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Biomedical subjects

D A Stevens

Publications and source records attributed to D A Stevens.

At least 343 records · Page 19Linked to original sources
PubMed1983

Activation of peritoneal macrophages by concanavalin A or Mycobacterium bovis BCG for fungicidal activity against Blastomyces dermatitidis and effect of specific antibody and complement.

With a new short-term assay, where the reduction of CFUs in the inoculum could be measured, we investigated the killing of the dimorphic fungal pathogen Blastomyces dermatitidis in its yeast phase by murine peritoneal macrophages. Peritoneal macrophages from concanavalin A- or Mycobacterium bovis BCG-treated mice, but not resident or thioglycolate-elicited macrophages, significantly reduced the CFUs of B. dermatitidis in the inoculum. The activation of peritoneal macrophages for fungicidal activity by concanavalin A treatment was shown to be dose dependent and transient, i.e., absent after 72 h. These results indicate that it is possible for murine peritoneal macrophages to kill B. dermatitidis in vitro. The addition of specific antibody or complement or both did not enhance the killing of B. dermatitidis by these nonspecifically activated macrophages.

Animals↗
PubMed1983

Susceptibility of Blastomyces dermatitidis strains to products of oxidative metabolism.

Three strains of Blastomyces dermatitidis which differ in their virulence for mice were exposed in their yeast form to various components of the peroxidase-hydrogen peroxide-halide system. Susceptibility to H2O2 alone correlated with virulence, with the most virulent strain (ATCC 26199) least susceptible (50% lethal dose, greater than 50 mM) and an avirulent strain (ATCC 26197) most susceptible (50% lethal dose less than 3.3 mM). A strain of intermediate virulence (ATCC 26198) was of intermediate susceptibility (50% lethal dose, 11.5 mM). The addition of a nontoxic concentration of KI (5 X 10(-4) M) did not increase H2O2 toxicity. However, the addition of either myeloperoxidase or horseradish peroxidase and KI markedly decreased the amount of H2O2 required to kill the organisms, with 100 +/- 0% of all strains killed at 5 X 10(-5) M H2O2 and 97 +/- 4, 100 +/- 0, and 94 +/- 8% of ATCC 26199, ATCC 26198, and ATCC 26197 killed, respectively, at 5 X 10(-6) M H2O2. Kinetic studies with H2O2 alone revealed a delayed onset of killing, but virtually 100% of organisms were killed by 120 min of exposure in all strains. By comparison, the peroxidase-hydrogen peroxide-halide system was 100% lethal for all strains at 1 min. The relatively high concentrations of H2O2 required to kill the yeast phase of B. dermatitidis suggest that H2O2 alone does not account for host resistance to the organism. However, the rapidly lethal effect of the peroxidase-hydrogen peroxide-halide system at physiologically relevant concentrations suggests that this may be one mechanism of host defense to B. dermatitidis.

Animals↗
PubMed1983

Analysis of Candida albicans phenotypes from different geographical and anatomical sources.

Strain phenotypes of 330 Candida albicans isolates from five areas in the United States were determined on the basis of nine biochemical tests. Statistical analysis of the distribution of phenotypes revealed no significant differences among types from different anatomical sources. However, there were some differences among the phenotypes of strains from the different geographical areas, and there were substantial differences in biochemical phenotypes associated with strains susceptible and resistant to 5-fluorocytosine and between strains of serotypes A and B. Geographical differences in phenotypes of C. albicans were also noted between the 330 U.S. isolates and 247 isolates from Britain. Cluster analysis of the U.S. strains alone and of all of the U.S. and U.K. strains showed that C. albicans phenotypes can be grouped into fewer than 20 clusters with common biochemical properties.

Candida albicans↗
PubMed1983

Murine pulmonary macrophages: evaluation of lung lavage fluids, miniaturized monolayers, and candidacidal activity.

Optimal yields of pulmonary macrophages (PuM) from lavage of normal murine lungs have been obtained by the study of several different lung lavage fluids. Approximately 1 X 10(6) PuM can be consistently recovered from mice weighing 20 to 30 g, using 15 ml of phosphate buffered saline with 0.1% EDTA, with or without 10% fetal calf serum at 37 degrees C. Use of Terasaki tray wells for monolayer formation has allowed a relatively small number of cells (75,000) to be used to prepare multiple replicate wells from each mouse. Simultaneous functional comparisons with other cell types, e.g., peritoneal macrophages (PeM) were performed using this practical and economical system. Data on the phagocytosis and killing of Candida albicans by PuM and PeM are presented as evidence of the utility of this miniaturized system.

Animals↗
PubMed1983

Miconazole in the treatment of coccidioidomycosis.

Intravenous miconazole can produce responses in patients with various manifestations of coccidioidal disease, even if they have failed to respond to amphotericin B. In 4 large series of 33, 33, 46 and 31 courses of miconazole for skin and soft tissue, chronic pulmonary, meningeal and skeletal coccidioidomycosis, response rates of 40, 72, 31 and 32%, respectively, were achieved; 60, 75, 78 and 56%, respectively, of those responding subsequently relapsed at the site(s) of earlier involvement. This suggests that the therapeutic effect of the relatively brief courses used (mean, 1 to 3 months) is fungistatic in vivo. Common side effects of intravenous miconazole include phlebitis, pruritus, anaemia, thrombocytosis, hyponatraemia, nausea, hyperlipidaemia, vomiting, central nervous system effects, and rashes. The place of miconazole relative to amphotericin B and ketoconazole has not been determined, and requires further comparative studies. Information on the results of different regimens, particularly longer courses, would also be of interest.

Adolescent↗
PubMed1983

Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients. National Institute of Allergy and Infectious Diseases collaborative antifungal study.

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.

Adolescent↗
PubMed1983

Enhancing effect of murine polymorphonuclear neutrophils (PMN) on the multiplication of Blastomyces dermatitidis in vitro and in vivo.

The purpose of this study was to determine the effect of murine polymorphonuclear neutrophils (PMN) on the multiplication of the fungal pathogen Blastomyces dermatitidis in vitro and in vivo. With a newly devised method, PMN were obtained in adequate numbers (7 X 10(6) per mouse) and purity (92%) for these studies. In 24 h co-cultures PMN, but not lymph node cells (LNC), enhanced the replication of virulent (V) and avirulent (AV) strains of B. dermatitidis 61% and 34%, respectively. In 72 h co-cultures, multiplication was enhanced even more (V, 180%; AV, 140%), when compared to cultures of B. dermatitidis in medium alone. Viability of PMN was not required, because PMN lysates, but not LNC lysates, were effective in enhancing multiplication. Subcutaneous injection of B. dermatitidis mixed with PMN enhanced multiplication by 90% compared to V alone in a subcutaneous abscess model, whereas mixing with LNC did not enhance multiplication. When AV, a strain which does not by itself replicate in vivo, was injected in vivo with PMN it increased 2.75-fold over 4 days. These findings document the in vivo significance of in vitro enhancement of B. dermatitidis replication by PMN, and support the contention that accumulation and death of PMN in B. dermatitidis lesions may exacerbate this infection in its early stages.

Animals↗
PubMed1982

Academy rash. A probable epidemic of erythema infectiosum ('fifth disease').

Over a few weeks, 69 children (13%) enrolled in a private school manifested an erythematous and migratory rash, most commonly on the extremities, along with fever or other systemic or respiratory symptoms. Fever lasted for a mean of four days, and rash, 11 days. Cases appeared in every grade from kindergarten through ninth, and the incidence peaked in the fifth through seventh grades. More boarding students were affected than day students. Secondary cases in households of affected children and among adults from the school were noted. Eighty-eight attempts at virus isolation were unsuccessful. The illnesses were consistent with erythema infectiosum, a disease of unknown etiology, which has occurred in epidemic form in schools and also in sporadic cases.

Adolescent↗
PubMed1982

Pathogen factors and host factors in murine pulmonary blastomycosis.

Factors related to pathogenesis were studied in a murine model of pulmonary fungal infection with strains of Blastomyces dermatitidis. Strain 26199V was greater than or equal to 10(5)-fold more lethal in pulmonary challenge than strain GA-1. This relationship between the two strains also occurred after intraperitoneal challenge. Serial studies with lung cultures and histology of sacrificed animals after pulmonary challenge with similar doses, and challenge studies in mice of differing maturity, indicated GA-1 is impaired in initial replication in situ, although the two strains grow equally well in the presence of murine substrates in vitro. In vitro studies indicated the two strains were indistinguishable in most studies of biochemical and metabolic markers, and in studies with chemical and physical inhibitors. The exceptions were their morphologic appearance in the yeast phase, ability to hydrolyze esculin, and susceptibility to crystal violet dye and bile. The last finding and previous work suggested possible differences in lipid content; these were confirmed in studies which also included two other strains. Greater phospholipid and palmitic acid content were associated with greater virulence.

Age Factors↗
PubMed1982

Oral ketoconazole for dermatophyte infections.

Nineteen patients with chronic dermatophyte infections were treated with 200 to 400 mg per day of ketoconazole orally. Sixteen had had their disease for 2 years or more. Sixty-three per cent achieved cure, and an additional 26% showed clinical improvement. Clearing of lesions occurred in 10 weeks (mean). The dose was increased to 600 mg per day in four patients. Of these, two achieved cure, for an overall cure rate of 74%. Seventy-five percent of patients who previously failed to respond to griseofulvin were cured or improved by ketoconazole. Four of eight patients with onychomycosis were cured, and the rest improved on therapy. One patient developed a generalized drug eruption after the first dose of ketoconazole, and possible minor side effects were noted in five. Three of eight patients followed off therapy after apparent cure subsequently showed relapse. The drug appears to have great potential value for the therapy of dermatomycoses.

Administration, Oral↗
PubMed1982

Disposition of ketoconazole, an oral antifungal, in humans.

The pharmacology of ketoconazole was studied in patients with fungal infections. After administration of 50-, 100-, and 200-mg doses of ketoconazole, there was a linear increase in the area under the curve of serum concentrations; this was not apparent when higher doses of ketoconazole were given. An increase in the area under the curve occurred in patients receiving 200 mg daily who were restudied after 1 to 12 months of therapy. However, normalized area under the curve appeared to decrease after higher doses were administered chronically. The half life ranged from 2.0 to 3.3 h. Peak serum concentrations up to 50 micrograms/ml were detected in this study, and potentially therapeutic concentrations were detectable up to 26 h after high doses. Ketoconazole penetrated the saliva and inflamed joint fluid and meninges, although variably, and could be demonstrated in some other tissue compartments. In the presence of renal failure, ketoconazole disposition was not altered, whereas in the presence of hepatic insufficiency, an alteration in disposition was suggested. The interactions of ketoconazole and other drugs were studied. Of note, antacids did not significantly affect ketoconazole pharmacokinetics (nor did meals), and ketoconazole and warfarin did not appear to affect the pharmacokinetics of the other.

Administration, Oral↗
PubMed1982

Synergistic interaction of trimethoprim and sulfamethoxazole on Paracoccidioides brasiliensis.

The in vitro interaction of trimethoprim and sulfamethoxazole on clinical isolates of Paracoccidioides brasiliensis was studied. With complete inhibition and a visual endpoint used as the criteria, three of four strains had minimal inhibitory concentrations that indicated resistance to sulfamethoxazole, and all four strains were resistant to trimethoprim. A marked synergism in inhibition was noted with the combination of these drugs against sulfa-resistant strains. A sulfamethoxazole/trimethoprim ratio of 5:1 was the most synergistic. Fifty percent inhibition, determined spectrophotometrically, of the strains could be achieved with sulfamethoxazole alone. In summary, the striking synergy observed suggests that combination chemotherapy with these drugs deserves further study.

Drug Combinations↗
PubMed1982

Susceptibility to 5-fluorocytosine and prevalence of serotype in 402 Candida albicans isolates from the United States.

Candida albicans isolates from 402 patients with no prior history of treatment with 5-fluorocytosine were collected at five medical centers from different areas of the United States. Isolates could be separated into four groups based on their minimum inhibitory concentrations (MICs) to 5-fluorocytosine. Group I isolates (60%) had MICs less than or equal to 12.5 micrograms/ml after 7 days, whereas groups II (22%), III (14%), and IV (4%) demonstrated MICs greater than 12.5 micrograms/ml on days 7, 2, and 1, respectively. Serotypes A and B accounted for 50.7 and 49.3%, respectively, of the 398 isolates typed. Serotype B was less prevalent in group I (26%), but predominated in the more resistant groups, groups II (85%), III (86%), and IV (53%). The common practice of identifying as "resistant" those isolates with MICs greater than 12.5 micrograms/ml after 48 h of incubation would yield a resistance rate in the United States of 11.5 to 15.5% in four centers and 35% in the fifth. Although serotype B and small agar disk diffusion zone sizes correlated with poor 5-fluorocytosine susceptibility, their ability to predict tube dilution MICs was limited. The true predictive value of such tests awaits correlation with in vivo studies.

Candida albicans↗
PubMed1982

Stimulation and suppression of cell-mediated immunity by endosporulation antigens of Coccidioides immitis.

The culture filtrate of Coccidioides immitis induced to replicate in its parasitic phase in vitro, termed endosporulation antigens (EA), was assayed for ability to stimulate human lymphocyte blastogenesis in vitro. Stimulation of lymphocytes from skin test-positive healthy subjects by EA was comparable to stimulation by spherulin at optimal dilutions, but EA are 500 times more potent when compared on the basis of weight. Both preparations slightly stimulated lymphocytes from skin test-negative subjects. Heating or dialysis of EA enhanced the effect on skin test-positive subjects, but concentration depressed it. Concentrated EA also depressed nonspecific stimulation caused by phytohemagglutinin. Dialysis of concentrated EA reduced the ability to depress responses. EA from an avirulent strain of C. immitis were as stimulatory as EA from a virulent strain, but concentrating the former did not produce as much depression as concentrating the latter did. A survey of subjects with an optimal dose of EA in lymphocyte transformation showed that EA could separate skin test-positive from -negative subjects as well as spherulin could. The survey also showed that a delta cpm (the difference of incorporated counts of tritiated thymidine per minute in the presence or absence of the reagent) of 10,000 is useful for this separation. These results also indicate the presence of suppressive substances in EA which are only partially dialyzable and which were significantly more prominent in a preparation from the virulent strain.

Animals↗
PubMed1982

Opposite effects of human monocytes, macrophages, and polymorphonuclear neutrophils on replication of Blastomyces dermatitidis in vitro.

The purpose of this study was to determine the effects of human monocytes, macrophages, and polymorphonuclear neutrophils (PMN) on the fungal pathogen Blastomyces dermatitidis in vitro. Peripheral blood monocyte monolayers significantly inhibited the replication of a virulent strain (V) and an avirulent strain (AV) of B. dermatitidis by 35 and 28%, respectively. Macrophage monolayers, derived from monocytes by in vitro culturing for 9 days, also inhibited the replication of V and AV in 24-h cocultures; in 72-h cocultures, the inhibition was increased (85 and 88%, respectively). By contrast, PMN stimulated the replication of V and AV in 24-h cocultures (i.e., 45%; AV, 18%) and in 72-h cocultures (V, 68%; AV, 65%). No effect was observed in 2-h cocultures of PMN and B. dermatitidis, even though Candida albicans was killed by PMN in concurrent experiments. PMN stimulated replication of V in a dose-dependent manner, and viability of PMN was not a requirement for the achievement of this effect. These results indicate that monocytes and macrophages significantly inhibited the replication of B. dermatitidis, whereas PMN had an opposite effect. Our findings raise the possibility that these phagocytic cells may have similar opposing effects on the replication of B. dermatitidis in vivo.

Blastomyces↗