Broccoli sprout supplementation during pregnancy prevents brain injury in the newborn rat following placental insufficiency.

Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200mg of dried BrSp from E15 - postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p<0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p<0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency.

Lysine and ornithine analogues of methotrexate as inhibitors of dihydrofolate reductase.

The ornithine (6a) and lysine (6b) analogues of methotrexate (1) have been synthesized via condensation of 4-amino-4-deoxy-N10-methylpteroic acid (2) with N gamma-carbobenzoxy-L-ornithine tert-butyl ester (3a) and N epsilon-carbobenzoxy-L-lysine tert-butyl ester (3b), respectively. Removal of the protecting groups gave 5a and 6b. Compounds 6a and 6b and their precursor Cbz acids (5a and 5b) show significant inhibition of dihydrofolate reductase.

A fluorescent analogue of methotrexate as a probe for folate antagonist molecular receptors.

A dansyl-L-lysine analogue of methotrexate, N alpha-(4-amino-4-deoxy-10- methylpteroyl )-N epsilon-(5-[N,N-dimethylamino]-1-naphthalenesulfonyl)-L-lysine, is a potent inhibitor of murine L1210 dihydrofolate reductase. The dansyl fluorescence emission was enhanced approximately 3-fold with a 10 nm blue shift upon binding to L1210 dihydrofolate reductase. The fluorescent analogue was only 10-fold less potent than methotrexate in inhibiting the growth of methotrexate-sensitive and -resistant L1210 cells and competes effectively for [3H]methotrexate transport with a Ki of 7.02 microM, a value virtually identical to the Kt for methotrexate in both cell lines. In addition, strong dansyl fluorescence was found to be associated with dihydrofolate reductase from methotrexate-resistant, dihydrofolate reductase-overproducing L1210 cells following incubation of viable cells with the fluorescent methotrexate analogue for 4 hr. The results demonstrate that the dansyl-L-lysine analogue of methotrexate was rapidly transported into L1210 cells where it formed a high-affinity, fluorescent complex with intracellular dihydrofolate reductase.

The effects of cardiopulmonary bypass temperature on neuropsychologic outcome after coronary artery operations: a prospective randomized trial.

UNLABELLED: The effect of systemic perfusion temperature on postoperative cognitive function was investigated in 96 adult patients undergoing elective coronary revascularization with cardiopulmonary bypass at 28 degrees C, 32 degrees C, or 37 degrees C. Neuropsychologic performance was assessed 1 day before the operation and 6 weeks after the operation. Five tests were adapted from the Wechsler Adult Intelligence Scale and two from the Wechsler Memory Scale. RESULTS: No patients had major neurologic complications. Ninety-three patients completed the five Wechsler Adult Intelligence Scale tests, but only 70 went on to complete the Wechsler Memory Scale tests as well. In these, there was an effect of cardiopulmonary bypass temperature on the number of neuropsychologic tests in which there was a preoperative to postoperative deterioration (p = 0.021), the number with bypass at 37 degrees C being significantly greater than the number with bypass at 32 degrees C (p = 0.015). Subsidiary analyses using a multivariate linear model examined the effect of cardiopulmonary bypass temperature on the magnitude of change, with or without allowing for other possible confounding influences. There was an adverse effect of normothermic (37 degrees C) versus moderately hypothermic (32 degrees C) perfusion---more convincingly displayed in the analyses of all seven scores rather than just the Wechsler Adult Intelligence Scale scores. Further cooling to 28 degrees C conferred no additional benefit in terms of cognitive function. The importance of the deterioration is open to question.

Performance of a miniaturised O2-Hb dissociation curve analyser on dog's blood.

Oxygen-haemoglobin dissociation curves were determined on dogs' blood using a modified and miniaturised dissociation curve analyser. The Bohr factor describes the way in which pH varies the PO2 corresponding to a particular oxyhaemoglobin concentration. The factor was similar for three saturations and was little affected by whether the pH was changed by changing PCO2, or by adding fixed acid or alkali. The haemoglobin saturations in the mid-range tended to be lower than those predicted by the equation of Rossing and Cain (1966).

A digital system for generating dynamic sinusoidal gas concentration signals.

A computer-controlled gas-mixing system is presented. It is capable of mixing four gases, the concentration of three of which will follow a path to be determined by the user. For our purposes the output O2 fraction is maintained constant and the levels of Ar and N2O vary sinusoidally and independently, with periods between 0.25 and 30 min. A fourth gas, N2 is necessary to make the sum of the individual fractions 100%. The system uses banks of between one and four solenoid valves each linked via a sonic choke to a common mixing chamber. A regime of pulse frequency modulation is employed. All calculations and timing of valve switching are performed by a dedicated microcomputer built for the purpose. The device has been used to provide respiratory gas forcing functions for a program of research in respiratory monitoring.

A compensation method for membrane-covered (Clark) electrodes.

Membrane-covered electrodes (Clark electrodes) are widely used for monitoring blood gases, particularly PO2. A method of compensating for the inherently limited speed of response of Clark electrodes is presented. The theoretical response in the time domain is related to that in the frequency domain, and the latter is deduced from measurement of the former. Although the response functions are both infinite series, both responses are nevertheless completely defined by a single time parameter Te characteristic of the electrode under given measurement conditions. Practical verification was performed using electrodes in the double-pulsed mode, but the theory is applicable equally to direct-current-polarized and simply pulsed electrodes.

Gas exchange in a three-compartment lung model analyzed by forcing sinusoids of N2O.

A mathematical gas exchange model, using sinusoidal forcing functions of inert inspired gas (A. Zwart, R. C. Seagrave, and A. Van Dieren. J. Appl. Physiol. 41: 419-424, 1976), has been extended by us to include dead space (VD), a single alveolar compartment (VA) perfused with blood flow (Qp), and a shunt (Qs). In this new work we use N2O as the indicator gas in the mathematical model and in the experimental studies, in low enough concentrations [<6% (vol/vol)] to avoid anesthetic effects. Mathematical relationships between the inspired and expired N2O gas partial pressures, the blood gas N2O partial pressures, and their variation with forcing frequency are derived for a continuous ventilation uptake and a conventional anesthetic gas distribution model. We show that these gas and blood gas N2O relationships give direct derivation of cardiorespiratory parameters such as VA, Qp, the dead space-to-total ventilation ratio (VD/VT), and the shunt-to-total blood flow ratio (Qs/QT) without altering the subject's oxygenation and that they are essentially free from recirculation effects at high forcing frequencies > or = 2 min-1. Theoretical results from the model are presented for a wide range of forcing frequencies between 2 x 10(-2) and 10 min-1 (sinusoid periods 30-0.1 min), and these show that VA, Qp, and VD/VT can all be measured by N2O forcing frequencies > or = 1 min-1. We also present results from five animal studies, with an experimental inspired gas forcing frequency range of 0.125 to 2 min-1, which show qualitative agreement with the predictions of the continuous ventilation model. During these animal studies both mass spectrometric N2O respiratory gas measurements and intravascular polarographic arterial and mixed venous blood N2O partial pressure measurements were made, and examples of these in vivo measurements are presented, together with examples of the calculations derived from them.

Assessment of cardiorespiratory function using oscillating inert gas forcing signals.

A theoretical model (Hahn et al. J. Appl. Physiol. 75: 1863-1876, 1993) predicts that the amplitudes of the argon and nitrous oxide inspired, end-expired, and mixed expired sinusoids at forcing periods in the range of 2-3 min (frequency 0.3-0.5 min-1) can be used directly to measure airway dead space, lung alveolar volume, and pulmonary blood flow. We tested the ability of this procedure to measure these parameters continuously by feeding monosinusoidal argon and nitrous oxide forcing signals (6 +/- 4% vol/vol) into the inspired airstream of nine anesthetized ventilated dogs. Close agreement was found between single-breath and sinusoid airway dead space measurements (mean difference 15 +/- 6%, 95% confidence limit), N2 washout and sinusoid alveolar volume (mean difference 4 +/- 6%, 95% confidence limit), and thermal dilution and sinusoid pulmonary blood flow (mean difference 12 +/- 11%, 95% confidence limit). The application of 1 kPa positive end-expiratory pressure increased airway dead space by 12% and alveolar volume from 0.8 to 1.1 liters but did not alter pulmonary blood flow, as measured by both the sinusoid and comparator techniques. Our findings show that the noninvasive sinusoid technique can be used to measure cardiorespiratory lung function and allows changes in function to be resolved in 2 min.

Effects of cardiopulmonary bypass temperature on pulmonary gas exchange after coronary artery operations.

BACKGROUND: Pulmonary dysfunction is one aspect of the postoperative morbidity associated with cardiopulmonary bypass. Normothermic systemic perfusion can result in shorter intubation times, which have been attributed to improved pulmonary gas exchange, but the influence of perfusion temperature on pulmonary gas exchange itself is not known. METHODS: Pulmonary gas exchange was assessed using alveolar-arterial oxygen pressure gradients in 45 patients undergoing routine coronary revascularization who were randomized to undergo cardiopulmonary bypass at 28 degrees C, 32 degrees C, or 37 degrees C. This was part of a more comprehensive study of the effects of temperature on bodily systems. The gradients were estimated preoperatively with the patients breathing air, again over a period between 2 and 4 hours postoperatively during mechanical ventilation with three different oxygen concentrations (30%, 40%, and 60%), and again 1 hour after extubation while breathing the same three oxygen concentrations. RESULTS: Preoperative alveolar-arterial oxygen pressure gradients on air were 24.4 +/- 8.2 mm Hg (mean +/- standard deviation) (28 degrees C), 24.5 +/- 20.4 mm Hg (32 degrees C), and 20.5 +/- 9.5 mm Hg (37 degrees C). Postoperatively, during ventilation and after rewarming, the gradients increased with the increase in inspired oxygen fraction concentrations (30% to 60%) from 67.1 +/- 12.0 mm Hg to 193.1 +/- 30.5 mm Hg (28 degrees C), from 76.4 +/- 20.6 mm Hg to 246.7 +/- 47.7 mm Hg (32 degrees C), and from 79.0 +/- 18.0 mm Hg to 222.9 +/- 40.5 mm Hg (37 degrees C), respectively. A similar pattern was noted 1 hour after extubation, when the gradients increased from 72.4 +/- 12.5 mm Hg to 256.6 +/- 26.5 mm Hg (28 degrees C), from 75.7 +/- 13.9 mm Hg to 252.7 +/- 38.3 mm Hg (32 degrees C), and from 69.1 +/- 19.3 mm Hg to 253.1 +/- 33.0 mm Hg (37 degrees C). There were no significant differences in alveolar-arterial oxygen pressure gradient between the three groups during ventilation or after extubation. CONCLUSIONS: Cardiopulmonary bypass perfusion temperature does not influence alveolar-arterial oxygen pressure gradients in the first 12 hours after routine coronary artery bypass grafting in patients with uncompromised pulmonary and left ventricular function.

A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

BACKGROUND: There is controversy about the value of evidence about the effectiveness of healthcare interventions from non-randomised study designs. Advocates for quasi-experimental and observational (QEO) studies argue that evidence from randomised controlled trials (RCTs) is often difficult or impossible to obtain, or is inadequate to answer the question of interest. Advocates for RCTs point out that QEO studies are more susceptible to bias and refer to published comparisons that suggest QEO estimates tend to find a greater benefit than RCT estimates. However, comparisons from the literature are often cited selectively, may be unsystematic and may have failed to distinguish between different explanations for any discrepancies observed. OBJECTIVES: The aim was to investigate the association between methodological quality and the magnitude of estimates of effectiveness by comparing systematically estimates of effectiveness derived from RCTs and QEO studies. Quantifying any such association should help healthcare decision-makers to judge the strength of evidence from non-randomised studies. Two strategies were used to minimise the influence of differences in external validity between RCTs and QEO studies: a comparison of the RCT and QEO study estimates of effectiveness of any intervention, where both estimates were reported in a single paper a comparison of the RCT and QEO study estimates of effectiveness for specified interventions, where the estimates were reported in different papers. The authors also sought to identify study designs that have been proposed to address one or more of the problems often found with conventional RCTs. DATA SOURCES: Relevant literature was identified from: The Cochrane Library, MEDLINE, EMBASE, DARE, and the Science Citation Index. References of relevant papers already identified experts. Electronic searches were very difficult to design and yielded few papers for the first strategy and when identifying study designs. CHOICE OF INTERVENTIONS TO REVIEW FOR STRATEGIES 1 AND 2: For strategy 1, any intervention was eligible. For strategy 2, interventions for which the population, intervention and outcome investigated were anticipated to be homogeneous across studies were selected for review: Mammographic screening (MSBC) of women to reduce mortality from breast cancer. Folic acid supplementation (FAS) to prevent neural tube defects in women trying to conceive. DATA EXTRACTION AND QUALITY ASSESSMENT: Data were extracted by the first author and checked by the second author. Disagreements were negotiated with reference to the paper concerned. For strategy 1, study quality was scored using a checklist to assess whether the RCT and QEO study estimates were derived from the same populations, whether the assessment of outcomes was 'blinded', and the extent to which the QEO study estimate took account of possible confounding. For strategy 2, a more detailed instrument was used to assess study quality on four dimensions: the quality of reporting, the generalisability of the results, and the extent to which estimates of effectiveness may have been subject to bias or confounding. All quality assessments were carried out by three people. DATA SYNTHESIS AND ANALYSIS: For strategy 1, pairs of comparisons between RCT and QEO study estimates were classified as high or low quality. Seven indices of the size of discrepancies between estimates of effect size and outcome frequency were calculated, where possible, for each comparison. Distributions of the size and direction of discrepancies were compared for high- and low-quality comparisons. FOR STRATEGY 2, THREE ANALYSES WERE CARRIED OUT: Attributes of the instrument were described by k statistics, percentage agreement, and Cronbach's a values. Regression analyses were used to investigate -variations in study quality. (ABSTRACT TRUNCATED)

Disturbed mother-infant interaction in association with congenital heart disease.

OBJECTIVE: To investigate whether difficulties are experienced in the interaction between infants with congenital heart disease and their mothers and to identify infants who show compromised emotional development, in order to offer intervention during the early stages of postoperative compensatory growth. METHODS: 20 infants and their mothers were compared with 20 non-cardiac mother-infant pairs. Infants were filmed in interaction for 30 minutes two days before and six months after corrective surgery. Fifteen minutes of film were analysed in 180 5-s units. The emotional tone (affect) and the interpersonal engagement were classified as positive or negative by prespecified criteria. The percentages of positive scores were analysed. The mental health of the mothers was also assessed. RESULTS: Cardiac infants showed less positive affect and engagement than the noncardiac group at both sessions. There was no correlation between of positive affect or engagement and the severity of the condition in either group. Cardiac mothers showed less positive affect and engagement than the comparison group, and were psychologically distressed at both sessions. The engagement scores of the mothers of the cardiac infants were also more variable. CONCLUSIONS: Cardiac infants and their mothers have lower levels of positive affect and engagement than non-cardiac mother-infant pairs. Thus some mothers are unable to adapt to their infant. This leads to disordered interaction which is maintained at six months. This information can be used to offer intervention during the early stages of postoperative compensatory growth.

Progress in non-invasive respiratory monitoring using uncalibrated breathing movement components.

The theory for optimal linear combination of uncalibrated breathing movements was developed and applied in non-invasive respiratory monitoring situations for assessment. 16 patients were monitored overnight for respiratory depression during postoperative pain treatment. Intranasal/extra-oral airway pressure monitoring and pulse oximetry signals were recorded at 50 Hz. Respiratory inductive plethysmography (RIP) provided guidance to nurses regarding sensitivity settings of the pressure device during slow, shallow breathing, and vital information about breathing movements to help distinguish central from obstructive apnoeas. Subsequent analysis showed that the principal components of the standardized RIP signals would be helpful in any automated identification of pressure indicator false alarms and could provide a simple means for supplementary breath classification. The sum and difference of the scaled RIP values tracked changes in tidal volume and indicated any breathing movement asynchrony or paradox associated with obstructions. A construction was developed for emulating RIP calibration predictions of relative changes in tidal volume to within about 1%, so that invasive or demanding monitoring preparations could be by-passed altogether. The necessary signal combination and linearcalibration model background is reviewed for this simple formulation, which arises from component analysis and least squares regression. The methods are illustrated for definitive non-invasive postoperative monitoring and calibration situations. Theoretical and physiological reasons for preferring the use of balanced ribcage and abdomen contributions to overall tidal volume are presented that also help clarify the greater limitations of traditional RIP monitoring practices.

The significance of the timing of chemoreceptor impulses for their effect upon respiration.

Alveolar partial pressure of carbon dioxide (PACO2) and alveolar partial pressure of oxygen (PAO2) oscillate at the frequency of respiration and the oscillations persist into the arterial blood as oscillations of arterial partial pressure of carbon dioxide (PaCO2) and arterial partial pressure of oxygen (PaO2). Arterial chemoreceptors respond quickly enough to changes in PaCO2 and PaO2 for the arterial oscillations to give rise to oscillations in their afferent discharge at the frequency of respiration. The respiratory centre responds with short latency to afferent impulses reaching it. If a burst of impulses reaches it during an inspiration, the depth of that inspiration, is increased but if the burst arrives during expiration, the succeeding inspiration is little affected. Thus if the peaks of chemoreceptor afferent discharge coincide with inspiration, they have a greater effect on respiration than if they coincide with expiration. The phase relation between the activity of the respiratory centre and the oscillations it produces is determined, inter alia, by the frequency of respiration and the heart output. Thus it may well change in exercise.

Scope of linear estimators of tidal and occluded volumes using thoracoabdominal indications of breathing movement coordination.

The basic theory for respiratory inductive plethysmography (RIP) applications was re-examined, refined and tested. A realistic model of the RIP interpretation of respiratory mechanics related tidal volumes (VT) to a linear combination of ribcage and abdomen movements. Lissajous plots of asynchronous thoracoabdominal movements revealed their net effect equivalent to the superposition of synchronous and antipathetic respiration modes at right angles, along the principal axes specific to the combined motion. Predictors of relative changes in VT, degree of asynchrony and volume thus being occluded were developed via least squares estimation theory, with an optional validation facility. The approach enabled clinically adequate analysis of 452 h of RIP data from 29 postoperative patients. Correct identification of only seven complete apnoeas in 111 incidences of obstruction during periodic, variable, asynchronous or paradoxical natural breathing was substantiated via non-invasive airflow monitoring. The modelling helped clarify RIP limitations--the possibility of misleading indications from obese or abnormal physiques or movement artefacts degrading its otherwise nearly optimal performance. Nevertheless, our uncalibrated predictors had better theoretical basis, improved reliability and more convenient practical utility than the traditional approach of calibrating RIP by spirometry prior to non-invasive monitoring and identifying and classifying apnoeas.

The pathophysiology and laboratory diagnosis of congenital portosystemic shunts in dogs.

Abstract Congenital portosystemic shunts generally arise as single vascular anomalies that cause the portal blood to bypass the liver and enter the systemic venous circulation directly. The liver is primarily affected, as it is deprived of perfusion by portal hepatotrophic factors such as insulin, glucagon, and amino acids. There is progressive hepatic atrophy, and as a consequence, dysfunction. Hepatic encephalopathy can result from increased levels of ammonia and gamma-aminobutyric acid within the systemic circulation. Variably toxic amines, captans and short chain fatty acids may act as false neurotransmitters. Hypoglycaemia will exacerbate the effects of these substances. Increased concentrations of ammonia and uric acid in the urine predispose to the precipitation of ammonium biurate crystals and the formation of calculi. Haematological changes include anaemia, microcytosis, hypoproteinaemia, leucocytosis, and coagulation abnormalities. Gastrointestinal effects are common. They may be displayed as anorexia, vomiting, ptyalism, pica, diarrhoea, or polyphagia. Most dogs are less than 1 year of age at initial presentation. Diagnosis from a laboratory viewpoint will involve a consideration of the history, clinical findings, haematology, serum biochemistry and urinalysis. If the findings are suggestive of a congenital portosystemic shunt, the demonstration of elevated fasting or, more consistently, post-prandial serum bile acid concentrations, and subsequent histological examination of a liver biopsy will provide a definitive diagnosis.