SUMMARY1. The acetylcholine-sensitive ionic channels at the neuromuscular junction were studied in voltage-clamped single muscle fibres from a monolayer preparation of the cutaneous pectoris muscle from Rana pipiens. The experimental observations were of three types: (a) reversal potential as a function of external Na and Ca concentrations, (b) the single channel conductance (y) from noise analysis as a function of these same concentrations, and (c) y as a function of membrane potential.2. The reversal potential in normal Na Ringer was -3-8 + 0-5 mV (+ S.E. of mean, n = 22) and decreased approximately linearly as the logarithm of the outside Na activity as this activity decreased to 10 % of normal.3. The single channel conductance in normal Na Ringer was 27-5 + 0-7 pS (n = 28) and reached a limiting value close to 10 pS as Na was replaced with sucrose. 4. Increasing [Ca]. from 2 to 10 mm made the reversal potential more positive and decreased the single channel conductance. Mg caused similar effects.5. Various theories that have been used to describe the mechanism of ion permeation throuch e.p.c. channels were tested. Constant field theory (eqns. (3), (4) and (5)), a modified Takeuchi approach (eqn. (6)), and a single barrier theory (eqns. (8), (9) and (10)) could not account for all of the experimental observations. 6. In particular, constant field theory, with no assumed surface charge density, could account for the following: (a) the reversal potential measurements for solutions containing 2 mM-Ca (with PK/PN. = 1-2 and PC./PNa = 1-02), (b) the single channel conductance values for solutions containing 2 mm-Ca and Na concentrations down to 20 % of normal, (c) that y has little voltage dependence.7. However, constant field theory, with no assumed surface charge density, could not account for the following: (a) the reversal potential observed for Ringer containing 80 mM-Ca, (b) the y values observed for very low Na concentrations, (c) the observation that increasing Ca from 2 to 10 mm in a solution containing 75 % normal Na results in a decrease in y.8. From thefailure of the Takeuchi approach (eqn. (6)), it is argued that ion interactions must occur at e.p.c. channels because ion flux independence is the only assumption in the derivation of eqn. (6) without experimental verification.9. The ion interactions at e.p.c. channels probably include both surface charge effects and competition for a binding site.

Use of up to 2 years of estrogen plus progestin was associated with increases in mammographic density.

High plasma homocyst(e)ine (Hcy) concentrations may be a determinant of coronary artery disease (CAD). Folate and vitamin B-12 are required for the primary metabolic pathway to reduce Hcy concentrations. The interrelationships of Hcy and these two vitamin cofactors were investigated in a case-control study of 101 white males aged 30-50 y with angiographically demonstrated CAD, and 108 white male, similarly aged, control subjects living in the same community as the patients. The odds ratio (OR) of CAD per quartile increase of plasma Hcy concentration based on control values was 1.6 (95% CI: 1.3, 2.1). After age, HDL and LDL cholesterol, body mass index, smoking, hypertension, and diabetes were controlled for, Hcy remained an independent risk factor (OR: 1.4; 95% CI: 1.0, 2.0). The OR change per quartile increase of folate concentration was 0.8 (95% CI: 0.6, 1.0). This difference was reduced (OR: 0.9; 95% CI: 0.7, 1.2) after Hcy adjustment. No difference in the geometric mean of vitamin B-12 concentration was found between patients and control subjects, both 5.8 nmol/L. However, after Hcy and the other CAD risk factors were controlled for, the OR per quartile increase in vitamin B-12 concentration was 1.5 (95% CI: 1.0, 1.8). Reduction in plasma Hcy by interventions to increase plasma folate concentration may decrease CAD risk.

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Background: Obesity in the United States has increased significantly during the past several decades. The role of calcium in the maintenance of a healthy body weight remains controversial. Methods: A randomized, double-blinded, placebocontrolled trial was performed with 36 282 postmenopausal women, aged 50 to 79 years, who were already enrolled in the dietary modification and/or hormone therapy arms of the Women's Health Initiative clinical trial. Women were randomized at their first or second annual visit to receive a dose of 1000 mg of elemental calcium plus 400 IU of cholecalciferol (vitamin D) or placebo daily. Change in body weight was ascertained annually for an average of 7 years. Results: Women receiving calcium plus cholecalciferol supplements vs women receiving placebo had a minimal but consistent favorable difference in weight change (mean difference, −0.13 kg; 95% confidence interval, −0.21 to −0.05; P =.001). After 3 years of follow-up, women with daily calcium intakes less than 1200 mg at baseline who were randomized to supplements were 11% less likely to experience small weight gains (1-3 kg) and 11% less likely to gain more moderate amounts of weight (Ͼ3 kg) (P for interaction for baseline calcium intake=.008). Conclusion: Calcium plus cholecalciferol supplementation has a small effect on the prevention of weight gain, which was observed primarily in women who reported inadequate calcium intakes.

The hydrophobicities of the 20 common amino acids are reflected in their tendencies to appear in interior positions in globular proteins and in deeply buried positions of membrane proteins. To determine whether these relationships might also have been valid in the warm surroundings where life may have originated, we examined the effect of temperature on the hydrophobicities of the amino acids as measured by the equilibrium constants for transfer of their side-chains from neutral solution to cyclohexane (K w>c ). The hydrophobicities of most amino acids were found to increase with increasing temperature. Because that effect is more pronounced for the more polar amino acids, the numerical range of K w>c values decreases with increasing temperature. There are also modest changes in the ordering of the more polar amino acids. However, those changes are such that they would have tended to minimize the otherwise disruptive effects of a changing thermal environment on the evolution of protein structure. Earlier, the genetic code was found to be organized in such a way that-with a single exception (threonine)-the side-chain dichotomy polar/ nonpolar matches the nucleic acid base dichotomy purine/pyrimidine at the second position of each coding triplet at 25°C. That dichotomy is preserved at 100°C. The accessible surface areas of amino acid side-chains in folded proteins are moderately correlated with hydrophobicity, but when free energies of vapor-tocyclohexane transfer (corresponding to size) are taken into consideration, a closer relationship becomes apparent.T he equilibrium conformations of proteins in neutral solution are strongly influenced by interactions between their constituent amino acids and solvent water. Early work on the crystal structure of hemoglobin and related proteins showed that the side-chains of the more polar amino acid residues tend to be exposed to solvent, whereas less polar side-chains tend to be buried within the interior of globular proteins (1). Later, those tendencies were put to a quantitative test by measuring equilibria of transfer of amino acid side-chains from neutral aqueous solution into less polar environments, such as the vapor phase (2, 3) or a nonpolar solvent such as cyclohexane (4), which dissolves only ∼2 × 10 −3 M water at saturation (5) and appears to be devoid of specific interactions with solutes. The water-to-cyclohexane distribution coefficients (K w>c ) of the 20 common sidechains [here termed "hydrophobicities" (6, 7) and expressed in concentration units of mol/L in each phase; SI Appendix] were found to span a range of 15 orders of magnitude at pH 7 and 25°C. Values of K w>c have been shown to be related to their outside-to-inside distributions in globular proteins (4,8) and to their tendencies to appear within the buried sequences of transmembrane proteins (9-11).Those solvent distribution experiments were conducted at what we would consider ordinary temperatures. However, there is widespread (12, 13)-if not universal (14)-agreement that life originated when the ea...

Design and MethodsSkeletal muscle adipose tissue (AT) infiltration (myosteatosis) increases with aging and may contribute to the development of type 2 diabetes mellitus (T2DM). It remains unclear if myosteatosis is associated to glucose and insulin homeostasis independent of total and central adiposity. We evaluated the association between intermuscular AT (IMAT) in the abdominal skeletal muscles (total, paraspinal and psoas) and fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 393 non-diabetic Caucasian men aged 65+. Abdominal IMAT, visceral (VAT) and subcutaneous (SAT) AT (cm3) were measured by quantitative computed tomography at the L4-L5 intervertebral space.ResultsIn age, study site, height and muscle volume adjusted regression analyses, total abdominal and psoas (but not paraspinal) IMAT were positively associated with glucose, insulin and HOMA-IR (all P < 0.003). The associations between total abdominal and psoas IMAT and insulin and HOMA-IR remained significant after further adjusting for lifestyle factors, as well as DXA total body fat, VAT or SAT in separate models (all P <0.009).ConclusionsOur study indicates a previously unreported, independent association between abdominal myosteatosis and hyperinsulinemia and insulin resistance among older Caucasian men. These associations may be specific for particular abdominal muscle depots, illustrating the potential importance of separately studying specific muscle groups.

A cross-sectional evaluation of dental caries in primary teeth and nutritional status was conducted involving 285 Peruvian children from low socioeconomic conditions aged 3-9 y. Forty-nine percent of the children were found to be chronically malnourished (stunted) whereas acute malnutrition (wasting) was infrequent (2%). Stunted children showed a delayed exfoliation of primary teeth. The caries prevalence curve as a function of age (ie, a plot of decayed, extracted, and filled teeth vs age) was found to be shifted to the right by approximately 15 mo in stunted children as compared with well-nourished children. Children aged 7-9 y with stunted growth showed a significantly higher percentage of carious teeth than did well-nourished children of the same age (40 and 29%, respectively; p less than 0.005). Nutritional deficits that lead to chronic malnutrition not only may affect tooth exfoliation but also appear to render the primary teeth more susceptible to caries attack later in life.