Preliminary study of etidronate for prevention of corticosteroid-induced osteoporosis caused by oral glucocorticoid therapy.

Glucocorticoids (GCs) are widely used for the treatment of various diseases, particularly in dermatology. However, there have been few reports about the outcome of treatment for GC-induced osteoporosis in patients with dermatological conditions receiving oral GCs. The present study was undertaken to prospectively evaluate the usefulness of etidronate for preventing steroid-induced osteoporosis in patients on prolonged GC therapy as routine clinical management. In total, 110 patients receiving oral GC therapy were enrolled into the study. Of these, 87 patients were evaluated (44 patients with collagen diseases, 13 patients with autoimmune bullous dermatoses, 19 patients with chronic eczema/dermatitis, 2 patients with toxicoderma/drug eruption and 9 others). Urinary deoxypyridinoline (DPD) was evaluated as a marker of bone resorption, and serum bone-specific alkaline phosphatase (BAP) as a marker of bone formation. Significant increases in urinary DPD were seen in the control group after oral GC therapy had been continued for ≥ 1 year. Treatment with etidronate suppressed this increase. When the patients were stratified according to gender, this improvement was more obvious in women. No significant difference in serum BAP level was found between the two groups. These results suggest that bisphosphonates may be useful for preventing steroid-induced osteoporosis in dermatology patients (particularly women) receiving oral GC therapy.

Male New Zealand Black/KN mice: a novel model for autoimmune-induced permanent alopecia?

BACKGROUND: Irreversible, permanent and scarring alopecia is associated with several autoimmune diseases, including all autoimmune connective tissue disorders. The pathogenesis of autoimmune-induced permanent alopecia (APA) is still poorly understood, and instructive, simple mouse models for the study of APA are needed urgently. During the course of our studies in a well-established mouse model for chronic rheumatoid arthritis, the New Zealand Black/KN (NZB/KN) mouse, we noticed that ageing male NZB/KN mice developed spontaneous APA. OBJECTIVES: To study whether alopecia seen in ageing male NZB/KN mice displays key features of human APA and may, thus, be a useful new mouse model for clinically relevant APA research. METHODS: NZB/KN, the F1 hybrid of NZW/N Slc x NZB/KN (W/BKN F1), the F1 hybrid of NZB/KN x NZW/N Slc (BKN/W F1), and the F2 hybrid of W/BKN F1 x W/BKN F1 mice were employed in this study, in order to check which strain carries the highest risk of alopecia development. Besides routine histology, CD3, CD4 and CD8 expression as well as immunoglobulin (Ig) G and IgM deposition in hair follicles were investigated by immunohistology/immunofluorescence. Mast cell distribution/degranulation and Ki-67 (proliferation)/TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling) (apoptosis) positive cells were also analysed. RESULTS: Only F2 male NZB/KN mice were prone to develop alopecia, suggesting that Y chromosome-associated gene(s) are involved in the pathogenesis of APA, which incidence rises with increasing age. The lesional alopecia skin in 12-month-old male NZB/KN mice showed a sharp decline in hair follicle density, thus meeting a key criterion of permanent alopecia. Both macroscopically and histologically, the alopecia seen in these mice resembled in many respects different stages of clinical APA, such as alopecia associated with chronic discoid lupus erythematosus (DLE) in humans. Lesional APA hair follicles in mice displayed intrafollicular and perifollicular mononuclear cell infiltrates, as well as an increased number of activated (degranulated) perifollicular mast cells. In the fully developed lesion, many CD4+ cells were seen in perifollicular locations, including the epithelial stem cell region (bulge), and also contained a few CD8+ T cells. IgM deposits were found in the follicular basement membrane zone (BMZ). Both in the bulge and the hair matrix region of the affected anagen hair follicles, there were signs of massive keratinocyte apoptosis. CONCLUSIONS: Our currently available data suggest that male but not female NZB/KN mice may indeed represent a suitable mouse model for APA, with some similarities to the permanent alopecia seen in human DLE patients, although additional and confirmatory investigations are needed before this mouse strain can be accepted as a murine equivalent of APA in humans.

Immunohistochemical staining of cutaneous tumours with G-81, a monoclonal antibody to dermcidin.

BACKGROUND: Recently, the novel antimicrobial peptide named dermcidin (DCD) was reported in human eccrine sweat glands. OBJECTIVES: We investigated the expression of DCD in a variety of cutaneous tumours in order to assess the usefulness of the monoclonal antibody (G-81), which recognizes a fragment of DCD. PATIENTS/METHODS: We studied the immunoreactivity of the G-81 antibody on 197 cutaneous tumours. RESULTS: A total of 13 of 26 cutaneous mixed tumours showed substantial immunoreactivity. In contrast all the following cases were completely unreactive: (i) epithelial tumours (seborrhoeic keratosis, squamous cell carcinoma, Bowen's disease, actinic keratosis, genital Paget's disease); (ii) follicular tumours (basal cell carcinoma, trichilemmoma, trichoepithelioma, trichoblastoma, keratoacanthoma, proliferating trichilemmal tumour, pilomatricoma); (iii) melanocytic tumours (malignant melanoma, naevus cell naevus, Spitz naevus, blue naevus); (iv) neural tumours (schwannoma, neurofibroma, Merkel cell neoplasm); (v) mesenchymal tumours (soft fibroma, dermatofibroma, dermatofibrosarcoma protuberans, vascular leiomyoma, leiomyosarcoma, lipoma, juvenile xanthogranuloma, angiomyoma); and (vi) other sweat gland tumours (poroid neoplasms, syringoma, cylindroma, clear cell hidradenoma, spiradenoma, syringoid eccrine carcinoma, mucinous carcinoma, apocrine cystadenoma, syringocystadenoma papilliferum, apocrine adenocarcinoma). Twenty-six cutaneous mixed tumours were considered from histopathological findings to be the apocrine type, but 13 of 26 mixed tumours contained some DCD-immunopositive cells that possibly differentiate into eccrine secretory glands. CONCLUSIONS: We found the expression of DCD in tubular structures of 50% of cutaneous mixed tumours with apocrine differentiation. These results suggest that a number of cutaneous mixed tumours show both eccrine and apocrine differentiation in the same neoplasm.

Susceptibility of T cell receptor-alpha chain knock-out mice to ultraviolet B light and fluorouracil: a novel model for drug-induced cutaneous lupus erythematosus.

The anticancer agent 5-fluorouracil (FU) frequently induces cutaneous lupus erythematosus (LE) lesions on sun exposed sites. Based on this observation, we have tried to establish a cutaneous LE model of C57BL/6 J (B6) mice, B6 T cell receptor (TCR)-alpha(-/-) mice and B6 TCR-delta(-/-) mice treated with FU and/or ultraviolet B light (UVBL) in order to clarify the role of T cells and the cytokine profile of cutaneous lupus lesions. Cutaneous LE-like skin lesions could be induced in TCR-alpha(-/-) mice with low FU (0.2 mg) plus UVBL, and in B6 mice treated with a high dose of FU (2.0 mg) plus UVBL. In contrast, low FU plus UVBL induced such skin lesions in TCR-delta(-/-) mice at a very low incidence. Specifically, the skin lesions of TCR-alpha(-/-) mice with low FU plus UVBL appeared more rapidly and were more severe than lesions in B6 mice. The former had the common characteristic features of human chronic cutaneous LE such as typical histology, positive IgG at the dermoepidermal junction, low antinuclear antibody and low mortality. Furthermore, a Th1 response was induced in the development of drug-induced cutaneous LE. FU and UVBL-induced cutaneous LE-like eruption is an excellent model for better understanding the pathomechanisms of skin lesion development in LE.

Skin manifestations in acute arsenic poisoning from the Wakayama curry-poisoning incident.

BACKGROUND: Four people died and 63 others became ill after eating arsenic-laced curry served at a community festival in Wakayama, Japan, on 25 July 1998. Although dermatological manifestations after the acute ingestion of arsenic have seldom been documented, they were observed in 56% of the victims in the Wakayama curry-poisoning incident. OBJECTIVES: To characterize the skin manifestations due to acute arsenic poisoning. METHODS: Four of the 67 patients with arsenic poisoning died, and the remaining 63 patients served as subjects for this study. The dermatological findings were extracted from the medical charts at the institutions which admitted the victims, and from the results of a medical inquiry and examinations during a health screening 3 months after the incident. RESULTS: Dermatological findings were observed in 56% of the victims during the acute stage of poisoning. Facial oedema was observed in 13 patients, transient flushing erythema in five, conjunctival haemorrhage in 15, maculopapular eruptions in the intertriginous areas in eight, acral desquamation in 11, and herpesvirus infection in three. The histopathological findings of the maculopapular eruptions showed moderate to marked perivascular infiltration with endothelial swelling. Examination of 21 patients at 3 months after their exposure to arsenic revealed ungual changes including Mee's or Beau's lines in 17 cases, periungual pigmentation in nine, and acral desquamation in four cases. CONCLUSIONS: Our observations indicate that skin lesions are common in patients with acute arsenic poisoning; these findings may provide information of diagnostic significance.

Skin metastasis of neuroendocrine carcinoma derived from the mediastinum.

We report a 46-year-old Japanese man with a metastatic skin tumor on his left palmar region. He underwent resection for a mediastinal neuroendocrine carcinoma in February of 1998. After the operation, he immediately noticed an elevated tumor on his left palm. In September 1999, a brain tumor was discovered. The skin and brain tumors were subsequently removed surgically. Neuron specific enolase (NSE) in the serum was elevated to 25 ng/ml. A skin biopsy specimen from the left palmar site revealed multiple tumor nests which showed the same histological features as the primary mediastinal tumor. Immunostaining was positive for chromogranin, synaptophysin, and NSE but negative for S-100 protein and CD57. To our knowledge, this is the first report of cutaneous metastasis of a neuroendocrine tumor derived from the mediastinum.

Discoid lupus erythematosus (DLE)-like lesion induced by uracil-tegafur (UFT).

A mixture of uracil and tegafur (UFT) is a common antineoplastic agent in Japan. We report a 64-year-old Japanese woman with discoid lupus erythematosus (DLE)-like lesions which were induced by UFT. After surgery to treat lung cancer, UFT (300 mg/day) was administered and she developed round erythema on her right cheek. A skin biopsy specimen taken from the right cheek site revealed atrophy of the epidermis, a slight liquefaction of the basal cell layer, and patchy lymphocytic infiltration in the perivascular and perifollicular regions. A test for antinuclear antibody was weakly positive (80 fold), and rheumatoid factor was slightly elevated (7.6 IU/ml). After discontinuation of UFT, the erythema completely regressed within 2 months. We reviewed 17 cases of DLE-like lesions induced by fluorouracil agents and summarized the common features.

[Renal cell carcinoma in the Birt-Hogg-Dubé syndrome: report of a case].

Birt-Hogg-Dubé (BHD) syndrome is a rare dermatological condition appearing with an autosomal dominant mode of inheritance. It was first reported in 1977 by Birt et al. and 28 cases have been reported since then. BHD syndrome is characterized by asymptomatic dome-shaped, skin-colored papules on the face and upper trunk. Recently, various neoplasms have been reported to associate with BHD syndrome, including three familial and one sporadic cases of renal tumors. We report another sporadic case with renal tumor. A 53-year-old woman complained of gross hematuria and visited our institute on November 1996. She visited the Department of Dermatology, Wakayama Medical College because of skin lesions on the face and upper trunk at her age of 44. These skin lesions were present since her mid twenties. Her daughter also had similar skin lesions and visited the same Department. There was no family history of renal tumor. The patient was diagnosed to have a right renal tumor, and radical nephrectomy was performed. Pathological diagnosis was renal cell carcinoma, papillary type. She underwent interferon injection therapy postoperatively, but died because of lung metastases on April 1997. This is the first reported case of renal tumor occurring in BHD syndrome in Japan.

T1 and T2 lip cancer: a superselective method of facial arterial infusion therapy--preliminary experience.

PURPOSE: To formulate and evaluate a facial arterial infusion chemotherapy for squamous cell lip carcinoma. MATERIALS AND METHODS: The study included six patients (age range, 46-84 years) with squamous cell carcinoma of the lower lip. There were two T1 tumors, three T2 tumors, and one T1-compatible postoperative recurrent tumor. A 4-F, double-lumen balloon catheter was inserted into the external carotid artery through the superficial temporal artery and placed for selective infusion into the tumor-feeding facial artery. Patients received a combination of mitomycin C (4.4 mg/m2 per body surface area) on day 1 and 3.2 mg/m2 of peplomycin sulfate on days 1-7 (22.4 mg/m2 per week), or, when peplomycin sulfate was contraindicated, 16 mg/m2 of cisplatin only on days 1-5 (80 mg/m2 per week). Two to three cycles of chemotherapy were given until tumor disappearance was histologically confirmed. RESULTS: Complete tumor disappearance was achieved in all cases. One patient had a self-limiting asthma attack during peplomycin sulfate treatment, and another had transient partial hair loss. No disfigurement, recurrence, or late complications were observed at a mean follow-up of 5.0 years (range, 2.3-11.2 years). CONCLUSION: The described facial arterial infusion chemotherapy appears to be a safe and curative treatment for T1 and T2 squamous cell lip carcinomas.

Interaction of polyanion against kanamycin ototoxicity.

We studied whether interference of the electron bindings between kanamycin (KM) and the outer plasma membranes of the hair cells with polyanion such as heparin can reduce ototoxicity. In a short course experiment, KM 200 mg/kg/day was injected intramuscularly 23 times with or without 1 U or 0.5 U of heparin/g/day differently to 22 guinea pigs. The reducing effect of heparin against KM ototoxicity was significant from a comparison of the N1 threshold obtained by the cochleogram. The number of surviving outer hair cells in the heparin groups was significantly greater in the third turn than in the group given KM alone. A long course experiment in which 50 injections of KM with or without 0.5 U of heparin were given intramuscularly to 16 guinea pigs revealed from the pinna reflex, cochlear microphonics and cell counting that heparin could reduce ototoxicity slightly at an early stage or before reaching crucial accumulation.

In vitro prediction of aminoglycoside ototoxicity.

The first step by which a basic aminoglycoside (AG) causes ototoxicity is thought to be electron binding to such acidic substances as phosphatidylinositol diphosphate and acidic glycosaminoglycans (AGAGs). We studied the competitive binding ability of AGs and basic dyes to AGAG in order to determine if this mechanism was indeed responsible for ototoxicity. The negative charge of heparin was the strongest among the AGAGs examined when the molar ratio of AG to AGAG was small. Toluidine blue was a better basic dye than acridine orange, methylene blue, alcian blue, or neutral red. After we mixed toluidine blue, heparin and an AG, the absorbance of free toluidine blue was measured at 625 nm. The difference in the free dye released by the well-established AG showed a fairly good correlation with the ototoxic activity found in vivo. However, the predicted ototoxicities of newly prepared AGs were greater than estimated when testing their effects on experimental animals. The basicity of AGs will determine their binding affinities to cochlear hair cell membranes and is an important factor in predicting ototoxicity.

Changes of ground substance in the inner ear in alloxan diabetic mice.

One of the important substances in the ground substance is acidic glycosaminoglycans (AGAGs). Changes of AGAGs in the inner ear and in other organs were investigated using alloxan diabetic mice in order to contribute to the understanding of diabetic hearing impairment. In the diabetic group, gradual increases of AGAGs were observed in each tissue. On the 60th day after alloxan injection, AGAG values were increased 3.5-fold in the cochlea, 2.5-fold in the brain, 13-fold in the liver, twofold in the kidney, and fivefold in the pancreas compared with the control values. It is interesting to note that both the cochlea and pancreas showed continuous increases of AGAGs.