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Biomedical subjects

J E Edwards

Publications and source records attributed to J E Edwards.

At least 91 records · Page 5Linked to original sources
PubMed1996

Causes of sudden unexpected cardiac death in the first two decades of life.

Sudden, unexpected cardiac death in the age group 1 to 21 years usually is due to myocarditis, hypertrophic cardiomyopathy, aortic valvar stenosis, and coronary arterial abnormalities. The hearts of 70 patients <21 years of age who died suddenly were reviewed. Twenty patients were <1 year of age and 50 were 1 to 21 years old. The cardiac findings were compared with those in 68 age-matched controls with known cardiac disease who did not die suddenly. Significant cardiac abnormalities were present in 13 (65%) of the 20 infants; 10 (50%) had anomalies of the aortic origin of the coronary arteries. Among the 50 older patients, cardiac abnormalities were found in 40 (80%), among whom coronary arterial anomalies existed in 12 (24%). Anomalies of aortic origin more frequently involved the left main than the right coronary artery in both groups.

Adolescent↗
PubMed1996

A survey to investigate potential dehydration in slaughtered broiler chickens.

A survey of 800 broilers arriving at two commercial slaughterhouses with a combined annual throughput of 40 million birds was carried out. Each plant was visited on four occasions throughout summer and winter and blood samples were collected from 100 broilers at exsanguination throughout the day of each visit. In all, the survey covered 16 lorry loads of broilers delivered to one plant and 20 loads delivered to the other. The blood collected was analysed for packed cell volume (PCV), plasma creatine kinase, total protein, sodium, glucose, osmolality and corticosterone. Based on the measures of PCV, plasma total protein, sodium and osmolality there was no evidence of dehydration amongst the lorry loads of birds delivered to the plants. There were differences between the two plants in the levels of all of the blood variables that were measured, except for those of plasma corticosterone.

Abattoirs↗
PubMed1996

Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of antifungal susceptibility testing.

No method currently exists to predict which patients with acute AIDS-associated cryptococcal meningitis can be effectively treated with fluconazole. The objective of this study was to determine the relationship of cryptococcal susceptibility to fluconazole, along with clinical variables, to the risk of treatment failure for patients with acute AIDS-associated cryptococcal meningitis. Results of in vitro fluconazole susceptibility testing of cryptococcal isolates and data from two clinical trials were analyzed. Susceptibility to fluconazole was determined by means of both microtiter and macrobroth (M27-P) dilution methods. Treatment was defined as successful if the patient was alive at 10 weeks and if a cerebrospinal fluid culture was sterile at that time. Seventy-six patients receiving fluconazole +/- flucytosine were included; therapy failed for 19. Patients whose therapy failed were more likely to have a positive blood and urine culture and a higher titer in serum and cerebrospinal fluid of cryptococcal antigen, and the MIC of fluconazole against their isolates (as determined by the microtiter method) was more likely to be higher; they were less likely to have received flucytosine. Logistic regression modeling revealed that a negative blood culture, a low MIC of fluconazole (per the microtiter method), and treatment with flucytosine were factors independently associated with successful treatment.

AIDS-Related Opportunistic Infections↗
PubMed1996

Gamma interferon protects endothelial cells from damage by Candida albicans by inhibiting endothelial cell phagocytosis.

Once Candida albicans comes in contact with endothelial cells, it induces cellular injury. This endothelial cell injury may be a mechanism by which blood-borne organisms escape from the intravascular compartment and invade the tissue parenchyma during hematogenous infection. We have been investigating the ability of cytokines to modulate endothelial cell injury caused by C. albicans. Previously we reported that pretreatment of endothelial cells with gamma interferon (IFN-gamma) protects these cells from candidal injury in vitro. In the current study, we examined potential mechanisms of the cytoprotective effects of IFN-gamma. Time course experiments demonstrated that maximal reduction in candidal injury of endothelial cells occurred after the endothelial cells had been exposed to IFN-gamma for at least 72 h. In other studies, we determined that IFN-gamma reduced endothelial cell phagocytosis of C. albicans by 41.3% compared with that of untreated endothelial cells (P < 0.01). Since endothelial cell phagocytosis of C. albicans is required for damage to occur, inhibition of phagocytosis is likely a mechanism by which IFN-gamma protects endothelial cells from candidal injury. We also found that the cytoprotective effect of IFN-gamma is not mediated by reducing access of the organisms to intracellular endothelial cell iron or by upregulating the synthesis of reactive oxygen intermediates (which could potentially reduce the ability of C. albicans to injure endothelial cells). Thus, inhibiting endothelial cell phagocytosis of C. albicans may be a mechanism by which IFN-gamma augments the host defense against hematogenously disseminated candidal infections.

Antioxidants↗
PubMed1996

Resistance to platelet microbicidal protein results in increased severity of experimental Candida albicans endocarditis.

Thrombin-induced platelet microbicidal protein (tPMP) exerts potent in vitro microbicidal activity against pathogens commonly found in the bloodstream, including Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. Localized platelet release of tPMP may be important in defense against infections involving the vascular endothelium caused by tPMP-susceptible organisms. In contrast, pathogens capable of surviving in the presence of tPMP could then exploit the platelet as an adhesive surface for attachment to damaged endothelium. To examine these hypotheses, we derived a tPMP-resistant (tPMP(r)) C. albicans strain from its tPMP-sensitive (tPMP(s)) parental strains were equivalent in vitro as assessed by genotyping (electrophoretic karyotype and restriction endonuclease analysis of genomic DNA), biotyping, germination, platelet aggregation, adherence to vascular endothelial cells, and growth characteristics. In addition, the tPMP(r) phenotype was stable following multiple in vitro and in vivo passages. We then investigated the in vivo relevance of tPMP susceptibility on endovascular infection using a rabbit model of endocarditis and hematogenous dissemination. Rabbits with transaortic catheters (n = 15 in each group) were challenged with either the tPMP(s) or tPMP(r) C. albicans strain. All rabbits developed C. albicans-induced endocarditis, as determined by the presence of infected vegetations. In rabbits challenged with tPMP(s) strain (P < 0.001). These results were seen in the absence of differences in either initial adherence of strains to cardiac valves or vegetation weights. Furthermore, although these C. albicans strains induced equivalent rates and extent of hematogenous renal infection, only the tPMP(r) strain disseminated hematogenously to the spleen (15 of 15 rabbits) versus 0 of 15 [tpmp(s) strain]; P < 0.0001). Thus, tPMP(r) C. albicans caused more-severe endocarditis and produced greater metastatic sequelae than the tPMP(s) counterpart.

Animals↗
PubMed1996

Candida albicans stimulates cytokine production and leukocyte adhesion molecule expression by endothelial cells.

Endothelial cells have the potential to influence significantly the host immune response to blood-borne microbial pathogens, such as Candida albicans. We investigated the ability (of this organism to stimulate endothelial cell responses relevant to host defense in vitro. Infection with C. albicans induced endothelial cells to express mRNAs encoding E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin 6, interleukin 8, monocyte chemoattractant protein 1, and inducible cyclooxygenase (cox2). All three leukocyte adhesion molecule proteins were expressed on the surfaces of the endothelial cells after 8 h of exposure to C. albicans. An increase in secretion of all three cytokines was found after 12 h of infection. Cytochalasin D inhibited accumulation of the endothelial cell cytokine and leukocyte adhesion molecule mRNAs in response to C. albicans, suggesting that endothelial cell phagocytosis of the organism is required to induce this response. Live Candida tropicalis, Candida glabrata, a nongerminating strain of C. albicans, and killed C. albicans did not stimulate the expression of any of the cytokine or leukocyte adhesion molecule mRNAs. These findings indicate that a factor associated with live, germinating C. albicans is required for induction of endothelial cell mRNA expression. Furthermore, since endothelial cells phagocytize killed C. albicans, phagocytosis is likely necessary but not sufficient for this organism to stimulate mRNA accumulation. In conclusion, the secretion of proinflammatory cytokines and expression of leukocyte adhesion molecules by endothelial cells in response to C. albicans could enhance the host defense against this organism by contributing to the recruitment of activated leukocytes to sites of intravascular infection.

Candida albicans↗
PubMed1995

Effects on sheep of transport by road for up to 24 hours.

Five groups of 20 slaughter sheep of approximately 37.9 kg liveweight were transported by road for either three, nine, 15, 18 or 24 hours and three groups were not transported, one of them being deprived of food and water for 24 hours. Before and after transport the liveweight and various blood variables were measured and heart rate and behavioural observations were recorded from subsets of the animals. With increased journey time there was a decrease in liveweight and an increase in the plasma levels of free fatty acids, beta-hydroxybutyrate and urea; however, the changes over 24 hours were similar to those in the group deprived of food and water. In the transported sheep, the heart rate and levels of plasma cortisol and glucose were increased by the stresses of loading and the initial stages of the journey, but after nine hours the sheep appeared, to some extent, to have adapted. They were able to lie down and did not appear to be physically stressed. Measurements of plasma osmolality, total plasma protein and albumin did not indicate that the sheep had become severely dehydrated after 24 hours of transport but upon their return, feeding and drinking activity was greater than that observed before the journey.

Adaptation, Physiological↗
PubMed1995

Effects on cattle of transport by road for up to 15 hours.

Twenty-four castrated male cattle aged between 12 and 18 months were transported by road for five, 10 or 15 hours, over distances of 286, 536 and 738 km. Half the animals were of Hereford x Friesian breeding and half of 'continental' type. The animals transported for five hours lost 4.6 per cent of their bodyweight, those transported for 10 hours lost 6.5 per cent and those transported for 15 hours lost 7.0 per cent; recovery to pre-transport values took five days. There was little evidence from changes in blood composition that a 15-hour journey was more stressful than a 10-hour journey. The cortisol concentrations were increased by the stresses of loading and the first part of the journey but then recovered as the journey continued. Creatine phosphokinase (CPK) activities increased progressively with the longer journeys and CPK, urea, albumin and osmolality levels recovered more slowly after the longer journeys. Increases in free fatty acids, beta-hydroxybutyrate and urea concentrations and the continued increase in urea levels after the end of the journeys suggested that the animals' normal pattern of feeding was disrupted. Increases in albumin, total plasma protein and osmolality indicated slight dehydration during transit which was quickly rectified by access to water. The two breed types responded similarly to transport, except that the increases in CPK were greater in the continental breeds, possibly as a result of their greater muscularity or greater sensitivity to stress. Based on the physiological measurements made and the subjective observations of behaviour a 15-hour transport period under good conditions is not unacceptable from the viewpoint of animal welfare.

Animal Husbandry↗
PubMed1995

Composite and plain tubular synthetic graft conduits in right ventricle-pulmonary artery position: fate in growing lambs.

Our goal was to identify the most appropriate material for right ventricle-pulmonary artery conduits in growing animals. We used 100 lambs that were 3 to 4 weeks old (mean weight 11.7 kg). Follow-up was up to 24 months. Group I received plain tubular conduits: (1) Dacron knitted fabric, (2) collagen-coated knitted fabric, (3) Milliknit and Microknit material, (4) woven Dacron fabric, (5) three-dimensional Dacron fabric (crossweave 500 and 800), or (6) polytetrafluoroethylene. Group II received either a (1) woven Dacron fabric conduit with a built-in tissue valve or (2) polytetrafluoroethylene graft with a built-in St. Jude Medical valve. We did angiograms and catheterizations every 3 to 6 months and killed the lambs at 6, 12, 18, or 24 months. Tubular Dacron fabric woven or knitted grafts, regardless of matrix, pore size, thickness, or coating, caused formation of a thick acellular pseudointima buildup, which led to progressive obstruction starting as early as 3 months. Polytetrafluoroethylene grafts in groups I and II showed the formation of thin inner and outer capsules (0.5 mm) and none developed obstruction despite wall calcification. Conduits of woven Dacron fabric with a built-in tissue valve degenerated rapidly, leading to calcification thrombosis and obstruction within 3 months; no lamb survived 12 months. Polytetrafluoroethylene conduits with a St. Jude Medical valve in lambs receiving anticoagulants remained free of obstruction and continued to function well. It appears that synthetic conduits of polytetrafluoroethylene perform well in either of the situations here tested and may be the best choice at present.

Animals↗
PubMed1995

Acute invasive rhinocerebral zygomycosis in an otherwise healthy patient: case report and review.

A previously healthy 19-year-old man developed rapidly progressive invasive rhinocerebral zygomycosis due to Apophysomyces elegans. He required extensive surgery and prolonged treatment with high-dose i.v. amphotericin B for cure. This is only the third reported case of acute invasive rhinocerebral zygomycosis in an otherwise healthy patient and the first reported case of infection due to A. elegans in any patient. We review the literature and clinical spectrum of rhinocerebral zygomycosis in otherwise healthy patients and discuss the recently recognized association between A. elegans and zygomycosis in immunocompetent patients.

Adult↗
PubMed1995

Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group.

During a comparative trial of amphotericin B vs. fluconazole for treatment of candidemia in nonneutropenic patients, data on the management of intravascular catheters were collected. Complete records were available for 91% of the 206 study patients. For the subset of patients with a catheter in place at the time of their first positive blood culture, removal and replacement of all intravascular catheters without exchange over a guidewire from a preexisting line on or before the first day the study drug was administered were associated with a reduction in the subsequent mean duration (+/- SE) of candidemia, from 5.6 +/ -0.8 days to 2.6 +/- 0.5 days (P < .001).

Amphotericin B↗
PubMed1995

In vitro determination of optimal antifungal combinations against Cryptococcus neoformans and Candida albicans.

There is currently no rapid, reliable, and reproducible in vitro technique to describe the growth-inhibitory interactions of antifungal drug combinations over a wide range of drug concentrations. We have developed a microdilution plate assay that was used to determine optimal drug combinations and concentrations of one-, two-, and three-drug regimens of amphotericin B (AmphB), fluconazole (FLU), and 5-fluorocytosine (5FC) for growth inhibition of three isolates each of Cryptococcus neoformans and Candida albicans. These growth inhibition data were then used in a multifactorial design technique to (i) generate contour and surface response plots to aid visual interpretation and (ii) develop mathematical equations describing the growth responses of the fungi to a wide range of antifungal concentrations and ratios. Our data indicated that (i) antifungal drug-drug interactions affecting yeast growth are complex functions of the drugs used in combination, their absolute concentrations, and also their relative (proportional) concentrations; (ii) AmphB-FLU combinations had additive effects against C. albicans over wide concentration ranges for each agent but were indifferent (i.e., were less than additive) in their inhibitory effect on C. neoformans; (iii) other two-drug combinations (FLU-5FC or AmphB-5FC) had indifferent effects on the growth of both fungi; and (iv) three-drug combinations (AmphB-FLU-5FC) showed an additive inhibitory effect on the growth of both C. albicans and C. neoformans. The finding that no antagonism was observed in combinations employing AmphB and FLU in this in vitro model is of critical importance since it argues against the current theoretical concept, based on the individual drug's mode of action, of antagonism between these two drugs. These microdilution techniques provide a method to determine rational regimens of antifungal agents in multidrug combinations for future testing to correlate in vitro activity with in vivo response. The use of this approach has made the evaluation of complex antifungal drug-drug interactions possible and provided important new information to the evolving field of antifungal drug combination.

Amphotericin B↗
PubMed1995

Sterol compositions and susceptibilities to amphotericin B of environmental Cryptococcus neoformans isolates are changed by murine passage.

Previous studies have shown that sequential isolates from patients with persistent Cryptococcus neoformans meningoencephalitis can vary in sterol composition and susceptibility to antifungal drugs. To investigate the potential of host factors as mediators of this phenomenon, we compared fungal susceptibilities of environmental and clinical isolates from a limited geographic area. Clinical isolates were less susceptible to amphotericin B than environmental isolates. Five environmental isolates were passaged through BALB/c murine hosts; the passaged isolates had changes in sterol composition and reduced amphotericin B susceptibilities relative to those of the parent isolates. In contrast, murine passage of these isolates did not alter their susceptibilities to fluconazole. The results confirm that changes in sterol composition and antifungal susceptibility can occur in vivo as a result of host factors and suggest that human infection can result in selection of variants with reduced susceptibilities to amphotericin B.

Amphotericin B↗
PubMed1995

Adherence to and damage of endothelial cells by Cryptococcus neoformans in vitro: role of the capsule.

Escape from the intravascular compartment is likely a critical step in the development of hematogenously disseminated cryptococcal infections, such as meningitis. The capsule of Cryptococcus neoformans is considered to be a virulence factor because of its antiphagocytic properties. To further investigate the role of the capsule in escape from the intravascular compartment, we used isogenic strain pairs, an acapsular mutant, and an encapsulated clinical isolate to determine the effects of the capsule of C. neoformans on adherence to, phagocytosis by, and damage of endothelial cells in vitro. Acapsular C. neoformans adhered significantly more to endothelial cells and caused greater endothelial cell injury than did encapsulated organisms. Coating of an acapsular strain with cryptococcal glucuronoxylomannan decreased both adherence to and damage of endothelial cells by 61.7% +/- 9.1% and 76.6% +/- 10.2%, respectively. Transmission electron microscopy demonstrated internalization of acapsular, but not encapsulated, organisms by endothelial cells. Internalization of an acapsular strain occurred through endothelial cell phagocytosis and was inhibited by cytochalasin D. Phagocytosis required a heat-labile serum factor, probably complement. These results suggest that acapsular or poorly encapsulated C. neoformans may be the form(s) that escapes from the vasculature during initiation of hematogenously disseminated disease.

Cell Adhesion↗
PubMed1995

Evidence implicating phospholipase as a virulence factor of Candida albicans.

Three different approaches were used to investigate the role of extracellular phospholipases in the pathogenicity of Candida albicans. First, we compared 11 blood isolates of this yeast with an equal number of commensal strains isolated from the oral cavities of healthy volunteers. Blood isolates produced significantly more extracellular phospholipase activity than the commensal strains did. Second, two clinical isolates of C. albicans that differed in their levels of virulence in a newborn mouse model were compared for their ability to secrete phospholipases. The invasive strain produced significantly more extracellular phospholipase activity than the noninvasive strain did. Third, nine blood isolates were characterized for their phospholipase and proteinase production, germ tube formation, growth, and adherence to and damage of endothelial cells in vitro. These factors were analyzed subsequently to determine whether they predicted mortality in a mouse model of hematogenously disseminated candidiasis. By proportional hazard analysis, the relative risk of death was 5.6-fold higher (95% confidence interval, 1.672 to 18.84 [P < 0.005]) in the mice infected with the higher-phospholipase-secreting strains than in the low-phospholipase secretors. None of the other putative virulence factors predicted mortality. Characterization of phospholipases secreted by three of the blood isolates showed that these strains secreted both phospholipase B and lysophospholipase-transacylase activities. These results implicate extracellular phospholipase as a virulence factor in the pathogenesis of hematogenous infections caused by C. albicans.

Acyltransferases↗