Drugs, 1997 Apr, 53(4), 539 - 49 Antifungal agents in the 1990s . Current status and future developments; Kauffman CA et al.; Significant advances in antifungal therapy have occurred in the last decade . Most of these advances have been tied to the introduction of the triazoles, itraconazole and fluconazole . Itraconazole has proved efficacious for the treatment of subacute to chronic infections with the endemic mycoses and other opportunistic filamentous fungi, including Aspergillus spp . Fluconazole is now routinely used for mucocutaneous and systemic candidiasis, and its use for coccidioidal meningitis has obviated the need for intrathecal amphotericin B in most patients . Large, well controlled trials in AIDS patients with cryptococcal meningitis have shown the benefit of induction therapy with amphotericin B and flucytosine, followed by consolidation and life-long maintenance therapy with fluconazole . Concomitant with the increased use of these well tolerated, effective oral triazole agents has come the emergence of drug resistance in AIDS patients and shifts in the species of yeasts causing infection in hospitalised patients . Amphotericin B remains the drug of choice for many fungal infections, especially those that are life-threatening . Lipid-containing formulations of amphotericin B have recently been approved: these preparations significantly reduce the risk of amphotericin B-induced nephrotoxicity . Several new fungicidal agents are currently in early trials . With the increasing number of available antifungal drugs, future studies will help define the appropriate niche for each and the possible benefit of therapy with combinations of drugs. Antimicrob Agents Chemother, 1997 Apr, 41(4), 850 - 2 In vitro activity of fluvastatin, a cholesterol-lowering agent, and synergy with flucanazole and itraconazole against Candida species and Cryptococcus neoformans; Chin NX et al.; Fluvastatin, a cholesterol-lowering drug, exhibited minimal activity (MICs of 64 to >128 microg/ml) against Candida species and Cryptococcus neoformans . When fluvastatin was combined with fluconazole or itraconazole, both synergistic and additive effects were noted (fractional inhibitory concentration indices of < or = 0.156 to 0.625; fractional lethal concentration indices of < or = 0.156 to 0.75) . This combined fungicidal activity was confirmed by time-versus-killing studies. Antimicrob Agents Chemother, 1997 Apr, 41(4), 802 - 7 Enhanced resistance to Cryptococcus neoformans infection induced by chloroquine in a murine model of meningoencephalitis; Mazzolla R et al.; Although the pathogenesis of cerebral cryptococcosis is poorly understood, local immune cells, such as microglia and astrocytes, likely play a critical role in containing infection . Chloroquine (CQ) is a weak base that accumulates within acidic vacuoles and increases their pH . Consequently, proteolytic activity of lysosomal enzymes and intracellular iron release/availability are impaired, resulting in decreased availability of nutrients crucial to microorganism survival and growth in the host . We found that CQ enhances BV2 microglial-cell-mediated anticryptococcal activity in vitro . The phenomenon is (i) evident when both unopsonized and opsonized microorganisms are used and (ii) mimicked by NH4Cl, another weak base, and by bafilomycin A1, an inhibitor of vacuolar-type H+-ATPases . In vivo, intracerebral administration of CQ before lethal local challenge with Cryptococcus neoformans results in a significant augmentation of median survival time and a marked reduction of yeast growth in the brain and is associated with the enhancement of local interleukin 1beta (IL-1beta) and IL-6 mRNA transcripts . Overall, these results provide the first evidence that CQ enhances anticryptococcal host defenses. Antimicrob Agents Chemother, 1997 Apr, 41(4), 748 - 51 Fluconazole tolerance in clinical isolates of Cryptococcus neoformans; Venkateswarlu K et al.; Eleven isolates of Cryptococcus neoformans were investigated to determine the biochemical basis of their tolerance to fluconazole . The MICs of fluconazole for three isolates with low-level resistance were 3- to 6-fold higher than those for sensitive isolates, while the MICs for four isolates with high-level resistance were 100- to 200-fold higher than those for sensitive isolates . The level of ergosterol present in the isolates varied, and those which had relatively low levels of ergosterol were resistant to amphotericin B . Changes in the affinity of the target enzyme (sterol 14alpha-demethylase) and decreases in the cellular content of fluconazole seemed to be responsible for the resistance in isolates with low-level and high-level resistance, respectively. J Infect Dis, 1997 Apr, 175(4), 963 - 6 Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage; Brew BJ et al.; The relationship between the presence and severity of AIDS dementia complex (ADC) and the levels of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF) were assessed . Nineteen patients with ADC (stages 1-3), 6 without ADC (group 1), and 10 (group 2) without ADC but with cryptococcal meningitis or progressive multifocal leukoencephalopathy were studied . There was a significant relationship between increasing CSF virus burden and ADC severity (P = .0006) but not with plasma burden and ADC severity . In group 2, CSF HIV-1 RNA levels in patients with cryptococcal meningitis were elevated . These results show that CSF HIV-1 RNA concentrations correlate well with ADC severity but may also be increased by central nervous system infections, such as cryptococcal meningitis. Biochem Pharmacol, 1997 Mar 21, 53(6), 823 - 8 Inhibition of swine microglial cell phagocytosis of Cryptococcus neoformans by femtomolar concentrations of morphine; Sowa G et al.; Microglia are important immune effector cells within the brain . The phagocytosis of nonopsonized Cryptococcus neoformans by swine microglia was used as an in vitro model for studies on cellular mechanisms of opiate-mediated immunomodulation in the brain . Morphine inhibited potently (IC50 approximately 10(-16) M) the phagocytosis of C . neoformans by primary cultures of neonatal pig microglia . The mu opioid agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) also suppressed phagocytosis but with a much lower potency than morphine (IC50 approximately 10(-8) M) . The inhibitory effects of morphine and DAMGO were blocked by equimolar concentrations of naloxone and by the selective mu opiate receptor antagonist beta-funaltrexamine . Pertussis toxin but not cholera toxin reversed the inhibitory effects of both morphine and DAMGO . Our data suggest that morphine inhibits phagocytosis of C . neoformans by swine microglia via a mechanism involving mu opiate receptors coupled to a pertussis toxin-sensitive Gi/G(o) protein signaling pathway. Proc Natl Acad Sci U S A, 1997 Mar 18, 94(6), 2483 - 8 T cells cooperate with passive antibody to modify Cryptococcus neoformans infection in mice; Yuan RR et al.; Cryptococcus neoformans is an encapsulated fungus that is a major cause of meningitis in patients with AIDS . In immunocompetent mice, administration of IgG1 mAb protects against cryptococcal infection, whereas administration of IgG3 is not protective and can accelerate the infection . In beige mice with impaired natural killer cell function, the effects of IgG1 and IgG3 are similar to those observed in immunocompetent mice, suggesting that natural killer cells are not crucial for antibody-mediated modulation of cryptococcal infection . In mice lacking CD4+ T cells, IgG1 is not protective and IgG3 accelerates infection, indicating that CD4+ T cells are required for antibody-mediated protection . In mice lacking CD8+ T cells, both IgG1 and IgG3 antibodies prolong survival, indicating that acceleration of the disease process by IgG3 involves CD8+ T cells . Both IgG1-mediated protection and IgG3-mediated acceleration of infection require interferon gamma . These results reveal a functional dependence of passively administered antibody on cellular immunity in cryptococcal infection in mice and have implications for antibody-based therapies in humans in the setting of CD4+ lymphopenia. Presse Med, 1997 Mar 8, 26(7), 344 - 7 {Prevention of opportunistic infections in HIV seropositive patients . Prevention of viral infections and mycoses}; Casassus P et al.; CYTOMEGALOVIRUS INFECTION: Primary prophylaxis is logical in high-risk subjects (CD4 < 50) who are asymptomatic; per os ganciclovir is under evaluation . Systematic secondary prophylaxis relies on intravenous ganciclovir or foscarnet . HERPES SIMPLEX AND ZOSTER: Secondary prevention with acyclovir is not recommended due to the risk of resistance . Herpes zoster retinitis is an absolute indication for continuous oral treatment with acyclovir . CRYPTOCOCCUS: Oral fluconazol is required for secondary prophylaxis . CANDIDIASIS: Due to the risk of resistant strains, neither primary nor secondary prophylasis is recommended . HISTIOPLASMOSIS: Risk of recurrence justifies secondary prophylaxis with itraconazole or fluconazole . COCCIDIODOMYCOSIS: Secondary prophylaxis with amphotericin B or fluconazole is mandatory . ASPERGILLOSIS: Itraconazole is the best agent when prophylaxis is needed. Tijdschr Diergeneeskd, 1997 Mar 1, 122(5), 128 - 32 {2 cases of cryptococcosis in cats}; Tjalsma EJ; In two cats, a Persian and a D.S.H . cat, cutaneous Cryptococcosis is described . No signs of involvement of other organ systems nor underlying causes were established . One cat seemed refractory to ketoconazole-therapy . In both cats the skin lesions disappeared within 2-3 months itraconazole treatment . Latex agglutination tests against Cryptococci capsula antigen were performed and stayed longtime elevated while clinical lesions were not present anymore . The test may give an indication about prognosis. Pneumologie, 1997 Mar, 51(3), 286 - 90 {Coincidence of pulmonary cryptococcoma in an immunocompetent patients with a chondrohamartoma and chronic tuberculoma--differential diagnostic considerations concerining pulmonary coin lesions}; Schulze HJ et al.; Of primary importance in the differential diagnosis of multiple circular foci in the lungs are the lung metastases . This study involves a patient with three circular foci, each of which could have been metastases . They proved, however, to be a rare coincidence of three benign lung affections, namely, an old tuberculoma, a chondrohamartoma, and a seldom encountered pulmonary cryptococcoma . Computerized tomography utilizing the spiral technique was valuable diagnostically, as it led to the discovery of the smallest of the three circular foci in the basodorsal left lower lobe . The form of the cryptococcosis among immunocompetent patients--only rarely localized in our experience--must be included in the differential diagnostical considerations of a circular focus in the lungs . In the event there are multiple circular foci with an unknown primary tumor, surgical intervention with a pathohistological clarification regarding a possible malignancy is absolutely necessary. J Med Vet Mycol, 1997 Mar-Apr, 35(2), 147 - 9 Differential killer toxin sensitivity patterns of varieties of Cryptococcus neoformans; Boekhout T et al.; Ten different killer sensitivity types are distinguished within Cryptococcus neoformans, namely four in var . neoformans and six in var . gattii . All strains of the var . gattii investigated were inhibited by killer toxins of C . laurentii CBS 139, whereas those of the var . neoformans were not . Killer sensitivity patterns are an easy-to-use method to differentiate between the two varieties of the clinically important yeast C . neoformans, and may be of help in epidemiological surveys. J Med Vet Mycol, 1997 Mar-Apr, 35(2), 139 - 41 A case of prosthetic valve endocarditis caused by Cryptococcus neoformans var . neoformans; Banerjee U et al.; A case of prosthetic valve endocarditis caused by Cryptococcus neoformans var . neoformans is described . The infection followed closed mitral valvotomy and insertion of a valvular prosthesis . Infection was manifested 2 weeks after the operation . The diagnosis was based on direct demonstration of the yeast with characteristic morphology in clinical material, isolation from an arterial thrombus and detection of cryptococcal antigen in the serum . The patient's infection could not be resolved despite institution of antifungal therapy. Antonie Van Leeuwenhoek, 1997 Mar, 71(3), 277 - 80 Influence of L-galactonic acid gamma-lactone on ascorbate production in some yeasts; Onofri S et al.; L-galactonic acid gamma-lactone appear to influence ascorbic and production in strains of Saccharomyces cerevisiae, Clavispora lusitaniae, Cryptococcus terreus, Pichia fermentans in which this is undetected whenever glucose represents the sole carbon source . Cryptococcus terreus (strains DBVP 6012 and 6242) does not show ascorbic acid production either in presence or in the absence of L-galactonic acid gamma-lactone . This feature is probably connected to the insensibility of the strain to the lycorine, an alkaloid which commonly inhibits cell division probably by blocking L-galactonic acid gamma-lactone conversion into ascorbate. Antonie Van Leeuwenhoek, 1997 Mar, 71(3), 243 - 8 Yeasts associated with nests of the leaf-cutting ant Atta sexdens rubropilosa Forel, 1908; Carreiro SC et al.; A total of 137 yeasts associated with the leaf-cutting ant Atta sexdens rubropilosa Forel, 1908 were characterized, being selected 93 for analysis . Twenty four species belonging to seven genera (Candida, Cryptococcus, Rhodotorula, Sporobolomyces, Tremella, Trichosporon, Pichia) were isolated from the different analysed material . The genus Candida was widely distributed, with C . homilentoma, C . colliculosa-like, C . famata and C . colliculosa being the most prevalent . A few isolates did not fit the standard descriptions and probably some of them could be new biotypes or even new species . Three strains of black yeasts were also isolated, and four other were identified as being Candida spp . The effective number of yeast species was higher in newer sponge . The origin, distribution and relative importance of these microorganisms for the ants are discussed. J Am Anim Hosp Assoc, 1997 Mar-Apr, 33(2), 118 - 22 Feline cryptococcosis: a retrospective evaluation; Gerds-Grogan S et al.; Cryptococcus neoformans causes the most common form of feline systemic fungal disease . Nineteen cats with cryptococcosis were seen at the Veterinary Hospital of the University of Pennsylvania between April 1986 and May 1995 . Compared to other studies, these 19 cases showed increased neurological and ophthalmological involvement . Males were affected more often than females . Season and environment appeared to influence time of onset or presentation to the hospital . Clinical pathology did not show typical changes . It is possible that the organism was present frequently in the urine but was mistaken for fat droplets . Treatment with ketoconazole was unrewarding in cases with central nervous system (CNS) involvement. Acta Cytol, 1997 Mar-Apr, 41(2), 493 - 6 Cytologic diagnosis of Cryptococcus neoformans in HIV-positive patients; Kanjanavirojkul N et al.; OBJECTIVE: To present experience with the cytologic diagnosis of pulmonary cryptococcosis in bronchial washings and bronchoalveolar lavage in human immunodeficiency virus (HIV)-positive patients in Thailand . STUDY DESIGN: The study group consisted of 54 HIV-positive patients admitted to the Faculty of Medicine, Srinagarind Hospital, during the period January 1992-June 1994 . Bronchial washing and bronchoalveolar lavage specimens were studied for Cryptococcus neoformans by routine Papanicolaou and special staining methods . RESULTS: The Cryptococcus organism, an encapsulated yeast with a clear halo on Papanicolaou-stained smears, was found both extracellularly and in histiocytes in 4 of 54 (7.4%) cases . A definitive diagnosis was confirmed by positive staining of the capsular mucopolysaccharides with periodic acid-Schiff and Mayer's mucicarmine stain and of the cell wall with methenamine silver . Lung biopsy was performed in one case and revealed cryptococcosis . CONCLUSION: This study underscores the usefulness of cytologic screening in the detection of this opportunistic pulmonary infection . The cytopathologist and cytotechnologist should be alert for the presence of Cryptococcus in cytologic specimens from HIV-positive patients. Mod Pathol, 1997 Mar, 10(3), 159 - 67 Renal changes in patients with acquired immunodeficiency syndrome: a post-mortem study on an unselected population in northwestern Italy; Monga G et al.; The renal pathologic features of 120 consecutively autopsied patients affected by acquired immunodeficiency syndrome was investigated by light microscopic analysis . Variously associated renal changes were found in 82 patients (68.3%) . Glomerular changes were present in 25 . The following diagnoses were made: mesangial glomerulonephritis (16 patients), defined by the presence of deposits in the mesangium and/or mesangial cell proliferation; membranous glomerulonephritis (4 patients), cirrhotic glomerulosclerosis (2 patients); and lupuslike glomerulonephritis (3 patients) . Glomerular diseases seemed to be significantly associated with chronic hepatitis or liver cirrhosis . Interstitial inflammation was present in 19 cases: chronic pyelonephritis (2 patients), focal nephritis (5 patients), multiple cortical abscesses (7 patients), granulomatous nephritis (5 patients) . Cryptococci were found in one and undetermined microorganisms in two cases of multiple cortical abscesses . Atypical mycobacteria were found in two cases of granulomatous nephritis . Mycotic infections were identified in another 6 patients, in whom they did not elicit any inflammatory response . It is worth stressing that, although various generalized infections are common in patients with acquired immunodeficiency syndrome, only cryptococci and atypical mycobacteria also frequently involve the kidney . Focal tubular necrosis was observed in 15 patients . Benign nephrosclerosis was the most common vascular change (27 patients) . Changes recalling hemolyticuremic and localized intravascular coagulation were found in three and six patients, respectively . Our data, dealing with a European Caucasian population, considerably differ from those reported in North American literature, in as much as we found no cases of human immunodeficiency virus nephropathy . Conversely, immune-mediated glomerular diseases were frequent, in agreement with recent studies on renal biopsy specimens from AIDS patients with acquired immunodeficiency syndrome . This type of infections, supplies multiple sources of antigens that may stimulate immune complex formation and, therefore, glomerular diseases. J Comput Assist Tomogr, 1997 Mar-Apr, 21(2), 175 - 82 Dentate nuclei involvement in AIDS patients with CNS cryptococcosis: imaging findings with pathologic correlation; Ruiz A et al.; PURPOSE: Our goal was to describe the involvement of the dentate nuclei in AIDS patients with CNS cryptococcosis since this finding has not been emphasized in previous radiological literature . METHOD: Plain and contrast-enhanced CT of the brain (10 and 10), MR studies (1 premortem and 1 postmortem), and autopsy findings in 11 AIDS patients with CNS cryptococcosis were reviewed . The imaging studies and pathological specimens were analyzed for signs of meningitis, presence of dilated Virchow-Robin spaces, gelatinous pseudocysts, cryptococcoma, ventriculomegaly, choroid plexus, and ependymal lesions . RESULTS: Five of 11 patients were found at autopsy to have macroscopically visible "cystic" lesions in the dentate nuclei that were not detected on CT (10 patients), but were seen on premortem MR (1 patient) . Macroscopic supratentorial (basal ganglia, thalamic, midbrain) lesions were detected by CT in 5 of 11 patients and by MR in 2 of 2 patients . Enhancement of the leptomeninges was seen in only 1 patient by CT despite pathological evidence of cryptococcal meningitis in all 11 patients . Dilated Virchow-Robin spaces were seen in all 11 pathologic specimens and in the 2 MR studies but not on CT . Communicating hydrocephalus was detected by CT in two patients . CONCLUSION: CT scans of the brain underestimate infratentorial parenchymal cryptococcal disease . MR is a more sensitive procedure to evaluate cerebellar and brainstem cryptococcosis, including the dentate nuclei, which in our autopsy series was not an uncommon site to be infected with cryptococcal gelatinous pseudocysts. Support Care Cancer, 1997 Mar, 5(2), 90 - 3 Pulmonary infections mimicking cancer: a retrospective, three-year review; Rolston KV et al.; Pulmonary infections can mimic or occasionally co-exist with pulmonary neoplasms . In order to determine the frequency and nature of these infections, we conducted a retrospective analysis, covering a 3-year period, of patients who were referred to our center with presumed lung cancer but turned out to have pulmonary infection instead . The overwhelming majority of patients (93.3%) referred to "rule out" lung cancer were documented as having a neoplastic process, and only 1.3% had an infection . Fungal infections (histoplasmosis, cryptococcosis, coccidiomycosis) accounted for 46%, mycobacteria for 27%, bacteria for 22%, and parasitic lesions (dirofilariasis) for 5% of these infections . The most common clinical manifestations were cough and chest pain, and the most common radiographic finding was a solitary pulmonary nodule . There were no specific clinical or radiographic features predictive of either infection or neoplastic disease . All patients responded to specific anti-infective therapy with or without surgical excision . Our data indicate that pulmonary infections mimic neoplasms very infrequently . However, establishing a specific diagnosis is critical, since the management and outcome of these two processes are entirely different. J Am Coll Surg, 1997 Mar, 184(3), 233 - 9 The role of cholecystectomy in acquired immunodeficiency syndrome; Flum DR et al.; BACKGROUND: Hepatobiliary disease is a common manifestation of acquired immunodeficiency syndrome, although the role of surgical intervention in the spectrum of therapy is unclear . STUDY DESIGN: A retrospective review was designed to evaluate the characteristics of patients given a diagnosis of human immunodeficiency virus infection or acquired immunodeficiency syndrome and undergoing cholecystectomy between January 1, 1986, and November 1, 1995 . RESULTS: The study included 40 patients (35 men, 5 women; mean age, 42 +/- 9 years), 33 (82.5 percent) with acquired immunodeficiency syndrome; their mean preoperative T-helper (CD4) cell count was 163/mL3 . Gross pathologic findings included acute (n = 9, 22.5 percent) and chronic (n = 31, 77.5 percent) cholecystitis . Gallbladder specimens were positive for cholelithiasis in 28 (70 percent), Cryptococcus organisms in 5 (12.5 percent), cytomegalovirus in 3 (7.5 percent), and lymphoma in 2 (5 percent) . The median follow-up time was 48 months (range, 6 to 63 months) . The percentage survival was 92.5 percent (n = 37) at 30 days, and 57.5 percent (n = 23), 37.5 percent (n = 15), and 25 percent (n = 10) at 12, 24, and 36 months, respectively . The mean survival time was 25.1 months . The likelihood of survival was directly linked to the CD4 cell count . The mean survival period was 25 months for patients with CD4 cell counts less than 200/mL3 compared with 48 months for those with CD4 cell counts greater than 200/mL3 . CONCLUSIONS: Although the pathologic changes identified in patients with acquired immunodeficiency syndrome may occasionally be atypical, the clinical presentation, indications for operation, and pathologic findings identified are quite common . Patients tolerate cholecystectomy well with good long-term outcome and minimal infectious complications . Even in patients with the most compromised immune status, a 2-year survival after operation is acceptable . Cholecystectomy has a clear role in the spectrum of treatment for biliary disease relative to acquired immunodeficiency syndrome. Antimicrob Agents Chemother, 1997 Mar, 41(3), 706 - 8 Potent antifungal effects of a new derivative of partricin A in a murine model of cerebral cryptococcosis; Luna T et al.; A new member of the polyene family, N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate (SPA), was investigated and was found to be more effective than amphotericin B (i) in vivo by enhancing mouse resistance to cryptococcal meningoencephalitis and (ii) in vitro by potentiating the anticryptococcal activity of murine microglial cells. J Clin Microbiol, 1997 Mar, 35(3), 751 - 5 Genetic relatedness and diversity of Cryptococcus neoformans strains in the Maltese Islands; Lo Passo C et al.; The genetic relatedness of clinical and environmental Cryptococcus neoformans strains in the Maltese Islands was investigated by randomly amplified polymorphic DNA fingerprinting with four primers . The clinical strains isolate over the course of 1 year from AIDS patients showed identical fingerprints . The electrophoretic patterns of the two clinical strains were also the most common patterns among the environmental strains, but the patterns among the environmental strains showed a wide variability and no correlation with the site of isolation. Infect Immun, 1997 Mar, 65(3), 931 - 5 Binding of Cryptococcus neoformans to heterologously expressed human complement receptors; Levitz SM et al.; Previously, we demonstrated that monoclonal antibodies (MAb) directed against any of the three defined complement receptors (CR) for the third component of complement (CR1, CR3, and CR4) profoundly inhibited the binding of serum-opsonized Cryptococcus neoformans to monocyte-derived macrophages . These studies suggested either that a synergistic interaction between multiple CR was required for optimal binding of C . neoformans or that the MAb were exerting nonspecific effects (such as receptor coassociation) . In the present studies, we took a novel approach to dissecting out the contributions of individual receptors to binding of a microbial pathogen . Chinese hamster ovary (CHO) cells stably transfected with human CR1, CR3, or CR4 were challenged with serum-opsonized C . neoformans . We found that CHO cells transfected with any of the three receptors bound C . neoformans, with the avidity of binding to CR3 being the greatest followed in decreasing order by CR1 and CR4 . Following binding of C . neoformans to transfected CHO cells, most organisms remained surface attached only, although for each receptor a significant percentage (18.5 to 27.3%) of C . neoformans was internalized . Both C . neoformans and sheep erythrocytes that were selectively opsonized with the fragments of the third component of complement, C3b and iC3b, were bound preferentially by CHO cells transfected with CR1 and CR3, respectively . These data establish CR1, CR3, and CR4 as receptors independently capable of binding C . neoformans opsonized with fragments of C3 . Moreover, our study demonstrates the usefulness of transfected cell lines as a powerful tool for identifying the contribution of individual receptors to the binding of a microbial pathogen. Infect Immun, 1997 Mar, 65(3), 903 - 8 Variables affecting production of monocyte chemotactic factor 1 from human leukocytes stimulated with Cryptococcus neoformans; Levitz SM et al.; The chemokine monocyte chemoattractant protein 1 (MCP-1) is produced predominantly by mononuclear phagocytes and stimulates recruitment into infected tissues of blood monocytes and T cells . These cell types are thought to be critical to host defenses against infections due to Cryptococcus neoformans, a major cause of disease in persons with AIDS and other disorders of cell-mediated immunity . Accordingly, in the present study, we examined the conditions under which human monocytes and bronchoalveolar macrophages (BAM) are stimulated by C . neoformans to produce MCP-1 . C . neoformans was a potent inducer of MCP-1 release from monocytes, with levels of chemokine secreted similar to that seen following stimulation with lipopolysaccharide (LPS) . BAM, in contrast, were stimulated by LPS, but not by C . neoformans, to secrete MCP-1 . A peak in MCP-1 mRNA was seen 8 h following cryptococcal stimulation of monocytes . Nine strains of C . neoformans stimulated monocytes to release MCP-1, and there was only modest variation between strains . However, when an individual strain was used, the capacity of C . neoformans to stimulate monocyte MCP-1 release did vary, depending upon the conditions used to grow the fungal stimuli . Finally, C . neoformans stimulated comparable quantities of MCP-1 release in monocytes from donors with and without human immunodeficiency virus infection . These data establish C . neoformans as a potent stimulator of MCP-1 in monocytes, but not in BAM . The failure of C . neoformans to stimulate MCP-1 in BAM, if occurring in vivo, could result in a diminished cell-mediated inflammatory response following inhalation of airborne fungi. J Exp Med, 1997 Feb 17, 185(4), 685 - 94 Epitope location in the Cryptococcus neoformans capsule is a determinant of antibody efficacy; Nussbaum G et al.; Monoclonal antibodies (mAbs) to the polysaccharide capsule of Cryptococcus neoformans can prolong survival in mice . However, the properties of antibodies that mediate protection are not fully understood . The IgM mAbs 12A1 and 13F1 originated from the same B cell and differ only by somatic mutations in their variable regions; yet mAb 12A1 protects against serotype D infection, while mAb 13F1 does not . Phage peptide display libraries were used to analyze the fine specificity of these two mAbs . The selection of distinct peptide motifs from identical libraries confirmed that mAbs 12A1 and 13F1 bound to two distinct epitopes . Immunofluorescence and immunoelectron microscopy studies revealed differences in antibody localization within the capsule of serotype D strain; mAb 12A1 bound to the outer rim of the capsule resulting in an annular pattern, whereas mAb 13F1 bound throughout the capsule and had a punctate appearance . The difference in the binding pattern of mAb 12A1 and 13F1 was not observed on serotype A organisms, where both mAbs bound to the capsule with an annular fluorescence pattern . The fluorescence pattern of binding correlated with protective efficacy; mAb 13F1 prolonged survival of mice infected with the J11 serotype A strain (annular fluorescence), but not serotype D strains (punctate pattern) . Annular binding, but not punctate binding, was associated with increased opsonic efficacy for phagocytosis of C . neoformans by J774.16 macrophage-like cells . The correlation between capsular binding pattern, opsonic activity, and ability to prolong survival suggests that the efficacy of anticryptococcal antibodies is dependent upon where they bind in the polysaccharide capsule. J Immunol, 1997 Feb 15, 158(4), 1772 - 8 Expression of lung inducible nitric oxide synthase protein does not correlate with nitric oxide production in vivo in a pulmonary immune response against Cryptococcus neoformans; Lovchik J et al.; Mice infected intratracheally with Cryptococcus neoformans (Cne) require CD4 and CD8 T cells, IFN-gamma, and M phi production of nitric oxide (NO) for effective resolution of the pulmonary infection . Differences exist among strains of mice in clearing the infection . C.B-17 mice reduced Cne lung burden at a significantly greater rate than C57BL/6 (B6) mice and resistance correlated with greater IFN-gamma production by C.B-17 lung-associated lymph node cells . We examined whether the differences observed in the ability of B6 vs C.B-17 mice to clear Cne was due to 1) numbers of inflammatory cells recruited to the lung, 2) the activation state of the recruited cells as measured by expression of inducible nitric oxide synthase (iNOS), and/or 3) the in vivo production of NO as measured by quantitating urine nitrates . The level of iNOS protein was identical in lungs from both strains of mice during Cne infection as determined by Western blot analysis of whole lung homogenates and immunocytochemistry of isolated lung macrophages . Surprisingly, in vivo studies of iNOS activity indicated that NO production in B6 mice was significantly less than that in C.B-17 mice . While single cell suspensions from lungs of either mouse strain produced identical amounts of NO, NO production by lung explants paralleled in vivo urinary nitrate excretion, suggesting that the maintenance of pulmonary architecture and cell-cell interaction was necessary for suppression of iNOS activity in B6 mice . These data strongly implicate the existence of mechanisms that regulate NO production at the level of enzyme activity during infections and have important implications for analyzing the role of iNOS during an immune response in in vivo models. J Infect Dis, 1997 Feb, 175(2), 414 - 20 Phospholipase activity in Cryptococcus neoformans: a new virulence factor? Chen SC, Muller M, Zhou JZ, Wright LC, Sorrell TC. Fifty isolates of Cryptococcus neoformans were examined for extracellular phospholipase production after inoculation onto egg yolk agar; 49 produced a pericolonial precipitate indicative of phospholipase activity . Phospholipase B (PLB), lysophospholipase, and lysophospholipase-transacylase activities were identified by radiometric analysis in supernatants from 4 clinical isolates . The ratio of colony diameter to colony plus precipitate on agar (Pz) correlated with PLB activity . Phospholipase production was similar in 12 environmental and 13 clinical isolates of C . neoformans var . gattii . Environmental strains of C . neoformans var . neoformans (n = 8) produced more phospholipase at 72 h than did 17 clinical isolates (mean Pz, 0.57 vs . 0.72; P < .01); however, Pz values were similar at 96 h . Quantitation of cryptococci in the lungs and brains of BALB/c mice inoculated intravenously with 4 strains expressing high, intermediate, or low phospholipase activity revealed a correlation between phospholipase activity and virulence . Phospholipases secreted by C . neoformans may be implicated in virulence. Immunology, 1997 Feb, 90(2), 189 - 97 Kinetics of cellular infiltration and cytokine production during the efferent phase of a delayed-type hypersensitivity reaction; Buchanan KL et al.; Cell-mediated immunity is a primary host resistance mechanism against many infectious organisms and is responsible for leucocyte recruitment to the infection site . Delayed-type hypersensitivity (DTH) reactions are in vivo correlates of cell-mediated immunity and have long been used to assess the level of cell-mediated immune (CMI) responsiveness to specific antigens . It has been difficult to study the kinetics of cellular influx and cytokine composition at the site of an on-going CMI reaction . Consequently, knowledge of the sequential events occurring during the efferent phase of a CMI response is incomplete . Here we report on the use of a gelatin sponge model for evaluating the progression of events during the effector phase of a DTH reaction to antigens of the mycotic organism Cryptococcus neoformans . Previously, we have shown that 24 hr after antigen injection into sponges in infected or immune mice, the leucocyte types infiltrating the sponges are consistent with a classical murine DTH reaction . Through kinetic studies, we show here that neutrophils are the first leucocytes to appear in DTH-reactive sponges, followed by increases in lymphocyte and then monocyte numbers . Tumour necrosis factor (TNF), interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and IL-5 were elevated in DTH-reactive sponges compared with control sponges, and each cytokine had a relatively unique temporal profile . IL-4 was not detectable in the sponges . Together our data indicate that the expression of a CMI response comprises a well-regulated sequential influx of leucocytes that contribute to the lymphokine composition of the reaction. Clin Infect Dis, 1997 Feb, 24(2), 179 - 84 Invasive fungal infections in liver transplant recipients receiving tacrolimus as the primary immunosuppressive agent; Singh N et al.; Invasive fungal infections and their risk factors were prospectively assessed in 130 consecutive liver transplant recipients receiving tacrolimus as the primary immunosuppressive agent . Eleven percent (14) of the 130 patients had 17 episodes of invasive fungal infections . These included candidiasis (5%; 6 patients), cryptococcosis (5%; 6), aspergillosis (3%; 4), and chromomycosis (1%; 1) . An elevated pretransplantation creatinine level, requirement of dialysis (pretransplantation or posttransplantation), duration of intensive care unit stay after transplantation surgery, and antibiotic use (other than for prophylaxis) within 4 weeks of transplantation were significant risk factors for fungal infections occurring within 100 days of transplantation . For fungal infections occurring after 100 days, persistence of renal dysfunction (serum creatinine level of >2.5 mg/dL at 3 months), dialysis, and histopathologically documented recurrence of hepatitis C virus hepatitis were significant risk factors . Mortality was significantly higher among patients with fungal infections than among all other patients (57% vs . 15%; P = .0009) . Our study identified specific risk factors for invasive fungal infections in liver transplant recipients receiving tacrolimus; strategies to prevent fungal infections or to initiate early antifungal therapy might be most effectively targeted at these patients. Clin Infect Dis, 1997 Feb, 24(2), 131 - 4 Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients; Moosa MY et al.; We retrospectively compared the clinical manifestations, laboratory features, and outcome of cryptococcal meningitis in 44 human immunodeficiency virus (HIV)-positive and 21 HIV-negative patients in Durban, South Africa, and contrasted our findings with those in the developed world . Cryptococcal meningitis was the initial AIDS-defining illness in 84% of patients . Headache, fever, convulsions, neck stiffness, and neurological signs were more common in HIV-positive patients . We detected neurological abnormalities in 50% of the HIV-positive group . Seventeen percent of HIV-positive patients had completely normal CSF indices . HIV-positive patients with cryptococcal meningitis frequently had oral candidiasis and tuberculosis as coexistent illnesses . Prognostic factors identified in the West do not appear to be applicable in Africa . Death during hospitalization was significantly higher in the HIV-positive group . HIV-associated cryptococcal meningitis in Africa is apparently associated with higher rates of neurological complications and death than is such disease in developed countries of the world. Eur J Clin Microbiol Infect Dis, 1997 Feb, 16(2), 150 - 2 A case of primary cutaneous cryptococcosis; Vogelaers D et al.; The case of a 77-year-old man in whom a large digital ulcer with undermined edges was due to cutaneous infection by Cryptococcus neoformans variety neoformans serotype D, probably following direct inoculation, is reported . Long-term steroid treatment for chronic obstructive pulmonary disease may have been a risk factor . A 12-day course of intravenous amphotericin B at a cumulative dose of 750 mg, followed by oral fluconazole at a daily dose of 600 mg for six weeks, resulted in healing of the skin lesion . Manifestations of primary cutaneous cryptococcosis in immunocompetent or immunocompromised patients are reviewed. Enferm Infecc Microbiol Clin, 1997 Feb, 15(2), 70 - 2 {Usefulness of the CHROM-agar Candida culture medium in the differentiation and presumed identification of yeast of clinical interest}; Garcia-Martos P et al.; BACKGROUND: The efficiency of a novel differential culture medium, CHROM-agar Candida, is evaluated in order to differentiation and presumptive identification of clinically important yeasts . METHODS: We studied 600 clinical yeast strains, pertaining to 8 genera (Candida, Cryptococcus, Geotrichum, Rhodotorula, Trichosporon, Kluyveromyces, Pichia and Saccharomyces) and 27 species . Strains were previously identified by conventional methods and by commercial system ATB ID32C (Bio-Merieux) . RESULTS: Four species (C . albicans, C . krusei, C . tropicalis and t . beigelii) were presumptive recognized after 48-72 hours of incubation, regarding their colonial morphology and color . Colony color of other species showed low specificity . CONCLUSION: CHROM-agar Candida medium is recommended for recognition of mixed yeast cultures and differentiation of the common clinically yeast species. J Antimicrob Chemother, 1997 Feb, 39(2), 261 - 4 Novel antifungal agents which inhibit lanosterol 14alpha-demethylase in Candida albicans CCH442; Zakula D et al.; We have identified four non-azole inhibitors of lanosterol 14a-demethylase in Candida albicans CCH442 . The most potent compound, A-39806, had IC50 values for ergosterol inhibition of 0.9 microM (0.3 mg/L) and 1.9 microM (0.6 mg/L) in whole cell and cell-free extract assays, respectively . A-39806 demonstrated broad in-vitro antifungal activity against several Candida species as well as against Cryptococcus albidus and Aspergillus niger . In-vitro antifungal activity was also demonstrated against a fluconazole-resistant clinical isolate of C . albicans. Clin Transplant, 1997 Feb, 11(1), 66 - 70 Clinical spectrum of invasive cryptococcosis in liver transplant recipients receiving tacrolimus; Singh N et al.; Invasive cryptococcal infections have been reported in 0.3-1% of the patients undergoing liver transplantation in the previous reports . In contrast, invasive cryptococcosis developed in 6% of 102 consecutive liver transplants at our institution receiving tacrolimus as primary immunosuppression . Cutaneous and/or osteoarticular infections due to cryptococcus were detected in 67% of the patients with cryptococcosis, whereas meningitis was present only in 17% . One of the six patients with cryptococcosis presented with refractory shock and multiorgan system failure attributable solely to cryptococcosis . Patients with cryptococcal infections were significantly older than all other liver transplant recipients (p = 0.017), suggesting reactivation as opposed to primary infection as pathogenesis of cryptococcosis . 100% of the patients with cryptococcosis resided on the Eastern coast of the United States as compared to 59% of the patients without cryptococcosis (p = 0.08) . There was no difference in the severity of underlying liver disease, degree of immunosuppression or CMV infection or disease between patients who did and did not develop cryptococcosis . Atypical manifestations, e.g . cutaneous diseases or sepsis syndrome, as opposed to subclinical meningitis, may be a clinical feature of cryptococcal infection in liver transplant recipients. FEMS Immunol Med Microbiol, 1997 Feb, 17(2), 111 - 9 Recognition of cytoplasmic yeast antigens of Cryptococcus neoformans var . neoformans and Cryptococcus neoformans var . gattii by immune human sera; Hamilton AJ et al.; The humoral immune response of patients infected with Cryptococcus neoformans var . neoformans and C . neoformans var . gattii to cytoplasmic (non-capsular) antigens from the two varieties of Cryptococcus has been investigated . Cytoplasmic antigens from C . neoformans (one clinical isolate and one acapsular mutant of var . neoformans and two clinical isolates from var . gattii) were subject to isoelectric focusing, SDS-PAGE and Western blotting; patients sera was then used in the immunoenzyme development of the Western blots . The humoral response from the 20 patients (all HIV+) infected with var . neoformans against the var . neoformans antigens was predominantly IgG based, with a large number of bands recognised: the most commonly recognised bands were at 26, 52, 74, 100, 115 and 144 kDa . The IgM response was less pronounced and the IgA response was practically non-existent . The humoral response of the sera from the 15 patients (all but one HIV-) infected with var . gattii against var . gattii antigens was also predominantly IgG based with bands at 37, 55, 65, 74, 94 and 115 kDa being most commonly recognised . Periodate treatment of cytoplasmic antigens reduced the intensity of antigen recognition, though it did not absolutely destroy reactivity to any individual antigen . Comparison of immunodevelopment of cytoplasmic antigens from both varieties grown at 25 degrees C and 37 degrees C revealed that culture temperature made no differences in the number of bands recognised although there were differences in the intensity of recognition . This is the first report on the pattern of serological recognition of the non-capsular antigens from the two varieties of Cryptococcus and it identifies a number of major antigenic components. Australas J Dermatol, 1997 Feb, 38(1), 29 - 32 Primary cryptococcal cellulitis caused by Cryptococcus neoformans var . gattii in an immunocompetent host; Hamann ID et al.; Primary cutaneous cryptococcal infection is uncommon . The cutaneous manifestations are most often the result of dissemination from the central nervous system or lung, usually in an immunocompromised host; cellulitis is regarded as the rarest cutaneous form . Primary cutaneous cryptococcosis has occasionally been reported in the immunocompetent, the causative organism being Cryptococcus neoformans var . neoformans . We present a case of cellulitis of the right arm in a 75-year-old man caused by Cryptococcus neoformans var . gattii, a fungus which is endemic in Australia and an important cause of infection in the immunocompetent . This is the first case described of a primary cutaneous infection due to Cryptococcus neoformans var . gattii . The interesting ecology of this organism is discussed. Clin Exp Immunol, 1997 Feb, 107(2), 293 - 9 Mannoproteins of Cryptococcus neoformans induce proliferative response in human peripheral blood mononuclear cells (PBMC) and enhance HIV-1 replication; Orendi JM et al.; To investigate the possible role of Cryptococcus neoformans var . neoformans in HIV disease progression, and to identify the responsible cryptococcal components, an in vitro cell culture model was set up to study the C . neoformans-induced enhancement of HIV replication in HIV-1-infected PBMC . Similar to whole C . neoformans, cell-wall membrane fraction and mannoproteins induced proliferation of PBMC and enhancement of lymphotropic HIV replication in HIV-infected PBMC, while galactoxylomannan did not . MoAbs capable of interfering with MHC class II-mediated antigen presentation prevented the induction of cell proliferation by whole C . neoformans or cryptococcal mannoproteins . MoAb binding to adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) also inhibited C . neoformans-induced cell proliferation . In addition, anti-MHC class II MoAb inhibited the enhancement of HIV replication by C . neoformans . The results suggest that: (i) C . neoformans may accelerate HIV disease progression by stimulation of HIV replication through MHC class II-mediated antigen presentation; and (ii) cryptococcal mannoprotein may be one of the responsible components . The ability to enhance HIV replication in PBMC in vitro is not unique for C . neoformans . However, this is the first report to study in detail a yeast-induced enhancement of HIV replication in PBMC. J Leukoc Biol, 1997 Feb, 61(2), 147 - 55 MIP-1 alpha contributes to the anticryptococcal delayed-type hypersensitivity reaction and protection against Cryptococcus neoformans; Doyle HA et al.; Leukocyte infiltration into infected tissues is essential for the clearance of microorganisms . In animals with a cell-mediated immune (CMI) response to the infectious agent, as opposed to naive animals, leukocyte migration is greatly enhanced into sites of the organism or antigen . The role of the,chemotactic cytokine or chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), in the expression phase of the CMI response and in protection against Cryptococcus neoformans was assessed . With the use of a gelatin sponge model in mice as a means of detecting an anti-cryptococcal delayed-type hypersensitivity (DTH) reaction, we found that MIP-1 alpha levels in fluids from cryptococcal antigen (CneF)-injected sponges in immunized mice (DTH-reactive sponges) were significantly increased over levels of MIP-1 alpha in fluids from saline-injected control sponges at 12 and 24-30 h after injection . MIP-1 alpha levels peaked before increases in neutrophils and lymphocytes in the DTH-reactive sponges, suggesting that MIP-1 alpha was responsible, at least in part, for attracting these leukocyte types . Immunized mice treated with neutralizing antibody to MIP-1 alpha before sponge injection with CneF had reduced numbers of neutrophils and lymphocytes in the DTH-reactive sponges and showed reduced clearance of C . neoformans from the lungs, spleens, livers, and brains when compared with controls . Furthermore, injection of rmMIP-1 alpha into sponges in naive mice resulted in an increase in the influx of neutrophils and lymphocytes into the sponges compared with saline-injected sponges . Together our findings provide solid evidence that MIP-1 alpha is a component of the anticryptococcal DTH reaction . In addition, MIP-1 alpha influences neutrophil influx and attracts lymphocytes into the DTH reaction site . Finally, we showed that MIP-1 alpha plays a role in protection against C . neoformans. Antimicrob Agents Chemother, 1997 Feb, 41(2), 331 - 6 Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro; Franzot SP et al.; Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy . Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis . We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C . neoformans, including 11 C . neoformans var . neoformans, 3 C . neoformans var . gattii, and 4 fluconazole-resistant isolates . The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C . neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays . Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination . A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index {FIC} of < or = 0.5) . Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates . Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0) . Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates . No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole . The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C . neoformans. Infect Immun, 1997 Feb, 65(2), 718 - 28 Reactivity patterns and epitope specificities of anti-Cryptococcus neoformans monoclonal antibodies by enzyme-linked immunosorbent assay and dot enzyme assay; Belay T et al.; Cryptococcus neoformans glucuronoxylomannans (GXM) are capsular polysaccharides important for virulence in cryptococcosis . This study used dot enzyme assays (DEA) and enzyme-linked immunosorbent assays (ELISA) to determine the reactivity patterns of 21 murine monoclonal antibodies (MAbs) with structurally defined GXMs from five serotypes . The MAbs were categorized into eight groups on the basis of DEA and five groups on the basis of ELISA . MAbs 302, 339, and 439 were studied extensively for their binding to various native and chemically modified GXMs . Quantitative variation in the inhibitory effects of GXMs on the binding of MAbs 302, 339, and 439 were observed by competitive ELISA . O-Deacetylation of serotype A, B, and D GXM resulted in the complete loss of their inhibitory properties . Carboxyl group reduction of GXMs from serotypes A and D resulted in a significant decrease of inhibitory activity for MAb . Xylomannans and methyl glycosides exhibited no detectable inhibitory activity on MAb binding to GXM . The results indicate (i) the existence of five to eight MAb-defined distinct epitopes in C . neoformans GXM that can elicit antibody responses, (ii) MAb detection of antigenic variation within GXMs assigned to a particular serotype, (iii) good correspondence between the patterns of MAb reactivities and polyclonal rabbit factor sera, (iv) good agreement between MAb molecular structure and serotype reactivity, and (v) a dependence of the serotype reactivity profile for a given MAb on the technique used to measure binding. Infect Immun, 1997 Feb, 65(2), 557 - 63 Cryptococcal polysaccharides bind to CD18 on human neutrophils; Dong ZM et al.; CD18, the beta chain of the beta 2 integrin family of adhesion molecules, is associated with three different alpha chains (CD11a, -b, and -c) and is expressed on the surface of all types of leukocytes . CD18-containing molecules are up-regulated on the surface of neutrophils (polymorphonuclear cells {PMN}) in response to chemotactic agents and are implicated in mediating adhesion to an inflamed endothelium, which is a prerequisite to migration of PMN into infected tissues . In a previous study, we found that a cryptococcal culture filtrate (CneF), when injected into the bloodstream of mice to simulate the antigenemia in cryptococcosis, inhibits PMN accumulation at the site of an inflammatory stimulus . In the present study, we assessed the ability of CneF and its individual components, i.e., glucuronoxylomannan (GXM), galactoxylomannan (GalXM), and mannoprotein (MP), to interact with CD18 on human PMN . CneF labeled with 14C was shown to bind to human PMN in a dose-dependent manner . Pretreatment of PMN with anti-CD18, but not an isotype-matched control monoclonal antibody (MAb) or anti-CD11a MAb, blocked the binding of 14C-labeled CneF to PMN . In addition, CneF, GXM, and GalXM but not MP significantly blocked the binding of the anti-CD18 MAb to CD18 on the surface of unactivated and formyl methionyl leucyl phenylalanine-activated PMN as determined by indirect immunofluorescence staining and flow cytometric analysis . In the same experiments, the cryptococcal polysaccharides did not affect the binding of an anti-CD11a or anti-L-selectin MAb to the surface of PMN at 4 degrees C . The results suggest that CneF and its components GXM and GalXM bind to CD18 on human PMN . Based on our findings, we propose that CD18 is a possible molecular target of cryptococcal polysaccharides and that binding of the polysaccharides to CD18 has the potential to inhibit leukocyte infiltration into inflammatory sites. Infect Immun, 1997 Feb, 65(2), 525 - 30 A role for B cells in resistance to Cryptococcus neoformans in mice; Aguirre KM et al.; The role of B cells in immunity to Cryptococcus neoformans was investigated . Genetically targeted, B-cell-deficient mice (mu Mt) examined at various times after intravenous infection with C . neoformans 184 had lung and brain yeast burdens that were equivalent to tissue burdens in control B-cell-sufficient mice . Both B-cell-deficient and B-cell-sufficient control mice were effectively vaccinated by a sublethal intratracheal instillation of strain 184 yeast against a systemic infection with the C . neoformans strain carrying ura5; vaccinated control and vaccinated B-cell-deficient mice had equivalent brain and lung burdens of the ura5 strain 10 days after intravenous rechallenge . Additionally, B-cell-deficient and B-cell-sufficient vaccinated mice survived an intravenous rechallenge with a dose of yeast cells which is normally lethal for unimmunized mice . In further studies of the role of B cells in murine cryptococcosis, SCID mice were reconstituted with lymphocytes from B-cell-deficient and B-cell-sufficient mice . SCID mice reconstituted with lymphocytes from vaccinated B-cell-deficient animals failed to express effective adoptive immunity to C . neoformans brain infection . In contrast, SCID mice reconstituted with lymphocytes from vaccinated B-cell-sufficient mice had 10-fold fewer yeast cells in their brains than did uninfused SCID controls . However, SCID mice given lymphocytes from B-cell-deficient immune donors had fewer yeast cells in their lungs than did uninfused controls . Fewer CD4+ lymphocytes were recovered at 7 and 11 days after infection from the peripheral blood and spleens of SCID mice reconstituted with lymphocyte suspensions from B-cell-deficient animals than from the peripheral blood and spleens of SCID mice reconstituted with suspensions from B-cell-sufficient control donors . These data suggest that B cells can play an important role in host defense against Cryptococcus in the brain under conditions in which T-cell-mediated immunity is impaired. Infect Immun, 1997 Feb, 65(2), 488 - 94 Biochemical comparison of the Cu,Zn superoxide dismutases of Cryptococcus neoformans var . neoformans and Cryptococcus neoformans var . gattii; Hamilton AJ et al.; Cu,Zn superoxide dismutases (SODs) have been purified to homogeneity from the two varieties of Cryptococcus neoformans, C . neoformans var . neoformans and var . gattii . The N-terminal amino acid sequences of the two enzymes were similar, though not identical, and demonstrated homology with Cu,Zn SODs from other organisms . SOD activity was present in supernatants from stationary-phase cultures of isolates of C . neoformans var . neoformans and was also present from the mid-log phase onwards in cultures of an acapsular mutant of C . neoformans var . neoformans . SOD activity was practically undetectable in culture supernatants from isolates of C . neoformans var . gattii . The C . neoformans var . neoformans SOD had a reduced relative molecular mass of 19 kDa, and in its nonreduced form the enzyme was present as a 125-kDa species . Isoelectric focusing indicated that four species with pIs of 5.9, 6.15, 6.35, and 6.6 were present . The equivalent reduced molecular mass of the C . neoformans var . gattii enzyme was 19 kDa, with a single species present under nonreducing conditions (relative molecular mass of 145 kDa) with a pI of 7.5 . The activities of the enzymes from both varieties were inhibited by KCN; however, the copper chelator diethyldithiocarbamate was inhibitory only against the C . neoformans var . gattii enzyme, as was sodium azide . The C . neoformans var . neoformans SOD was not affected by preincubation for 1 h at 70 degrees C, and it also retained most of its activity when incubated at 37 degrees C relative to its activity when incubated at 20 degrees C, in contrast to the C . neoformans var . gattii enzyme . The pronounced differences in the physical and biochemical characteristics of the Cu,Zn SODs from the two Cryptococcus varieties complement recent reports illustrating the biochemical and genetic differences between C . neoformans var . neoformans and C . neoformans var . gattii, and the successful purification of the two enzymes comprises the first step in determining what role, if any, the cryptococcal Cu,Zn SODs might have in protection against externally generated superoxide. Infect Immun, 1997 Feb, 65(2), 434 - 8 Ferric iron reduction by Cryptococcus neoformans; Nyhus KJ et al.; The pathogenic yeast Cryptococcus neoformans must reduce Fe(III) to Fe(II) prior to uptake . We investigated mechanisms of reduction using the chromogenic ferrous chelator bathophenanthroline disulfonate . Iron-depleted cells reduced 57 nmol of Fe(III) per 10(6) cells per h, while iron-replete cells reduced only 8 nmol of Fe(III) . Exponential-phase cells reduced the most and stationary-phase cells reduced the least Fe(III), independent of iron status . Supernatants from iron-depleted cells reduced up to 2 nmol of Fe(III) per 10(6) cells per h, while supernatants from iron-replete cells reduced 0.5 nmol of Fe(III), implying regulation of the secreted reductant(s) . One such reductant is 3-hydroxyanthranilic acid (3HAA), which was found at concentrations up to 29 microM in iron-depleted cultures but <2 microM in cultures supplemented with iron . Moreover, when washed and resuspended in low iron medium, iron-depleted cells secreted 20.4 microM 3HAA, while iron-replete cells secreted only 4.5 microM 3HAA . Each mole of 3HAA reduced 3 mol of Fe(III), and increasing 3HAA concentrations correlated with increasing reducing activity of supernatants; however, 3HAA accounted for only half of the supernatant's reducing activity, indicating the presence of additional reductants . Finally, we found that melanized stationary-phase cells reduced 2 nmol of Fe(III) per 10(6) cells per h--16 times the rate of nonmelanized cells--suggesting that this redox polymer participates in reduction of Fe(III). Infect Immun, 1997 Feb, 65(2), 405 - 11 Identification of extracellular phospholipase B, lysophospholipase, and acyltransferase produced by Cryptococcus neoformans; Chen SC et al.; We recently identified phospholipase activity as a potential virulence factor of Cryptococcus neoformans . We have now defined the nature of the phospholipase activity produced by a clinical isolate of C . neoformans var . neoformans, under native conditions, by 1H and 31P nuclear magnetic resonance (NMR) spectroscopy and thin-layer chromatography (TLC) of radiolabelled substrates . Glycerophosphocholine was identified by NMR spectroscopy as the sole phospholipid degradation product of the reaction between substrate phosphatidylcholine (PC) and cryptococcal culture supernatants indicating the presence of phospholipase B (PLB) . No lysophosphatidylcholine (lyso-PC) or products indicative of phospholipase C, phospholipase D, or other lipase activity were identified . Use of PC and lyso-PC containing radiolabelled acyl chains and separation of products by TLC confirmed the PLB and lysophospholipase (LPL) activities . Lysophospholipase transacylase (LPTA) activity was identified by the formation of radioactive PC from lyso-PC . Extracellular enzyme production was maximal after 6 to 10 h in fresh medium . Assay conditions were optimized for pH, linearity with time, enzyme concentration, and saturation by substrates to allow comparison with phospholipases from other organisms . LPL activity was 10- to 20-fold greater than PLB activity, with mean (+/- standard deviation) specific activities of 34.9 +/- 7.9 and 3.18 +/- 0.2 micromol of substrate hydrolyzed per min per mg of protein, respectively . The response of PLB to increasing substrate concentrations was bimodal, whereas inhibition of LPL and LPTA activities occurred at concentrations of substrate lyso-PC greater than 200 microM . Enzyme activities were stable at acid pH (3.8), with pH optima of 3.5 to 4.5 . Activities were unchanged in the presence of exogenous serine protease inhibitors, divalent cations, and EDTA . We conclude that C . neoformans produces highly active extracellular PLB, LPL, and LPTA under native conditions. J Immunol, 1997 Jan 15, 158(2), 790 - 9 Effect of serum IgG1 to Cryptococcus neoformans glucuronoxylomannan on murine pulmonary infection; Feldmesser M et al.; Little is known about the role of Ab in protection against pulmonary fungal pathogens . The ability of murine IgG1 mAb 2H1 to modify pulmonary Cryptococcus neoformans infection was investigated in intratracheal infection . mAb 2H1 binds C . neoformans glucuronoxylomannan . mAb 2H1 was given to A/JCr mice 24 h before infection . Two C . neoformans strains were studied: ATCC 24067 (serotype D) and 62070 (serotype A) . Fungal burden was determined by CFU 14 days after infection for both strains, and at 2 h, 24 h, 48 h, 7 days, and 28 days after infection for strain 24067 . On day 14, mAb 2H1 treatment reduced CFU in the lung, brain, and liver for strain 62070 infection . Minor reductions in lung CFU followed infection with strain 24067 in mAb 2H1-treated mice, despite prolonged survival . The limited ability of mAb 2H1 to reduce lung CFU may reflect rapid phagocytosis of yeast by alveolar macrophages, seen by electron microscopy 2 h after infection, regardless of whether mice had received mAb . Alveolar macrophages phagocytosed and reduced C . neoformans CFU in vitro only in the presence of mAb 2H1 . Differences were apparent in phagocytosis and in vitro killing between strains 24067 and 62070 . Serum IgG1 modified the course of pulmonary infection in mice by prolonging survival, reducing CFU, and reducing tissue glucuronoxylomannan Ag . mAb administration was associated with enhanced granulomatous inflammation, but did not prevent infection or dissemination . Despite incomplete protection by serum Ab against pulmonary infection, our results provide encouragement for continued vaccine development. Arch Intern Med, 1997 Jan 13, 157(1), 64 - 9 Fluconazole as prophylaxis against fungal infection in patients with advanced HIV infection; Manfredi R et al.; BACKGROUND: There is limited information regarding the usefulness of primary antifungal prophylaxis in patients with advanced human immunodeficiency virus (HIV) disease . OBJECTIVE: To evaluate the efficacy and safety of oral fluconazole treatment for the prevention of systemic fungal diseases related to the acquired immunodeficiency syndrome . METHODS: We evaluated the clinical records of more than 1300 HIV-infected patients followed up for 6 years to identify subjects with a CD4+ lymphocyte count less than 0.20 x 10(9)/L (200/microL) and no prior systemic fungal disease . We compared 128 patients who received oral fluconazole (100 mg/d every third week) with 121 subjects who received no antifungal treatment . MAIN OUTCOME MEASURES: The occurrence of visceral mycoses or death was considered an end point . The frequency of esophageal candidiasis and extrapulmonary cryptococcosis and their related clinical and laboratory features, as well as overall patient survival, were assessed and compared between the 2 study groups . RESULTS: Subjects not treated with fluconazole experienced a significantly higher incidence of systemic mycoses than patients who received fluconazole: 28.4 vs 8.8 cases per 100 patient-years (P < .001) . Fluconazole treatment was more effective in preventing esophageal candidiasis than cryptococcosis and was more effective in subjects with a CD4+ cell count less than 0.10 x 10(9)/L . Moreover, fungal complications occurred later and were associated with a significantly lower CD4+ cell count among treated vs untreated patients, while the duration of antiretroviral therapy did not play a significant role . Although mortality rates were similar in the 2 study groups, the fatal outcome of disease was less frequently caused by a fungal disease in subjects who underwent fluconazole prophylaxis . Fluconazole had a favorable tolerability profile . CONCLUSIONS: In our experience, primary fluconazole prophylaxis proved safe and effective in the prevention of systemic candidiasis and cryptococcosis in patients with advanced HIV disease but it did not improve overall survival . Prospective controlled trials are advisable to confirm efficacy, to find the drug of choice and its best dosage and schedule of administration, to identify patient subgroups showing the most favorable cost-benefit ratios, and to evaluate the effects on overall life expectancy and the risk of emergence and spread of antifungal drug resistance. J Aerosol Med, 1996 Spring, 9(1), 111 - 22 Liposomal aerosols in the management of pulmonary infections; Gilbert BE; The combination of liposomes and aerosols has been utilized to directly target the lungs with chemotherapeutic agents that might not have been used because of low solubility or toxicity . There are a variety of antibacterials, antifungals, and antivirals that have good in vitro activity, but are not effective because of their systemic toxicity and/or poor penetration into the lungs . Incorporation of many lipophilic drugs into liposomes decreases their toxicity without affecting effectiveness, thus increasing the therapeutic index . We have focused on aerosol delivery of amphotericin B (ampB) for the treatment of pulmonary and systemic fungal diseases . We have tested a variety of ampB-lipid formulations for the optimal treatment regimen for Cryptococcus and Candida infections in mouse models . The AeroTech II nebulizer (MMADs of 1.8-2.2 microns) produced aerosols with the highest concentrations in the breathable range . Pharmacokinetic studies revealed that pulmonary drug was present for hours to weeks . AmBisome retained its anticryptococcal activity even when animals were challenged 14 days after aerosol treatment . Aerosols may also be effective in systemic diseases . In our Candida-mouse model, systemic candidiasis and mortality were reduced by aerosolized ampB-liposome treatment . The ability to utilize lipophilic drugs, to deliver high concentrations of drug directly to the site of infection, and to reduce toxicity makes aerosol liposomes an attractive, alternative route of administration. Acta Med Austriaca, 1997, 24(1), 8 - 9 {Community-acquired pneumonia--current status of pathogen diagnosis}; Mittermayer H; Procedures for the microbiological diagnosis of acute community-acquired pneumonia are based on the expected pathogens . Although a great variety of microorganisms are able to cause community-acquired pneumonia only a few pathogens play an important role in daily practice . The most important investigations are blood cultures and sputum cultures to detect bacteria like pneumococci, Haemophilus influenzae and Staphylococcus aureus as well as antibody tests for Mycoplasma pneumonia and Chlamydia pneumonia . According to anamnesis and clinic presentation tests such as for Legionella or viruses have to be added . Sometimes also rare pathogens have to be considered such as Coxiella burnetii, Leptospira, Hantaviruses, cryptococci or Chlamydia psittaci . The standard procedure for diagnosis of tuberculosis is the microscopical examination and the standardized culture in liquid and on solid media . Amplification methods such as PCR are also useful for a rapid diagnosis . However, the application of amplification procedures alone without culture is not recommended. Rev Pneumol Clin, 1997, 53(2), 79 - 84 {Pulmonary complications of human immunodeficiency virus infection in sub-Saharan Africa}; Domoua K et al.; Based on a selection of articles published in the literature and reports from international AIDS conferences, we present the main pulmonary complications of HIV-infection observed in sub-Saharan Africa . The different clinical studies demonstrate the predominance of infectious complications, mainly tuberculosis (29 to 44%) and bacterial pneumonia (21 to 35%) . The frequency of Pneumocystis carinii pneumonia remains low (5 to 19%) . Other complications (mycobacterial infection, cytomegalovirus, toxoplasmosis, cryptococcus, aspergillosis, interstitial lymphoid pneumonia, Kaposi sarcoma) are less frequent . The autopsy studies report similar results and mention the predominance of tuberculosis and pneumonia due to common germs as well as the low frequency of pneumocystosis . This analysis of work conducted in sub-Saharan Africa clearly indicate that tuberculosis remains the leading cause of morbidity and mortality in HIV-infected patients. Scand J Infect Dis, 1997, 29(2), 205 - 6 CD4 lymphopenia in a patient with cryptococcal osteomyelitis; Kumlin U et al.; Cryptococcus neoformans is a rarely reported cause of osteomyelitis . In most cases, no obvious underlying condition is found . Immunological laboratory data, however, are not generally available . In the present case of cryptococcal osteomyelitis, idiopathic CD4 lymphopenia was detected . This immunodeficiency is found in cases of disseminated cryptococcosis by chance . Possibly, it may be one so far unrecognized underlying condition in cryptococcal osteomyelitis. Folia Microbiol (Praha), 1997, 42(1), 39 - 46 Ascomycetous yeasts associated with naturally occurring fruits in a tropical rain forest; Prada GM et al.; Fruits from twenty different species of angiosperms were collected during the period from November, 1991 to January, 1992 . Two hundred and two strains of yeasts and yeast-like fungi were isolated, of which 74% showed ascomycetic affinity . Candida was the predominant genus, followed by (in descending order of occurrence): Cryptococcus, Kloeckera, Sporobolomyces, Pichia, Hanseniaspora and Bullera . Black yeasts and other strains showing basidiomycetic affinity were also isolated . The genus Candida represented the highest number of identified species and the greatest variety of associated substrates . Among the ascomycetes and their anamorphs, 38 species were identified, with Kloeckera apiculata being the most frequent among the isolates and the one which occurred in the largest variety of substrates . Some of the biotypes designated as Candida sp . A, B, C, D, E, F, G, H, I, and Pichia sp . did not correspond to the standard species description found in the literature, and may represent new species . The strains of yeasts isolated in this study were characterized and incorporated into the Tropical Culture Collection of the Fundaao Tropical de Pesquisas e Tecnologia Andre Tosello, Campinas, Sao Paulo. Zhonghua Yi Xue Za Zhi (Taipei), 1997 Jan, 59(1), 50 - 4 Cryptococcal meningitis and primary CNS lymphoma in a patient with acquired immunodeficiency syndrome: a case report; Wang JH et al.; This report describes a case of cryptococcal meningitis as the initial manifestation of acquired immunodeficiency syndrome (AIDS) . During the admission, computed tomography (CT) of brain revealed multiple lesions with ring-enhancement over the cerebellum, frontal and temporal lobes . Autopsy findings showed diffuse cryptococcal meningoencephalitis and central nervous system (CNS) lymphoma forming multiple round ring abscesses . The case demonstrated that opportunistic cryptococcal infection and primary CNS lymphoma may coexist in a patient with AIDS. J Vet Intern Med, 1997 Jan-Feb, 11(1), 1 - 4 Cryptococcal infection in cats: factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats; Jacobs GJ et al.; The relationship between treatment outcome and location of cryptococcal infection, gender, magnitude of pretreatment cryptococcal antigen titers, results of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) serology, and serial changes in antigen titers during and after treatment were evaluated in a prospective and nonrandomized study of 35 cats with cryptococcosis . A commercial cryptococcal latex agglutination kit (CALAS; Meridian Diagnostic Inc, Cincinnati, OH) was used to detect cryptococcal antigen in sera . All cats were treated with itraconazole (Sporanox; Janssen Pharmaceutica Inc, Titusville, NJ) . Pretreatment mean log titers for serum cryptococcal antigen were not influenced by location of the infection . Treatment outcome was not influenced by gender, location of the infection, or magnitude of pretreatment serum antigen titer . Treatment outcome was influenced by FeLV and FIV status; cats seropositive for FeLV or FIV had a higher likelihood of treatment failure (P = .008) . The cryptococcal antigen titers of cats successfully treated decreased with significant linearity over time during treatment (r = -.64, P < .000001), whereas the corresponding titers for cats not treated successfully did not decrease with significant linearity (r = -.03, P > .9) . For cats in which treatment was successful, antigen titers decreased significantly from pretreatment values by 1.3 orders of magnitude at 2 months after initiation of treatment . By 10 months after initiating treatment, log titers decreased by at least 2 orders of magnitude in all cats successfully treated, and 9 of 16 cats had undetectable titers . In contrast, in 5 of 6 cats in which treatment failed, antigen titers were unchanged or increased in magnitude even after at least 6 months of treatment. Scand J Infect Dis, 1997, 29(1), 51 - 5 Cryptococcosis in Denmark: an analysis of 28 cases in 1988-1993; Knudsen JD et al.; A total number of 31 events of systemic cryptococcal infection in 28 patients was identified in a nation-wide survey over 6 years from 1988 to the end of 1993 . All medical records were reviewed, 24 of the patients were HIV-infected . Meningitis was diagnosed in 25 patients, and fungemia in 8 patients . The most frequent symptom was headache followed by fever . The median duration in days of fever, headache, and other neurological signs/symptoms before diagnosis was 12, 8 and 2 days, respectively, and, after diagnosis and start of treatments 7, 11 and 12 days, respectively . There was a significant correlation between the duration of headache and the duration of neurological signs/symptoms but not between headache and fever . More than 50% of the patients died within 5 months after the diagnosis . In 39% of the cases, the patients were orally treated with various antifungal drugs before the diagnosis . The rate of cryptococcosis (cumulative) in Danish AIDS patients was estimated to be 1.7% . The HIV-positive patients were, at the time of the cryptococcal diseases, profoundly immunocompromised, with a median CD4+ cell count of 18 (range: 0-78)/microliters . From 24 patients at least 1 isolate of Cryptococcus neoformans was typed, all being var . neoformans, identical with serotype A/D. Eur J Clin Pharmacol, 1997, 51(6), 505 - 6 Acute cerebellopathy as a probable toxic effect of flucytosine; Cubo Delgado E et al.; Cryptococcosis is the commonest fungal infection of the CNS and it is an important cause of morbidity and mortality in immunodeficient patients {1} . It has been occasionally described in immunocompetent patients {2} . We report a patient with no predisposing factors who was treated with flucytosine and amphotericin B for cryptococcal meningitis . Following treatment, she developed a reversible acute cerebellar syndrome that was probably secondary to the administration of flucytosine, an adverse effect that has not previously been described {3, 4} . An 87-year old women with no relevant personal or family history was admitted to the hospital for headache, fever, and confusion over the past week . The vital signs, general and neurological examination were normal . In laboratory tests, the urine, urea nitrogen, glucose, bilirubin, electrolytes, aspartate aminotransferase, creatine kinase, alkaline phosphatase, haematocrit, white-cell count, and platelet were also normal . A lumbar puncture was performed which showed: 60 typical lymphocytes per ml, adenosine deaminase (ADA) activity 6 U.l-1 (normal under 4 U.l-1), proteins 75.7 mg.dl-1, and glucose 13 mg.dl-1 with a glycaemia of 120 mg.dl-1 . The microbiology study showed staining and a positive culture for Cryptococcus neoformans, and an antigen titre of 1/2080 . The serology for HIV infection was negative, and other predisposing factors for this fungal infection, such as immunological defects, a lymphoreticular malignancy and sarcoidosis were excluded . A CT scan of the cranial-thoracic-abdominal regions was normal and tumour markers were absent. Trans R Soc Trop Med Hyg, 1997 Jan-Feb, 91(1), 50 - 2 The effect of corticosteroids on visual loss in Cryptococcus neoformans var . gattii meningitis; Seaton RA et al.; In Papua New Guinea visual loss is a frequent sequal to Cryptococcus neoformans var . gattii meningitis in immunocompetent patients . We have previously postulated that visual loss may occur as a result of the immunological response to infection around the optic nerve . This retrospective study set out to explore the effect of corticosteroids on visual outcome . Sixteen patients received varying doses of corticosteroid (mainly 100-250 mg of hydrocortisone daily for the prevention of febrile reactions to amphotericin) and 10 received anticryptococcal therapy alone . Visual deterioration occurred less frequently in those treated with corticosteroids (2/16 {12.5%} vs . 7/10 {70%}, P = 0.007), blindness was less frequent (1/16 {5.3%} vs . 5/10 {50%}, P = 0.018), and in 3 patients vision improved . Corticosteroids may have a role in preventing or halting visual loss in C . neoformans var . gattii meningitis in immunocompetent patients. Trans R Soc Trop Med Hyg, 1997 Jan-Feb, 91(1), 44 - 9 Visual loss in immunocompetent patients with Cryptococcus neoformans var . gattii meningitis; Seaton RA et al.; In Papua New Guinea cryptococcal meningitis occurs predominantly in immunocompetent patients in whom Cryptococcus neoformans var, gattii is implicated in 95% of cases . Ocular complications are common . We have reviewed ophthalmic findings in 82 immunocompetent patients and have attempted to identify those features of the disease that predict an unfavourable visual outcome . Visual loss occurred in 52.6% of survivors and was associated with optic atrophy following optic disc swelling in 60.9% . Progression of disc swelling to optic atrophy was predicted by the presence of an abducens palsy (P = 0.049) and cerebrospinal fluid (CSF) cryptococcal antigen titres > 1:1024 (P = 0.036) . Raised intracranial pressure (defined as opening CSF pressure > or = 300 mm on admission) was not associated with visual loss . Vision deteriorated in 17.3% of patients despite anticryptococcal therapy and in 3.7% it followed curative therapy . The high rate of visual loss in immunocompetent patients with C . neoformans var . gattii infection contrasts with others' experience of immunosuppressed patients with C . neoformans var . neoformans infection, in whom visual loss was rare . This difference may reflect immune mediated optic nerve dysfunction in C . neoformans var . gattii meningitis caused by either compression due to arachnoid adhesions or oedema and inflammatory cell-mediated damage. Gastroenterol Clin Biol, 1997, 21(1), 78 - 81 {Neuromeningeal cryptococcosis and alcoholic cirrhosis}; Artru P et al.; Cryptococcal infections are usually described in immunosuppressed patients, but have also been described in patients with cirrhosis . We report a case of cryptococcal meningitis in a 62 year old man with Child class C alcoholic cirrhosis . Clinical signs associated mental confusion and discrete meningeal stiffness without fever . Diagnosis was confirmed by lumbar puncture which identified specific antigens and isolated Cryptococcus on Sabouraud medium . In patients with cirrhosis, cryptococcal meningitis infection should be considered in cases of isolated and unexplained mental confusion. Nihon Kyobu Shikkan Gakkai Zasshi, 1997 Jan, 35(1), 129 - 35 {Radiographic and pathological findings in 4 patients with pulmonary cryptococcosis}; Hidaka T et al.; We reviewed the records of 4 patients with pathologically diagnosed pulmonary cryptococcosis to determine whether there was any relationship between radiographic and pathological findings . The underlying disease were diabetes mellitus (patient 1), rheumatoid arthritis treated with glucocorticoids (patient 2), and adultonset T cell leukemia (patients 3 and 4) . All radiographs showed multiple nodules, and patchy and localized infiltrates, which progressed to diffuse interstitial infiltration . According to Mark's classification, the pathological findings in patients 1 and 2 showed granulomatous pneumonia, those in patient 3 showed histiocytic pneumonia, and patient 4 had intercapillary cryptococci with no inflammatory response . The granuloma appeared larger in patient 1 than in patient 2 . This concurred with the clinical findings, i.e . large granulomas formed in immunocompetent patients, and diffuse pulmonary infiltrates developed in those whose immune systems had been compromised . When a granuloma formed, roentgenograms showed a well defined nodular shadow, with some nodules developing in the cavity . When granuloma formation became unclear, roentgenograms tended to show localized-to-diffuse infiltration, or interstitial shadows. Eur J Clin Microbiol Infect Dis, 1997 Jan, 16(1), 93 - 7 Pradimicins: a novel class of broad-spectrum antifungal compounds; Walsh TJ et al.; Pradimicins are a new class of antifungal compounds currently undergoing preclinical and early phase I clinical trials . The pradimicin structure is characterized by an aglycone of dihydrobenzo (alpha) naphthacenequinone with substitutions by a D-amino acid and hexose sugar . Pradimicins possess a novel mechanism of action consisting of a specific binding recognition to terminal D-mannosides of the cell wall of Candida albicans, resulting in the formation of a ternary complex consisting of D-mannoside, pradimicin, and calcium that leads to disruption of the integrity of the fungal cell membrane . Pradimicin in the form of BMS-181184 has broad-spectrum in vitro antifungal activity against Candida spp., Cryptococcus neoformans, Aspergillus spp., dematiaceous molds, and the Zygomycetes . Fusarium spp . are comparatively resistant to high concentrations of pradimicin . Initial vivo studies indicate that pradimicins have antifungal activity against experimental murine disseminated candidiasis and disseminated aspergillosis . Early studies indicate an excellent therapeutic index with no major end-organ toxicity . Pradimicins warrant further investigation for treatment of opportunistic mycoses in immuno-compromised hosts. Eur J Clin Microbiol Infect Dis, 1997 Jan, 16(1), 51 - 5 Trends in immunotherapy of fungal infections; Kullberg BJ; Fungal infections are the primary cause of mortality in patients with severely impaired host defense mechanisms, such as neutropenic patients with acute leukemia or those who have undergone bone marrow transplantation . In view of the unacceptably high mortality due to disseminated candidiasis, it is rational to focus on augmentation of host defense mechanisms in addition to conventional antifungal therapy . In vitro, a variety of immunomodulators, including tumor necrosis factor, interferon-g, and the hematopoietic growth factors, enhance the killing of Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans . Various studies have demonstrated beneficial effects of immunomodulatory therapy in animal models of disseminated candidiasis . For further preclinical and clinical studies, recombinant interferon-g, interleukin-1, granulocyte colony-stimulating factor, and the other hematopoietic growth factors are currently the most promising immunomodulators. J Med Vet Mycol, 1997 Jan-Feb, 35(1), 57 - 9 Crytococcus neoformans var . gattii in an AIDS patient: first observation in Mexico; Castanon-Olivares LR et al.; We report the first, as far as we know, Mexican case of meningitis caused by Cryptococcus neoformans var . gattii serotype B associated with AIDS in a female patient . The HIV was transmitted to the patient through a blood transfusion . This patient represents, worldwide, the ninth case of C . neoformans var . gattii in patients with AIDS. J Med Vet Mycol, 1997 Jan-Feb, 35(1), 27 - 31 Asymptomatic carriage of Cryptococcus neoformans in the nasal cavity of dogs and cats; Malik R et al.; Nasal washings, obtained from a random source of dogs and cats, were concentrated by centrifugation and plated onto bird seed agar containing antibiotics . Cryptococcus neoformans var . neoformans was isolated from eight of 56 dogs (14%) and three of 45 cats (7%) . More than 100 colonies of C . neoformans were present on the plates from seven of the 11 positive animals . Absence of cryptococcal antigen in the serum of these animals, and failure to demonstrate yeast-like organisms or significant pathology in nasal biopsies, suggests that the nasal cavity of these animals was not infected by C . neoformans but rather that blastoconidia and/or basidiospores were carried asymptomatically . These findings are discussed in relation to the likelihood of the upper respiratory tract being the primary site for cryptococcal infection in dogs and cats. J Med Vet Mycol, 1997 Jan-Feb, 35(1), 7 - 11 Cell-mediated immunity in HIV seronegative patients recovered from Cryptococcus neoformans var . gattii meningitis; Seaton RA et al.; Cell-mediated immunity was assessed in 37 HIV seronegative healthy patients cured of Cryptococcus neoformans var . gattii meningitis and compared with matched controls using a multitest device which simultaneously injects seven standardized common antigens intradermally . Responses in patients and controls were similar: however, male patients had significantly higher compound (average) scores than controls (P = 0.041) . Male scores were higher than female scores in both patient (P = 0.002) and control (P = 0.017) groups . In eight patients with acute cryptococcal meningitis, seven were anergic to challenge with 5 IU of tuberculin on admission . Two of these patients had positive reactions after treatment . Three of four patients tested prior to treatment with the multitest device were anergic to all seven antigens but all three survivors showed improved responsiveness following cure . These data suggest that patients are immunosuppressed on presentation (due to overwhelming var . gattii infection) but that following cure, cell-mediated immunity improves to its premorbid state . A transient state of immunosuppression prior to the development of the disease cannot be excluded. J Clin Lab Anal, 1997, 11(2), 73 - 7 Comparison between Wako-WB003 and Fungitec G tests for detection of (1-->3)-beta-D-glucan in systemic mycosis; Hossain MA et al.; The limulus factor G reacts with (1-->3)-beta-D-glucan, a major structural component of fungal cell walls . The Fungitec G test is a colorimetric assay that measures the concentration of (1-->3)-beta-D-glucan and is used as a serodiagnostic test for deep mycosis . Wako-WB003 is another assay for (1-->3)-beta-D-glucan that determines the change in turbidity of the gelatin reaction of limulus factor G with (1-->3)-beta-D-glucan . In five rabbits inoculated intravenously with 1 x 10(7) CFU of Candida albicans, the concentration of (1-->3)-beta-D-glucan measured by the fungitec G test increased gradually reaching a peak of 660.9 +/- 427.9 pg/ml (mean +/- SD) 4 days after inoculation, but to 42.225 +/- 41.275 ng/ml on day 6 in the Wako-WB003 test . In one rabbit challenged intravenously with 5 x 10(6) CFU of C . albicans, (1-->3)-beta-D-glucan increased to 101.5 pg/ml on day 4 on the fungitec G test, whereas the level remained below the detection limit of the Wako-WB003 test throughout the course of the disease . We also detected high concentrations of (1-->3)-beta-D-glucan in 11 patients with candidemia, 4 with suspected candidemia, 1 with invasive pulmonary aspergillosis, and 12 patients with aspergilloma . The concentration of (1-->3)-beta-D-glucan measured by the Fungitec G test was > 150, > 1006.8; 312.1, and 55.6 +/- 37.4 pg/ml (range, 20.1-138.0 pg/ml), and by the Wako-WB003 test > 153.000, > 17.70, 153.000 and 2.645 +/- 7.248 ng/ml (range, < 25.20 ng/ml) in these patients, respectively . In contrast, the concentration of (1-->3)-beta-D-glucan in 9 patients with pulmonary cryptococcosis and 6 with superficial candida colonization ranged from < 13.2 and < 15.3 pg/ml in the Fungitec G test and < 0.53 and < 0.12 ng/ml in Wako-WB003 test . There was a weak relationship between the concentration of (1-->3)-beta-D-glucan measured by the Fungitec G test and Wako-WB003 test (r = 0.521) . Our results indicate that the sensitivity of the Wako-WB003 test is lower than that of the Fungitec G test. J Antimicrob Chemother, 1997 Jan, 39(1), 71 - 7 The in-vivo activity of an antifungal antibiotic, benanomicin A, in comparison with amphotericin B and fluconazole; Ohtsuka K et al.; The in-vivo antifungal activity of benanomicin A administered intravenously or subcutaneously was compared with that of amphotericin B and fluconazole using animal models of systemic infections with Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans . The efficacy of benanomicin A in C . albicans infection was more pronounced when administered in multiple doses than in a single dose . This was also true of fluconazole, but not of amphotericin B, which showed no difference between single and multiple dosings . Benanomcin A eradicated C . albicans cells from the kidneys of infected mice in a manner comparable to that of amphotericin B, but more effectively than fluconazole . The histopathological findings obtained from the kidneys of the C . albicans-infected mice confirmed the therapeutic efficacy of benanomicin A . The subcutaneous ED50 values of benanomicin A were 1.30 mg/kg/day (C . albicans) and 19.0 mg/kg/day (A . fumigatus) which were intermediate between those of amphotericin B and fluconazole in the two models . The subcutaneous ED50 value of benanomicin A for C . neoformans was 21.5 mg/kg/day, which was higher than that of amphotericin B. Int J STD AIDS, 1997 Jan, 8(1), 44 - 9 Travels with HIV: the compliance and health of HIV-infected adults who travel; Kemper CA et al.; We examined the effects of travel on the health of a group of HIV-infected adults (n = 89) cared for in a public hospital HIV clinic . In a period of 2 years, 45% travelled to a median of 3 US destinations for at least one week and 20% travelled to at least one international destination for a mean duration of 20 days . At the time of completion of the survey, the majority of these patients were severely immunosuppressed (median CD4+ count, 120/mm3) . A physician was consulted concerning travel before 53% of the trips, but only one person consulted a travel medicine expert . All but one patient (98%) who was receiving medical therapy carried sufficient supplies of medication; 95% estimated their compliance with medication at 75% or better . None of the travellers to developing countries received gamma globulin, but one received yellow fever vaccine . Fifteen travellers (43%) became ill either during their trip or immediately thereafter; 3 required hospitalization . While most illnesses were not severe, 4 patients developed potentially life-threatening infections including coccidioidomycosis, cryptococcosis, PCP, and bacterial pneumonia . This survey provides information by which the clinician can anticipate the health care needs of HIV-infected patients who travel . HIV-infected patients should be more aware of the necessity for medical counsel prior to travel. Infection, 1997 Jan-Feb, 25(1), 27 - 31 In vivo and in vitro antifungal activity of the polyene derivative SPA-S-753 against encapsulated form of Cryptococcus neoformans; Strippoli V et al.; The in vitro and in vivo activity of SPA-S-753 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate), a new water soluble polyene, was compared with amphotericin B against Cryptococcus neoformans in encapsulated (K) and nonencapsulated (N) morphological forms . In vitro tests against 17 isolates of C . neoformans (in K or N form) showed that SPA-S-753 activity is about ten times higher than that of amphotericin B . In direct contact tests the SPA-S-753 cytocidal action was significantly higher than that of amphotericin B; the K cells are, however, less sensitive to the cytocidal action exerted by the two polyenes even when using concentrations 4-fold higher than those used against the N cells and they present a smaller potassium ion release . The cytocidal activity of the two polyenes is favoured by a low electrolyte concentration and an acid pH . SPA-S-753 microbicidal activity by contact in vivo, in mice infected with C . neoformans N cells by i.p . route, is more powerful than that of amphotericin B . In protection tests in mice infected with 10 LD50 of C . neoformans K cells, SPA-S-753 action is again more powerful, but not to a significant degree, than that of amphotericin B . In conclusion, both substances showed a reduced in vitro and in vivo activity against C . neoformans in the K morphological form . Nevertheless our results demonstrate that SPA-S-753 exerts an antifungal overall activity that is more effective than that of amphotericin B under similar experimental conditions. Diagn Cytopathol, 1997 Jan, 16(1), 31 - 4 Fine-needle aspiration biopsy in fungal infections; Das R et al.; To evaluate the role of fine-needle aspiration biopsy (FNAB) in diagnosis of fungal infections, a retrospective analysis of 26 cases of fungal infection is described . The spectrum of various fungi encountered on cytologic microscopy of aspirated material and fungal culture was as follows: Aspergillus sp (16 cases), Cryptococcus neoformans (six cases), Mucorales (one case), Candida sp (one case), Phialophora parasiticus (one case), Sporothrix schenkii and Cladosporium sp (the last two isolated from a single case) . In majority (71%) of cases, fungal infection was not clinically suspected but was picked up on cytologic material in all the cases . An accurate diagnosis based on morphology could be made in 21 cases (80%) . Predisposing factor was found in three patients, two of them had diabetes mellitus and one was on immunosuppression . HIV serology was negative in seven cases tested . Commonest tissue reaction (75%) was foreign body giant cells with foamy macrophages and variable amount of necrosis . Although FNAB is helpful in the rapid diagnosis of fungal infections, culture is essential for more accurate identification. J Oral Pathol Med, 1997 Jan, 26(1), 53 - 6 Oral cryptococcosis: case report of salivary gland involvement in an AIDS patient; Monteil RA et al.; Salivary cryptococcosis was disclosed at autopsy in an AIDS patient with disseminated C . neoformans infection . H & E staining was not suitable to demonstrate the occurrence of C . neoformans in many tissues; Alcian blue gave the best results. Clin Neuropathol, 1997 Jan-Feb, 16(1), 45 - 8 Pathologic correlations between ocular and cerebral lesions in 36 AIDS patients; Leger F et al.; The eyes and brain have rarely been studied simultaneously in AIDS patients . We have examined both the eyes and brain of 36 patients autopsied these past 3 years . Ten cases had concomitant involvement of eyes and brain by the same pathology: cryptococcus neoformans in 1, aspergillus in another, cytomegalovirus (CMV) infection in 5, and B cell lymphomas in 2 (1 patient had the last 2 disorders associated) . One patient presented pericapillary microhemorrhages in the retina of the left ocular globe as well as in the right occipital lobe . Six other patients had isolated CMV retinopathy and 4 others had B cell cerebral lymphomas . Eleven patients with foci of cerebral toxoplasmosis did not have visible cysts of toxoplasma gondii in their retina, in agreement with the other series devoted to the concomitant study of the eyes and brain in AIDS patients . On the other hand, their simultaneous involvement in an AIDS patient must first point to CMV infection. Drugs, 1997 Jan, 53(1), 40 - 73 Drug treatment of HIV-related opportunistic infections; Klepser ME et al.; The AIDS epidemic has led to the emergence of several disease entities which in the pre-AIDS era were rare or seemingly innocuous . Experience of treating these diseases varies . In some instances, such as Pneumocystis carinii pneumonia, there is an abundance of published literature to direct our course of action . However, for many of these newly recognised diseases our treatment experience is limited . Furthermore, in many instances, well controlled trials evaluating treatment modalities in the AIDS population are lacking . We have identified 13 disease entities (P . carinii pneumonia, toxoplasmosis, cryptococcosis, histoplasmosis, Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus, coccidioidomycosis, isosporiasis, candidosis, Kaposi's sarcoma, herpes simplex virus, and varicella zoster virus) and have reviewed the current literature with regard to their treatment. AJNR Am J Neuroradiol, 1997 Jan, 18(1), 107 - 9 Central nervous system cryptococcosis: parenchymal calcification and large gelatinous pseudocysts; Caldemeyer KS et al.; In an 11-year-old immunocompetent girl with protracted cryptococcal infection of the central nervous system, CT showed multiple areas of parenchymal calcification . MR imaging showed large gelatinous pseudocysts around the brain stem . These imaging features and the child's age are unusual for intracranial cryptococcosis. J Neurol Neurosurg Psychiatry, 1997 Jan, 62(1), 96 - 8 Pseudotumour cerebri syndrome due to cryptococcal meningitis; Cremer PD et al.; Three cases are reported of the pseudotumour cerebri syndrome-that is, intracranial hypertension without mass lesion or enlarged ventricles, due to cryptococcal meningitis . In these patients the papilloedema was successfully treated with optic nerve sheath decompression, and the intracranial hypertension with lumboperitoneal CSF shunting . These cases support the concept that pseudotumour cerebri is a syndrome of intracranial hypertension that can be due to any disorder producing obstruction of the CSF pathways at the level of the arachnoid villi . This concept is important because it directs therapy to normalise the intracranial pressure and preserve vision. FEMS Microbiol Lett, 1997 Jan 1, 146(1), 59 - 64 Mycocinogeny in the genus Bullera: taxonomic specificity of sensitivity to the mycocin produced by Bullera sinensis; Golubev W et al.; A strain of Bullera sinensis that secretes a fungicidal thermolabile and protease-sensitive toxin was found . Its killer phenotype was cureless . Ascomycetous, ustilaginaceous yeasts and the members of the Sporidiales are insensitive to the B . sinensis killer toxin . The mycocin acts against tremellaceous yeasts only, except for Cystofilobasidium, Fellomyces and Trichosporon spp . The genera Mrakia, Bullera, Cryptococcus and Udeniomyces are heterogeneous in sensitivity pattern . The different responses of some anamorphic species to this mycocin are often consistent with the origin of the strains and the differences in sexual, chemotaxonomic and physiological characteristics between them. Kyobu Geka, 1997 Jan, 50(1), 55 - 8 {CT-guided localization for thoracoscopic pulmonary wedge resection}; Tajiri M et al.; Recently the identification of small-sized peripheral lung lesions has rapidly increased due to advancements in roentgenology . But for smaller lesions, definitive diagnoses by means of transbronchial or percutaneous biopsy have become more difficult . So we must resort to thoractomic or thoracoscopic biopsy . However, for thoracoscopic surgery palpation is inadequate, so the identification of deep or small lesions is difficult . Thoracotomy seems to be too invasive when used only for examination and not for therapy . Therefore, we tried CT-guided localization for thoracoscopic pulmonary wedge resection . Thus far we have performed CT-guided localization in 24 cases . Immediately prior to thoracoscopic surgery we placed marking devices in or beside the lesions after percutaneous puncture . As marking devices we used Kopans spring hook wire or a Naruke point marker . Pathological diagnoses of these lesions indicated 13 primary lung cancers (11 adenocarcinomas, 1 carcinoid, 1 squamous cell carcinoma), 4 focal fibroses, 2 metastases of renal cell carcinoma, 1 hamartoma, 1 tuberculoma, 1 cryptococcosis, 1 interstitial pneumonia, and 1 subpleural lymph node . The tumor diameters at their greatest dimension ranged from 3 to 33 mm (9.0 +/- 6.6 mm) . The distance from the viceral pleura to the tumor surface ranged from 0 to 24 mm (10.9 +/- 6.7 mm) . In one case pneumothorax occurred due to the shallow position of the tumor and the loss of the marking device . If these problems (pneumothorax, bleeding, loss of marking devices and others) are prevented, CT-guided localization should be performed as soon as possible before surgery . The identification of small peripheral lesions can almost be determined by CT now, so such identification may be the most reliable technique to employ during surgery. Antimicrob Agents Chemother, 1997 Jan, 41(1), 180 - 3 In vitro studies of activities of the antifungal triazoles SCH56592 and itraconazole against Candida albicans, Cryptococcus neoformans, and other pathogenic yeasts; Galgiani JN et al.; We investigated the effects of various assay conditions on the activities of two antifungal drugs, SCH56592 and itraconazole, against seven species of fungi by the broth macrodilution testing procedure proposed by the National Committee for Clinical Laboratory Standards (NCCLS) . For both drugs, which are insoluble in water, the concentration and type of solubilizing agent produced differences in drug activity . Starting inoculum size differences from 10(2) to 10(5) yeast cells per ml resulted in approximately a fourfold effect on the MIC of both drugs, but other significant differences were not observed with variations in synthetic medium composition, pH, buffering reagent, or incubation temperature . Under standardized conditions of reference method M27-T with 1% polyethylene glycol as the solubilizing agent, median MICs of SCH56592 and itraconazole of 60 and 125 mg/ml, respectively, were demonstrated for 110 strains (12 to 23 strains for each of seven species) . Broth microdilution results were typically severalfold higher than broth macrodilution results . We conclude that the NCCLS standard reference method can be applied without modification to the testing of SCH56592 and itraconazole, but particular attention to solubilizing the agents is critical to obtaining consistent results. Antimicrob Agents Chemother, 1997 Jan, 41(1), 156 - 61 The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein; Odom A et al.; The immunosuppressant FK506 (tacrolimus) is an antifungal natural product macrolide that suppresses the immune system by blocking T-cell activation . In complex with the intracellular protein FKBP12, FK506 inhibits calcineurin, a Ca(2+)-calmodulin-dependent serine-threonine protein phosphatase . We recently reported that growth of the opportunistic fungal pathogen Cryptococcus neoformans is resistant to FK506 at 24 degrees C but sensitive at 37 degrees C and that calcineurin, the target of FKBP12-FK506, is required for growth at 37 degrees C in vitro and pathogenicity in vivo . These findings identify calcineurin as a potential antifungal drug target . In previous studies the calcineurin inhibitor cyclosporin A (CsA) was effective against murine pulmonary infections but exacerbated cryptococcal meningitis in rabbits and mice, likely because CsA does not cross the blood-brain barrier . Although we find that FK506 penetrates the CNS, FK506 also exacerbates cryptococcal meningitis in rabbits . Thus, FK506 immunosuppression outweighs antifungal action in vivo . Like FK506, the nonimmunosuppressive FK506 analog L-685,818 is toxic to C . neoformans in vitro at 37 degrees C but not at 24 degrees C, and FK506-resistant mutants are resistant to L-685,818, indicating a similar mechanism of action . Fluconazole-resistant C . neoformans clinical isolates were also found to be susceptible to both FK506 and L-685,818 . Our findings identify calcineurin as a novel antifungal drug target and suggest the nonimmunosuppressive FK506 analog L-685,818 or other congeners warrant further consideration as antifungal drugs for C . neoformans. Antimicrob Agents Chemother, 1997 Jan, 41(1), 30 - 4 T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations; Yotsuji A et al.; T-8581 is a new water-soluble triazole antifungal agent . The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml . For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml . For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml . Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively . Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively . T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg . Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span . The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs . Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order . These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use. J Immunol, 1997 Jan 1, 158(1), 459 - 63 Priming with IFN-gamma restores deficient IL-12 production by peripheral blood mononuclear cells from HIV-seropositive donors; Harrison TS et al.; Production of IL-12 is deficient in PBMC from HIV-infected individuals . Because of recent studies demonstrating that IFN-gamma priming increases the production of IL-12 in normal PBMC, we examined the role of IFN-gamma in the production of IL-12 in PBMC from HIV-seropositive donors . In response to Staphylococcus aureus, production of IFN-gamma and IL-12 was reduced in PBMC from HIV-seropositive compared with that from HIV-seronegative donors . Priming with IFN-gamma, through increases in both IL-12 p40 and p35 mRNA levels, caused a significant increase in IL-12 release by PBMC from both HIV-seropositive and HIV-seronegative donors . However, the increase was greater for PBMC from HIV-seropositive donors, largely restoring the deficit in IL-12 production seen in unprimed cells . In response to Cryptococcus neoformans, Candida albicans, and Mycobacterium tuberculosis, three pathogens that frequently cause opportunistic infections in persons with AIDS, IFN-gamma production was also reduced in PBMC from HIV-seropositive compared with seronegative donors . When primed with IFN-gamma, PBMC from both HIV-seropositive and seronegative donors released substantial and similar quantities of IL-12 in response to these organisms . Taken together, these results demonstrate that IFN-gamma can restore the deficit in IL-12 production seen in HIV infection. Infect Immun, 1997 Jan, 65(1), 272 - 8 Cryptococcus neoformans and cryptococcal glucuronoxylomannan, galactoxylomannan, and mannoprotein induce different levels of tumor necrosis factor alpha in human peripheral blood mononuclear cells; Chaka W et al.; Tumor necrosis factor alpha (TNF-alpha) release by peripheral blood mononuclear cells (PBMC) during disseminated infection by Cryptococcus neoformans may initiate and amplify the immune response of the host, leading to elimination of the fungus . The ability to induce TNF-alpha in PBMC by four clinical strains of C . neoformans, a laboratory strain (NIH 37), and the purified cryptococcal components glucuronoxylomannan (GXM), galactoxylomannan (GalXM), and mannoproteins (MP1 and MP2) were investigated under different opsonic conditions .