Onygenales, plectomycetous ascomycetes, is a group that has many parallels with Eurotiales (teleomorphs of Aspergillus and Penicillium). This order has many dermatophytic fungi and has long been of medical interest. It has the following four families:
The Arthrodermataceae comprise a homogenous group based on ascospore morphology, peridial characteristics, and in having an aleurioconidial anamorphic state in the genera Chrysosporium, Microsporum and Trichophyton.
The Gymnoascaceae includes members which have brightly colored ascomata with or without simple appendages, ascomatal peridium of a loose hyphal network, oblate ascospores with a slightly irregular wall and keratinolytic or cellulolytic activity. Unnamed arthroconidia are present in some species.
The Myxotrichaceae is characterized by dark-colored ascomata with or without dendroid appendages, ascomatal peridium of a thick hyphal network, fusoid ascospores that are usually longitudinally striate, arthroconidia (genera Malbranchea and Oidiodendron), and cellulolytic properties.
Genera of the Onygenaceae exhibit a remarkable diversity. notably in the construction of ascomatal peridium. Aphanoascus and Arachnomyces have a cleistothecium with a membranaceous peridium. Amauroascus and Nannizziopsis have a loose network of simple peridial hyphae, while highly specialized ascomata of Onygena have a stalk, the hyphae of which are spread out at the apex to form a globose head. The family is usually characterized by pitted ascospores and at least some ability to degrade keratin.

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This paper deals with a DNA sequencing-based phylogenetic analysis and generation of molecular systems for identification of dermatophytes. The DNA sequencing-based analyzing systems provide us with useful tools to clear the way for phylogenetic classification of pathogenic fungi including dermatophytes, as well as for the rapid identification of medically important fungal species. This will contribute to the progress of not only the biology of dermatophytes, but also epidemiology and laboratory diagnosis of dermatophytosis.

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A survey of dermatophytes isolated from patients was made from 1980 to 1996 in Northeast China. We analyzed 2031 strains of dermatophytes, which are positive in culture in 3 provinces (Heilongjiang, Jilin, Liaoning): 742 strains were obtained from the China-Japan Friendship Hospital of Heilongjiang (1980-1993), 846 strains from the 2nd Hospital of Bethuene Medical University (1986-1989), and 443 strains from the People's Hospital of Liaoning Province (1989-1996).
The result of the survey indicated that the main etiologic fungus of dermatophytosis in Northeast China was T. rubrum 1163 strains (57.26%), T. mentagrophytes 402 (19.79%), M. canis 296 (14.57%), E. floccosum 100 (4.92%), T. verrucosum 28 (1.38%), M. ferrugineum 10 (0.49%), M. gypseum 10 (0.49%), T. schoenleinii 4 (0.20%), T. tonsurans 3 (0.15%), and the root 15 strains were Candida albicans (4) Aspergillus (7), Penicillum (2) and Alternaria (2).
The first 3 species are basically the same as those in Beijing, Tianjing, and Taiyuan. M. canis is rarely seen in Huanan, Huazhong, and Qinghai. However, T. verrucosum is notably influenced by geographical factors. Kerion celsi and sycosis trichophytica are caused by T. verrucosum (43.75%) in Heilongjiang. T. verrucosum is hardy and can live in cold areas. It once exploded simultaneously in human and animals in Hellongjiang, Xinjiang, and NingXia China.

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The dermatophyte flora of Japan were reviewed in reports recently published by the Epidemiological Investigation Committee for Human Mycoses in the Japanese Society for Medical Mycology and by some other clinics.
The number of causative dermatophyte species is relatively limited in Japan: Trichophyton rubrum is the most prevalent followed by Trichophyton mentagrophytes and Microsporum canis; other species, Microsporum gypseum, Trichophyton violaceum, Trichophyton verrucosum and Epidermophyton floccosum, are quite rarely isolated.
T. rubrum was isolated from more than 80% of tinea corporis lesions, 90% of tinea cruris and more than a half of tinea pedis. M. canis was isolated mainly from tinea capitis and tinea corporis, and T. mentagrophytes from tinea pedis that is the most prevalent among clinical types.
It is assumed that T. rubrum will become more important as a causative species in parallel with increase of the aged population.

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The author has determined that Trichophyton mentagrophytes and T. rubrum in keratinous particles are viable for several months. A total of 110 colonies was isolated from a hospital environment: 98 (90%) colonies of T. mentagrophytes, 6 (5%) colonies of T. rubrum and 6 (5%) other colonies. This low percentage of T. rubrum is noteworthy since a recent 6-year survey on the epidemiologic investigation of tinea pedis showed T. rubrum was twice as often the cause of tinea pedis as T. mentagrophytes. Dermatophytes in the environment have been believed to be primarily distributed in the keratinous particles shed from the feet of persons with tinea pedis. But cellophane adhesive tapes applied to the planta of 20 tinea pedis patients revealed that fungal filaments were detected not only inside squama but also outside squama. Consequently, T. rubrum outside squama is considered to be viable for only several days in the environment.
T. mentagrophytes was isolated from 75 percent of tinea pedis which appeared to develop during inpatient visits. This finding suggests that T. mentagrophytes which is isolated at a relatively high frequency in communal environments could be a source of infection.

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Since some species of dermatophytes are geophilic or zoophilic, soil and animals should be considered as sources of human dermatophytosis. The dermatophytes M. canis, M. nanum and T. mentagrophytes were isolated from soil samples, as well as M. gypseum complex which lives in soil. As for the zoophilic dermatophytes, M. canis was detected mainly in dogs and cats and T. mentagrophytes in rats, hamsters, rabbits and squirrels. T. verrucosum was also obtained from cattle and goats. It should be stressed that animal apparently harbor and carry the dermatophytes and that house dust can contain large amounts of fungal elements from infected animals.

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One of the key functional parameters determining the immune response to dermatophyte antigen is the nature of cytokines produced by T cells. IFN-γ (T cell-derived cytokine) is involved in the elicitation of delayed-type hypersensitivity (DTH). In response to stimulation by trichophytin, IFN-γ was produced in peripheral lymphocytes obtained from patients with extremely acute inflammatory dermatophytosis. In contrast, markedly lower levels of IFN-γ production were found in chronically infected patients. These results suggest that IFN-γ-mediated DTH is responsible for producing the cutaneous manifestations associated with dermatophytosis and host defenses against dermatophyte infections.
Subcorneal pustules during dermatophytic infections are not a characteristic of DTH. The stimulation of trichophytin significantly enhanced the release of IL-8 from keratinocytes, perhaps accounting for the accumulation of neutrophils beneath the stratum corneum.
It therefore appears that some clinical manifestations of dermatophytosis and host defenses can be attributed to DTH and keratinocyte-stimulation by dermatophyte antigen.

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Over the last decade, among 73 published studies on animal models of dermatophytoses, the backs of guinea pigs, the plantar parts of guinea pigs and other animals were used in 51, 14 and 16 studies, respectively. Animals were infected with Trichophyton mentagrophytes, T. mentagrophytes var. quinckeanum, T. rubrum, Microsporum canis and other dermatophytes in 61, 4, 3, 11 and 4 studies, and experiments were performed to evaluate antifungal agents and for other purposes in 50 and 23 of theses.
In experimental dermatophytoses on the backs of guinea pigs, the induced lesions are stereotyped and follow the same course, but they are quite different from human dermatomycoses clinically and histologically, and they heal spontaneously. Experimentally induced lesions on the plantar parts of guinea pigs closely resemble human tinea pedis histologically, clinically and in terms of chronicity. The lesions on the backs of hairless guinea pigs resemble human tinea corporis more than those of hairy guinea pigs. The lesions on the backs of mice are useful for immunological analysis of dermatophytoses. The lesions on the human skin grafted on the backs of nude mice are models of dermatophytoses in cellular-immunodeficient patients.

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This report discusses recent progress in the treatment of dermatophytosis. The fundamentals of treatment have not changed, however, in recent years, many antifungal drugs including fluconazole, itraconazole, and terbinafine have been developed. In selecting the best possible regimen, three points should be considered: 1. the spectrum of activity, 2. the mode of action, and 3. the pharmacokinetic profile. Since systemic antifungal drugs have proven to be safe and to have minimal side effects, we are now able to use them easily and to try new treatments. First, topical treatment with terbinafine cream against serious tinea pedis showed an excellent rate of 81%; however, a comparison test between terbinafine cream on the right foot and sulconazole cream on the left foot found no difference between them. Second, in intermittent and pulse therapy the systemic antifungal drugs showed excellent results against tinea glabrosa, tinea unguium and kerion celsi. These treatments are easy to perform and have been demonstrated to provide excellent results. Third, combination therapy of topical and systemic drugs, which is given only as an example, showed an excellent success rate of 70-80% against serious tinea pedis. There is no doubt that, with the introduction of these new antifungals, further developments will be made in the treatment of dermatophytosis.

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A case of a 9-year-old female with chronic mucocutaneous candidiasis (CMCC) is described. She had onychomycosis and stomatitis at the age of 5, and developed deep dermal nodules on the scalp 1 year ago. Histological finding in PAS stain revealed fungal elements in the upper dermis. Candida albicans was cultured from the lesions. Lymphocytic transformation test to Candida showed hyporeponsiveness, but delayed dermal reaction (delayed-type hypersensitivity) to Candida was normal. She had no other disorder such as endocrine failure. Treatment with fluconazole was successful. Her mother was CMCC with hypothyroidism and her brother had candidial stomatitis, so this patient was diagnosed with familial CMCC.

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An elastolytic proteinase was isolated from Aspergillus flavus by column chromatography using diethylaminoethyl (DEAE)-cellulose and carboxymethyl (CM)-Sephadex C-50. The proteinase was found to be homogeneous as indicated by a single band after disc polyacrylamide gel electrophoresis (PAGE). The enzyme had a molecular weight of 40, 000Da as determined by sodium dodecyl sulfate (SDS)-PAGE.
The elastolytic activity was inhibited by leupeptin, diisopropyl fluorophosphate (DFP), α₁-antitrypsin, α₂-macroglobulin and ethylenediaminetetraacetic acid (EDTA). However, neither N-bromo-succinimide (NBS) nor antithrombin-III showed any inhibitory effect on the enzyme activity. The enzyme contained 414 amino acid residues and exhibited an isoelectric point of 8.6. Its carbohydrate content was calculated to be 3.6% using glucose as a standard, but elastolytic proteinase from A. fumigatus did not contain any carbohydrates. The Aα, Bβ and γ chains of human fibrinogen were cleaved by the enzyme.
Elastolytic proteinase from A. flavus hydrolyzed Ser(9)-His(10), Val(12)-Glu(13), Glu(13)-Ala(14), Ala(14)-Leu(15), Leu(15)-Tyr(16), Tyr(16)-Leu(17), Glu(21)-Arg(22), Phe(25)-Tyr(26), Tyr(26)-Thr(27), Pro(28)-Lys(29) and Lys(29)-Ala(30) bonds of oxidized insulin B chain, showing that enzyme has proteolytic activity.
However, elastolytic proteinase from A. fumigatus had a molecular weight of 32, 000Da, and the enzyme did not contain carbohydrate.

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Meth-A fibrosarcoma-implanted mice were examined for protective activity to lethal Candida albicans infection. The number of peripheral blood polymorphonuclear leukocytes (PMNs) was markedly increased in the mice, and their candidacidal function was also activated. The growth of C. albicans in vitro was inhibited by the addition of serum from Meth-A-implanted mice. This activity was inhibited by the addition of an inhibitor of transferrin, ferric sulphate.
These findings indicated that C. albicans cells were efficiently eliminated by the activated PMNs and that the elimination was increased by the serum transferrin in Meth-A-implanted mice.

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In a statistical survey of 3, 978 dermatomycosis patients (7.1% of all new patients) visiting the dermatology clinic of Otaru City Hospital between 1971 and 1988, dermatophytosis (2, 645 cases) was the most freqent complaint followed by cutaneous candidiasis (1, 216 cases), tinea versicolor (96 cases), and other dermatomycoses (10 cases).
Dermatophytosis patients were composed of 1, 840 cases of tinea pedis, 369 tinea cruris, 342 tinea unguium, 277 tinea corporis, 69 tinea manuum (2.3%), 53 tinea faciei, 15 tinea capitis, and 1 tinea profunda. The incidence of tinea pedis and tinea unguium (especially among aged females ) increased during the survey period. The incidence of tinea manuum in Hokkaido district was lower than in any other area in Japan.
Of the 2, 311 samples, 930 Trichophyton rubrum (TR), 542 Trichophyton mentagrophytes (TM), 3 Trichophyton verrucosum, 1 Trichophyton violaceum, 49 Microsporum canis (MC), and 17 Epidermophyton floccosum were isolated. TR was the predominant species in all clinical types except tinea of the scalp and face, and was responsible for 54% of tinea pedis, 88% of tinea unguium, 78% of tinea corporis, and 87% of tinea cruris. The number of patients with tinea pedis due to MC increased after 1978.
Of 1, 216 candidiasis patients, there were 494 infantile candidiasis, 199 erosio interdigitaris, 179 candidial intertrigo, 96 genital candidiasis, 93 candidial paronychia et onychia, 66 oral candidiasis and 89 cases with atypical clinical signs. Temporary increase of infantile candidiasis was observed between 1972 and 1978.

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Cutaneous protothecosis sometimes poses diagnostic and therapeutic problems. Isolation of the causative organism may not be successful and spores may be mistaken for other diseases unless the characteristic sporangia are detected in tissue sections. Because there are few cases, the optimal therapy is still being debated. Our purposes were to detect any characteristic findings of Prototheca wickerhamii under light microscopy in order to aid diagnosis and to determine which drugs were effective. On crystal violet staining we found characteristic bluish dots in Prototheca spores; these correspond to the amyloplasts or dense bodies found under electron microscopy. In vitro the isolated organisms were inhibited by itraconazole, amphotericin B, ketoconazole, and amorolfine and we were able to successfully treat three patients with itraconazole. Crystal violet staining can be helpful in diagnosing protothecosis, especially when the causative organism has not been isolated. The therapeutic effect of itraconazole was confirmed in vivo and in vitro.

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A 19-year-old man with acute lymphocytic leukemia (ALL) FAB classification ALL L2, was admitted to our hospital for induction chemotherapy in September 1992. The patient achieved complete remission after one course of chemotherapy according to the Japan Adult Leukemia Study Group (JAL-SG) protocol. In August 1994, bone marrow biopsy demonstrated a relapse.
The patient was treated with prednisolone and vincristine, followed by therapy with cytosine-arabinoside and L-asparaginase a few weeks later.
Myelosuppression led to a long period of neutropenia, and a high grade fever appeared. He developed erythematous nodules on the penis and right leg. One of these nodules ( about 1cm in diameter) was very inflamed and painful and had a dark black necrotic center. Similar lesions became prominent on the trunk, extremities, and scalp. The biopsy finding of the skin lesion showed separate hyphae and yielded Fusarium solani.
Human recombinant granulocyte colony stimulating factor of 350μg/day was begun.
Amphotericin B was begun at a dose of 1mg/day and increased to 40mg/day. The patient remained severely neutropenic, and new skin lesions appeared. Despite this treatment, he died of septic shock. Culture of the intravenous line catheter showed Pseudomonas aeruginosa. At autopsy, nodules were disseminated through multiple organs, especially the lungs, gastrointestinal tract, kidney, heart, pancreas and muscles. The nodules were about 1cm in diameter with a black necrotic center and partial thrombosis. Histologically, they were areas of deep-seated mycosis due to Fusarium solani.

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A double-blind, comparative study on the usefulness of shampoo containing 0.75% miconazole nitrate (MZS) for the treatment of dandruff was conducted at 8 institutions, using the shampoo vehicle (BSS) without the reagent as the control. The relationship between improvement in clinical symptoms, such as dandruff and itching, and the decrease in the count of Malassezia furfur, that is, mycological response, was also studied.
Of a total of 134 subjects studied, 58 were shampooed with MZS, and 50 with BSS. One hundred thirty of these were included in a safety analysis, and 108 in an efficacy and usefulness analysis. MZS was evaluated as useful in 34 (58.6%) of the 58, and BSS in 19 (38.0%) of the 50 subjects, thus MZS was significantly more useful than BSS (p=0.020). Dandruff improved in 42 (72.4% ) of the 58 with MZS, and in 26 (52.0%) of the 50 subjects with BSS, MZS significantly reduced the dandruff and thus was more effective than BSS (p=0.017).
With regard to the relationship between the mycological response of M. furfur and the efficacy of shampooing against dandruff, the count of M. furfur decreased significantly in the subjects for whom the shampooing was evaluated as effective (p=0.0001), whereas there was no significant difference between the baseline and posttreatment counts in those for whom the shampooing was evaluated as ineffective. Stratification of results of efficacy evaluation according to the baseline count revealed that MZS was more effective than BSS in subjects with relatively high counts of M. furfur (p=0.038). No adverse reactions to either shampoo were observed in any of the 130 subjects.
The above results suggested that MZS is effective against dandruff, and further, that the usefulness of this shampoo shows a relatively close correlation between the improvement in dandruff and decrease in the count of M. furfur.

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Efficacy of anti-dandruff shampoo containing 0.75% miconazole nitrate was evaluated in clinical trials conducted at 8 institutions.
Out of 60 subjects, 58 were evaluated for safety, 49 for effectiveness, excluding those deviating from the protocol, and 50 for usefulness.
In the assessment of effectiveness, of the 49 subjects there was significant improvement in 12 (24%), moderate improvement in 24 (49%), a mild effect in 6 (12%) and no effect in 7 (14%). The final improvement rating of effectiveness was 73%, indicating clinical usefulness of the shampoo. Decrease in dandruff and itching was observed in 82% and 74% of the subjects, respectively.
An adverse effect was seen in one out of 58 subjects (2%), with irritation by miconazole nitrate or one of the basic ingredients of the shampoo being suspected from the results of patch testing. Three days after using the shampoo this subject complained of mild pruritus in the post-auricular region, though there was no visible sign such as erythema. The symptom disappeared without treatment when the individual stopped using the shampoo.
Evaluations by the subjects at the end of the trial showed that dandruff and itching decreased in 76% and 79%, respectively, which corresponded well to evaluations by doctors. Compared with shampoo containing conventional anti-dandruff agents it was also evaluated as more effective by 13 out of 17 subjects (76%).
In conclusion, a shampoo containing miconazole nitrate was found to be effective and safe when used as an anti-dandruff shampoo, confirming its benefits as the first anti-dandruff shampoo with this antifungal agent in Japan.

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