Bruns in 1992 first used nucleotide sequences of the small subunit ribosomal RNA (18S) gene to investigate the evolutionary relationship within the fungi and to construct their phylogenetic trees. The inferred tree topologies are in general agreement with the traditional classification, although some discrepansies exist especially with regard to morphology. The molecular approach permits new and exciting insights never before possible in the study of fungi. Molecular systematics, however, is posing a new problem in the nomenclature of organisms.
The problem is discussed here with reference to Actinomycetes. The name, Actinomyces, was given to the causative agent of lumpy jaw on grounds of its morphology in the lesion. In the pus and diseased tissue actinomyces forms characteristic grains or sulfur granules. The grain consists of a finely meshed filamentous network with a border of radially arranged striations. Accordingly, the prefix actino- was combined with the term -myces meaning fungi. True fungi usually do not form such radially arranged hyphae in the tissue. However, soil microbiologists later broadened the definition of actinomyces to include soil filamentous microorganisms among which streptomyces, nocardia, thermoactinomyces, actino-planes and others are known. With the advent of molecular systematic bacteriology, however, the genus actinomyces was excluded from the realm of actinomycetes and placed in the suprageneric section of actinobacteria. Some examples of morphological relatedness between actinomycetes and fungi which are assumed to be the results of convergent or parallel evolution are also discussed. In the course of updating the International Code of Botanical Nomenclature, it seems important to resolve the conflict between morphological and genetical characters from the viewpoint of nomenclature.

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Development of antifungal therapy continues to be lively, as we strive to approach the ideal therapy. The newest agents include lipid delivery systems for amphotericin B, which promise relief from some of that drug's side effects. The triazoles, itraconazole and fluconazole, have proven their value as non-toxic and orally effective therapy. Newer members of this class, e. g., SCH 56592 and voriconazole, appear to be promising extensions. To date the triazoles' properties enable new strategies of prophylaxis and of early intervention. Areas needing improvement include treatment for newer fungal pathogens not covered by available therapy, and the need for rapid diagnostic capabilities, comparative clinical trials, and better definitions and scoring in trials. Drugs with new and fungal-specific targets may provide a quantum leap in our weaponry. Examples included drugs targeted at chitin synthase (e. g., nikkomycin Z) or beta glucan synthase (e. g., LY303366). Another approach is immunomodulation, and several cytokines can stimulate the host synergistically with conventional antifungal therapy.

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Aspergillus species, especially A. fumigatus is known to cause a wide spectrum of illness, however, the pathogenic mechanisms are still poorly understood. We investigated the effects of A. fumigatus mycotoxins (gliotoxin, fumagillin, helvolic acid, and Asp-hemolysin) on human phagocytic functions in vitro, and demonstrated that these mycotoxins interfered with inhibition of conidia germination by AM, migration of PMN, superoxide anion release from PMN and hyphal damage by PMN in vitro. These suppressive effects of A. fumigatus mycotoxins were dose dependent, with relative potencies of gliotoxin>>fumagillin≥helvolic acid>>Asp-hemolysin. A. fumigatus mycotoxins, especially gliotoxin may play important roles in the pathogenesis of pulmonary infection by A. fumigatus, presumably via suppression of the phagocytic functions, since these functions are the central parts of the host defence network against Aspergillus species.

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An elastase was isolated from Aspergillus fumigatus by four step column chromatography. This enzyme had a molecular weight of 32, 000Da, optimum temperature of 37°C, and optimum pH of 8.0; collagenase activity was also detected. We infused the enzyme into the trachea of a guinea pig and observed pathological changes in the lung. Strong changes, in which many inflammatory cells such as neutrophils, fibrine-like substances, and erythrocytes filling the alveoli were observed, causing presentation of a hemorrhagic pneumonia.
Next, we studied the possibility of clinically applying the fungus in treatment by inhibiting its enzyme activity. Ulinastatin, a strong inhibitor against various pancreatic enzymes and human neutrophil elastase, is a glycoprotein with a molecular weight of about 67, 000Da, and was separated from human urine and purified. The elastase activity from Aspergillus fumigatus was inhibited by this enzyme inhibitor. Thus, Ulinastatin was administered by intravenous drip infusion concomitantly with antifungal agents and hemostatics to patients of pulmonary aspergillosis.
The early disappearance of hemosputum and hemoptysis was seen in 11 out of 23 episodes in 14 patients. The treatment had no related side effects, and thus was considered valuable.

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Asp-hemolysin from Aspergillus fumigatus (A. fumigatus) Fresenius-Muramatsu is a heat-labile protein toxin, which causes lysis of a wide range of erythrocyte species in vitro. The mature Asp-hemolysin consists of 126 amino acid residues, which is deduced from the nucleotide sequence of Asp-hemolysin cDNA and the N-terminal amino acid sequence of purified Asp-hemolysin. The relationship between the biological activities of Asp-hemolysin and the infection of A. fumigatus in mice was examined. With simultaneous inoculation of viable spores and Asp-hemolysin in mice, Asp-hemolysin showed a tendency to help the realization and expansion of infection. Actually, the secretion of Asp-hemolysin from mycelia in the foci of infection was immunohistochemically observed in the kidney and brain. In histopathological aspects, necrotic lesions of various degrees were observed in the heart and liver of mice inoculated with Asp-hemolysin, and the toxin was definitely bound to arterial walls in the kidney and brain. Asp-hemolysin showed high cytotoxicity to human leukocytes and guinea pig peritoneal macrophages in vitro. We also found that, depending on the levels of protein or mRNA, several clinical isolates of A. fumigatus also produce Asp-hemolysin. Our results indicate that Asp-hemolysin with multiple biological functions may play an important role as a virulence factor in the pathogenesis of infection by A. fumigatus.

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Genus Aspergillus is an important causative allergen/antigen of a variety of allergic pulmonary diseases such as bronchial asthma, allergic bronchopulmonary aspergillosis and hypersensitivity pneumonitis. Not only A. fumigatus but also A. restrictus and A. versicolor have been cultivated from housedust and shown to sensitize humans so that they produce IgE antibody. A. fumigatus is known as the most common causative allergen/antigen of allergic bronchopulmonary aspergillosis (ABPA). In Japan A. oryzae is also an important causative allergen/antigen of ABPA as it affects workers in factories of soybean product such as soysauce and soybean paste. Homology to the mitogillin family, manganese superoxide dismutase and peroxisomal membrane proteins have been reported as major allergens of A. fumigatus.

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Non-invasive pulmonary aspergillosis is generally accepted as a non-active and static condition because the passage is long and the subjective symptoms are mild in the early stage. New concepts of “semi-invasive pulmonary aspergillosis” and “chronic necrotizing pulmonary aspergillosis” have recently been acquiesced citation. However, these new categories have caught confusion of the terminology and improper clinical application because of their incomplete definition. The process of typical pulmonary aspergilloma has still not examined. By X-ray image, we analyzed the progression of non-invasive pulmonary aspergillosis in 41 patients. These were able to recognize all passages until full development of the disease from prior to the individual's recovery from the preceding lung disease. We found that non-invasive pulmonary aspergillosis does not progress in only one direction, but repeatedly become worse and then improves. This process ultimately leads to a largely destroyed pulmonary parenchyma and a fatal outcome. Non-invasive pulmonary aspergillosis has a dynamic course, and we therefor do not believe that a distinction of “semi-invasive pulmonary aspergillosis” is needed. Once fungus ball formation is confirmed, the anti-fungal drugs available at present are not effective for treatment. Early diagnosis and early chemotherapy is critical.

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In addition to a histological study on experimental pulmonary aspergillosis in rats, pulmonary lesions from 54 autopsies of invasive pulmonary aspergillosis were examined. Three distinct patterns were seen in the lesions of autopsied lungs. The pathological characteristics of each patterns were affected by three important factors: the width and type of necrosis, the distribution of fungi and the degree of the neutrophilic response. The neutrophilic response might play an important role in creating a cavity in the center of the lesion as well as transforming from coagulation necrosis to colliquative necrosis. Furthermore, cytotoxic agents released by the aspergilli and local ischemia might be important factors which modify the features of lesions.

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The effects of the kampo medicine, Juzen-taiho-to (TJ-48) on the capacity to produce tumor necrosis factor α (TNF) of Candida albicans-infected mice was examined. ICR mice was challenged intravenously with Candida albicans and given TJ-48, which had been reported to prolong the life span of Candida-infected mice, at 6hr after Candida infection. No TNF activity was detected in the sera of these mice within 24hr after the infection. Sera of the animals were tested 2hr after intraveneous injection of the TNF-inducer, OK432, to estimate the capacity to produce TNF. TNF levels of the sera of the OK432-injected mice infected 3-6hrs earlier or 24-48hrs earlier were significantly higher or lower than those of uninfected mice, respectively. Oral administration of TJ-48 significantly prevented repression of the capacity to produce TNF in C. albicans-infected mice.

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Tinea unguium was originally looked upon as a recalcitrant disease. Griseofulvin (GRF) has been the only effective drug for treatment of tinea unguium for the past thirty years, however, the cure rates reported in earlier studies, all of whose observation periods were less than one-and-a-half years, were controversial. Since nail changes by tinea unguium are extremely slow, a long-term follow up study is necessary to better evaluate the effectiveness of GRF. We have studied patients with tinea unguium treated by this drug for thirty years. This is the longest observation period for this kind of study that has ever been made. Over that time, the mean age of patients rose slightly, but the treatment period did not change significantly. The overall cure rate treated by GRF is 32.4% (91/281), but the cure rate for patients successfully followed-up over 4 months is 52.9% (91/172). Adverse effects occur in 8.5% (24/281) of the patients but are not dangerous. Our data suggest that over half of the patients successfully followed-up over 4 months are cured at last, and there is no severe adverse effect caused by GRF even over a longer period. We therefore conclude that GRF is an effective and safe drug for treatment of tinea unguium if patients are able to continue the treatment over 4 months.

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