The problem of peristaltic transport of blood in a uniform and non-uniform tube has been investigated, under zero Reynolds number and long wavelength approximation. Blood is represented by a two-layered fluid model consisting of a central layer of suspension of all erythrocytes, etc., assumed to be a Casson fluid, and a peripheral layer of plasma as a Newtonian fluid. A comparison of results with those without peripheral layer shows that the magnitude of the pressure rise, under a given set of conditions is smaller in the case of model with peripheral layer. It is found that, for a given flow rate, the pressure rise decreases as the viscosity of the peripheral layer decreases, and for a given non zero pressure drop, the flow rate increases as the viscosity of the peripheral layer decreases. However, the flow is independent of the presence of the peripheral layer, for zero pressure rise. Further, the pressure rise in the case of non-uniform geometry is found much smaller than the corresponding value in the uniform geometry.

On two-phase model of pulsatile blood flow with entrance effects.

A particle fluid suspension model is applied to the problem of pulsatile blood flow through a rigid circular tube with entrance effects. Flow is generated by an arbitrary (time and axial flow variable dependent) as well as a particular pressure gradient of physical importance. Fluid and particle phase velocities are explicitly determined for both, with and without entrance effects. Further, steady pulsatile velocities for both cases are deduced by taking time t -greater than . Several other limiting cases of physical and biological importance have been obtained and discussed in detail.

Peristaltic transport of a physiological fluid. Part-I. Flow in non-uniform geometry.

The problem of peristaltic transport of a fluid of variable viscosity in a non-uniform tube and channel has been investigated under zero Reynolds number, and long wavelength approximation. It is found that, the pressure rise decreases as the fluid viscosity decreases at zero flow rate, is independent of viscosity variation at a certain value of flow rate, and increases if flow rate exceeds further. The difference between two corresponding values (for constant and variable viscosity) of pressure rise, under a given set of conditions increases with increasing amplitude ratio at zero flow rate. Further, for a given zero pressure rise, the flow rate increases as viscosity of fluid decreases. The pressure rise, in the case of non-uniform geometry is found to be much smaller than the corresponding value in the case of uniform geometry. In Part II (a companion paper), results for uniform tube and channel are obtained and comparison with other theories are made in detail. Finally, the models developed in Part I and Part II are applied and compared with observed flow rates in vas deferens of rhesus monkeys, the small intestine, and the ductus deferens of the male reproductive tract in the other companion paper, Part III.

Peristaltic transport of a physiological fluid. Part - II. Flow in uniform geometry.

Using the model of peristaltic flow in non-uniform geometry, developed in the companion paper (Part I), results for uniform tube and channel are obtained in closed form. Comparison of analysis with other theories and the effect of viscosity variation are discussed in detail. Finally, quantitative comparison are made between theory and experiments of Weinberg et al. and Latham.

Peristaltic transport of a physiological fluid. Part - III. applications.

The models of peristaltic flow in non-uniform and uniform tube and channel, developed in the companion papers, Part I and Part II, are applied and compared with the observed flow rates in vas deferens of rhesus monkeys, the small intestine, and the ductus deferens of the male reproductive tract.

Peristaltic transport of a two-layered model of physiological fluid.

The problem of peristaltic transport of a two-fluid (peripheral and core fluid) model in a non-uniform tube and channel has been investigated under long wavelength approximation. A comparison of these results with those for without peripheral layer fluid shows that the magnitude of the pressure rise under a given set of conditions is smaller in the case of with peripheral layer fluid. For a given non zero pressure drop, the flow rate increases as the viscosity of the peripheral layer fluid decrease. However, for zero pressure drop, the flow rate is independent of the presence of peripheral layer fluid. Pressure rise in the case of non-uniform geometry is found to be much smaller than the corresponding values in the case of uniform geometry. The analysis has been applied and compared with the observed flow rates of spermatic fluid (semen) in vas deferens of rhesus monkeys and to the experimental results of Weinberg et al. (1971).