An Investigation of the Metabolic Response to Cardiopulmonary Bypass and the Effects of Two Levels of Intraoperative Hypothermia on the Response

The metabolic response to trauma has been an area of intense clinical research since Studley's identification of an increase in postoperative mortality and morbidity in patients with preoperative weight loss. Consequently, considerable efforts have been made to modify the response, including the use of nutritional, pharmacologic and environmental manipulations, and have met with varying degrees of success. The concept of using intraoperative hypothermia to reduce the "stress response to surgery" was first postulated in the 1950s but there has been little evidence to support this premise. Recently, however, a reduction in "post-traumatic proteolysis" following open-heart surgery, using a combination of moderate hypothermia (2

Seasonal changes in the ejaculate of the male tammar wallaby, Macropus eugenii: implications for fertility and assisted breeding

The tammar wallaby, Macropus eugenii is a seasonally breeding macropodid marsupial. The seasonality observed in males is known to be driven by the reproductive state of the females. There is a significant increase in male prostate and Cowper's gland weights and testosterone concentration during the breeding season in January/February and again in October when the young females leave their i;nothers pouches and enter puberty. The dynamics of sperm production in the male tammar wallaby was assessed using changes in ejaculatory and sperm characteristics in and out of the breeding season in order to determine more accurately true seasonality in the male. Semen was collected from wild-caught adult males by electro-ejaculation at four times during the year (January, February, June/July and October). Ejaculates were assessed for semen volume, plug formation, sperm index, percentage and rating of motility, sperm and motile sperm concentration, and total sperm count. Increases were observed during the two breeding seasons in all traits assessed. Semen volume showed a steady increase from June/July (0.7 ml) to reach a peak in February (10.25 ml). In conclusion, we found a significant decrease in the size and coagulation properties of the ejaculate, and in sperm quality out of season. Implications for captive and assisted breeding programs are discussed

Bridging the gap between computation and clinical biology: validation of cable theory in humans

Introduction: Computerized simulations of cardiac activity have significantly contributed to our understanding of cardiac electrophysiology, but techniques of simulations based on patient-acquired data remain in their infancy. We sought to integrate data acquired from human electrophysiological studies into patient-specific models, and validated this approach by testing whether electrophysiological responses to sequential premature stimuli could be predicted in a quantitatively accurate manner. Methods: Eleven patients with structurally normal hearts underwent electrophysiological studies. Semi-automated analysis was used to reconstruct activation and repolarization dynamics for each electrode. This S(2) extrastimuli data was used to inform individualized models of cardiac conduction, including a novel derivation of conduction velocity restitution. Activation dynamics of multiple premature extrastimuli were then predicted from this model and compared against measured patient data as well as data derived from the ten-Tusscher cell-ionic model. Results: Activation dynamics following a premature S(3) were significantly different from those after an S(2). Patient specific models demonstrated accurate prediction of the S(3) activation wave, (Pearson's R(2) = 0.90, median error 4%). Examination of the modeled conduction dynamics allowed inferences into the spatial dispersion of activation delay. Further validation was performed against data from the ten-Tusscher cell-ionic model, with our model accurately recapitulating predictions of repolarization times (R(2) = 0.99). Conclusions: Simulations based on clinically acquired data can be used to successfully predict complex activation patterns following sequential extrastimuli. Such modeling techniques may be useful as a method of incorporation of clinical data into predictive models

The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung

Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease

Timing of intrauterine artificial insemination (IUAI) in relation to ovulation in the tammar wallaby, Macropus eugenii

The window for fertilization is narrow in marsupials because the oocyte is transported rapidly through the oviduct (<24h) and acquires a mucoid coat that entraps and inhibits sperm penetration. Knowledge of the precise time of ovulation is required in the tammar wallaby, Macropus eugenii, to maximise artificial insemination (AI) success. In this study, the timing of ovulation in female tammars was monitored in relation to different times for intrauterine artificial insemination (IUAI). The reproductive tracts of 10 females were dissected at 36 to 41h post coitum (p.c.) and assessed for ovulation. After ovulation, tracts were flushed for embryos. A further 13 females were isolated from males for AI and checked for births every 12h. Semen (3 x 10power6 sperm) was deposited into the uterus via laparotomy at different times between 21.7-42.6h after birth was first detected. Ovaries were examined and tracts flushed for embryos in 4 females at 6h post AI, while 9 were left to give birth. Mating occurred 12.4 ± 2.7h (n=lO; 4.l-28.4h) after birth was first detected. Graafian follicles were observed at 36.0 ± 0.0h p.c. (n=3; all 36.0h) and embryos at 39.4 ± 1.4h p.c. (n=7; 36.0-41.0h). Thus ovulation occurs 36.0 to 39.4h p.c. (~48.4 to 51.8h post partum). A fertilized embryo was recovered 6.4h post AI (~49.0h p.p.) and one AI offspring was born after insemination 34.0h p.p. This confirms that anaesthesia and laparotomy do not suppress ovulation, and that spermatozoa reach the oocyte in time for successful fertilzation after IUAI between 34.0 and 42.6h after birth

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: A computational study

Background Regional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood. Methods We simulated a 150 × 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution. Results Wavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms). Conclusion Regional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve

Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis

Background and Objectives: Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions. Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, β-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in β-adrenergic stimulation (β-AS) and mechanical stretch at Mayer wave frequencies within the 0.03–0.15 Hz band. Results: Our results show that there are large inter-individual differences in the time lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to β-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If β-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow IKs phosphorylation kinetics, with its relevance being modulated by the IKs conductance of each individual cell. Cells presenting short oscillation time lapses are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium overload and reduced repolarization reserve. Conclusions: The time course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the IKs current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions