Parameter inference for a stochastic kinetic model of expanded polyglutamine proteins.

The presence of protein aggregates in cells is a known feature of many human age-related diseases, such as Huntington's disease. Simulations using fixed parameter values in a model of the dynamic evolution of expanded polyglutaime (PolyQ) proteins in cells have been used to gain a better understanding of the biological system. However, there is considerable uncertainty about the values of some of the parameters governing the system. Currently, appropriate values are chosen by ad hoc attempts to tune the parameters so that the model output matches experimental data. The problem is further complicated by the fact that the data only offer a partial insight into the underlying biological process: the data consist only of the proportions of cell death and of cells with inclusion bodies at a few time points, corrupted by measurement error. Developing inference procedures to estimate the model parameters in this scenario is a significant task. The model probabilities corresponding to the observed proportions cannot be evaluated exactly, and so they are estimated within the inference algorithm by repeatedly simulating realizations from the model. In general such an approach is computationally very expensive, and we therefore construct Gaussian process emulators for the key quantities and reformulate our algorithm around these fast stochastic approximations. We conclude by highlighting appropriate values of the model parameters leading to new insights into the underlying biological processes.

Bayesian calibration of a stochastic kinetic computer model using multiple data sources.

In this article, we describe a Bayesian approach to the calibration of a stochastic computer model of chemical kinetics. As with many applications in the biological sciences, the data available to calibrate the model come from different sources. Furthermore, these data appear to provide somewhat conflicting information about the model parameters. We describe a modeling framework that allows us to synthesize this conflicting information and arrive at a consensus inference. In particular, we show how random effects can be incorporated into the model to account for between-individual heterogeneity that may be the source of the apparent conflict.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during normotensive and preeclamptic pregnancy.

OBJECTIVE: We sought to determine whether the enhanced forearm vascular activity of nitric oxide during pregnancy and preeclampsia is associated with altered smooth muscle sensitivity to nitric oxide or with stimulated nitric oxide release. STUDY DESIGN: Forearm blood flow responses to brachial artery infusion of glyceryl trinitrate (a nitric oxide donor), serotonin (an endothelium-dependent nitric oxide-mediated agonist), and ritodrine (a beta-adrenergic receptor agonist) were studied in 10 nonpregnant women, 12 pregnant women, and 7 women with preeclampsia by means of strain-gauge plethysmography. Responses to each drug (maximum dilator response and the sum of the percentage of dilator responses to each drug) were compared by analysis of variance. RESULTS: Compared with nonpregnant women, pregnant subjects showed reduced responses to serotonin (summary response, 117 +/- 19 vs 221 +/- 30; P <.05). Responses to serotonin were reduced in the group with preeclampsia compared with those in the nonpregnant group (summary response, 71 +/- 28; P <.05) but did not differ from the responses in pregnant women. There were no differences between responses to glyceryl trinitrate and responses to ritodrine in any of the groups. CONCLUSION: Vascular smooth muscle sensitivity to nitric oxide is not altered in normal pregnancy or preeclampsia, but dilator responses to serotonin appear blunted. Alterations in serotonin receptor coupling to nitric oxide synthase, or a limitation of availability of the substrate for nitric oxide synthase (L-arginine) during pregnancy, could account for the reduction in stimulated nitric oxide release.

Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy.

We investigated the role of nitric oxide (NO) in the vascular resistance changes of normotensive and preeclamptic pregnancy. Forearm blood flow (FBF) responses to brachial artery infusion of N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, and angiotensin II (ANG II), an NO-independent vasoconstrictor, were determined by plethysmography in 20 nonpregnant women, 20 normotensive primigravidae, and 15 primigravidae with untreated preeclampsia. In pregnant subjects, FBF was reduced to nonpregnancy levels by infusion of norepinephrine (NE), which was then coinfused with ANG II (2, 4, and 8 ng/min) and L-NMMA (200, 400, and 800 microgram/min) each for 5 min. In separate studies, responses to NE (20, 50, and 100 ng/min) were determined in 8 nonpregnant women, with FBF elevated to pregnancy levels by concomitant infusion of glyceryl trinitrate, and 10 pregnant women. Vasoconstrictor responses to L-NMMA were increased in pregnant compared with nonpregnant subjects [mean +/- SE summary measure (in arbitrary units): 60 +/- 7 vs. 89 +/- 8, respectively; P < 0.01], whereas responses to ANG II were blunted (125 +/- 11 vs. 79 +/- 7, respectively; P < 0.001). Compared with normotensive pregnant subjects, preeclamptic subjects had an enhanced response to ANG II (79 +/- 7 vs. 103 +/- 8, respectively; P < 0.05) but no difference in response to L-NMMA (89 +/- 8 vs. 73 +/- 10, respectively; P = 0.30). Responses to NE were similar in pregnant and nonpregnant subjects (110 +/- 20 vs. 95 +/- 33, respectively; P = 0.66). During the third trimester of pregnancy, forearm constrictor responses to L-NMMA are increased. The responses to NE are unchanged, whereas responses to ANG II are blunted. Increased NO activity contributes to the fall in peripheral resistance. In preeclampsia, forearm constrictor responses to ANG II but not L-NMMA are increased compared with those in normal pregnancy. Changes in vascular NO activity are unlikely to account for the increased vascular tone in this condition.

Estimation of pulmonary arterial pressure in the newborn: study of the repeatability of four Doppler echocardiographic techniques.

Despite the increasing use of Doppler echocardiographic (DE) techniques to determine pulmonary arterial pressure in the neonate undergoing intensive care, there have been no studies comparing their repeatability in this population. Our objective was to compare the repeatability of four such techniques in neonates. The study was conducted in two regional neonatal units serving the North East of England. Group A (repeatability between observers): Two experienced observers performed detailed DE examinations, one directly after the other. Group B (within observer repeatability/temporal variability): One observer performed two examinations 1 hour apart. Group A comprised 15 preterm babies (26-36 weeks' gestation, 975-2915 g), most with mild respiratory failure; 4 healthy term babies; and 7 with congenital heart disease, in whom tricuspid regurgitation (TR) only was measured. Their ages were 18 hours to 12 days. Group B comprised 11 babies aged 12-64 hours with moderate to severe respiratory failure; 10 were preterm (26-36 weeks, 785-2800 g). We recorded four measurements: (1) Peak velocity of TR in m/s; (2) peak left-to-right ductal flow velocity (PDAmax in m/s); (3) TPV/RVET ratio; and (4) PEP/RVET ratio, where TPV = time to peak velocity at the pulmonary valve, PEP = right ventricular preejection period, and RVET = right ventricular ejection time. The Bland-Altman analysis was used to produce the coefficient of repeatability (CR: 95% confidence limits of repeatability), also expressed as a repeatability index (CR/mean value) and as a number of "confidence steps"-a measure of sensitivity of the technique to hemodynamic change (range of values within the population/CR). Between-observer and within-observer repeatabilities were similar. Within-observer CR and index (%) results were for TR +/- 0.26 m/s (9%); for PDAmax, +/- 0.48 m/s (39%); TPV/RVET 0.1:1.0 (34%), PEP/RVET 0.12:1.00 (36%). TR and PDAmax had the largest number of confidence steps in the expected range of values (TR 8.5; PDA max 6.5; TPV/RVET 3.2; PEP/RVET 3.2). The most repeatable technique was TR, but PDAmax would also be useful for a serial study owing to the potential for large change. Systolic time interval ratios were less repeatable and likely to be less sensitive indicators of hemodynamic change.

Newcastle satisfaction with nursing scales: an instrument for quality assessments of nursing care.

OBJECTIVES: To test the validity and reliability of scales for measuring patients' experiences of and satisfaction with nursing care; to test the ability of the scales to detect differences between hospitals and wards; and to investigate whether place of completion, hospital, or home influences response. DESIGN: Sample survey. SETTING: 20 wards in five hospitals in the north east of England. PATIENTS: 2078 patients in general medical and surgical wards. MAIN MEASURES: Experiences of and satisfaction with nursing care. RESULTS: 75% of patients approached to complete the questionnaires did so. Construct validity and internal consistency were both satisfactory. Both the experience and satisfaction scales were found to detect differences between randomly selected wards and hospitals. A sample of patients (102) were sent a further questionnaire to complete at home. 73% returned this; no significant differences were found in either experience or satisfaction scores between questionnaires given in hospital or at home. CONCLUSION: Scales to measure patients' experiences of and satisfaction with nursing in acute care have been developed and found to be valid, reliable, and able to detect differences between hospitals and wards. Questionnaires can be given before patients leave hospital or at home without affecting scores, but those given at home have a lower response rate.

Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section.

Thirty-eight healthy women undergoing elective Caesarean section under spinal anaesthesia at term were allocated randomly to receive boluses of either phenylephrine 100 micrograms or ephedrine 5 mg for maintenance of maternal arterial pressure. The indication for administration of vasopressor was a reduction in systolic pressure to < or = 90% of baseline values. Maternal arterial pressure (BP) and heart rate (HR) were measured every minute by automated oscillometry. Cardiac output (CO) was measured by cross-sectional and Doppler echocardiography before and after preloading with 1500 ml Ringer lactate solution and then every 2 min after administration of bupivacaine. Umbilical artery pulsatility index (PI) was measured using Doppler before and after spinal anaesthesia. The median (range) number of boluses of phenylephrine and ephedrine was similar; 6 (1-10) vs 4 (1-8) respectively. Maternal systolic BP and CO changes were similar in both groups, but the mean [95% CI] maximum percentage change in maternal HR was larger in the phenylephrine group (-28.5 [-24.2, -32.9]%) than in the ephedrine group (-14.4 [-10.6, -18.2]%). As a consequence atropine was required in 11/19 women in the phenylephrine group compared with 2/19 in the ephedrine group (P < 0.01). Mean umbilical artery pH [95% CI] was higher in the phenylephrine group (7.29 [7.28-7.30]) than in the ephedrine group (7.27 [7.25-7.28]). The results of the present study support the use of phenylephrine for maintenance of maternal arterial pressure during spinal anaesthesia for elective Caesarean section.

Right heart pressure determination by Doppler in infants with tricuspid regurgitation.

Doppler and direct measurements of right ventricle to right atrial pressure drop were made during cardiac catheterisation on 28 occasions in 26 infants with congenital heart disease. Age was 10 days to 12 months (median 4.5 months), and weight was 3.1 to 9.0 kg (median 4.7 kg). We measured peak velocity of tricuspid regurgitation by continuous wave Doppler, and the pressure drop was calculated using the modified Bernoulli equation (delta p = 4v2). There was a high correlation (r = 0.95) between direct and Doppler measurements. Doppler values tended to underestimate the right ventricle to right atrial pressure drop, but this was not of clinical significance (mean 2 mm Hg). The 95% confidence interval for the Doppler velocity was -0.41 to +0.26 m/sec, and was consistent across the range of pressures studied. Variability between observers was tested, by two observers performing sequential paired examinations on 16 newborn babies with tricuspid regurgitation. The coefficient of repeatability was 6.3 mm Hg (95% confidence interval 4.7 to 9.5 mm Hg) or 0.26 m/sec (0.18 to 0.50 m/sec). This method of right ventricular pressure estimation, validated previously only in older children and adults, is a reproducible and accurate technique in infants with tricuspid regurgitation.

Incremental spinal anaesthesia for elective caesarean section: maternal and fetal haemodynamic effects.

We have performed serial haemodynamic investigations in 20 women undergoing elective Caesarean section under continuous spinal anaesthesia with a 32-gauge catheter with 0.5% heavy bupivacaine. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Doppler flow velocity waveforms were recorded also from the umbilical artery. A block to T4 or above was achieved in all patients. The median dose of 0.5% bupivacaine administered was 2.0 ml (range 1.5-4.5 ml). Mean cardiac output increased from 7 to 8 litre min-1 after preloading with Ringer lactate solution 1.5 litre and then remained unchanged after injection of bupivacaine. Two subjects developed hypotension, although mean values of arterial pressure and umbilical artery pulsatility index did not change. The median umbilical artery pH was 7.27 (range 6.98-7.32) and there was a significant correlation between pH and the maximum percentage decrease in cardiac output. The results suggest that continuous spinal anaesthesia is associated with greater haemodynamic stability than single bolus spinal injection.

Prediction of the small for gestational age infant: which ultrasonic measurement is best?

OBJECTIVE: To determine the most appropriate ultrasonic measurement for the prediction of a small for gestational age (SGA) infant. DATA SOURCES: A literature search of all English language journals over the last 15 years was undertaken. One hundred seventeen articles on the use of morphometric and Doppler ultrasonic measurements in the diagnosis of SGA were reviewed. METHODS OF STUDY SELECTION: Studies were included if antenatal and postnatal criteria for diagnosis were clearly defined and data for SGA and normal fetuses were reported, allowing the construction of a 2 x 2 table. DATA EXTRACTION AND SYNTHESIS: Studies with the same criteria were grouped according to whether the population was high or low risk. The sensitivity, odds ratio (OR), and false-positive rate were calculated for each study; summary statistics were then calculated for each ultrasonic measurement provided the individual sensitivities, ORs, and false-positive rates were not significantly different (P > .01). CONCLUSIONS: In high-risk subjects, abdominal circumference below the tenth percentile had the highest common sensitivity, and estimated fetal weight below the tenth percentile had the highest common OR. In studies in which morphometric and Doppler ultrasonic measurements were compared in the same subjects, the Doppler ORs tended to be lower than the ORs for morphometric measurements. In low-risk subjects, much lower ORs were found for all ultrasonic measurements. The heterogeneous nature of the studies reviewed may have contributed to the different results within each group.

Pulmonary and systemic arterial pressure in hyaline membrane disease.

Systolic pulmonary arterial pressure was determined serially over the first 10 days of life in 33 babies with hyaline membrane disease by measuring the peak velocity of pansystolic tricuspid valve regurgitation, using Doppler ultrasound, and applying the Bernoulli equation. Results are presented in age groups 0-12, 13-36, 37-72, and 73-96 hours respectively. The incidence of tricuspid valve regurgitation was 92, 97, 80, and 64% (falling to 35% by day 10) compared with 53, 50, 31, and 0% in 17 healthy premature infants. In comparing healthy babies with those with hyaline membrane disease, no allowance was made for right atrial pressure. The derived 'right ventricle to right atrial (RV-RA) pressure difference', was expressed as a ratio of systemic arterial (systolic) pressure. Over the first three days, this ratio fell much faster in the healthy babies. Values were 0.78:1, 0.77:1, and 0.72:1 in babies with hyaline membrane disease and 0.87:1, 0.53:1, and 0.44:1 in healthy babies. Ductal patency was prolonged in babies with hyaline membrane disease (75% on day 4 compared with 6% in healthy babies). The incidence of bidirectional ductal flow, indicating balanced pulmonary and systemic arterial pressures, was 79, 53, 30, and 20%, and in healthy babies was 41% at 0-12 hours and zero thereafter. Pulmonary arterial pressure was then calculated by adding a right atrial pressure estimate of 5 mm Hg to the RV-RA difference when the babies were ventilated. Babies of lower gestation had lower values. The pulmonary: systemic arterial pressure ratio showed considerable temporal variability, but fell with age and was raised by high mean airway pressure and pneumothorax (through a reduction in systemic pressure), and less noticeably by carbon dioxide tension. It did not correlate significantly with other indices of disease severity. Hyaline membrane disease is associated with delayed postnatal circulatory adaptation characterized by pulmonary hypertension, systemic hypotension, and prolonged ductal patency.

Maternal and fetal haemodynamic effects of spinal and extradural anaesthesia for elective caesarean section.

Serial haemodynamic investigations were performed in 32 women who were allocated randomly to receive either spinal or extradural anaesthesia for elective Caesarean section. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Doppler flow velocity waveforms were recorded also from the umbilical artery. Preloading with Ringer lactate solution 1 litre increased cardiac output in both groups. After injection of bupivacaine, cardiac output remained increased in the extradural group, but decreased in the spinal group. This was associated with an increase in umbilical artery pulsatility index in the spinal group. Umbilical artery pH was less in the spinal group (7.22 vs 7.27), although no neonate was depressed at birth. The maximum percentage change in cardiac output and umbilical artery pulsatility index correlated with umbilical artery pH (r = 0.54, r = 0.72, respectively). There was no significant correlation with change in arterial pressure.

Incidence of Doppler regurgitant flow velocities during normal pregnancy.

The incidence of regurgitant flow velocities were determined using colour flow mapping and pulse Doppler in 107 pregnant women, 55 of whom were less than 28 weeks gestation. The results were compared with 51 non-pregnant controls. The incidence of tricuspid regurgitant velocities increased from 42% in the control group to 67% at greater than or equal to 28 weeks gestation with a median peak regurgitant velocity of 1.7 ms-1. The incidence of pulmonary regurgitant velocities increased from 50% in the control group to 96% at greater than or equal to 28 weeks gestation with a median peak regurgitant velocity of 1.1 m s-1. Mitral and aortic regurgitant velocities were recorded in 27% and 2% of non-pregnant controls respectively. No statistically significant increase in left sided regurgitant velocities was evident during pregnancy. The increase in incidence of right heart regurgitant velocities may be secondary to the dilatation of the respective value orifices due to the volume loading of pregnancy.

Mortality from causes amenable and non-amenable to medical care: the experience of eastern Europe.

OBJECTIVE: To investigate comparative national trends in mortality from conditions amenable to timely, appropriate medical care and from those considered not to be amenable to such care. DESIGN: Analysis of trends in direct age standardised mortality from the 1950s to 1987. SETTING: Four eastern European nations (Hungary, Czechoslovakia, Poland, the German Democratic Republic) and two western European (the Federal Republic of Germany and England and Wales) and two North American nations (United States and Canada). SUBJECTS: The total populations of the relevant countries during the period examined. MAIN OUTCOME MEASURES: Proportional changes over time in age standardised mortality. Mortality from amenable and non-amenable causes was restricted to the age group 0-64. RESULTS: A divergence in the trends for all cause mortality between eastern Europe and the western nations occurred in about 1970, when the rates in western countries steadily declined but those in eastern Europe remained fairly static. In the age group 0-64 mortality from causes considered amenable to medical care fell less quickly in eastern Europe than in the West, particularly after 1970. In the same age group, mortality from non-amenable causes rose in eastern European countries from the late 1960s compared with substantial declines in such mortality in the West. CONCLUSIONS: Non-amenable causes of death seem to be the principal, but not exclusive, reason for lack of improvement in trends in all cause mortality in eastern Europe from 1970. The agenda for action in eastern Europe should give priority to a healthier lifestyle and improvement of the environment though not neglect enhancements in the quality and efficiency of direct health services.

Inhalation induction of anaesthesia with isoflurane: effect of added carbon dioxide.

Fifty children underwent inhalation induction of anaesthesia with isoflurane and nitrous oxide in oxygen with or without the addition of 5% carbon dioxide. Addition of carbon dioxide resulted in more rapid induction and significantly reduced the incidence and severity of airway related problems.

Non-invasive assessment of pulmonary arterial pressure in healthy neonates.

Doppler echocardiograms were carried out on 51 healthy babies three times during the first 72 hours of life to estimate pulmonary arterial systolic pressure by measuring regurgitant tricuspid jet velocity and applying the Bernoulli equation. Tricuspid regurgitation was detected at some stage in all preterm babies and most of those born at full term. Pulmonary arterial pressure could be measured from peak regurgitant velocity in babies with pansystolic regurgitation. The incidence of pansystolic regurgitation among 34 term babies at 0-12, 13-36, and 32-72 hours of age was 22, 27, and 19%, and in 17 preterm babies (within the same age groups) was 53, 50, and 31%, respectively. Estimates of pulmonary artery pressure in the term babies were in accord with known catheter values. Pressure fell rapidly during the first day in all 51 babies. The ratio of pulmonary:systemic arterial pressure was comparable between the two groups throughout. Ductal flow patterns mirrored the fall in this ratio with age--bidirectional flow was associated with a ratio of between 0.88:1 and 1.22:1 and high velocity left to right flow with a ratio of between 0.49:1 and 0.66:1. Both these techniques are noninvasive ways of assessing neonatal pulmonary arterial pressure.

Serial changes in pulmonary haemodynamics during human pregnancy: a non-invasive study using Doppler echocardiography.

1. Serial pulmonary haemodynamic investigations were performed in 13 women before conception, at monthly intervals throughout pregnancy, and then at 6 months after delivery. 2. Mean pulmonary artery pressure was calculated from pulsed Doppler pulmonary velocities. Pulmonary flow was measured by Doppler and cross-sectional echocardiography. These two measurements were used to calculate pulmonary vascular resistance. 3. Mean non-pregnant pulmonary artery pressure was 13.8 mmHg and no significant change was demonstrated during pregnancy. 4. Pulmonary flow increased from 4.88 to 7.19 litres/min during pregnancy. 5. Pulmonary vascular resistance decreased from 2.85 resistance units before pregnancy to 2.17 resistance units at 8 weeks gestation. Thereafter there was no further significant change, values returning to pre-pregnant levels by 6 months after delivery.

Apparent liver blood flow during pregnancy: a serial study using indocyanine green clearance.

Serial measurements of apparent liver blood flow and cardiac output were performed in 12 women at 12-14, 24-26 and 36-38 weeks of pregnancy and then at 10-12 weeks after delivery. Apparent liver blood flow was calculated from indocyanine green clearance. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Postnatal apparent liver blood flow was 1.81 l/min and no significant change was demonstrated during pregnancy. In contrast cardiac output decreased from 7.46 l/min at 36-38 weeks gestation to 4.90 l/min after delivery. Apparent liver blood flow accounted for 24% of cardiac output during pregnancy. This increased to 37% after delivery.

Hemodynamic changes during twin pregnancy. A Doppler and M-mode echocardiographic study.

Serial hemodynamic investigations were performed in 10 women with twin pregnancies at 20, 24, 28, 32, and 36 weeks' gestation and at 6 months after delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. The hemodynamic results were compared with those of 13 women with singleton pregnancies. Mean Doppler cardiac output was increased at 20 weeks of twin pregnancy (7.63 L/min) and showed no significant change during the remainder of pregnancy, but fell to 5.07 L/min after delivery. This increase was significantly greater than that recorded during singleton pregnancy, because of a relatively greater increase in heart rate. Twin pregnancy was associated with a significantly greater increase in left atrial dimension, but the increases in left ventricular dimensions, wall thickness, and function were comparable to those recorded in singleton pregnancy.