Effect of positive-pressure ventilatory frequency on regional pleural pressure

Regional lung ventilation is modulated by the spatiotemporal distribution of alveolar distending forces. During positive-pressure ventilation, regional transmission of airway pressure (Paw) to the pleural surface may vary with ventilatory frequency (f), thus changing interregional airflow distribution. Pendelluft phenomena may result owing to selective regional hyperventilation or phase differences in alveolar distension. To define the effects of f on regional alveolar distension during positive-pressure ventilation, we compared regional pleural pressure (Ppl) swings from expiration to inspiration (delta Ppl) and end-expiratory Ppl over the f range 0-150 min-1 in anesthetized, paralyzed, close-chested dogs with normal lungs. We inserted six pleural balloon catheters to analyze Ppl distribution along three orthogonal axes of the right hemithorax. Increases in regional Ppl were synchronously coupled with inspiratory increases in Paw regardless of f. However, at a constant tidal volume and percent inspiratory time, end-expiratory Paw and Ppl increased in all regions once a f threshold was reached (P less than 0.01). Supradiaphragmatic delta Ppl were less than in other regions (P less than 0.05), but thoracoabdominal binding abolished this difference by decreasing thoracoabdominal compliance. We conclude that the distribution of forces determining dynamic regional alveolar distension are temporally synchronous but spatially asymmetric during positive-pressure ventilation at f less than or equal to 150/min.     

Biological and methodological implications of prostaglandin involvement in mouse brain lipid peroxidation measurements

Enhanced cyclooxygenase-mediated prostaglandin (PG) turnover occurring during sacrifice and biochemical processing of tissues also generates malondialdehyde (MDA), a product of lipid peroxidation (LPO). Studies reporting on LPO estimated by thiobarbituric acid reactive substances (TBARS) have failed to consider such artefactual increases. This study reports the relative proportion of PG metabolism-derived MDA (PG-MDA) in mouse brain regions during the TBARS assay. The cyclooxygenase inhibitor indomethacin significantly lowered MDA in fronto-parietal cortex and corpus striatum. Indomethacin (50–800 g/ml, in vitro) increased estimated TBARS in whole brain. Such enhancement was absent when indomethacin (20–80 g/sample) was added to the MDA standard curve, reflecting its interaction with TBARS other than MDA. PG-MDA contributes as much as 15% to the total estimated value of MDA in fronto-parietal cortex and corpus striatum and must be corrected for in LPO studies.     

Estimation and Prediction for Cancer Screening Models Using Deconvolution and Smoothing

The model that specifies that cancer incidence, I, is the convolution of the preclinical incidence, g, and the density of time in the preclinical phase, f, has frequently been utilized to model data from cancer screening trials and to estimate such quantities as sojourn time, lead time, and sensitivity. When this model is fit to the above data, the parameters of f as well as the parameter(s) governing screening sensitivity must be estimated. Previously, g was either assumed to be equal to clinical incidence or assumed to be a constant or exponential function that also had to be estimated. Here we assume that the underlying incidence, I, in the study population (in the absence of screening) is known. With I known, g then becomes a function of f, which can be solved for using (numerical) deconvolution, thus eliminating the need to estimate g or make assumptions about it. Since numerical deconvolution procedures may be highly unstable, however, we incorporate a smoothing procedure that produces a realistic g function while still closely reproducing the original incidence function I upon convolution with f. We have also added the concept of competing mortality to the convolution model. This, along with the realistic preclinical incidence function described above, results in more accurate estimates of sojourn time and lead time and allows for estimation of quantities related to overdiagnosis, which we define here.     

Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke

BACKGROUND: Soluble complement receptor-1 (sCR1), a potent complement inhibitor, confers neuroprotection in a murine stroke model. Additional neuroprotective benefit is achieved by sLe x-glycosylation of sCR1. In an effort to translate sCR1-sLe x to clinical trials, we evaluated this agent in a primate stroke model. METHODS: Adult male baboons randomly received either sCR1-sLe x or vehicle. Stroke volume was assessed on day 3, and neurological examinations were conducted daily. Complement activity (CH50) was measured at 30 minute, 2, 6, 12 hour, 3, and 10 days post-ischemia. RESULTS: The experiment was terminated prematurely following an interim analysis. In a preliminary cohort (n = 3 per arm), infarct volume was greater in the treated animals. No difference in neurological score was found between groups. CH50 levels were significantly reduced in the sCR1sLe x-treated groups. A hypotensive response was also observed in animals treated with sCR1-sLe x. Conclusions Further work is necessary to explain the hypotensive response observed in primates prior to further clinical development of sCR1-sLe x.     

Toward a conceptual synthesis for climate change responses

Aim To identify hypotheses for how climate change affects long‐term population persistence that can be used as a framework for future syntheses of ecological responses to climate change. Location Global. Methods We surveyed ecological and evolutionary concepts related to how a changing climate might alter population persistence. We organized established concepts into a two‐stage framework that relates abiotic change to population persistence via changes in the rates or outcomes of ecological and evolutionary processes. We surveyed reviews of climate change responses, and evaluated patterns in light of our conceptual framework. Results We classified hypotheses for population responses to climate change as one of two types: (1) hypotheses that relate rates of ecological and evolutionary processes (plasticity, dispersal, population growth and evolution) to abiotic change, and (2) hypotheses that relate changes in these processes to four fundamental population‐level responses (colonization, acclimatization, adaptation or extinction). We found that a disproportionate emphasis on response in the climate change literature is difficult to reconcile with ecological and evolutionary theories that emphasize processes. We discuss a set of 24 hypotheses that represent gaps in the literature that limit our ability determine whether observed climate change responses are sufficient to facilitate persistence through future climate change. Main conclusions Though theory relates environmental change to fundamental ecological and evolutionary processes and population‐level responses, clear hypotheses based on theory have not been systematically formulated and tested in the context of climate change. Stronger links between basic theory and observed impacts of climate change are required to assess which responses are common, likely or able to facilitate population persistence despite ongoing environmental change. We anticipate that a hypothesis‐testing framework will reveal that indirect effects of climate change responses are more pervasive than previously thought and related to a few general processes, even though the patterns they create are incredibly diverse.     

Gradual changes in range size accompany long‐term trends in species richness

Species richness has long been used as an indicator of ecosystem functioning and health. Global richness is declining, but it is unclear whether sub‐global trends differ. Regional trends are especially understudied, with most focused on island regions where richness is strongly impacted by novel colonisations. We addressed this knowledge gap by testing for multi‐decade trends in species richness in nine open marine regions around North America (197 region‐years) while accounting for imperfect observations and grounding our findings in species‐level range dynamics. We found positive richness trends in eight of nine regions, four of which were statistically significant. Species' range sizes generally contracted pre‐extinction and expanded post‐colonisation, but the ranges of transient species expanded over the long‐term, slowly increasing their regional retention and driving increasing richness. These results provide more evidence that sub‐global richness trends are stable or increasing, and highlight the utility of range size for understanding richness dynamics.     

Effect of positive pressure on venous return in volume-loaded cardiac surgical patients.

The hemodynamic effects of increases in airway pressure (Paw) are related in part to Paw-induced increases in right atrial pressure (Pra), the downstream pressure for venous return, thus decreasing the pressure gradient for venous return. However, numerous animal and clinical studies have shown that venous return is often sustained during ventilation with positive end-expiratory pressure (PEEP). Potentially, PEEP-induced diaphragmatic descent increases abdominal pressure (Pabd). We hypothesized that an increase in Paw induced by PEEP would minimally alter venous return because the associated increase in Pra would be partially offset by a concomitant increase in Pabd. Thus we studied the acute effects of graded increases of Paw on Pra, Pabd, and cardiac output by application of inspiratory-hold maneuvers in sedated and paralyzed humans. Forty-two patients were studied in the intensive care unit after coronary artery bypass surgery during hemodynamically stable, fluid-resuscitated conditions. Paw was progressively increased in steps of 2 to 4 cmH(2)O from 0 to 20 cmH(2)O in sequential 25-s inspiratory-hold maneuvers. Right ventricular (RV) cardiac output (CO(td)) and RV ejection fraction (EF(rv)) were measured at 5 s into the inspiratory-hold maneuver by the thermodilution technique. RV end-diastolic volume and stroke volume were calculated from EF(rv) and heart rate data, and Pra was measured from the pulmonary artery catheter. Pabd was estimated as bladder pressure. We found that, although increasing Paw progressively increased Pra, neither CO(td) nor RV end-diastolic volume changed. The ratio of change (Delta) in Paw to Delta Pra was 0.32 +/- 0.20. The ratio of Delta Pra to Delta CO(td) was 0.05 +/- 00.15 l x min(-1) x mmHg(-1). However, Pabd increased such that the ratio of Delta Pra to Delta Pabd was 0.73 +/- 0.36, meaning that most of the increase in Pra was reflected in increases in Pabd. We conclude that, in hemodynamically stable fluid-resuscitated postoperative surgical patients, inspiratory-hold maneuvers with increases in Paw of up to 20 cmH(2)O have minimal effects on cardiac output, primarily because of an in-phase-associated pressurization of the abdominal compartment associated with compression of the liver and squeezing of the lungs.