Improving the Functional Control of Aged Ferroelectrics Using Insights from Atomistic Modeling.

We provide a fundamental insight into the microscopic mechanisms of the aging processes. Using large-scale molecular dynamics simulations of the prototypical ferroelectric material PbTiO_{3}, we demonstrate that the experimentally observed aging phenomena can be reproduced from intrinsic interactions of defect dipoles related to dopant-vacancy associates, even in the absence of extrinsic effects. We show that variation of the dopant concentration modifies the material's hysteretic response. We identify a universal method to reduce loss and tune the electromechanical properties of inexpensive ceramics for efficient technologies.

A randomised trial of peri-operative positive airway pressure for postoperative delirium in patients at risk for obstructive sleep apnoea after regional anaesthesia with sedation or general anaesthesia for joint arthroplasty.

Previous pilot work has established an association between obstructive sleep apnoea and the development of acute postoperative delirium , but it remains unclear to what extent this risk factor is modifiable in the 'real world' peri-operative setting. In a single-blind randomised controlled trial, 135 elderly surgical patients at risk for obstructive sleep apnoea were randomly assigned to receive peri-operative continuous positive airway pressure (CPAP) or routine care. Of the 114 patients who completed the study, 21 (18.4%) experienced delirium. Delirium was equally common in both groups: 21% (12 of 58 subjects) in the CPAP group and 16% (9 of 56 subjects) in the routine care group (OR = 1.36 [95%CI 0.52-3.54], p = 0.53). Delirious subjects were slightly older - mean (SD) age 68.9 (10.7) vs. 64.9 (8.2), p = 0.07 - but had nearly identical pre-operative STOP-Bang scores (4.19 (1.1) versus 4.27 (1.3), p = 0.79). Subjects in the CPAP group used their devices for a median (IQR [range]) of 3 (0.25-5 [0-12]) nights pre-operatively (2.9 (0.1-4.8 [0.0-12.7]) hours per night) and 1 (0-2 [0-2]) nights postoperatively (1.4 (0.0-5.1 [0.0-11.6]) hours per night). Among the CPAP subjects, the residual pre-operative apnoea-hypopnea index had a significant effect on delirium severity (p = 0.0002). Although we confirm that apnoea is associated with postoperative delirium, we did not find that providing a short-course of auto-titrating CPAP affected its likelihood or severity. Voluntary adherence to CPAP is particularly poor during the initiation of therapy.

Fluorometric studies of oxidative metabolism in isolated papillary muscle of the rabbit.

The fluorometric technique for measuring the levels of reduced pyridine nucleotides was used to study oxidative metabolism in isolated rabbit papillary muscle at 23 degrees C. The 100% standard level of tissue fluorescence was defined as that measured for muscles resting in oxygenated 10 mM pyruvate solution. This level increased 15% with anoxia and decreased 45% with stimulation in substrate-free solution. Thus, about one-half of the standard tissue fluorescence was metabolically labile and this labile fraction is suggested to be mitochondrial in origin. Decreased tissue fluorescence following mechanical activity was identified with increased oxidation of mitochondrial reduced nicotinamide adenine dinucleotide (NADH) owing to stimulation by adenosine diphosphate (ADP), released during activity, of mitochondrial respiration. The kinetics of the fluorescence transients were slowed fourfold by removal of pyruvate. This effect was not significantly reversed by addition of 10 mM glucose. The time integrals of the fluorescence transients were linearly related to the amounts of mechanical activity in the presence, but not in the absence, of pyruvate. A positive correlation was observed between the steady-state peak tension at constant stimulus rate and the resting level of reduction of pyridine nucleotides in various media. The fluorometric results are interpreted to be indicative of the steady and transient states established by the substrate dehydrogenases and the respiratory chain during oxidative phosphorylation in mitochondria.

Gallstone size and risk of pancreatitis.

BACKGROUND: The treatment of patients with gallstones who have suffered a first episode of acute biliary pain is controversial. Recent guidelines suggest that such patients may choose to observe the "pattern" of their pain over time before deciding about therapy. OBJECTIVE: To determine clinical factors that would identify patients at high risk for 2 important complications: acute biliary pancreatitis and acute cholecystitis. METHODS: We collected sociodemographic and clinical data on patients undergoing cholecystectomy after acute biliary pancreatitis, acute cholecystitis, or uncomplicated biliary pain. The physical characteristics of gallstones recovered at surgery were also recorded. Patients with pancreatitis and patients with cholecystitis were compared with patients with uncomplicated pain. RESULTS: In univariate analyses, patients with acute pancreatitis were significantly more likely to have at least 1 gallstone smaller than 5 mm in diameter, 20 or more gallstones, gallstones described as mulberry shaped, and a lower total gallstone weight than patients with uncomplicated pain. Pancreatitis was unrelated to patient age, sex, race or ethnicity, use of alcohol or tobacco, or clinical comorbidity. In a logistic regression model, acute pancreatitis was associated with a stone diameter of less than 5 mm (odds ratio, 4.51; P = .007) and with mulberry-shaped gallstones (odds ratio, 2.25; P = .04). No sociodemographic, clinical, or gallstone characteristics were consistently associated with acute cholecystitis. CONCLUSIONS: Patients with at least 1 gallstone smaller than 5 mm in diameter have a more than 4-fold increased risk of presenting with acute biliary pancreatitis. A policy of watchful waiting in such cases is unwarranted.

Sodium valproate: effects on maternal behaviour in the mouse.

The behaviour of lactating mice in their home cages was examined by ethological procedures at 1, 7, 14 and 21 days postpartum. Early in lactation, maternal behaviour was more frequent in the light phase of the 24 hr cycle, whereas non-social activity occupied a greater amount of time during the dark phase. As the pups became older, maternal behaviour declined, and at 21 days the dams showed a marked increase of solitary immobility. Behavioural alterations produced by the administration of sodium valproate at 600 mg/l as drinking fluid during pregnancy and lactation (group SVP), and during lactation only, (group PN) were assessed. (Intake of drug amounted to 153 mg/kg during gestation and 186 mg/kg in lactation). Dams of group PN showed behavioural differences from controls in late lactation, pup nursing being prolonged at day 14 postpartum and the frequency of all categories of active behaviour, other than nursing and nestbuilding, was increased at day 21 postpartum in the dark phase of their daily cycle. There was not significant effect on categories of behaviour in dams of the SVP group. Overall, sodium valproate, at this dose, did not reduce maternal care.

Phenobarbitone: adverse effects on reproductive performance and offspring development in the Mongolian gerbil, (Meriones unguiculatus).

Phenobarbitone at a concentration of 500 mg/l in drinking fluid of gerbils during pregnancy (60 mg/kg) and lactation (136 mg/kg) markedly reduced the proportion of animals bearing litters, decreased pup weights at birth and during later life and delayed development of the self-righting reflex, auditory startle reaction, eye opening and full fur coverage. It also prolonged the period of suckling. Scars of implantation were evident in uterine horns of 60% of treated and in none of control females that had failed to give birth. Treated offspring after weaning were given phenobarbitone (500 mg/l; 42-124 mg/kg) as their drinking fluid throughout life and a further group of gerbils received this concentration of the drug from the time of weaning. Seizure susceptibility was unaltered by the drug treatment, and the only evidence of behavioural change was seen in offspring gerbils at 6 weeks when the bout length of social investigation during encounters was increased. Drug-treated offspring showed no abnormality in brain weight relative to body weight. Weight gain and brain weight remained normal among the gerbils given phenobarbitone after weaning. The drug treatment reduced scent gland size in breeding males, though not in the offspring, and had no effect on weights of the testes or ovaries and uterus. no effect on weights of the testes or ovaries and uterus. Plasma concentrations of phenobarbitone in females of the postweaning group amounted on average to 4.4 mg/kg. Most of the adverse effects of this dose of phenobarbitone in the gerbil can thus be seen to be associated either with reproductive impairment or with exposure during sensitive periods of early development.

Behavioral effects of phenobarbitone II. Effects in nursing female mice.

Phenobarbitone supplied at concentrations of 187.5 mg/l and 500 mg/l (50--60 mg/kg and 120--190 mg/kg daily) in the drinking fluid of mice throughout pregnancy and lactation did not affect gestation period, numbers born or resorbed or pup weights at birth and weaning. The higher dose caused significant retardation in eye-opening, development of forelimb extension, negative geotaxis, in appearance of washing and self-grooming behaviours and in cessation of suckling. The lower dose had no detectable effects. Ethological methods were used to examine spontaneous behaviour of nursing dams within home cages on days 1, 7, 14 and 21 postpartum. Treated dams showed differences in behaviour from controls, the most marked of which were increased levels of Maternal Behaviour and decreases in Non-Social Activity in the high-dose group at day 1, and continuance of pup Nursing in both treated groups and Nest Building in the high-dose group at day 21 when controls were ceasing these behaviours. At 21 days all treated dams also showed less Immobility than controls and high-dose dams a smaller amount of pup Social Investigation. Many behavioural differences at 21 days were related to developmental delay of treated pups. Overall, phenobarbitone did not impair maternal care.

Behavioural effects of phenobarbitone. 1. Effects in the offspring of laboratory mice.

Phenobarbitone at a concentration of 187.5 mg/l in drinking fluid of breeding mice and their offspring after weaning did not affect gestation period, litter size, litter weight or pup development before weaning, although a slight retardation of weight gain after weaning occurred. This level of phenobarbitone given to mice after weaning did not affect weight gain. The average daily intake of phenobarbitone ranged from 30 to 52 mg/kg body weight depending on age and sex. Behaviour of offspring and mice treated after weaning was examined by ethological analysis of encounters between unfamiliar mice of the same sex and treatment group in a neutral enclosure. After lifelong exposure to phenobarbitone mice at 5 and 15 weeks of age showed an increased amount of scanning and exploration of the unfamiliar cage coupled with a decrease of time spent in immobility. Difference from control levels was more pronounced at 15 than at 5 weeks of age, in part because controls showed more immobility and explored less as they matured. No behavioural changes were detected in mice treated with this level of phenobarbitone after weaning. Lifelong exposure to phenobarbitone did not affect agonistic behaviour in pair-housed males at 30 weeks of age, and under these circumstances no longer stimulated exploration to a significant extent.

Sodium valproate: effects on social behaviour and physical development in the mouse.

Sodium valproate given in drinking fluid at 600 mg/l (160-180 mg/kg daily) to breeding mice did not affect fertility, birth weights or physical development of pups. Postnatal and postweaning administration of this dose also had no effects upon development or weight gain. The offspring ingested 103-158 mg/kg valproate daily after weaning. Behaviour was examined in a neutral enclosure by ethological methods. Offspring exposed to valproate in utero and throughout postnatal life showed no behavioural changes at 5 weeks, although at 15 weeks Immobility was reduced in females and Social Investigation increased. At 25 weeks when encountering mice of the opposite sex, treated males showed increase in Social Investigation and treated females increases in Other Non-social Activity. Postnatal and postweaning treatment with valproate caused behavioural changes both in juveniles and adults. After postnatal exposure, reduced Immobility with increased Social Investigation and Explore and Scan occurred at 5 and 15 weeks, at 25 weeks valproate increased Social Investigation in males encountering females and at 30 weeks enhanced Aggression in pair-housed males. Stimulation of Social Investigation was the only significant behavioural effect after postweaning exposure. Overall valproate appears to enhance behaviour stimulated by the test situation; urinary pheromones do not appear to play a part in this behavioural action.

Effects of sodium valproate on development and social behaviour in the Mongolian gerbil.

Sodium valproate is an anticonvulsant widely prescribed because of its broad spectrum of activity. While acute toxicity from high doses is well recognized, there have been few animal studies of its chronic toxicity at therapeutic dose levels. Sodium valproate given continuously in drinking fluid (600 mg/l) throughout pregnancy and lactation to breeding gerbils caused developmental delay of the self-righting reflex in their pups. Dams ingested 97 mg/kg daily during gestation and 151 mg/kg on average during lactation, a dose in the lower range of anticonvulsant effectiveness. Reproductive performance, birth weights and subsequent growth of the pups remained normal, as did brain weights in adulthood. Drug-treated offspring, continuing to receive valproate as drinking fluid after weaning (600 mg/l; 82 to 111 mg/kg) showed negligible behavioural alteration at 6 weeks of age as assessed by ethological procedures, although behavioural change did occur at 20 weeks in the female animals. These females were characterised by significant enhancement of exploration and scanning during dyadic encounters in an unfamiliar cage, and showed a concomitant reduction of other nonsocial activities. Short-term administration of this dose of the drug did not affect behaviour. These results suggest an increased reactivity to the environment which becomes evident only after long-term treatment with valproate and to which female animals are more susceptible than males. These findings of developmental delay and of modifications to behaviour later in life points to the need for more detailed clinical assessments of the effects of valproate in human patients.

Cardiac mechanics and energetics: chemomechanical transduction in cardiac muscle.

When a heart is in a stable inotropic state, the end-systolic pressure-volume points of each work cycle fall on a straight line regardless of the magnitude of the afterload or the initial end-diastolic volume: cardiac O2 consumption (MVO2) per beat is linearly correlated with ventricular systolic pressure-volume area (PVA), defined in terms of stroke work and potential energy components. Moreover, if the basal and activation components of the cardiac energy cycle are subtracted, hearts operate at a constant PVA/MVO2 efficiency. The present review examines the energetic implications of these results for current muscle models, discussing the energetic background of earlier skeletal muscle viscoelastic models and examining differences between the vectorial outputs of ion transport ATPases and myofibrillar ATPases. The PVA data point to a unique stoichiometric relationship between myocardial energy flux and vectorial output, and it is shown that most existing myocardial O2 consumption data can be reconciled with the PVA concept. However, most muscle models would not predict a linear stoichiometric relation between energy flux and pressure-volume potential energy. We pose the question as to whether there is an undiscovered autoregulatory process at work in muscle.

Steady-state flux ratio analysis: application to biological transport.

A thermodynamically constrained method of flux ratio analysis, based upon a previously developed thermodynamic rate ratio equation has been developed. In this paper it is demonstrated that, for a complex reaction, application of the thermodynamic rate ratio equation may provide a useful tool for the interpretation of unidirectional flux data thought to be mediated by the reaction, provided that: (i) a clearly defined mechanism for the reaction has been proposed; (ii) a set of partial reaction components may be defined for the reaction from the proposed mechanism, with the rate ratio of at least one of these components being amenable to experimental measurement. This paper defines the conditions for which the rate ratio of a component reaction may be measured, and illustrates the basic principles underlying this approach to flux ratio analysis by direct application to a number of hypothetical mechanisms for biological transport phenomena.

Steady-state rate analysis: application to biological transport.

A novel method for defining the steady-state unidirectional rates of complex reactions has previously been developed (Wagg, 1988 Ph.D. Thesis, Monash University, Australia). This methodology is based upon the method of Wagg (1987, J. theor. Biol. 128, 375-385) for defining the steady-state unidirectional fluxes of chemical species through branched chemical, osmotic and chemiosmotic reactions. It offers a number of distinct advantages over existing approaches to steady-state rate analysis: it is relatively simple to apply to complex reactions and is readily amenable to computer-based application. The method is demonstrated by direct application to a number of hypothetical models for biological transport phenomena.

An energetic model of muscle contraction.

Initial energy utilization in the twitch is visualized as the result of the activity of two distinct processes. The first is the calcium-pumping activity of the sarcoplasmic reticulum, which has a constant energy requirement under normal conditions. The second is the chemomechanical transduction process consisting of a variable number of quantal contractile events, each with a fixed enthalpy equal to the molecular enthalpy of adenosine triphosphate (ATP) hydrolysis in vivo. This enthalpy appears either as heat or as contractile element work. Total enthalpy varies according to the number of quantal contractile events that occur in the twitch cycle. The basis of the variation is suggested to be velocity-dependent activity of the actomyosin ATPase, allowing more quantal events to occur in a contraction cycle when shortening occurs. The classical designation "activation heat" is held to be appropriate for the first process. The partition of the enthalpy of the second process that is currently in vogue is held to be misleading and a new formulation is suggested in which the properties of the quantal contractile event are reflected in general terms. The formulation of the proposed transduction model represents a conceptual return to the viscoelastic theory, but at a quantal level. The model can explain the results of the preceding paper and is adaptable to different muscles without having to postulate fundamental differences in energy utilization.

Fluorometric studies of recovery metabolism of rat fast- and slow-twitch muscles.

Recovery metabolism of fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles of the rat has been investigated using fluorometric monitoring of reduction of nicotinamide adenine dinucleotide (NAD). In both EDL and SOL, groups of twitch contractions produced a decrease in fluorescence (oxidation of NADH) which returned to the resting base line after contraction ceased. These responses proceeded more quickly in EDL than SOL and were abolished by anoxia. A 1-s tetanus of SOL produced an initial reduction which could be abolished with iodoacetate followed by a prolonged oxidation which could be blocked by anoxia. The fluorescence of EDL was decreased immediately following a 1-s tetanus but then rapidly increased well beyond the resting level of reduction and persisted throughout the recovery period. This reduction was largely depressed by iodoacetate. The results indicate marked differences in the recovery metabolism of these muscles, consistent with predominantly mitochondrial oxidative activity in the slow-twitch muscles and predominantly glycolytic activity in the fast-twitch muscles.