Comparison of pulmonary vascular function and structure in early and established hypoxic pulmonary hypertension in rats

In pulmonary hypertension, changes in pulmonary vascular structure and function contribute to the elevation in pulmonary artery pressure. The time-courses for changes in function, unlike structure, are not well characterised. Medial hypertrophy and neomuscularisation and reactivity to vasoactive agents were examined in parallel in main and intralobar pulmonary arteries and salt-perfused lungs from rats exposed to hypoxia (10% O-2) for 1 and 4 weeks (early and established pulmonary hypertension, respectively). After 1 week of hypoxia, in isolated main and intralobar arteries, contractions to 5-hydroxytryptamine and U46619 (thromboxane-mimetic) were increased whereas contractions to angiotensins I and II and relaxations to acetylcholine were reduced. These alterations varied quantitatively between main and intralobar arteries and, in many instances, regressed between 1 and 4 weeks. The alterations in reactivity did not necessarily link chronologically with alterations in structure. In perfused lungs, constrictor responses to acute alveolar hypoxia were unchanged after 1 week but were increased after 4 weeks, in conjunction with the neomuscularisation of distal alveolar arteries. The data suggest that in hypoxic pulmonary hypertension, the contribution of altered pulmonary vascular reactivity to the increase in pulmonary artery pressure may be particularly important in the early stages of the disease.

NMR structure and backbone dynamics of a concatemer of epidermal growth factor homology modules of the human low-density lipoprotein receptor

The ligand-binding region of the low-density lipoprotein (LDL) receptor is formed by seven N-terminal, imperfect, cysteine-rich (LB) modules. This segment is followed by an epidermal growth factor precursor homology domain with two N-terminal, tandem, EGF-like modules that are thought to participate in LDL binding and recycling of the endocytosed receptor to the cell surface. EGF-A and the concatemer, EGF-AB, of these modules were expressed in Escherichia coli. Correct protein folding of EGF-A and the concatemer EGF-AB was achieved in the presence or absence of calcium ions, in contrast to the LB modules, which require them for correct folding. Homonuclear and heteronuclear H-1-N-15 NMR spectroscopy at 17.6 T was used to determine the three-dimensional structure of the concatemer. Both modules are formed by two pairs of short, anti-parallel beta -strands. In the concatemer, these modules have a fixed relative orientation, stabilized by calcium ion-binding and hydrophobic interactions at the interface. N-15 longitudinal and transverse relaxation rates, and {H-1}-N-15 heteronuclear NOEs were used to derive a model-free description of the backbone dynamics of the molecule. The concatemer appears relatively rigid, particularly near the calcium ion-binding site at the module interface, with an average generalized order parameter of 0.85 +/- 0.11. Some mutations causing familial hypercholesterolemia may now be rationalized. Mutations of D41, D43 and E44 in the EGF-B calcium ion-binding region may affect the stability of the linker and thus the orientation of the tandem modules. The diminutive core also provides little structural stabilization, necessitating the presence of disulfide bonds. The structure and dynamics of EGF-AB contrast with the N-terminal LB modules, which require calcium ions both for folding to form the correct disulfide connectivities and for maintenance of the folded structure, and are connected by highly mobile linking peptides. (C) 2001 Academic Press.

NMR imaging of water sorption into poly(hydroxyethyl methacrylate-co-tetrahydrofurfuryl methacrylate)

The diffusion of water into a series of hydroxyethyl methacrylate, HEMA, copolymers with tetrahydrofurfuryl methacrylate, THFMA, has been studied over a range of copolymer compositions using NMR imaging analyses. For polyHEMA the diffusion was found to be consistent with a Fickian model. The mass diffusion coefficient of water in polyHEMA at 37 degreesC was determined from the profiles of the diffusion front to be 1.5 x 10(-11) m(2) s(-1), which is less than the value based upon mass uptake, 2.0 x 10(-11) m(2) s(-1). The profiles of the water diffusion front obtained from the NMR images showed that stress was induced at the interface between the rubbery and glassy regions which led to formation of small cracks in this region of the glassy matrix of polyHEMA and its copolymers with mole fractions of HEMA greater than 0.6. Water was shown to be able to enter these cracks forming water pools. For copolymers of HEMA and THFMA with mole fractions of HEMA less than 0.6 the absence of cracks was attributed to the ability of the THFMA sequences to undergo stress relaxation by creep.

Ring flexibility within tricyclic antidepressant drugs

The internal flexibility of the central seven-membered ring of a series of tricyclic antidepressant drugs (TCAs), imipramine {l}, amitriptyline {2}, doxepin {3}, and dothiepin {4}, has been investigated by H-1 and C-13 nuclear magnetic (NMR) techniques. Two dynamic processes were examined: ring inversion and bridge flexing. H-1 NMR lineshape analysis was used to obtain ring inversion barriers for 2-4. These studies yielded energy barriers of 14.3, 16.7, and 15.7 +/- 0.6 kcal/mol for the hydrochloride salts of doxepin, dothiepin, and amitriptyline, respectively. The barriers for the corresponding free bases were lower by 0.6 kcal/mol on average. (CT1)-C-13 relaxation measurements were used to determine the degree of bridge flexing associated with the central seven-membered ring for all four compounds. By fitting the T-1 data to a two-state jump model, lifetimes and amplitudes of rapid bridge flexing motions were determined. The results show that imipramine has the fastest rate of bridge flexing, followed by amitriptyline, doxepin, and dothiepin. The pharmacological profiles of the TCAs are complex and they interact with many receptor sites, resulting in numerous side effects and a general lack of understanding of their precise mode of action in different anxiety-related disorders. They all have similar three-dimensional structures, which makes it difficult to rationalize their differing relative potency in different assays/clinical settings. However, the clear finding here that there are significantly different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:713-721, 2001.

The effects of stress management on symptoms of upper respiratory tract infection, secretory immunoglobulin A, and mood in young adults

Objective: To investigate the efficacy of a stress management programme on symptoms of colds and influenza in 27 university students before and after the examination period. Method: The incidence of symptoms, levels of negative affect, and secretion rate of secretory immunoglobulin A (sIgA) were recorded for 5 weeks before treatment, for the 4 weeks of treatment, and for 8 weeks after treatment in treated subjects and in 25 others who did not participate in stress management. Results: Symptoms decreased in treated subjects but not in controls during and after the examination period. Although sIgA secretion rate increased significantly after individual sessions of relaxation, resting secretion rate of sIgA did not increase over the course of the study. Negative affect decreased after examinations in both groups, but was not affected by treatment. Conclusion: Stress management reduced days of illness independently of negative affect and sIgA secretion rate. Although the component of treatment responsible for this effect has yet to be identified, psychological interventions may have a role in reducing symptoms of upper respiratory tract infection. (C) 2001 Elsevier Science Inc. All rights reserved.

The calibre of the Foramen of Panizza in Crocodylus porosus is variable and under adrenergic control

The foramen of Panizza is located within the outflow tract of the crocodilian heart, between the left and right aortas. It has been suggested that the foremen of Panizza has a variable calibre, which could explain the profound changes in the distribution of flows and pressure profiles recorded in the right and left aortas. We investigated this possibility using a modified in-situ perfused heart preparation in combination with isolated strip preparations from the outflow tract. In the perfused heart preparation, bolus injections of adrenaline increased the resistance in the foramen of Panizza, indicating a decrease in its diameter. Isolated strip preparations from the outflow tract showed a concentration-dependent increase in tension in response to adrenaline, while vasoactive intestinal polypeptide caused a relaxation in adrenaline pre-contracted strip preparations. We propose that an increase in the diameter of the foremen of Panizza may be important during pulmonary to systemic shunts to allow blood to flow from the left to right aorta (reverse foramen flow) in order to supply the carotid and coronary arteries. During non-shunting conditions, a constricted foramen may prevent excess flow from the right to left aorta during diastole.

Molecular motion in nanocomposites of poly(ethylene oxide) and montmorillonite

Motion of chains of poly(ethylene oxide) within the interlayer spacing of 2:1 phyllosilicate/montmorillonite was studied with H-1 and C-13 NMR spectroscopy. Measurements of the H-1 NMR line widths and relaxation times across a large temperature range were used to determine the effect of bulk thermal transitions on polymer chain motion within the nanocomposites. The results were consistent with previous reports of low apparent activation energies of motion. Details of the frequency and geometry of motion were obtained from a comparison of the C-13 cross-polarity/magic-angle spinning spectra and relaxation times of the nanocomposite with those of the pure polymer. (C) 2001 John Wiley & Sons, Inc.

H-1 NMR study of the states of water in equilibrium Poly(HEMA-co-THFMA) hydrogels

The spin-spin relaxation times, T-2, of hydrated samples of poly(hydroxymethyl methacrylate), PHEMA, poly(tetrahydrofurfuryl methacrylate),PTHFMA, and the,corresponding HEMA-THFMA copolymers have been examined to probe the states of,the imbibed water in these polymers. The decay in the transverse magnetization of water. in fully hydrated samples of PHEMA, PTHFMA, and copolymers of HEMA and THFMA was described by a multiexponential function. The short component of T-2 was interpreted as water molecules that were strongly interacting with the polymer chains. The intermediate component of T-2 was assigned to water residing in the porous structure of the samples. The long component of T-2 was believed to arise from water residing in the remnants of cracks formed in the polymer network during water sorption.

The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis

Although cardiac dysfunction in hereditary hemochromatosis (HHC) can be evaluated by conventional echocardiography, findings are often not specific. To test the hypothesis that the assessment of (1) conventional Doppler left ventricular filling indexes and (2) intrinsic elastic properties of the myocardium by Doppler tissue echocardiography can both enhance the accuracy of echocardiographic diagnosis of cardiac involvement in HHC, a group of 18 patients with HHC (mean age 50+/-7 years) and 22 age-matched healthy subjects were studied. The following indexes were characteristic for HHC: (1) the duration of atrial reversal measured from pulmonary venous flow (ms) was longer(118+/-20 vs 90+/-16; P

PFG-NMR measurements of the self-diffusion coefficients of water in equilibrium poly(HEMA-co-THFMA) hydrogels

The self-diffusion coefficients for water in a series of copolymers of 2-hydroxyethyl methacrylate, HEMA, and tetrahydrofurfuryl methacrylate, THFMA, swollen with water to their equilibrium states have been studied at 310 K using PFG-NMR. The self-diffusion coefficients calculated from the Stejskal-Tanner equation, D-obs, for all of the hydrated polymers were found to be dependent on the NMR storage time, as a result of spin exchange between the proton reservoirs of the water and the polymers, reaching an equilibrium plateau value at long storage times. The true values of the diffusion coefficients were calculated from the values of D-obs, in the plateau regions by applying a correction for the fraction of water protons present, obtained from the equilibrium water contents of the gels. The true self-diffusion coefficient for water in polyHEMA obtained at 310 K by this method was 5.5 x 10(-10) m(2) s(-1). For the copolymers containing 20% HEMA or more a single value of the self-diffusion coefficient was found, which was somewhat larger than the corresponding values obtained for the macroscopic diffusion coefficient from sorption measurements. For polyTHFMA and copolymers containing less than 20% HEMA, the PFG-NMR stimulated echo attenuation decay curves and the log-attenuation plots were characteristic of the presence of two diffusing water species. The self-diffusion coefficients of water in the equilibrium-hydrated copolymers were found to be dependent on the copolymer composition, decreasing with increasing THFMA content.

Physical aging of amorphous fructose

Physical aging of amorphous anhydrous fructose at temperature 5 degreesC and at 22 degreesC was studied using differential scanning calorimetry (DSC). The dynamic glass transitions temperature, T-g0 for unaged samples was 16 degreesC and 13.3 degreesC for heating rate of 10 degreesC/min and 1 degreesC/min, respectively. The fictive temperature, T-f0 for unaged samples calculated by Richardson and Savill method was 12 degreesC, which is close to the dynamic value obtained from the lower DSC heating rate. The fictive temperature T-f of the aged fructose glasses at temperatures both below and above the transition region was fitted well by a non-exponential decay function (Williams-Watts form). Aging above the transition region (22 degreesC) for 18 d increased both the dynamic glass transition temperature T and the fictive temperature T-f. However, aging below the transition region (5 degreesC) for I d increased the dynamic glass transition temperature T-g but decreased the fictive temperature T-f.

Quadriceps concentric and eccentric exercise 1: Changes in contractile and electrical activity following eccentric and concentric exercise

The purpose of this study was to determine whether or not losses of strength or endurance following eccentric and concentric exercise are associated with reduced excitation. The effects of eccentric and concentric work on maximal voluntary isometric contraction (MVC) and surface electromyogram (EMG) of the quadriceps were studied in 10 healthy male subjects following bench-stepping for 20 min with a constant leading leg. Prior to stepping and at 0, 0.25, 0.50, 0.75, 1, 3. 24 and 48 h afterwards the subjects performed a 30 s leg extension MVC with each leg during which the isometric force and the root mean square voltage of the EMG were recorded. In the eccentrically exercised muscles (ECC), MVC0-3 (force during the first 3 s of contraction) fen immediately after the bench-stepping exercise to 88 +/- 2% (mean SE) of the pre-exercise value and remained significantly lower than the concentrically exercised muscles (p < 0.05). The muscle weakness in the ECC could not be attributed to central fatigue as surface EMG amplitude at MVC0-3 increased during the recovery period. Muscle weakness after eccentric exercise appears to be due to contractile failure, which is not associated with a reduction in excitation as assessed by surface EMG. Muscular fatigue over 30 s did not change in the two muscle groups after exercise (p = 0.79), indicating that the ECC were weaker but not more fatiguable after exercise.

The morals of metaphysics: Kant's 'Groundwork' as intellectual paideia

To approach philosophy as a way of working on the self means to begin not with the experience it clarifies and the subject it discovers, but with the acts of self‐transformation it requires and the subjectivity it seeks to fashion. Commenting on the variety of spiritual exercises to be found in the ancient schools, Pierre Hadot remarks that: Some, like Plutarch’s ethismoi, designed to curb curiosity, anger or gossip, were only practices intended to ensure good moral habits. Others, particularly the meditations of the Platonic tradition, demanded a high degree of mental concentration. Some, like the contemplation of nature as practiced in all philosophical schools, turned the soul toward the cosmos, while still others—rare and exceptional—led to a transfiguration of the personality, as in the experiences of Plotinus. We also saw that the emotional tone and notional content of these exercises varied widely from one philosophical school to another: from the mobilization of energy and consent to destiny of the Stoics, to the relaxation and detachment of the Epicureans, to the mental concentration and renunciation of the sensible world among the Platonists.1 While successfully applied to ancient philosophy,2 this approach has not been widely exploited in the history of philosophy more broadly. There is, however, at least one study of medieval metaphysics in these terms,3 and there are some important discussions of early modern Stoicism and Epicureanism.4 And a recent study of Hume shows the fruitfulness of the approach for Enlightenment philosophy.5 It is all the more surprising then that there seems to have been no serious attempt to approach Kant’s moral philosophy in this way.

Conservation of the cardiostimulant effects of (-)-Norepinephrine across Ser49Gly and Gly389Arg Beta1-adrenergic receptor polymorphisms in human right atrium in vitro

OBJECTIVES The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. BACKGROUND Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). METHODS The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery. RESULTS (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. CONCLUSIONS The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers. (C) 2002 by the American College of Cardiology Foundation.

Polyethylene flow prediction with a differential multi-mode Pom-Pom model

We report the first steps of a collaborative project between the University of Queensland, Polyflow, Michelin, SK Chemicals, and RMIT University; on simulation, validation and application of a recently introduced constitutive model designed to describe branched polymers. Whereas much progress has been made on predicting the complex flow behaviour of many - in particular linear - polymers, it sometimes appears difficult to predict simultaneously shear thinning and extensional strain hardening behaviour using traditional constitutive models. Recently a new viscoelastic model based on molecular topology, was proposed by McLeish and Larson (1998). We explore the predictive power of a differential multi-mode version of the pom-pom model for the flow behaviour of two commercial polymer melts: a (long-chain branched) low-density polyethylene (LDPE) and a (linear) high-density polyethylene (HDPE). The model responses are compared to elongational recovery experiments published by Langouche and Debbaut (1999), and start-up of simple shear flow, stress relaxation after simple and reverse step strain experiments carried out in our laboratory.