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Biomedical subjects

R Hayward

Publications and source records attributed to R Hayward.

At least 55 records · Page 3Linked to original sources
PubMed1998

Mechanisms of cardioprotection by peroxynitrite in myocardial ischemia and reperfusion injury.

Peroxynitrite (ONOO-), an intermediate formed from the equimolar interaction of nitric oxide (NO) and superoxide, is thought to be an important mediator of tissue injury in myocardial ischemia-reperfusion. However, physiologically relevant (i.e., maximally achievable) concentrations of ONOO- significantly decreased neutrophil-endothelium interactions in the rat mesentery. We therefore examined the dose-response relationship of infusion of different concentrations of ONOO- in a feline model of myocardial ischemia-reperfusion and provide data on the cellular mechanisms responsible for these observed effects. Cats subjected to 90 min of ischemia followed by 270 min of reperfusion were infused with different concentrations of ONOO- 10 min before reperfusion and continuing throughout reperfusion. We observed that infusion of 2 microM ONOO- provided significant cardioprotection, whereas either 0.2 or 20 microM ONOO- did not protect. ONOO- at 2 microM also preserved coronary endothelial function, decreased P-selectin expression, and attenuated polymorphonuclear leukocyte (PMN) adherence to the vascular endothelium. ONOO- did not exert its cardioprotective effects by acting as a direct NO donor in solution. However, in vitro, ONOO- can react with glutathione to form S-nitrosoglutathione, which can act as an NO carrier and exert beneficial effects. Thus only maximally achievable concentrations of ONOO- exert significant cardioprotective effects, in part by decreasing surface expression of P-selectin and decreasing PMN-endothelium interactions.

Animals↗
PubMed1998

Time course of endothelial-neutrophil interaction in splanchnic artery ischemia-reperfusion.

Splanchnic artery occlusion and reperfusion (SAO/R) results in a severe form of circulatory shock that has a high mortality rate. To examine the time course of the early events involved in SAO/R, occlusion of the superior mesenteric artery (SMA) and the celiac artery (120 min) were followed by reperfusion periods of 0, 2.5, 5, 20, 30, 60, or 120 min. Relaxation of isolated SMA vascular rings to the endothelium-dependent vasodilator ACh was unimpaired following 120 min of ischemia (86 +/- 5%); however, significant (P < 0.01) reductions in endothelium-dependent vasorelaxation were observed following 2.5 min (53 +/- 6%) of reperfusion with severe dysfunction (P < 0.001) observed at 20 min (29 +/- 4%). Neutrophil adherence to the endothelium increased as a function of reperfusion time with a 2.3-fold increase observed at 20 min (P < 0.01) and a 3.4-fold increase observed at 120 min (P < 0.001). Intestinal myeloperoxidase activity was significantly increased 30 min after reperfusion (P < 0.05), whereas surface expression of P-selectin progressively increased at 5 (P < 0.05) and 30 min (P < 0.001) postreperfusion. These findings demonstrate that endothelial dysfunction is a very early event in the pathophysiology of SAO/R, subsequently resulting in increased surface expression of P-selectin and the adherence of neutrophils to the endothelium that leads to neutrophil accumulation in the splanchnic viscera.

Animals↗
PubMed1998

Potential prognostic factors of relapse-free survival in childhood optic pathway glioma: a multivariate analysis.

There is still no consensus on the natural history and optimal management of optic pathway gliomas (OPG) in children. In order to tackle optimal management issues, we need to clearly understand the prognostic and confounding factors affecting relapse of OPG. We propose the use of the Cox proportional hazards (PH) model in a retrospective study of childhood OPG of 69 children seen from 1977 to 1994. We have developed a comprehensive model capable of multivariate analyses and handling time-dependencies. Our studies showed that relapse-free survival improves with increasing age, the presence of neurofibromatosis 1 (NF1), and chemotherapy and radiotherapy (p < 0.0005). Sex, tumor position and surgery do not significantly affect survival. Older children with NF1 have extremely good prognosis. We noted behavior that departs from the strictly proportional hazards model, but results were inconclusive.

Adolescent↗
PubMed1998

Patient outcomes after initiation of Sabbath closure of a methadone maintenance clinic in Israel.

The study examined whether closing of a methadone maintenance clinic in Israel on the Sabbath was associated with adverse patient outcomes. One take-home dose of methadone was given to all patients for that day regardless of whether they had earned take-home privileges. No difference was found in dropout rates for the six-month periods before and after Saturday closure was initiated. Results of random, twice-weekly urinalyses for all patients did not indicate increased use of heroin. The findings suggest that closure of a methadone clinic at least one day a week does not jeopardize patient outcome. Cutting hours of operation would reduce workload and enable clinics to function more economically.

Adult↗
PubMed1998

Breathing patterns in children with craniofacial dysostosis and hindbrain herniation.

In the past few years, hindbrain herniation has become recognized as a frequent feature of the child with syndromic craniofacial dysostosis. The clinical significance of hindbrain herniation in these disorders is unclear. Abnormalities of respiratory control have frequently been reported. The aim of the present study was to document the incidence of obstructive and central respiratory abnormalities during sleep in craniofacial syndromes with hindbrain herniation. We performed cardiorespiratory sleep studies during unsedated night-time sleep in a group of 13 children. Hindbrain herniation was confirmed by magnetic resonance imaging (MRI) and ranged 1.5-26.9 mm below the cranial base. Sleep studies revealed central respiratory pauses associated with important reduction of the arterial oxygen saturation (Sa,O2) in only two of 13 cases (minimum Sa,O2 86% and 87%). In contrast 10 of 13 children had some degree of upper airway obstruction (four mild, three moderate and three severe). Of the remaining three children, two had previous long-term tracheostomies. Changes in the breathing pattern were proportional to the severity of the obstruction and comprised increased respiratory efforts and arterial oxygen desaturation. Infrequent mixed apnoeas were observed in five patients, and their severity reflected the severity of the obstructive component. In conclusion, obstruction of the upper airways was the predominant sleep-related respiratory problem in this group of patients. Hindbrain herniation was not associated with a high incidence of central sleep apnoea.

Airway Obstruction↗
PubMed1998

L-arginine attenuates endothelial dysfunction and prolongs survival in rats subjected to traumatic shock.

We investigated the effects of L-arginine administration in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to drum trauma developed a severe shock condition characterized by marked hypotension to 55-70 mmHg, a survival time of only 90 +/- 21 min, and significant increases in ileal myeloperoxidase (MPO) activity (P < 0.01). In addition, superior mesenteric artery (SMA) rings isolated from rats subjected to traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine significantly less than rings isolated from control rats (p < 0.01). Administration of L-arginine (30 mg/kg bolus + 10 mg/kg/hr, i.v.) 10 min following trauma prolonged survival time to 213 +/- 33 min (p < 0.05) and attenuated ileal MPO activity (p < 0.01) indicative of reduced neutrophil infiltration. Furthermore, SMA endothelial function was significantly (p < 0.01) preserved in L-arginine treated traumatic shock rats. These results indicate that L-arginine plays a key role in the endothelial dysfunction associated with traumatic shock and affords significant protective effects which may be manifested by an inhibition of leukocyte-endothelial cell interactions.

Animals↗
PubMed1998

Insurance type and choice of hospital for coronary artery bypass graft surgery.

OBJECTIVE: To examine the effect of insurance type on the relationship between hospital attributes and patient flows, with particular attention to whether HMO enrollees are more or less likely than other patients to receive care at high-quality hospitals and whether HMO enrollees travel farther to receive care. DATA SOURCES/STUDY SETTING: Data on patient flows, taken from discharge abstracts compiled by the California Office of Statewide Health Planning and Development. Our sample consists of patients undergoing coronary artery bypass graft surgery (CABG) in 1991 who resided in three California markets. Only patients under the age of 65 and insured by HMOs, Blue Cross/Blue Shield, or other commercial insurance were included. Hospital quality is based on hospital-specific measures of excess mortality from CABG. Other hospital attributes were taken from American Hospital Association survey data. STUDY DESIGN: Conditional-choice models were used to estimate the probability that patients would receive care at any given hospital as a function of their insurance type and the hospital's attributes. PRINCIPAL FINDINGS: Patients were more likely to receive care from hospitals closer to their residence. However, HMO patient flows were less sensitive to proximity. In general, the likelihood that an HMO enrollee received care at a given hospital was positively related to hospital quality. Moreover, quality had a greater effect on patient flows for HMO enrollees than for non-HMO enrollees. However, the evidence suggests that the effect of quality on patient flows is neither uniform across markets nor across HMOs. CONCLUSIONS: HMOs do not appear to direct patients to low-quality hospitals. However, heterogeneity among HMOs and across markets suggests that buyers must recognize that choosing an HMO involves greater scrutiny than simply picking a plan labeled "HMO."

California↗
PubMed1997

Laboratory evaluation in the diagnosis of Lyme disease.

PURPOSE: To provide a qualitative evaluation of the predictive value of the laboratory diagnosis of Lyme disease and to use the resultant data to formulate guidelines for clinical diagnosis. DATA SOURCES: A MEDLINE search of English-language articles or articles with English-language abstracts published from 1982 to 1996. DATA EXTRACTION: Sensitivity, specificity, and likelihood ratios were calculated, and a random-effects model was used to combine the proportions from the eligible studies. Prespecified criteria were used to determine which studies were eligible for analysis. DATA SYNTHESIS: Laboratory testing in general is not clinically useful if the pretest probability of Lyme disease is less than 0.20 or greater than 0.80. When the pretest probability is 0.20 to 0.80, sequential testing with enzyme-linked immunosorbent assay and Western blot is the most accurate method for ruling in or ruling out the possibility of Lyme disease. CONCLUSIONS: Laboratory testing is recommended only in patients whose pretest probability of Lyme disease is 0.20 to 0.80. If the pretest probability is less than 0.20, testing will result in more false-positive results than true-positive results; a negative test result in this situation effectively rules out the disease.

Bacteriological Techniques↗
PubMed1997

Peroxynitrite reduces myocardial infarct size and preserves coronary endothelium after ischemia and reperfusion in cats.

BACKGROUND: Peroxynitrite (ONOO-) is purported to exert cytotoxic effects at high doses. However, physiologically relevant concentrations of ONOO- inhibit polymorphonuclear neutrophil (PMN) adhesion to the endothelium and attenuate PMN-mediated contractile dysfunction in isolated perfused rat hearts. We are unaware of any reports in vivo showing effects of peroxynitrite in myocardial ischemia and reperfusion (MI/R). Thus, the purpose of this study was to examine the in vivo effects of a physiologically relevant concentration of ONOO- (1 micromol/L) in a feline model of MI/R injury. METHODS AND RESULTS: ONOO- (1 micromol/L) or its vehicle (0.9% NaCl at pH 8.4) was infused intraventricularly, starting 10 minutes before reperfusion in cats subjected to 90 minutes of myocardial ischemia and 4.5 hours of reperfusion. ONOO(-)-treated cats demonstrated marked attenuation of cardiac necrosis after MI/R compared with cats receiving only vehicle (P<.001). Moreover, vasorelaxation of ischemic-reperfused left anterior descending (LAD) coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in rings isolated from ONOO(-)-treated MI/R cats compared with MI/R cats receiving only vehicle, indicating that postreperfusion coronary vascular endothelial function was preserved by ONOO-. ONOO- also significantly reduced adherence of neutrophils to the ischemic-reperfused LAD coronary endothelium. Immunohistochemical localization of P-selectin was also significantly attenuated in hearts from ONOO(-)-infused MI/R cats. CONCLUSIONS: These data suggest that physiologically relevant concentrations of ONOO- exert significant cardioprotective and vasculoprotective effects in MI/R in cats, at least partially by attenuating PMN-endothelium interactions.

Animals↗
PubMed1997

Cardioprotective effect of interleukin-10 in murine myocardial ischemia-reperfusion.

We investigated the cardioprotective effects of rat interleukin-10 in a murine model of myocardial ischemia-reperfusion (20 min ischemia, 24 h reperfusion). Interleukin-10 (100 microg/rat) administered 15 min prior to reperfusion, significantly (P < 0.01) attenuated myocardial injury compared to rats receiving only 0.9% saline as a vehicle, as indicated by a reduced loss of myocardial creatine kinase from the ischemic-reperfused myocardium. Cardiac myeloperoxidase activity was also significantly (P < 0.01) attenuated by interleukin-10 within the ischemic-reperfused region compared to vehicle treated rats. To further investigate the mechanism of interleukin-10 we observed the in vitro adherence of neutrophil to rat vascular endothelium. Interleukin-10 treatment significantly (P < 0.05) attenuated neutrophil adherence to rat superior mesenteric artery endothelium stimulated with interleukin-1beta. Thus, interleukin-10 demonstrated significant cardioprotective effects as evidenced by a decrease in myocardial creatine kinase loss as well as an inhibition of neutrophil accumulation within the myocardium. It appears as though interleukin-10 mediates its effects, at least in part, by inhibiting leukocyte-endothelial interactions.

Animals↗
PubMed1997

Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats.

Peroxynitrite (ONOO-) anion, formed by the interaction of superoxide with nitric oxide (NO), has previously been implicated as a cytotoxic agent. However, the effects of this free radical species on neutrophil (PMN)-endothelial cell interactions is largely unknown. We investigated the direct actions of ONOO- on PMN adhesion to endothelial cells in vitro and in vivo, as well as the effects of ONOO- on PMN-mediated myocardial ischemia-reperfusion injury. In vitro, peroxynitrite (100-1,000 nM) inhibited the adhesion of rat PMNs to the endothelium of isolated thrombin- or H2O2-stimulated rat mesenteric artery (P < 0.01 vs. thrombin or H2O2 alone). In vivo, in the rat mesentery, thrombin (0.5 U/ml) or N(G)-nitro-L-arginine-methyl ester (50 microM) significantly increased venular leukocyte rolling and adherence, which were also significantly (P < 0.01) attenuated by ONOO (800 nM) accompanied by reduced P-selectin expression on the endothelial cell surface. Isolated perfused rat hearts were subjected to global ischemia and reperfusion with rat PMNs (10(8) cells), which resulted in profound cardiac depression (i.e., a marked reduction in left ventricular developed pressure and maximal rate of development of left ventricular pressure). Infusion of ONOO- reversed the myocardial contractile dysfunction of ischemic-reperfused rat hearts to near baseline levels, and markedly attenuated the accumulation of PMNs in the postischemic heart. The present study provides strong evidence that nanomolar concentrations of ONOO- both inhibit leukocyte-endothelial cell interactions and exert cytoprotective effects in myocardial ischemia-reperfusion injury. Furthermore, our results suggest that the inhibition of P-selectin expression by peroxynitrite is a key mechanism of the modulatory actions of ONOO- on leukocyte-endothelial cell interactions.

Animals↗
PubMed1997

A study and meta-analysis of lay attributions of cures for overcoming specific psychological problems.

Lay beliefs about the importance of 24 different contributors to overcoming 4 disorders that constitute primarily cognitive deficits were studied. A meta-analysis of previous programmatic studies in the area was performed so that 22 different psychological problems could be compared. In the present study, 107 participants completed a questionnaire indicating how effective 24 factors were in overcoming 4 specific problems: dyslexia, fear of flying, amnesia, and learning difficulties. Factor analysis revealed almost identical clusters (inner control, social consequences, understanding, receiving help, and fate) for each problem. The perceived relevance of those factors differed significantly between problems. Some individual difference factors (sex and religion) were found to predict certain factor attributions for specific disorders. A meta-analysis of the 5 studies in this series yielded a 6-factor structure comparable to those of the individual studies and provided results indicating the benefits and limitations of this kind of investigation. The clinical relevance of studying attributions for cure is considered.

Adult↗
PubMed1997

Intrinsic brainstem tumours in childhood: a report of 35 children followed for a minimum of 5 years.

The presentation, pathology and outcome of 35 children with intrinsic brainstem tumours treated at our institution between 1980 and 1990 have been reviewed. Eight children remain alive. There were 19 girls and 16 boys. Mean age at diagnosis was 5 years. The mean duration of symptoms prior to diagnosis was 5 months. The diagnosis was made by computed tomography (CT) in all children and magnetic resonance imaging (MRI), in addition, for 24 children. Twenty-seven tumours (77%) were diffuse, three (8.6%) were predominantly cystic, three (8.6%) were exophytic and two (5.7%) were focal. Cervicomedullary tumours were not included in this study. Definitive histology was obtained in 13 children (37.1%), eight (22.9%) by biopsy alone and five (14.3%) after surgery to debulk the tumours. Eleven of these cases were astrocytomas and two were primitive neuroectodermal tumours (PNET). Twelve children (34.3%) required shunt placement for hydrocephalus. Twenty-eight children (80%) were irradiated using conventionally fractionated radiotherapy to a total dose between 50 and 55 Gy. Six children (17.1%) also received chemotherapy. The overall mean survival time was 10 months, but five of six children who had their tumours debulked survived free of progressive disease for more than 5 years following their diagnosis. The prognosis for brainstem tumours in children remains poor with only a minority falling into the surgically resectable (good prognosis) group.

Adolescent↗
PubMed1997

Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis.

Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.

Acrocephalosyndactylia↗
PubMed1997

Regulation of P-selectin expression in human endothelial cells by nitric oxide.

P-selectin translocation to the surface of endothelial cells is increased after exposure to the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), resulting in increased endothelial adhesiveness. L-NAME (3 mM) was added to human cultured iliac vein endothelial cells for 1, 2, 4, and 6 h, and P-selectin mRNA expression was quantified by a ribonuclease protection assay. In parallel experiments, the NO donor, SPM-5185 (10 microM), was added to human iliac venous endothelial cells, and P-selectin mRNA expression quantified. P-selectin protein synthesis was quantified by Western blot analysis. L-NAME caused increased expression of P-selection RNA at 2-4 h, whereas D-NAME, the stereoisomer lacking NO synthase-inhibitory activity, had no effect. The stimulatory effect of L-NAME was reversed by addition of 3 mM L-arginine. SPM-5185 decreased P-selectin mRNA over the same time period (P < 0.02). The increased P-selectin mRNA expression induced by L-NAME was paralleled by an increase in P-selectin protein synthesis. The effects of SPM-5185 and L-arginine were also paralleled by decreases in P-selectin protein synthesis and in decreased adherence of human neutrophils to human iliac venous endothelial cells. The peak effect of inhibition of NO synthesis or addition of exogenous NO occurred at 2-4 h. These results suggest a regulatory effect of NO on endothelial P-selectin expression that modulates early leukocyte-endothelial cell interactions to preserve vascular homeostasis.

Arginine↗
PubMed1997

Upper airway obstruction and raised intracranial pressure in children with craniosynostosis.

In children with craniosynostosis, raised intracranial pressure (ICP) and upper airway obstruction (UAO) are both common features. However, potential interactions between UAO and ICP during sleep are poorly understood. The aim of the present study was to compare the levels of ICP during sleep between a group of patients with syndromic craniosynostosis (with facial involvement and consequent UAO) and a group of control patients with isolated unicoronal synostosis (with no facial involvement and normal upper airways). Polygraphic cardiorespiratory sleep studies with continuous monitoring of ICP were performed during unsedated sleep in 13 children with syndromic craniosynostosis and 7 control patients with isolated unicoronal synostosis only. In the syndromic group, UAO was present in 11 out of 13 patients, with 8 out of 13 having frank obstructive sleep apnoea. In contrast, none of the control patients showed signs of UAO during sleep. There was no evidence of central apnoeas in any of the patients studied. Clinical histories taken from parents tended to underestimate the severity of the respiratory problems. Elevated ICP was seen in 10 of the 13 syndromic patients, with borderline raised ICP in the remaining three cases. In contrast, raised ICP was seen in only 3 of the 7 control patients, with borderline raised levels in 2 of the 7. For both patient groups, ICP was higher during active sleep compared to quiet sleep. Multiple regression analysis showed that ICP during active sleep was dependent upon disease severity (unicoronal/ multiple synostosis) and to the baseline ICP level during quiet sleep. Both raised ICP and airway obstruction were more apparent during active sleep. There was a significant correlation between severity of UAO and increased ICP in active sleep. We conclude that obstructive respiratory problems are frequent in the syndromic patients, and can be severe in a large proportion of cases; intracranial hypertension is also frequent in this group. Further studies are required to investigate the possibility of a causal relationship between upper airway obstruction and raised intracranial pressure.

Child↗
PubMed1997

Heparinase III exerts endothelial and cardioprotective effects in feline myocardial ischemia-reperfusion injury.

The initial phase of neutrophil (PMN) adherence in the pathophysiology of myocardial ischemia-reperfusion (MI/R) injury depends on the selectins, particularly P- and L-selectin. Several ligands for these selectins have been identified, one of which may be a heparan sulfate proteoglycan (HSPG). Cats subjected to 90 min of MI and 270 min of R were given either heparinase III (0.033, 0.33 or 3.33 IU/kg/min) or its vehicle beginning 10 min before R and continuing throughout the 270-min R period. Heparinase III at 3.33 IU/kg/min provided a marked cardioprotective effect compared with cats receiving only vehicle as evidenced by a significant attenuation in myocardial necrosis (P < .01). In addition, endothelium-dependent vasorelaxation to acetylcholine in coronary artery rings isolated from MI/R cats treated with heparinase III was significantly preserved (P < .01). Adherence of PMNs to the coronary vascular endothelium after 270 min of R was also significantly attenuated in heparinase III-treated cats compared with vehicle (P < .01). At 0.33 IU/kg/min, heparinase III exerted modest, significant cardioprotective effects, whereas at 0.033 IU/kg/min, no significant beneficial effects were observed. Our results indicate that heparinase III is cardioprotective in a dose-dependent manner, preserves endothelial function and attenuates PMN adherence to the coronary vascular endothelium.

Animals↗