Biomedical subjects

R D Piper

Publications and source records attributed to R D Piper.

14 recordsLinked to original sources

PubMed2004

TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study.

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

Australia↗

PubMed1999

Microvascular perfusion deficits are not a prerequisite for mucosal injury in septic rats.

Our major objective was to investigate whether injury to the mucosa of the small intestine occurred in a normotensive model of sepsis and whether such injury was associated with microvascular perfusion deficits. Using fluorescence intravital microscopy, we show direct evidence of cell injury within the mucosa (pneumonia 12.4 +/- 2.6 cells/field, sham 2.2 +/- 0.7 cells/field), whereas use of 51Cr-labeled EDTA showed evidence of increased mucosal permeability (pneumonia 1.90 +/- 0.67 ml. min-1. 100 g-1; sham 0.24 +/- 0.04 ml. min-1. 100 g-1), 48 h following induction of pneumonia. Despite such injury the capillary density in the ileal mucosa and submucosa of pneumonic rats (1,027 +/- 77 and 1,717 +/- 86 mm2) was not significantly different compared with sham (998 +/- 63 and 1,812 +/- 101 mm2). However, a modest albeit significant decrease in capillary perfusion was measured in the muscularis layer of pneumonia (11.0 +/- 1.3 mm) compared with sham (13.9 +/- 0.63 mm) and appeared to be associated with leukocyte entrapment. Pretreatment using low doses of endotoxin to induce endotoxin tolerance not only increased muscularis capillary density but reduced the number of leukocytes trapped within the microvasculature, decreased myeloperoxidase activity within the ileum in pneumonic rats, and prevented mucosal injury. In conclusion, we have shown that pneumonia results in remote injury to the mucosa of the ileum and that such injury was not associated with concurrent mucosal perfusion deficits.

Animals↗

PubMed1999

Effects of isoproterenol on myocardial structure and function in septic rats.

In this study we sought to determine the effect of sepsis on two sequelae of prolonged (24-h) beta-agonist administration, myocardial hypertrophy and catecholamine-induced cardiotoxicity. Sprague-Dawley rats were randomized to cecal ligation and perforation (CLP) or sham study groups and then further randomized to receive isoproterenol (2.4 mg. kg-1. day-1 iv) or placebo treatment. At 24 h, myocardial function was assessed by using the Langendorff isolated-heart technique or the heart processed for plain light microscopy. We found that 1) sepsis reduced contractile function, indicated by a rightward shift in the Starling curve (ANOVA with repeated measures, sepsis effect, P < 0.002); 2) sepsis-induced myocardial depression was reversed by isoproterenol treatment (isoproterenol effect, P < 0.0001); 3) sepsis reduced, but did not block, isoproterenol-induced myocardial hypertrophy (isoproterenol effect, P < 0.0001); 4) sepsis did not protect the heart from catecholamine-induced tissue injury; 5) the septic heart was protected against the effects of ischemiareperfusion (decreased postreperfusion resting tension, ANOVA with repeated measures, P < 0.01), an effect attenuated by isoproterenol treatment (P < 0.005); and 6) sepsis reduced the incidence of sustained asystole or ventricular fibrillation after ischemia-reperfusion (P < 0.05), an effect also attenuated by isoproterenol treatment (P < 0.01). We conclude that, in sepsis, beta-agonists induce changes in myocardial weight and function consistent with acute myocardial hypertrophy. These changes occur at the expense of significant tissue injury and increased sensitivity to ischemia-reperfusion-induced tissue injury.

Adrenergic beta-Agonists↗

PubMed1998

Myocardial dysfunction in sepsis.

1. Sepsis is the leading reversible cause of death in patients requiring modern intensive care services. 2. In this group of patients, death usually results from progressive multiple organ failure, rather than overwhelming primary infection. 3. The pathophysiology of sepsis-induced remote organ dysfunction is incompletely understood, although it is believed to result from a systemic inflammatory process that causes tissue injury in the absence of septic shock. 4. As septic shock is the most common early manifestation of severe sepsis, an understanding of mechanisms of myocardial dysfunction is of clinical relevance. In the present review, we will discuss mechanisms of remote organ failure in sepsis, focusing in particular on the pathogenesis of myocardial dysfunction.

Animals↗

PubMed1998

Leukocyte activation and flow behavior in rat skeletal muscle in sepsis.

In animal models of endotoxemia, sepsis is associated with the accumulation of leukocytes and altered microvascular perfusion. In order to test the hypothesis that bacterial sepsis upregulates leukocyte-endothelial adhesion, we used intravital microscopy to examine the flow behavior of leukocytes in the postcapillary venules (PCV) of rats made septic by cecal ligation and perforation (CLP). Animals were randomized to CLP or sham study groups and studied 6 h, 24 h, or 48 h later. In postcapillary venules of the extensor digitorum longus muscle, we found that: (1) over the course of the study, leukocyte adhesion and extravasation increased in both experimental groups (analysis of variance [ANOVA], significant time effect: adhesion, p < 0.001; extravasation, p < 0.05); (2) leukocyte adhesion was decreased by CLP treatment (ANOVA, sepsis effect, p = 0.05), particularly after 24 to 48 h of sepsis (ANOVA, sepsis x time interaction, p < 0.05); and (3) the reduction in leukocyte adhesion in CLP animals was associated with a decrease in leukocyte extravasation (ANOVA, sepsis effect, p < 0.01). After correction for the reduction in systemic leukocyte count associated with CLP, the effect of sepsis on leukocyte adhesion and extravasation no longer reached statistical significance. These findings suggest that chronic (6 to 48 h) bacterial sepsis does not upregulate leukocyte adhesion in a manner similar to that seen in models of acute endotoxemia. These data suggest that the increased microcirculatory flow heterogeneity seen in this and other models of bacterial sepsis may not be explained by leukocyte entrapment in postcapillary venules.

Acute Disease↗

PubMed1997

Structure-function relationships in the septic rat heart.

Myocardial edema and histologic changes consistent with tissue injury are reported in association with sepsis-induced myocardial depression. The objective of the present study was to determine whether, in the absence of shock, such changes (assessed by studying microvascular albumin flux, tissue edema, and morphometry) are prerequisites for the development of contractile dysfunction in sepsis. Sprague-Dawley rats were randomized into groups for either cecal ligation and perforation (CLP) or sham study. Twenty-four hours after entry of animals into the study, their myocardial function was assessed with the Langendorff isolated heart technique. Left-ventricular developed pressure (preload: 5 mm Hg) was reduced in CLP animals (34.9 +/- 3.3 mm Hg, n = 10) as compared with time-matched controls (46.4 +/- 4.0 mm Hg, n = 8, p < 0.05, unpaired t test). This was associated with a significant reduction in the maximal rate of increase (+ dP/dt(max)) and decrease (-dP/dt(max)) in left ventricular pressure in the CLP group (sham versus CLP, unpaired t test, p < 0.05). Upon reperfusion, after 30 min of ischemia, left ventricular resting tension was decreased in CLP as compared with sham-treated animals (sham versus CLP, analysis of variance (ANOVA) with repeated measures, p < 0.05). At 24 h, sepsis was not associated with myocardial edema (wet:dry weight ratio, sham = 4.094 +/- 0.098, n = 10; CLP = 4.185 +/- 0.066, n = 7), and tissue albumin flux was reduced (sham = 194 +/- 27 microliters. h-1. g dry wt-1, n = 10; CLP = 100 +/- 14 microliters. h-1. g dry wt-1, n = 7). In tissue processed for electron microscopy, we found no evidence of tissue injury or edema at either 24 or 48 h after CLP. We conclude that polymicrobial normotensive sepsis causes myocardial contractile depression in the absence of changes in myocardial structure.

Animals↗

PubMed1996

Inhalational anesthetics inhibit spreading depression: relevance to migraine.

Cortical spreading depression (SD) has not been shown in the human neocortex by direct cortical recordings. However, animal studies suggest that cortical injury, such as that occurring during neurosurgical procedures, should result in the initiation of SD. It is possible that inhibition of SD by volatile anesthetic agents may partially explain the failure to observe SD in the human neocortex during surgery. This study examines the effect of the anesthetic agents alpha-chloralose, halothane, nitrous oxide and isoflurane on the initiation of cortical SD in the cat neocortex. SD was seen in 100% of cats anesthetized with alpha-chloralose (n = 15), in 3 of 7 (42%) animals anesthetized with isoflurane (p < 0.05, chi 2 with Yates correction) and none of the animals (n = 4, 6 hemispheric preparations) anesthetized with halothane (p < 0.005, chi 2 with Yates correction, halothane vs alpha-chloralose group). In all cases this inhibitory effect was reversible. In four animals the administration of nitrous oxide (66%) reduced the inspired concentration of isoflurane required to inhibit SD by 0.75%. This study suggests that halothane, and to a lesser extent isoflurane and nitrous oxide, protect against the initiation of cortical SD. This observation may partially explain why SD has not been demonstrated in human neocortex during surgery. Further studies are needed to determine if SD may occur under pathological conditions, such as during migraine with aura, where the cortex may be predisposed to SD.

Anesthetics, Inhalation↗

PubMed1996

Introducing Critical Appraisal to studies of animal models investigating novel therapies in sepsis.

OBJECTIVES: To discuss theoretical and practical aspects relating to the design of animal studies investigating the efficacy of novel therapeutic agents for the treatment of sepsis, and to make explicit the process whereby these studies can be evaluated for the purpose of designing clinical trials in humans. DATA SOURCES: Relevant articles from the pertinent literature were reviewed. STUDY SELECTION: Studies relevant to an evidence-based assessment of clinical studies on therapeutic efficacy, and studies relevant to the design of animal models of sepsis were selected. DATA EXTRACTION: Concepts relevant to an evidence-based assessment of the animal literature were extracted. DATA SYNTHESIS: Articles were reviewed and an evidence-based framework for the assessment of animal studies was developed. In this process, we discuss the steps that are necessary to assess the internal validity of an individual study and review topics relevant to the application of animal data to the design of clinical trials. CONCLUSIONS: The success of clinical trials of sepsis therapies is predicated on the generation and interpretation of sound preclinical data. In this review, we have attempted to outline an evidence-based approach to the assessment of preclinical animal studies evaluating novel therapeutic interventions in sepsis.

Animals↗

PubMed1996

Microcirculatory changes in rat skeletal muscle in sepsis.

The aim of this study was to confirm that microvascular perfusion was abnormal during the early phases of normotensive sepsis and to determine whether these changes were due to the development of tissue edema. Skeletal muscle red blood cell (RBC) flow was studied in rats made septic by cecal ligation and perforation (CLP). After anesthesia with halothane, arterial and venous cannulae were inserted and, in the treatment group, a CLP performed. At 6, 24, and 48 h after entry into the study, the incidence of microcirculatory absence of flow in the extensor digitorum longus muscle (EDL) was examined with intravital microscopy. The number of capillaries containing RBCs were counted over a 60-s interval, and the flow status of each capillary was recorded. A significant increase in the number of stopped-flow capillaries was observed in the CLP group (p < 0.01) as compared with time-matched controls. In both groups the number of capillaries with stopped flow was greater than in naive animals. The severity of absence of flow was negatively correlated with the systemic hemoglobin concentration. These changes were not associated with an increase in tissue wet/dry weight ratio or albumin flux. This study shows that sepsis was associated with increased RBC flow heterogeneity. These changes, which occur within 24 h of the septic insult, are a persistent feature of the evolving septic process in the absence of tissue edema. These observations support the view that extrinsic compression of the microcirculation by tissue edema is not the primary cause of alterations in microcirculatory flow in sepsis.

Animals↗

PubMed1993

Cortical spreading depression does not result in the release of calcitonin gene-related peptide into the external jugular vein of the cat: relevance to human migraine.

There is circumstantial evidence that cortical spreading depression (SD) may account for the scotoma and the "spreading cortical oligemia" seen during migraine with aura. It has been shown that calcitonin gene-related peptide (CGRP) is increased in blood taken from the external jugular vein (EJV) in humans during migraine and after stimulation of the trigeminal ganglion. To test the hypothesis that cortical SD may elevate the concentration of this vasoactive peptide in the EJV during migraine, we have measured its concentration in the external jugular vein of cats during cortical SD. This study demonstrates that SD has no effect on the concentration of CGRP either during the passage of a wave of spreading depression across the cortex or, 60 min later, during the period of post-SD cortical oligemia.

Animals↗

PubMed1991

Cortical blood flow changes during spreading depression in cats.

Changes in cortical blood flow and cerebrovascular activity occurring during and after cortical spreading depression (CSD) were studied in alpha-chloralose-urethan-anesthetized cats. CSD was induced by superficial cortical pinprick, and laser-Doppler velocimetry (LDV) was used to measure cerebral blood flow (CBFLD). CSD resulted in a wave of cortical hyperemia during which there was a 215 +/- 48% peak increase in cortical blood flow that lasted for 2.7 +/- 0.4 min. This hyperemic phase was followed by prolonged cortical oligemia, with a reduction in flow of 20 +/- 4% at 1 h and 28 +/- 4% at 2 h. After CSD, cerebrovascular reactivity to the inhalation of CO2 was abolished and did not fully recover for at least 10 h. Spontaneous vasomotor activity in the cerebral microcirculation was significantly decreased after CSD, and autoregulation of cortical blood flow in response to hypotension was preserved. The abnormal cerebrovascular reactivity seen after CSD in the gyrencephalic cortex of the cat has possible significance for human migraine with aura.

Animals↗

PubMed1985

Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. I. The monkey.

The dorsal raphe nucleus (DRN) and surrounding midbrain of 16 anaesthetized monkeys were stimulated electrically, and carotid blood flows were measured with electromagnetic flow probes. Stimulation of the DRN caused a frequency-dependent decrease (vasodilatation) in both internal and external carotid vascular resistance, which was abolished in both circulations by bilateral section of the facial nerve intracranially. These vasodilator responses were unaltered by intravenous administration of muscarinic cholinergic or by alpha- or beta-adrenoceptor antagonists. A postdilatation constrictor response, observed in the external carotid circulation, was blocked by the alpha-adrenoceptor antagonist phentolamine. It is concluded that projections of the DRN through the greater superficial petrosal branch of the facial nerve mediate vasodilatation in both internal and external carotid circulations.

Animals↗

PubMed1985

Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. II. The cat.

The dorsal raphe nucleus (DRN) and surrounding midbrain of 74 cats were stimulated both electrically and chemically, and carotid flows were measured with electromagnetic flow probes. Stimulation of the DRN caused a frequency-dependent decrease in common carotid vascular resistance, which was abolished by bilateral section of the facial nerve intracranially. Injection of DL-homocysteic acid into the DRN reproduced the effect of electrical stimulation, indicating that the responses arose from excitation of cell bodies within the DRN, not from fibers of passage. The responses were mediated entirely within the brain stem since they remained intact after high spinal cord section. The vasodilator response was blocked by the intravenous administration of the nicotinic ganglion blocker hexamethonium but not by the alpha-adrenoceptor blocker phentolamine. The responses were unaffected by intravenous administration of methysergide but were markedly reduced after depletion of central serotonin by pretreatment with the serotonin depletor, p-chlorophenylalanine. A poststimulus constrictor response was mediated by release of catecholamines from the adrenal medulla and was blocked by the alpha-adrenoceptor antagonist phentolamine. No response involved supracollicular mechanisms since they persisted after decerebration.

Animals↗

PubMedDate not supplied

Pressor response to electrical and chemical stimulation of nucleus raphe dorsalis in the cat.

The dorsal raphe nucleus was stimulated electrically and chemically in 57 cats with blood pressure being measured by an arterial catheter. Blood pressure rose by a mean of 119.5 +/- 8.9% on stimulation of the dorsal raphe nucleus at a frequency of 200 sec-1. This pressor response was frequency-dependent over the range 0.2 to 200 sec-1 and the site of origin was localized to the dorsal raphe nucleus. The pressor response could also be obtained by the injection of D,L-homocysteic acid into the nucleus, and is therefore likely to be due to activation of cell bodies rather than axons of passage. The response was blocked by high spinal cord section but was not affected by bilateral clamping of the adrenal glands or supracollicular decerebration. The pressor response was significantly reduced by pretreatment of the cats with parachlorophenylalanine (PCPA) and abolished by the alpha receptor blocker phentolamine, suggesting that both serotonergic and noradrenergic synapses are involved.

Animals↗