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Biomedical subjects

D A Stevens

Publications and source records attributed to D A Stevens.

At least 361 records · Page 20Linked to original sources
PubMed1982

Maturity as a critical determinant of resistance to fungal infections: studies in murine blastomycosis.

Marked resistance of 9-week-old mice as compared to that of 5-week-old mice was demonstrated after pulmonary challenge with three strains of Blastomyces dermatitidis of various virulences. Quantitative studies with graded doses of the strain that was intermediate in virulence indicated that the difference in resistance between the two age groups was 1,000-fold. Acquisition of resistance appeared to be gradual between the ages of 5 and 9 weeks. Maturational differences among individual mice appeared to be most crucial at 5 weeks of age. With two fungal strains, susceptibility of the younger mice was also demonstrated after intraperitoneal challenge; with one of these strains, the differences between the two groups of mice were much smaller, suggesting that maturation of defenses in the peritoneal cavity may develop faster. Studies with serial sacrifice of different groups of mice given pulmonary challenges (of comparable amounts) indicated that the differences are not due to the amount of challenge reaching the lungs or its clearance. The infection-limiting effect in the lungs of older mice occurred within 4 days after challenge. These differences in resistance over this narrow age interval appear to be unique; resistance appears to occur later than resistance to other infectious agents and at a time when most murine immune functions have matured. This model and these observations provide an opportunity for further studies of the mechanism of resistance and are relevant to clinical observations of susceptibility of infants and children to deep mycoses.

Aging↗
PubMed1982

Specificity of immunoglobulin E in coccidioidomycosis and correlation with disease involvement.

Serum immunoglobulin E (IgE) antibodies were quantitated in 26 patients with active pulmonary coccidioidomycosis, 59 patients with active disseminated disease, 12 patients in clinical remission, and 91 healthy subjects. Significant differences were obtained in IgE serum levels of patients with active disease versus healthy subjects (P less than 0.0001). Patients with pulmonary coccidioidomycosis did not differ in their IgE levels when compared with patients with disseminated disease. However, serum IgE levels were significantly increased in patients with disease involving two or more organ systems when compared with patients with pulmonary disease or extrapulmonary disease involving a single organ system (P less than 0.02). Total serum IgE correlated with anti-Coccidioides IgE (P less than 0.001), but with only six exceptions, patients with anti-Coccidioides IgE also exhibited IgE antibodies to 1 or more of 12 common allergens. The correlation between hyperproduction of IgE and disease severity coupled with the depressed cell-mediated immune status of patients with this disease suggests a defect(s) in the T-lymphocyte population which functions to regulate IgE synthesis.

Allergens↗
PubMed1982

Protection against pulmonary blastomycosis: correlation with cellular and humoral immunity in mice after subcutaneous nonlethal infection.

A model of pulmonary blastomycosis in the mouse, in which the portal of entry is the same as natural human infection, was used to study resistance to challenge after subcutaneous infection. One week after subcutaneous infection, mice were partially resistant to pulmonary challenge, and mice challenged two weeks after infection were resistant. Measurement of cellular and humoral immune responses to Blastomyces dermatitidis antigens after subcutaneous infection showed the following. (i) Delayed-type hypersensitivity appeared 1 week after infection, and responses increased for 3 weeks thereafter. (ii) Proliferative responses in vitro appeared in spleen cells at 1 week and in contralateral lymph node cells at 3 weeks, (iii) Serum antibody, detected by an enzyme-linked immunosorbent assay, appeared 1 week after infection and then increased in titer. (iv) Peritoneal macrophages were activated to inhibit replication of B. dermatitidis in vitro by the first week after infection. Prior subcutaneous infection also resulted in rapid clearing of a second subcutaneous challenge, as well as resistance to a lethal intraperitoneal challenge. This resistance was associated with the development of cell-mediated and humoral immune responses. These data provide a chronological framework for selective transfer experiments.

Animals↗
PubMed1982

Immune complexes in coccidioidomycosis. Correlation with disease involvement.

Circulating immune complexes were quantitated by Clq-binding assays of serum from 73 patients with active coccidioidomycosis, 5 patients with inactive disease, and 34 healthy subjects. Immune complexes were detected in serums of 8 (44%) of 18 patients with active pulmonary disease only and 22 (40%) of 55 patients with active disseminated disease. Results in none of 5 patients with inactive disease and in only 2 (9%) of 34 healthy subjects were positive by the Clq-binding assay. Immune complex levels did not differ in patients with pulmonary disease versus those with disseminated disease. However, immune complexes did correlate with disease involvement. Of 57 patients with coccidioidomycosis involving a single organ system (pulmonary or extrapulmonary), 19 (33%) had immune complexes compared with 6 (67%) of 9 patients with disease involving 2 organ systems, and 5 (71%) of 7 patients with disease of 3 or more organ systems. Immune complex levels correlated with serum IgG, but did not correlate with serum complement-fixing antibody titers to coccidioidin. Rather, the correlation curve between immune complexes and complement-fixing antibody titers yielded a bell-shaped distribution. This distribution pattern suggests that changes in antibody concentration may have effected the size and lattice of immune complexes, resulting in altered detection and/or clearance from the bloodstream.

Antibodies, Fungal↗
PubMed1982

Ketoconazole blocks adrenal steroid synthesis.

Ketoconazole, a broad-spectrum, antifungal drug that is administered orally, has been shown to inhibit sterol synthesis in fungi. When gynecomastia developed in some patients taking this drug, we investigated the effects of ketoconazole on steroid synthesis in humans and in isolated adrenal cells from rats. In healthy humans, the cortisol response to adrenocorticotropic hormone was significantly blunted 4 hours after a 400-mg or 600-mg dose. The inhibition persisted for up to 8 hours and was absent by 16 hours. This finding indicated that adrenal androgen response was reduced. Easily achieved therapeutic concentrations of ketoconazole virtually eliminated corticosterone production by isolated adrenal cells from rats. Although ketoconazole at currently used doses has never been documented to cause clinical hypoadrenalism, caution is urged in high- or multiple-dose trials. The drug may prove useful as an agent to block steroid synthesis.

Adrenal Cortex↗
PubMed1982

Ketoconazole blocks testosterone synthesis.

Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo.

Adult↗
PubMed1982

Spontaneous mutant of Blastomyces dermatitidis attenuated in virulence for mice.

A spontaneous mutation occurred in cultures of a virulent strain of Blastomyces dermatitidis during serial passage at 35-37 degrees C. The mutant strain was shown to be 10,000-fold less virulent for mice than the parent strain, and this was independent of the challenge dose, the age of the challenged host, and the route of challenge (although attenuation was greater for pulmonary than for peritoneal challenge). The mutant grows as well as the parent in fungal media or in the presence of murine substrates. Studies of the chronology of pulmonary infection indicate the mutation affects an early event (first week after challenge) in establishment of infection and interaction with host defenses. Scanning electron microscopy showed that the mutant lacks deep irregular surface ridges and grooves present in the parent. It had increased resistance to crystal violet in vitro, increased susceptibility to bile, and could hydrolyze esculin. The latter findings are of interest because they place the mutant in an intermediate position with respect to these properties between the virulent parent and a previously studied avirulent strain. Lipid analyses indicated a marked increase in fatty acids in the mutant. Studies of four B. dermatitidis strains have also associated increasing palmitic acid and phospholipid content with increasing virulence.

Aging↗
PubMed1981

Laboratory evaluation of an outbreak of nocardiosis in immunocompromised hosts.

Seven patients in a renal unit were proved to have nocardiosis in an interval of nine months. Six of these patients had received renal transplants. Serologic investigation suggested that two additional cases of undiagnosed pulmonary disease were also nocardial, and that there were no subclinical cases in patients or staff. Clinical-serologic correlations indicate that serologic evaluation may be a useful adjunct in diagnosis of nocardiosis, if used early and repeatedly, and to follow response to therapy. Epidemiologic investigations yielded cultures of Nocardia asteroides from air and dust inside the unit and elsewhere in the hospital. Biochemical, metabolic, physical and immunologic characterization of the isolates indicated that those from patients and those from the unit environment were identical, whereas some from outside the unit could be differentiated from these. The "epidemic strain" had type III antigen, which surveys indicated is not the most common type in human nocardiosis (it occurs in association with a minority of human cases). The isolates were of subgroup B, which has been associated with virulence. The characterization methods employed could be useful in studies of nocardial epidemiology. The laboratory studies indicate epidemic spread within the unit of a single organism, and current epidemiologic guidelines, which do not recommend respiratory isolation of cases of pulmonary nocardiosis, may need reconsideration particularly when there are immunocompromised hosts in the environment.

Antigens, Bacterial↗
PubMed1981

Susceptibility differences of inbred strains of mice to blastomycosis.

The susceptibility of inbred strains of mice to pulmonary blastomycosis was studied to derive information relevant to host resistance and genetic background. Initial studies with eight strains with various H-2 backgrounds revealed the C3H/HeJ strain to be highly susceptible and DBA/1J mice to be resistant. These observations were confirmed with various challenge inocula. These differences were not dependent on the size of the challenge, the strain of Blastomyces dermatitidis, host age, or ability of the challenge to penetrate to the lower airways. Differences between the susceptible and resistant strains in lymphocyte proliferation in vitro and delayed-type hypersensitivity in vivo after nonlethal subcutaneous infection were not demonstrated; the susceptible strain made a significantly greater antibody response to blastomyces antigens as determined by an enzyme-linked immunosorbent assay. The resistance of the C3H/HeN strain of mice, which differs from the C3H/HeJ in sensitivity to lipopolysaccharide and lacks the macrophage cytotoxicity defect of the latter, suggests that the susceptibility of C3H/HeJ mice is not related to their C3H background or the H-2 locus. As the A/HeJ strain, which also has a macrophage cytotoxicity defect, was found in this study to be the second most susceptible strain, this also suggests macrophages as the subject for further study with respect to the mechanism of genetic resistance to this infection.

Aging↗
PubMed1981

Virulence of fungi: correlation of virulence of Blastomyces dermatitidis in vivo with escape from macrophage inhibition of replication in vitro.

Strains of Blastomyces dermatitidis which are virulent (V), attenuated (A), or avirulent (AV) in mice have been identified. Virulence of V has been reported to be associated with its ability to replicate in vivo, causing lethal infections in the lungs or in the peritoneal cavity. We report here that V, but not A or AV, has the ability to replicate in vivo in nonlethal subcutaneous lesions. The possibility that V was able to replicate in vivo by evading primary host defenses was investigated. We studied the interaction of macrophages and strains of B. dermatitidis in vitro. In 24-h cocultures, the replication of all three strains of B. dermatitidis was inhibited by macrophages from: (i) untreated mice (20 to 40%), (ii) mice that had recovered from nonlethal blastomycosis (40 to 60%), (iii) concanavalin A-treated mice (50 to 70%), or (iv) peritoneal exudates elicited by thioglycolate (65 to 80%). However, at 72 h in the first three types of cocultures A and AV remained inhibited, whereas V was not inhibited (0 to 4%). Only the most inhibitory macrophages, those induced by thioglycollate, inhibited V at 72 h, though V was again less inhibited than A or AV at that time. Thus, we show a correlation between virulence of V in vivo and its ability to escape from macrophage inhibition of replication in vitro.

Animals↗