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Biomedical subjects

A Schaffner

Publications and source records attributed to A Schaffner.

108 records · Page 6Linked to original sources
PubMed1986

In vitro susceptibility of fungi to killing by neutrophil granulocytes discriminates between primary pathogenicity and opportunism.

Pathogenic fungi, according to their propensity to cause infection of apparently normal individuals, can be grouped into either primary pathogens (e.g., Coccidioides, Histoplasma, Paracoccidioides, Blastomyces, and Sporothrix) or opportunists (e.g., Candida, Mucoraceae, Aspergillus spp., Petriellidium, and Trichosporon). There is, however, no unifying concept explaining the difference between the virulence of the two fungal categories. Previously we have speculated that neutrophils are the common denominator of the high natural resistance to opportunistic fungi. Accordingly, we then compared the susceptibility to killing by neutrophil granulocytes of Histoplasma, Blastomyces, Paracoccidioides, and Sporothrix with that of 14 opportunistic fungi. We found the four virulent dimorphic yeasts, in contrast to opportunistic fungi, to be resistant to killing by neutrophils. Virulent dimorphic yeasts were ingested by neutrophils, and triggered a respiratory burst comparably to opportunists but were less susceptible to hydrogen peroxide, suggesting that differences in the susceptibility to microbicidal products of leukocytes may explain the difference in virulence.

Blastomycosis↗
PubMed1985

The hypersplenic spleen. A contractile reservoir of granulocytes and platelets.

Epinephrine-induced mobilization of noncirculating granulocytes and thrombocytes was evaluated in 13 subjects with marked variation in spleen size and correlated with the sonographically recorded contraction of the spleen. The effects of epinephrine on blood granulocyte and thrombocyte counts correlated highly with splenic contraction but not with spleen size. The findings provide further insight into mechanisms of hypersplenism, suggest that the big spleen of hypersplenism mimics the contractile reservoir function of the spleen of certain animals, and point out that the "marginal" granulocyte pool mobilized by epinephrine is not randomly distributed throughout the body.

Adult↗
PubMed1985

The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis.

The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus flavus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to greater than 2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P less than .001) or not (P less than .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinical importance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

Amphotericin B↗
PubMed1985

Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon.

By exposing human blood-derived macrophages and alveolar macrophages in vitro to dexamethasone, we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lymphokines. As little as 2.5 X 10(-8) mol/liter of dexamethasone prevented macrophages from inhibiting germination of Aspergillus spores or from eliminating ingested bacteria such as Listeria, Nocardia, or Salmonella. Damage to macrophage function was inhibited by progesterone and appeared to be receptor-mediated. In accordance with in vivo observations, dexamethasone required 24-36 h to suppress antimicrobial activity. While glucocorticoids interfered with base-line activity of macrophages, dexamethasone concentrations comparable to drug levels in patients had no effect on macrophage activation. Proliferating lymphocytes and gamma-interferon thus increased the antimicrobial activity of phagocytes exposed to glucocorticoids over that of control cells. Macrophage activation and correction of the dexamethasone effect by gamma-interferon, however, was dependent on the pathogen. The lymphokine enhanced the antimicrobial activity of dexamethasone-treated macrophages against Listeria and Salmonella but not against Aspergillus or Nocardia. Dexamethasone-induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and aspergillosis by damaging resident macrophages. Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids; its prevention by gamma-interferon might be beneficial for some but not all pathogens.

Aspergillus fumigatus↗
PubMed1983

[Acute osteomyelofibrosis. An overview and 2 personal cases].

Two cases of acute myelofibrosis are described which exemplify diagnostic and therapeutic possibilities in this clinical and morphologic entity. Delimiting criteria against other diseases with bone marrow fibrosis are also presented. This malignant myeloproliferative disorder is characterized by acute onset, minimal or absent splenomegaly, blood cytopenias with a highly variable percentage of blast cells in circulating blood, often unimpressive tear-drop poikilocytosis, intense marrow fibrosis, and a rapid clinical course. In one case, typical proliferation of all three hematopoietic cell lines was lacking and proliferating blast cells could be classified as myeloblasts/promyelocytes histochemically. In the other case, a single course of intensive combination chemotherapy resulted in marked dissolution of the marrow fibrosis and prolonged survival in partial remission.

Adult↗
PubMed1983

Trichosporon capitatum: thrush-like oral infection, local invasion, fungaemia and metastatic abscess formation in a leukaemic patient.

A thrush-like oral infection with subsequent alveolar abscess formation and a positive blood culture due to Trichosporon capitatum developed in a patient with acute myelogenous leukaemia. Later T. capitatum was identified by indirect immunofluorescence in multiple splenic abscesses. The infection was controlled by immediate aggressive treatment with amphotericin B, flucytosine and rifampicin and by splenectomy. This case of systemic T. capitatum infection resembles somewhat the invasive mycosis due to candida.

Abscess↗
PubMed1983

Killing of Aspergillus spores depends on the anatomical source of the macrophage.

To resolve the controversy over the capacity of macrophages to kill or inhibit germination of Aspergillus spores, we compared this function in peritoneal and alveolar macrophages. Alveolar macrophages from rabbits killed 82 to 90% and completely digested 72 to 82% of spores of Aspergillus fumigatus in 30 h. In contrast, peritoneal macrophages could not even inhibit the germination of ingested spores; more than 85% transformed into mycelia within 24 h. Killing by alveolar macrophages was delayed for 3 to 6 h after phagocytosis and was independent of oxidative killing mechanisms and immune activation. The ability of alveolar macrophages to kill Aspergillus spores without modulation by T lymphocytes or the generation of oxygen intermediates points out that concepts built on studies of peritoneal macrophages may be misleading and underscores the importance of studying the role of macrophages in immunity with cells from the appropriate anatomical site.

Animals↗
PubMed1983

Models of T cell deficiency in listeriosis: the effects of cortisone and cyclosporin A on normal and nude BALB/c mice.

It is often difficult to test the role of T lymphocytes in resistance to infection because most models of T cell deficiency are associated with altered nonspecific resistance. In an attempt to address this problem, we compared the effects of cyclosporin A (CyA), cortisone (CA), and the athymic state on the course of murine listeriosis. We chose listeriosis because resistance to Listeria monocytogenes occurs in two phases. Bacterial multiplication is controlled by nonspecific defense mechanisms in the early phase and by acquired T cell-dependent immunity in the second phase. Mice treated with CA died during the early phase, probably because of inhibition of the antimicrobial activity of nonimmune macrophages. Accordingly, the immunosuppressive effect of CA was similar in athymic and normal mice. Untreated nude mice developed chronic low grade infection, probably because of heightened activity of nonimmune macrophages. In contrast, immunosuppression with CyA did not affect early resistance but induced overwhelming, fatal disease in the later phase when control mice began to acquire resistance. CyA did not change the course of listeriosis in nude mice, confirming its specificity for T cell-dependent immunity. Thus, this study shows that CyA is a potent and specific inhibitor of T cell-mediated immunity and that T cell-dependent resistance is essential for survival from listeriosis, a conclusion that could not have been established by studies of the nude mouse or immunosuppression by CA.

Animals↗
PubMed1982

Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes.

By comparing natural immunity to Aspergillus fumigatus (AF) in vivo with the action of human or mouse phagocytes against AF in vitro, we delineated two sequential lines of defense against AF. The first line of defense was formed by macrophages and directed against spores. Macrophages prevented germination and killed spores in vitro and rapidly eradicated conidia in vivo, even in neutropenic and athymic mice. The second was the neutrophilic granulocyte (PMN), which protected against the hyphal form of AF. Human and mouse PMN killed mycelia in vitro. Normal, but not neutropenic mice, stopped hyphal growth, and eradicated mycelia. Either line of defense acting alone protected mice from high challenge doses. Natural immunity collapsed only when both the reticuloendothelial system and PMN were impaired. These findings are in keeping with the clinical observation that high doses of cortisone and neutropenia are the main risk factors for invasive aspergillosis. Cortisone inhibited the conidiacidal activity of mouse macrophages in vivo and of human or mouse mononuclear phagocytes in vitro. Cortisone damaged this first line of defense directly and not through the influence of T lymphocytes or other systems modifying macrophage function as shown in athymic mice and in vitro. In addition, daily high doses of cortisone in mice reduced the mobilization of PMN so that the second line of defense was also impaired. Thus, cortisone can break down natural resistance on its own. Myelosuppression rendered mice susceptible only when the first line of defense was overpowered by high challenge doses, by activated spores that cannot be killed by macrophages, or by cortisone suppression of the conidiacidal activity of macrophages. The host, thus, can call upon two independent phagocytic cell lines that form graded defense systems against aspergillus. These lines of defense function in the absence of a specific immune response, which seems superfluous in the control and elimination of this fungus.

Animals↗
PubMed1981

Granulocyte demargination by epinephrine in evaluation of hypersplenic states.

The usefulness of the epinephrine stimulation test in detecting granulocytic hypersplenism is evaluated. In 8 hypersplenic patients, an increment of the granulocyte count of 170% over baseline values was found, compared to 38% (P less than 0.001) in normal subjects and 44% )P less than 0.002) in patients neutropenic from other causes. No overlap of individual test results was found among the hypersplenic and the control groups. Epinephrine test discriminates between neutropenia from hypersplenism and neutropenia from other causes. Furthermore, this test is found to be a valuable adjunct to the hydrocortisone stimulation test in kinetic evaluation of neutropenia from any cause.

Adult↗
PubMed1978

Glomerular permeability in the bullfrog Rana catesbeiana.

Filtration studies suggest similar size pores in the glomerular filters of mammals and amphibians. However, the glomerular wall in the bullfrog exhibits several structural features not found in mammals. The subendothelial space of the basement membrane is often greatly enlarged and infiltrated by cellular elements. The lamina densa of the basement membrane shows extensive variation in thickness and packing of its filaments. On the other hand, the epithelial slits in the bullfrog are closed by a slit diaphragm which appears similar in size and structure to the slit diaphragm in mammals. Horse spleen ferritin, a protein with a hydrodynamic radius of 61 A, was used as an ultrastructural tracer to determine whether the highly variable structure of the basement membrane renders this layer more permeable than its mammalian counterpart. Within 10 min after intravenous injection, ferritin was found throughout the basement membrane and often in clusters within the subepithelial layer adjacent to the slit diaphragm. Virtually no ferritin was found within the urinary space, podocytes, or cells of the proximal tubule. Ferritin distribution was the same in both superficial glomeruli and more deeply lying glomeruli regardless of the method of fixation. These results indicate that in the bullfrog the slit diaphragm is a principal filtration barrier to ferritin and thus to smaller plasma proteins.

Animals↗
PubMedDate not supplied

Glucocorticoid-induced impairment of macrophage antimicrobial activity: mechanisms and dependence on the state of activation.

Experimental observations indicate that tissue macrophages deployed in great numbers at critical anatomic sites such as the liver, spleen, and lung are major targets for glucocorticoids compromising natural resistance of the host. Therapeutic concentrations of glucocorticoids appear to prevent destruction of microorganisms ingested by macrophages without interfering with phagocytosis, phagolysosomal fusion, and/or secretion of reactive oxygen intermediates. These findings indicate that at the cellular level the glucocorticoid target should be sought for in the nonoxidative armature of the phagocyte and that nonoxidative killing systems of resident tissue macrophages play an important role in natural resistance to opportunistic pathogens. Glucocorticoids do not prevent lymphokine-induced activation of oxidative killing systems. Thus, lymphokines such as interferon-gamma can restore the microbicidal activity of macrophages functionally impaired by glucocorticoids. Counterbalance of the suppressive effect of glucocorticoids by lymphokines might only be possible, however, for pathogens susceptible to oxidative killing and not for microorganisms that are more resistant to reactive oxygen intermediates such as Aspergillus spores and Nocardia, opportunists that appear to be particularly associated with hypercortisolism.

Animals↗
PubMedDate not supplied

Amphotericin B refractory aspergillosis after itraconazole: evidence for significant antagonism.

Failure of amphotericin B to halt aspergillosis in a patient previously treated with itraconazole raised the question of whether amphotericin B lost its activity as a result of antagonism between the two antifungal drugs. Azoles exhaust the target of amphotericin B on the fungal cell membrane. Accordingly amphotericin B in vitro lost its activity against six isolates of Aspergillus fumigatus after exposure to subfungicidal concentrations of itraconazole. Prior treatment of mice with itraconazole abolished the protective effect of amphotericin B, even when itraconazole was stopped before starting amphotericin B therapy. These observations raise concern about sequential therapy of aspergillosis with itraconazole followed by amphotericin B.

Amphotericin B↗