Further observations on the mechanism of reticuloendothelial blockade.

The mechanism of the reticuloendothelial "blockade" which followed injection of large quantities of chromic phosphate without exogenous stabilizing material was investigated in Wistar rats. The RE blockade observed for several hours after induction appeared related to the continuing circulation of the chromic phosphate-blockading dose, and a reduction in the size of the particles used enhanced blockade. RE blockade appeared to be particles specific and was not related to a generalized depression of RE-phagocytic cell function. Studies in isolated perfused rat livers appeared to eliminate saturation of particle-specific macrophage clones as a likely explanation of blockade, and blockade could not be explained on the basis of depletion of serum opsonins. In the system employed, it is postulated that blockade occurs when large numbers of circulating particles saturate specific macrophage cell membrane-binding sites rather than from physical stuffing of RE-phagocytic cells.

Leukocyte antimicrobial function in patients with leprosy.

Patients with lepromatous leprosy are unresponsive to lepromin skin-test material and possess defective lymphocyte function in vitro, including impaired mitogenesis in response to antigens of Mycobacterium leprae. It has been claimed that their macrophages cannot digest M. leprae in vitro; such a defect could explain both lepromin nonreactivity and impaired lymphocyte function on the basis of failure of the afferent limb of the immune response (i.e., defective macrophage "processing" of M. leprae). The present studies indicate that macrophages from patients with lepromatous and tuberculoid leprosy and from normal donors do not differ in their ability to digest heat-killed M. leprae in vitro, or in their ability to sustain the viability of M. leprae in tissue culture; that monocytes, macrophages, and polymorphonuclear leukocytes of leprosy patients and controls possess equivalent microbicidal activity against Listeria monocytogenes, Escherichia coli, Proteus vulgaris, Staphylococcus aureus, and Candida albicans; and that polymorphonuclear leukocytes from patients with lepromatous leprosy iodinate ingested bacteria normally. Whether the basic immune defect leading to the development of lepromatous leprosy resides in the lymphocyte or in the macrophage remains to be determined. However, the present study shows that phagocytic cells from patients with either principal form of leprosy function normally in a variety of sophisticated tests of antimicrobial function.

Reconstitution of the vitamin D-responsive osteocalcin transcription unit in Saccharomyces cerevisiae.

The human osteocalcin gene is regulated in mammalian osteoblasts by 1,25(OH)2D3-dependent and -independent mechanisms. The sequences responsible for this activity have been mapped to within the -1339 region of the gene. We show here that this enhancer region functions analogously in Saccharomyces cerevisiae cells engineered to produce active 1,25(OH)2D3 receptor. When fused to the proximal promoter elements of the yeast iso-1-cytochrome c gene, the enhancer demonstrated substantial promoter activity. This activity was elevated further by 1,25(OH)2D3 when the reporter constructs were assayed in cells containing the 1,25(OH)2D3 receptor. This system affords a model for 1,25(OH)2D3 action and represents a simple assay system that will enable definition of the important cis-acting regulatory sequences within the osteocalcin gene and identification of their cognate transcription factors.

Pityrosporum folliculitis. Its potential for confusion with skin lesions of systemic candidiasis.

Development of an erythematous, papulonodular to papulopustular skin eruption in four febrile, immunocompromised patients raised the possibility of a systemic mycosis when Gram's stains of unroofed lesions disclosed budding yeasts. Candidiasis, torulopsosis, sporotrichosis, and cryptococcosis were considered in the differential diagnosis, and therapy with amphotericin B was begun. Skin biopsy specimens disclosed fungi to be located exclusively within intact and ruptured hair follicles. Inability of the fungi to grow on media that were not supplemented with lipid and their structure and location all suggested the presence of Pityrosporum sp. When hematogenous dissemination of a mycosis to the skin is suspected, the diagnosis must be based on biopsy specimen demonstration of dermal invasion, ideally with positive cultures. Pityrosporum sp, common skin saprophytes, may produce folliculitis, and be mistaken for pathogenic yeasts.

Amikacin therapy of patients with multiply antibiotic-resistant Serratia marcescens infections: development of increasing resistance during therapy.

Over a recent 22 month period, 222 patients in two adjacent hospitals became infected with a multiply antibiotic-resistant strain of Serratia marcescens; 13 were bacteremic. Nineteen patients with clinically significant infections received amikacin. Nine of 11 patients with urinary tract infections were cured. In contrast, only one of eight patients with pneumonia or other deep tissue infections was cured and four died. These eight patients were severely ill; many had infections with multiple microorganisms. In four of five patients in whom the infection failed to clear promptly. Serratia strains became increasingly resistant to amikacin during therapy and these strains contributed to the death of two of these patients. Amikacin proved useful in treating patients with infections due to gentamicin-resistant S. marcescens organisms, especially urinary tract infections. However, the capacity of some strains of S. marcescens to develop resistance to amikacin may limit the usefulness of this antibiotic in the treatment of deep tissue infections which involve this microorganism.

Amphotericin B in the treatment of coccidioidomycosis.

In the 25 years since its introduction, amphotericin B has demonstrated clear value in the management of coccidioidomycosis. However, its effectiveness is less certain than in diseases due to other fungal aetiological agents, even when the loci of infection and in vitro drug susceptibilities are identical. The refractoriness of coccidioidomycosis may relate to the unique ability of each Coccidioides immitis spherule to release hundreds of endospores, thus maximally challenging host defence mechanisms. Amphotericin B is most likely to be effective where there is evidence of intact cell-mediated immunity against C. immitis (i.e. positive coccidioidin or spherulin skin test; low titre of complement fixing antibody), and structural damage to tissues. When bones and joints are involved, as is frequently the case, adjunctive surgical management is generally required. Patients with structural lung disease (i.e. cysts and/or cavities) show variable, often minimal, response to treatment. Amphotericin B has transformed coccidioidal meningitis from a routinely fatal disease to one where prolonged survival is possible. However, the drug must be given by the intrathecal route, and for periods of years, before the possibility of cure can be considered. Relapses of bone, joint and meningeal coccidioidomycosis are common and should be anticipated, especially in patients with impaired immunity.

Murine amebiasis: the role of the macrophage in host defense.

The congenitally athymic nude (nu/nu) mouse was studied as a model for amebic liver disease, using Entamoeba histolytica. Despite intrahepatic inoculation of massive numbers of amebae, we could not produce sustained infections in nu/nu mice. We also failed to induce hepatic amebiasis in thymus-intact nu/+ and +/+ littermates, or in nu/+ mice pretreated with rabbit antimouse thymocyte globulin. Humoral response was measured in both the nu/nu and nu/+ mice. Nu/+ but not nu/nu animals developed a specific IgG response after challenge with E. histolytica. There were no significant IgM responses. Pretreatment with silica increased susceptibility of both nu/nu and nu/+ mice to development of liver abscesses. These studies suggest that host resistance in murine amebiasis is critically dependent upon the macrophage, but not upon T cell-mediated defenses.

Autochthonous cutaneous-subcutaneous leishmaniasis on Taiwan.

Leishmaniasis was not considered to be endemic on Taiwan, but during and after World War II a number of cases of kala-azar and post-kala-azar dermal leishmaniasis have been seen. The majority of the cases occurred in soldiers (Japanese and Chinese) who acquired infections on the China mainland. This paper presents the first reports of autochthonous cutaneous-subcutaneous leishmaniasis in 2 native-born aborigine Taiwanese.

Activities of newer beta-lactam antibiotics against ampicillin, chloramphenicol, or multiply-resistant Haemophilus influenzae.

The susceptibilities of singly or multiply-resistant clinical isolates of Haemophilus influenzae were determined by agar dilution to aztreonam, imipenem, and six third-generation cephalosporins. These included selected isolates that were resistant to ampicillin only, chloramphenicol only, and four isolates that were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. All of the isolates were highly susceptible to these newer beta-lactam antibiotics. Isolates resistant to trimethoprim-sulfamethoxazole and/or chloramphenicol had susceptibilities similar to those of strains resistant only to ampicillin. Ceftriaxone, ceftizoxime, and cefotaxime were the most active of the study antibiotics (MIC90 = 0.004-0.016 micrograms/ml), and were also bactericidal at concentrations no more than twice the minimum inhibitory concentration (MIC). Minimum inhibitory concentrations of cefoperazone increased dramatically with only a 10-fold increase in inoculum size of beta-lactamase producing strains, while MICs of the other new agents were not significantly affected by elevation of the inoculum. These new antibiotics appear to be promising candidates for therapy of infections due to resistant H. influenzae.

Development of amphotericin B-resistant Candida tropicalis in a patient with defective leukocyte function.

Emergence, during therapy, of fungi resistant to amphotericin B is purportedly rare, as fungi with altered cell membrane ergosterol content are considered too fragile to survive normal host defenses. Progressive amphotericin B resistance arose in a strain of Candida tropicalis isolated repeatedly from the urine of a patient with pyelonephritis. The most resistant isolate (R-2) lacked cell membrane ergosterol, the usual attachment site for amphotericin B, and was not inhibited by greater than 500 micrograms/ml of the drug. R-2 infected and killed embryonated eggs, but was unable to produce progressive renal infection in steroid-treated mice because of a reduced capacity to produce pseudomycelia. Persistent infection of the patient by this altered fungus was attributed to defective leukocyte candidacidal activity, especially marked in autologous serum, and to defective Candida-related cell-mediated immunity. A literature review suggests that amphotericin B resistance may not be as rare as many authorities have indicated. It is apparent that few laboratories routinely monitor fungi for amphotericin B susceptibility. In patients with defective antimicrobial defenses, amphotericin B-resistant fungi may survive, produce progressive infection, and require alternative chemotherapy for eradication.

Hepatic granulomas in leprosy. Their relation to bacteremia.

A clinicopathologic study of liver disease was conducted on 28 patients with leprosy who lived in Taiwan. None of the patients exhibited symptoms or signs of liver disease. Hepatic granulomas were found in 21 patients. Histologically, the infiltrates were epithelioid, foam cell, and histiocytic in type. Hepatic dysfunction was absent, except for mild sulfobromophthalein elevations in the severely infected cases. Hepatic granulomas correlated with the cutaneous reactions in lepromatous leprosy, but the association was poor for other stages of disease. Hepatic involvement varied with the severity of cutaneous infection and with the frequency and intensity of bacteremia. An estimated 1,000 to 10,000 acid-fast bacilli/ml of blood was required to generate the hepatic infiltrates.

Introduced leishmaniasis on Taiwan.

Leishmaniasis is not known to be indigenous to Taiwan but a number of imported cases of visceral as well as post-kala-azar dermal leishmaniasis have been seen. Only two autochthonous cases of cutaneous-subcutaneous diseases have been documented in aborigines but no cases of visceral leishmaniasis have been reported. Although a significant number of imported cases of leishmaniasis have been seen, the disease has apparently not been established on the island.