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Biomedical subjects

D A Stevens

Publications and source records attributed to D A Stevens.

At least 289 records · Page 16Linked to original sources
PubMed1987

Enhancement of responses to sequential presentation of oral chemical irritants.

The irritative flavor compounds, capsaicin and piperine, were presented in sequence to the oral cavity of human subjects and rated for perceived intensity of irritation. Marked increases in perceived irritation were reported when the second-presented irritant differed from the first, as compared with control conditions in which the same irritant was repeated. This cross-enhancement is explained most simply by recruitment of additional receptors or fiber types, and implies a greater degree of specificity (narrowness of tuning) of trigeminal receptors than previously suggested by desensitization studies.

Alkaloids↗
PubMed1987

Chronic pulmonary and disseminated paracoccidioidomycosis in mice: quantitation of progression and chronicity.

An animal model of chronic paracoccidioidomycosis was established in male adult BALB/cByJIMR mice by intranasal instillation of different doses of yeast form Paracoccidioides brasiliensis. The inoculum was standardized in terms of virulence, age of the culture, percentage of multicellular fungal units containing 1-3 cells, and viability. Progression and chronicity of the infection was measured by quantitative counts of colony forming units (CFU) of P. brasiliensis from infected lungs, spleens, and livers in a newly developed culture medium. The body weight of the mice and the organ weights were also used to monitor the disease process. Infection with several challenge sizes progressed in the lungs until a maximum of 10(7)-10(8) CFU per lung was reached; in general, the higher the inoculum, the sooner this maximum was reached. In mice infected with 2.5 X 10(6) CFU the maximum was reached at 8 weeks, whereas in mice infected with 3 X 10(4) CFU the maximum was reached 14 weeks after infection. Dissemination of the disease progressed until there were 10(6)-10(7) CFU per spleen or liver. The higher the infective dose, the shorter the time required to reach a maximum stable population of yeasts in spleen and liver (12 weeks with inoculum of 2.5 X 10(6) CFU, 18-26 weeks with inoculum of 7.0 X 10(3) CFU). The body weight of mice tended to diminish with time after infection compared to uninfected controls. In contrast, the weight of lung and spleen increased with time after infection. This model of chronic paracoccidioidomycosis permits evaluation of progression of the disease process and of the multiplication of the yeast in organs.

Animals↗
PubMed1987

Pharmacology and toxicity of high-dose ketoconazole.

One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.

Clinical Trials as Topic↗
PubMed1987

Fungicidal mechanisms of activated macrophages: evidence for nonoxidative mechanisms for killing of Blastomyces dermatitidis.

The mechanism(s) by which lymphokine-activated peritoneal macrophages kill Blastomyces dermatitidis was studied. Resident peritoneal macrophages from BALB/cByJ mice, when treated overnight with lymph node cells plus concanavalin A, supernatants from concanavalin A-stimulated spleen cells, or recombinant gamma interferon, were then able to kill a virulent B. dermatitidis isolate (ATCC 26199) (at levels of 25% +/- 4%, 28% +/- 8%, and 21% +/- 5%, respectively). Killing was not significantly decreased or enhanced in the presence of superoxide dismutase (450 U/ml), catalase (20,000 U/ml), dimethyl sulfoxide (300 mM), or azide (1 mM). Viable B. dermatitidis elicited a brisk oxidative burst and superoxide anion production in activated macrophages as measured by lucigenin-enhanced chemiluminescence, e.g., 10(4) cpm. However, these responses were not significantly different from those of control macrophages. Luminol-enhanced chemiluminescence responses by activated or control macrophages were meager (less than or equal to 10(2) cpm). These results indicate that activated macrophages kill B. dermatitidis by a mechanism(s) independent of products of the oxidative burst.

Animals↗
PubMed1987

Application of DNA typing methods to epidemiology and taxonomy of Candida species.

Methods are described for extraction of DNA from the yeast form of Candida spp., followed by digestion and electrophoresis of DNA fragments. The resulting gel patterns (greater than 100 bands) were used to type Candida isolates. Four intense bands identified, three of which are present in each isolate (6 to 7, 3.7 or 4.2, and 2.5 to 3 kilobases), appear to be DNA encoding the rRNA. The methods proved to be both simple and reproducible. The patterns were shown to be stable through several hundred doublings from multiple single colonies. A survey of isolates showed that, on the basis of similarity of gel patterns, several Candida species could be sorted into mutually exclusive groups, and subgroups could be created. Analyses of this survey suggested the possible epidemiologic and taxonomic applications of these methods. DNA typing methods appear to offer important potential advantages over phenotyping methods. The methods provide a base for further epidemiologic studies and for further development of techniques, such as the use of cloned probes for studies of DNA homology.

Candida↗
PubMed1987

Effect of murine polymorphonuclear leukocytes on the yeast form of Paracoccidioides brasiliensis [corrected].

The fungicidal activity of murine polymorphonuclear neutrophils from the peripheral blood or elicited intraperitoneally with thioglycollate or with antigen in Paracoccidioides brasiliensis-sensitized [corrected] or nonsensitized mice was studied. Although peripheral blood, thioglycollate-elicited, and antigen-elicited neutrophils from normal mice or thioglycollate-elicited neutrophils from P. brasiliensis-sensitized [corrected] mice killed Candida albicans (57% to 84%), they failed to significantly reduce inoculum colony forming units of P. brasiliensis [corrected] (0% to 13%). In contrast, antigen-elicited neutrophils from sensitized mice reduced colony forming units of P. brasiliensis [corrected] by 40%, and exhibited significantly enhanced candidacidal activity compared to thioglycollate-elicited neutrophils from normal or sensitized mice but not peripheral blood neutrophils from normal mice. Fresh serum, but not specific antibody, was required for optimal killing of P. brasiliensis [corrected], presumably representing an essential role for complement. Killing of P. brasiliensis [corrected] by antigen-elicited neutrophils from sensitized mice correlated with their ability to produce an enhanced oxidative burst, as measured by luminol-assisted chemiluminescence, when interacting with killed P. brasiliensis [corrected] cells. These results indicate that in P. brasiliensis-sensitized [corrected] hosts an inflammatory reaction to P. brasiliensis [corrected] results in activation of neutrophils for significant killing of the pathogen.

Animals↗
PubMed1987

Activation of pulmonary macrophages for fungicidal activity by gamma-interferon or lymphokines.

The ability of murine recombinant gamma interferon (IFN) or lymphokines to enhance the fungicidal activity of murine pulmonary macrophages (PuM) was studied in in vitro. PuM monolayers were incubated overnight with IFN, lymph node cells (LNC) plus concanavalin A, supernatants from Con A stimulated LNC or spleen cell cultures (Con A Sup), or tissue culture medium (TCM) +/- Con A (5 micrograms/ml) or +/- lipopolysaccharide (LPS, 10 ng to 10 micrograms/ml). After treatment, culture fluids were removed and PuM were challenged for 4 h with the yeast-form Blastomyces dermatitidis or 2 h with Candida albicans. Inoculum colony forming units (CFU) of B. dermatitidis were significantly reduced by PuM treated with 1000 U/ml of IFN (25 +/- 3%), Con A Sup (25 +/- 3%) or LNC plus Con A (37-44%), but not by TCM, ConA or LPS. Candida albicans was killed by PuM treated with Con A Sup (33 +/- 8%) or LNC plus Con A (30-43%), but not by TCM, Con A, or LPS, and the activity of Con A Sup was neutralized by anti-IFN antibody. Candida albicans was not significantly killed by PuM treated with IFN doses ranging from 1 to 10(5) U/ml; nor did addition of LPS to IFN, or prolonged (3 day) treatment with IFN, result in significant killing of C. albicans by PuM. However, IFN (100 U/ml) could activate resident peritoneal macrophages for significant candidacidal activity (63%). These data indicate that PuM can be activated for fungicidal activity, and that PuM differ from resident peritoneal macrophages with regard to induction of candidacidal activity by recombinant gamma-IFN.

Animals↗
PubMed1986

Studies with a plant fungicide, imazalil, with vapor-phase activity, in the therapy of human alternariosis.

The use of a plant fungicide, the imidazole imazalil, in the therapy of human alternariosis is described. The patient's disease involved the palate, nose and sinuses, and had been unresponsive to conventional therapy. Imazalil has been used to treat Alternaria infections of plant materials. The patient's isolate was susceptible in vitro. We also showed that the drug was inhibitory to fungi in vitro as a vapor, not requiring contact by diffusion through agar or broth. The drug was used topically, by installation and irrigation, in this case and administered orally in doses of up to 1 200 mg daily, for 6 months. Peak serum concentrations exceeded 4 mcg/ml. The infection was arrested but not cured. The drug was tolerated without evident toxicity, though an unpleasant taste and nausea at high doses were limiting.

Administration, Oral↗
PubMed1986

An evaluation of the enzyme-linked immunoabsorbent assay (ELISA) for quantitation of antibodies to Paracoccidioides brasiliensis.

The ELISA procedure was adapted for quantitation of antibodies against Paracoccidioides brasiliensis. Using a yeast cytoplasmic antigen and sera from patients with proven paracoccidioidomycosis, we found that 66% of sera reacted at titers greater than or equal to 1:128. Titers of this magnitude were obtained only for 4-5% of sera from healthy blood donors, tuberculosis patients and patients with other systemic mycoses. The exception was sera from patients with histoplasmosis (36% had titers greater than or equal to 1:128). Follow-up of 10 paracoccidioidomycosis patients during the course of therapy indicated a gradual decrease in antibody titers. Because of the technical advantages of the ELISA procedure in comparison with the standard complement fixation test, the ELISA test has potential utility for the quantitative determination of antibodies in patients with paracoccidioidomycosis.

Antibodies, Fungal↗
PubMed1986

Survival in cerebro-rhino-orbital zygomycosis and cavernous sinus thrombosis with combined therapy.

An alcoholic man with uncontrolled diabetes mellitus had right conjunctivitis, facial numbness, and periorbital edema progressing to bilateral visual loss, and left ptosis in association with a large necrotic palatal ulcer due to zygomycosis. The infection progressed to bilateral retinal vein engorgement; left-sided ophthalmoplegia, fixed dilated pupil, and absent corneal reflex; and right-sided ophthalmoplegia, ptosis, and facial nerve paralysis. Work-up revealed disease of both ethmoid sinuses and the right maxillary sinus, with bilateral thromboses of the cavernous sinuses. An aggressive combined therapeutic attack (three Caldwell-Luc procedures, exploration of orbit walls, control of diabetes, systemic and local amphotericin therapy) led to survival with a three-year follow-up thus far.

Amphotericin B↗
PubMed1986

Gallium accumulation in early pulmonary Pneumocystis carinii infection.

The accumulation of gallium 67 citrate in pulmonary Pneumocystis carinii is well known. The sensitivity of gallium uptake in detecting early inflammatory processes, even when conventional roentgenograms are normal, would seem to make it possible in immunocompromised patients to make a presumptive diagnosis of this serious infection early in its course without using invasive techniques to demonstrate the organism. However, the presence of gallium uptake in radiation pneumonitis, pulmonary drug toxicity, and other processes that also occur in this group limit its usefulness. In our two patients--a young woman with Hodgkin's disease and an elderly woman with small cell lung cancer--this technique proved helpful. Although the latter patient was successfully treated empirically, such empiric treatment should be reserved for patients unable or unwilling to undergo invasive tests. Pulmonary gallium uptake in patients with respiratory symptoms, even with a normal chest film, should prompt attempts to directly demonstrate the organism.

Adult↗
PubMed1986

Fungicidal activity of murine broncho-alveolar macrophages against Blastomyces dermatitidis.

The fungicidal activity of murine broncho-alveolar macrophages (BAM) against the yeast form of a virulent strain of Blastomyces dermatitidis was studied in the small-volume wells of a Terasaki plate. In a 4-h fungicidal assay, significant killing (16-33%) of the fungus by unstimulated BAM was demonstrated with BAM from normal mice and from mice rendered immune to lethal infection with B. dermatitidis. No significant differences between the activity of BAM from these two sources could be identified. Addition of 10% autologous normal or immune serum did not augment the macrophage fungicidal activity. Simultaneous experiments with peritoneal macrophages (PM) also gave reproducible killing of the yeast form in the wells of the Terasaki plate, but in the larger wells of microtitration plates, PM showed no significant fungicidal activity. On the other hand, BAM had similar fungicidal activity against B. dermatitidis in Terasaki and microtitration-plate wells. The modest fungicidal activity of BAM from immune mice against B. dermatitidis suggests that the resistance of immune mice to respiratory challenge is likely to be based on some augmentation of this first line of defence.

Animals↗
PubMed1986

Estradiol-binding proteins from mycelial and yeast-form cultures of Paracoccidioides brasiliensis.

Paracoccidioides brasiliensis, the etiologic agent of paracoccidioidomycosis, causes disease much more frequently in men than it does in women, suggesting that the hormonal milieu of the host might influence P. brasiliensis pathogenicity. We recently demonstrated that cytosol from yeast cultures of P. brasiliensis contains a high-affinity, low-capacity, tritiated 17 beta-estradiol [( 3H]estradiol)-binding protein. Estradiol and, to a lesser degree, diethylstilbestrol (DES), inhibited the transformation of P. brasiliensis cultures from the mycelial to the yeast form, an event critical to the establishment of infection. Our current studies demonstrated a somewhat higher affinity (apparent dissociation constant [Kd], approximately equal to 6 to 12 nM) of the estrogen-binding protein for [3H]estradiol than was previously described for yeast cytosol. The presence of both high- and low-affinity estrogen-binding sites in yeast-form P. brasiliensis cytosol was detected after warming the cytosol to 37 degrees C. The high-affinity protein was labile to further heating (56 degrees C), although the low-affinity protein was stable. Additional experiments demonstrated the presence of an estrogen-binding protein in cytosol prepared from mycelial-form P. brasiliensis. This estrogen-binding protein had a slightly lower affinity for [3H]estradiol (Kd approximately equal to 13 nM), and its cytosol contained somewhat fewer binding sites (approximately equal to 78 fmol/mg of protein) than did yeast-form P. brasiliensis cytosol. Of particular interest was the finding that DES, a weak competitor for [3H]estradiol binding in yeast cytosol, displaced [3H]estradiol from the mycelial-form binding moiety. DES had a 50- to 100-fold-lower affinity for the [3H]estradiol-binding protein than did estradiol, consistent with its lower bioactivity in the mycelial-to-yeast-form transformation studies. The current results lend further support to our hypothesis that endogenous estrogens in the host, acting through the cytosol binding protein in the fungus, inhibit mycelial-to-yeast-form transformation, thus explaining the resistance of women to paracoccidioidomycosis.

Binding, Competitive↗
PubMed1986

Progesterone binding and inhibition of growth in Trichophyton mentagrophytes.

Specific binding of [3H]progesterone to cytosol of Trichophyton mentagrophytes was demonstrated. Scatchard analysis of [3H]progesterone binding showed a single class of binding sites with a dissociation constant of 9.5 X 10(-8) [corrected] +/- 2.4 X 10(-8) M (standard deviation) and a maximal binding capacity of 4,979 +/- 3,489 fmol/mg of cytosol protein. Deoxycorticosterone and dihydrotestosterone competitively inhibited binding by 50% at molar ratios of 10:1 and 20:1, respectively. Other steroid hormones that were tested had minimal activity, indicating binding specificity. Steroid hormone actions in T. mentagrophytes were examined in growth studies. Growth was assessed by determination of cellular ATP content. Progesterone inhibited growth in a dose-responsive manner, with a 50% inhibition concentration of 5.5 X 10(-6) M. Partial recovery from inhibition occurred after 24 to 48 h; inhibition could be enhanced by dividing the amount of added progesterone every 24 h. In the same rank order as was their relationship to each other and progesterone in binding studies, deoxycorticosterone and dihydrotestosterone were less effective inhibitors; other steroid hormones that were tested showed no consistent effect. We hypothesize that the binder described, acting as a hormone receptor, is the molecular site of action for the functional effect of the hormone. The functional effect may be related to the observed resistance of females to dermatophytosis.

Binding, Competitive↗
PubMed1986

In vitro antibacterial activity of enoxacin (CI-919).

Antibacterial activity of enoxacin was evaluated against more than 3,700 clinical isolates using the agar-dilution method and an inoculum of 10(4)-10(5) cells per site. For comparison other antibiotics appropriate for each species were also included. For most enterobacteria and for Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, the MIC90 of enoxacin was below 2 mg/l. Serratia marcescens was more resistant; the MIC90 being 4 mg/ml. Enoxacin also showed high activity against Campylobacter jejuni and Neisseria gonorrhoeae. Streptococci were comparatively resistant, 32 mg/l to 64 mg/l of the compound being required to inhibit 90% of strains.

Anti-Bacterial Agents↗
PubMed1986

Fungicidal activity of murine inflammatory polymorphonuclear neutrophils: comparison with murine peripheral blood PMN.

A characteristic of inflammation is the influx of polymorphonuclear neutrophils (PMN) from peripheral blood to the inflammatory reaction. We report on metabolic alterations and alterations in fungicidal activity in PMN elicited intraperitoneally with different inflammatory agents. The fungicidal activity of murine peripheral blood PMN (PB-PMN) against phagocytosable Candida albicans and nonphagocytosable Blastomyces dermatitidis was compared to that of murine inflammatory PMN. PMN elicited with sodium caseinate exhibited enhanced killing of B. dermatitidis (93 +/- 3%) compared to PB-PMN (38 +/- 11.7%). In contrast, thioglycollate medium elicited PMN had significantly less ability to kill B. dermatitidis (3 +/- 5%) than PB-PMN. Incubation of caseinate PMN with thioglycollate medium for 1 h significantly reduced their ability to kill B. dermatitidis (95% vs 25%). This effect was not due to cytotoxicity of thioglycollate medium for PMN. Candidacidal activity of inflammatory PMN (caseinate or proteose peptone-elicited) was not significantly greater than that of peripheral blood PMN. However, inflammatory PMN had significantly greater candidacidal activity than thioglycollate-elicited PMN.

Animals↗
PubMed1985

Candida rugosa in immunocompromised infection. Case reports, drug susceptibility, and review of the literature.

Candida rugosa was isolated from two patients. One patient had acute leukemia and developed invasive disease due to this yeast on two occasions while granulocytopenic. Her infection was eventually cured after treatment with amphotericin B. In another immunocompromised patient, the yeast was isolated from the sputum in the presence of a pulmonary infiltrate, but there was no other evidence for a pathogenic role. Antifungal susceptibility testing of the first patient's isolate and three environmental isolates showed all four to be susceptible to amphotericin B, miconazole, and flucytosine, and only the patient isolate was resistant to ketoconazole. These results suggest possibilities for therapy in future encounters. It appears that C. rugosa, a common pathogen in cattle, can be pathogenic in humans under the appropriate circumstances.

Aged↗