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Recent studies have suggested that cytokines play a critical role in the pathophysiology of alopecia areata; however, no information is available regarding the difference in cytokine profiles in these patients. Serum levels of cytokines, including interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), IL-2, IL-4, and IL-6, were measured using radioimmunoassay or enzyme-linked immunosorbent assay techniques in patients with the localized form and the extensive form (alopecia universalis). The serum levels of IL-1 alpha and IL-4 were significantly elevated in patients with the localized form. In contrast, the serum levels of IFN-gamma and IL-2 were significantly elevated in patients with the extensive form. These results indicate that immune responses in the localized form and the extensive form of alopecia areata are regulated by Th2 cytokines and Th1 cytokines, respectively.

Background and Objective: Eosinophilic pustular folliculitis (EPF) is a distinct inflammatory dermatosis of unknown etiology. The aim of this study is to evaluate the serum levels of cytokines in 3 patients with EPF before and after treatment with indomethacin., Results: Serum levels of interleukin 4 (IL-4) were elevated in patients with EPF. The remission of EPF was associated with increased serum concentrations of interferon gamma with no essential change of serum levels of IL-4., Conclusion: These results suggest that subtle changes in serum levels of cytokines are involved in the remission of EPF and that indomethacin may provide the remission of EPF by altering cytokine production in patients with EPF.

The mechanism(s) and the factor(s) that contribute to preferential localization of fixed drug eruption (FDE) lesions to certain skin sites remain speculative. Previous studies suggested that populations of T cells residing in the lesional epidermis may be involved in selective destruction of the epidermis in FDE. In this study, to define the earliest cellular and molecular events with potential relevance to activation of the epidermal T cells, expression of adhesion molecules on keratinocytes (KC) and vascular endothelium was examined sequentially in the lesional skin of FDE patients after challenge with the causative drug. Rapid and intense intercellular adhesion molecule-1 (ICAM-1) expression was induced on the vascular endothelium and KC as early as 1.5 hours after challenge, at which time E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were not up-regulated. In vitro studies using skin organ culture showed that the lesional KC and endothelium responded more rapidly and intensely to express ICAM-1 to tumor necrosis factor-alpha or interferon-gamma compared with those in the nonlesional skin. Surprisingly, such selective induction of KC ICAM-1 restricted to the lesional skin was also observed after exposure to the causative drug alone in skin organ culture. Pretreatment of the lesional skin with anti-tumor necrosis factor completely abrogated in vitro induction of KC ICAM-1 expression by the drug. Drug-induced, TNF-alpha-dependent KC ICAM-1 expression in the lesional skin suggests that induction of ICAM-1 expression by the lesional KC after ingestion of the drug would probably provide a localized initiating stimulus for activation of the disease-associated epidermal T cells.

Over the 90 year history of dermatology in Japan, about 30 skin diseases have been first described by our colleagues. Although some of them have become well known internationally, many of them are less well known outside of Japan. In this article, we introduce those conditions first described in Japan which are lesser known but have international significance.

A malignant epithelioid schwannoma occurred on the right second toe of a 30-year-old Japanese man. It was a firm, flesh-colored, benign-appearing nodule and measured 13 x 9 mm in diameter and 6 mm in height. To our knowledge, this is the first case of malignant epithelioid schwannoma occurring on the toe. Histopathology was characterized by a circumscribed nodule in the dermis that predominantly consisted of atypical large epithelioid cells with some spindle cells whose proliferation was similar to that of the Verocay bodies seen in ordinary schwannoma. Fontana-Masson staining demonstrated no melanin pigment in the tumor at the light microscopic level. The eosinophilic cytoplasm contained abundant glycogen and was positive for S-100 protein and HMB-45, as usually seen in melanomas. Electron microscopy revealed that there was an abundance of long-spacing collagen in the extracellular matrix, and the cells contained numerous dense-cored granules. But no definite melanosomes were observed in any stage. As far as we are aware, this is the first case of a malignant epithelioid schwannoma showing HMB-45 positivity.

Background: Eosinophilic pustular folliculitis is a distinctive dermatosis that was first described in Japan. Although the histopathologic feature of eosinophilic pustular folliculitis is characterized by follicular infiltrates with numerous eosinophils, its pathophysiology remains unclear. The lesional skin of five patients with eosinophilic pustular folliculitis was examined using several monoclonal antibodies including a variety of anti-leukocyte adhesion molecules: endothelial cell adhesion molecule 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1, by means of immunohistochemical techniques., Observation: Intercellular adhesion molecule 1 expression by keratinocytes was observed on follicular epithelium, but not on epidermis. The migration of eosinophils and lymphocytes, which were intensely positive for antilymphocyte function-associated antigen 1, was limited to follicular epithelium. Endothelial cell adhesion molecule 1 and vascular cell adhesion molecule 1 expression of vascular endothelium was more often observed around hair follicles. There was no reactivity for interleukin 8 in follicular epithelium., Conclusions: These findings may explain the selective migration of eosinophils and lymphocytes to the hair follicles in eosinophilic pustular folliculitis.

Immunohistochemical studies were carried out on the skin lesions of two cases of prurigo pigmentosa. There was a predominance of CD4+ cells in the dermal infiltrate, whereas those lymphocytes in the epidermis were mainly CD8+ cells. The majority of dermal and epidermotropic lymphocytes showed an intense expression of lymphocyte function-associated antigen 1 (LFA-1). The number of CD1+ cells was increased in the epidermis. There was intense expression of ICAM-1 by keratinocytes in the erythematous papules. Focal expression of ICAM-1 was still observed in the residual pigmented areas and could explain the recurrence of the lesions at these sites.

The chemosensory gustatory cells in taste buds form chemical synapses with intragemmal neurites. We investigated the ultrastructure of the guinea pig gustatory cells after stimulation with a mixture of monosodium L-glutamate and guanosine 5'-monophosphate. The gustatory cells responded to the stimulus. The dense-cored vesicles localized in the presynaptic regions discharged the contents into the synaptic cleft by means of exocytosis, which resulted in a marked decrease of their population. These findings strongly suggest that the transmitter or transmitters contained in the vesicles are released in response to the taste stimulation at the cell apex, to conduct the excitement of the cell to the nerves.

The localization of spot 35 protein, a cerebellar Purkinje cell-specific protein, was studied in guinea pig taste buds by means of electron-microscopic immunocytochemistry. The immunoreactivity was localized in the cytoplasmic matrix of discrete bud cells. The ultrastructural features of the reactive cells indicated that they corresponded to the Type III or gustatory cells making a synaptic contact with the intragemmal nerves. All other cells specified as basal, Type I, and Type II were immunonegative for spot 35 protein. This finding indicates a method for specifically demonstrating the gustatory cells in the guinea pig taste bud and, further, gives new evidence that paraneurons may share neuron-specific substances with neurons.

We describe a 7-year-old girl with recurrent pruritic vesiculopustular lesions involving the trunk, extremities, face, and oral mucosa. Histopathologic examination revealed intraepidermal bullae containing neutrophils and eosinophils, and direct immunofluorescence test showed the deposition of IgA in the intercellular space of the epidermis. Circulating IgA anti-intercellular antibodies were also detected by indirect immunofluorescence test. Immunofluorescence studies using monoclonal antibodies to human IgA subclasses showed that these IgA antibodies belonged to IgA1. Antisera against J chain and secretory component did not show any specific intercellular staining. Surface IgA(+)-B cells were transiently increased in the peripheral blood during the active stage of the disease. These results indicated the extragut origin of these IgA antibodies. Dapsone therapy was shown to be very effective.

We report a patient with scalp lesions of primary localized cutaneous nodular amyloidosis. The extensive examination revealed no systemic involvement. Analysis of glycosaminoglycans (GAGs) in amyloid deposits showed a twofold increase as compared with normal skin, which was due to the increase in dermatan sulfate. Local disorders of GAG metabolism may be related to the amyloid fibril formation. Amyloid fibrils were purified and identified electron-microscopically, which consisted of two major 12,000- and 13,000-dalton and minor 29,000- and 48,000-dalton peptides. Western blotting analysis showed a minor 29,000-dalton peptide reactive with antibodies against both kappa and lambda light chains of immunoglobulin. There is a possibility that some components of amyloid in some cases of primary localized cutaneous nodular amyloidosis may consist of both kappa and lambda immunoglobulin light chains.

Elemental analyses of the tooth and bone tissues were carried out by X-ray fluorescence element mapping spectrometry, a technique we have recently developed. This analytical system has the advantage of providing data on distribution of element concentration in a given specimen in overhead view without involving destruction of the tissue architecture. This paper briefly introduces the apparatus of this system and presents analytical data obtained for several elements (calcium, iron, arsenic, zinc and strontium) in the tooth and bone tissues of rats bearing tumor induced with lead acetate. Lead distributed in the maxillary incisive bone and femur was demonstrated in rats with lead acetate-induced tumor sacrificed at 42 weeks after injections. Arsenic observed in the femur of control rats was found replaced by lead in the tumor bearing rats. The findings are of interest as viewed with reference to chelating activity of lead.

Elemental analysis of plaque-like black deposits noted on the surface of teeth in zinc-deficient rats at necropsy was performed. Rats deficient in zinc show signs of abnormality in iron metabolism and increase or accumulation of iron in plasma and tissues. This study was designed, therefore, to examine the plasma and salivary levels of iron and other elements and to determine the distribution of mineral elements in the dental substances of zinc-deficient rats by contact microradiography, electron probe microanalysis (EPMA) and X-ray fluorescent element mapping spectrometry (XEMS) on ground sections of teeth. Rat tooth specimens were analyzed also for zinc, iron, copper and manganese using colorimetry and Inductively Coupled Plasma, ICP. EPMA and XEMS analyses revealed the presence of iron on the enamel surface of maxillary molars teeth of zinc-deficient rats. However, no such deposition was seen on those of controls. The zinc-deficient rats showed higher iron concentration in mixed saliva and in plasma, compared with the controls. Thus, the sign of abnormality in iron metabolism noted in the oral cavity of zinc-deficient rats was investigated by EPMA and XEMS analyses, with discussion on the origin of supradental iron deposits.

Biological effects of such metals as nickel and chromium alloys used as dental materials, particularly their metabolism and potential toxicity have not been well elucidated. Certain metallic materials are known to be toxic and arsenic, nickel, chromium and lead have been shown to have carcinogenic potential in laboratory animals. This study was performed to assess carcinogenicity and accumulation in tissues of metals in rats. Three-week old male F344/NSle rats were injected s. c. with 30 mg/kg of nickel acetate or 60 mg/kg of lead acetate weekly for 5 weeks after 2 weeks of acclimatization, and were followed by observation for 80 weeks. The group treated with lead acetate showed a greater incidence of tumor, compared with the nickel acetate-treated group. Teeth, femora, other bones and neoplastic tissue from tumor-bearing animals were subjected to elemental analysis by spectrophotometry and ICP. High concentrations of Pb were detected in the mandibula, femur and tumor tissue of rats with Pb-induced tumor. In rats with Ni-induced tumor, Ni was not demonstrable in the mandibula, maxilla or tumor tissue and detected in small quantities in the nasal bone and femur. Thus, Pb proved to be retained in tissue at the site of injection and also markedly accumulated in the tooth and femur as assessed 46 weeks after injections; whereas Ni was no longer detectable in tissue at the injection site, nor in tumor tissue but only small quantities in the said bones.

Histological features of the tooth plate of lungfish were investigated by light and electron microscopy and contact microradiography with primary reference to the fine structure and formation of petrodentine, one of the principal constituents of the tooth plates. Petrodentine is a highly mineralized tissue noticeably analogous to that of enameloid, and is deposited intermittently in a proximal direction by the sole participation of mesenchymal petroblasts. The petroblasts appear very likely to have prominent biphasic functions of secreting the petrodentine matrix and of eliminating the matrix by resorption. The petrodentine thus may be capable of attaining hypermineralization with the participation mesenchymal cells alone. Mineral crystals constituting the petrodentine are large, hexagonal or similar but irregularly shaped columns. Initially these crystals appeared extremely thin, with curled ones frequently noted. The petrodentine of lungfish tooth plates is considered to be structurally distinct from the pleromin (Kosmin) of holocephalian tooth plates because of the difference between their constituent crystals.

Guinea pig taste buds were observed by transmission electron microscopy with special reference to cell types and innervation. The taste bud comprised four distinct cell types: basal, type I, type II, and type III cells. Basal cells, residing at the baso-lateral region of the taste bud without extending to the taste pore, were considered precursors of the other types of cells. The rest were all spindle-shaped cells reaching apically to the taste pit. Type I cells were characterized by the darkest appearance of the cytoplasm, apically possessing large, electron-dense granules and basally enveloping intragemmal nerves. This cell type, intervening between the other types of cells, was postulated to be sustentacular in nature. Type II cells, the largest and lightest cells in the taste bud, possessed a conspicuous stack of smooth endoplasmic reticulum above the nucleus. Due to their intimate and specialized relationships with nerves, the type II cells were presumed to receive an efferent innervation. Type III cells made synaptic contacts with nerves and contained dense-cored vesicles, which accumulated in the synaptic areas. This finding strongly suggests a gustatory function for the cells. The occurrence of such numerous peptidergic-type granules gathering to gustatory synapses as demonstrated in this report has not been recorded in previous papers on mammalian taste buds. The nerve terminals on the type III cell also contained synaptic vesicles, thus suggesting a reciprocal synapse here. The taste bud often included degenerating cells which were demonstrated to be phagocytosed by extrinsic cells identified as macrophages.

Tooth plates of extant lungfishes were examined by contact microradiography, light microscopy and TEM, to elucidate the nature and origin of the hypermineralized surface layer. TEM indicated that the matrix of this layer consisted of organic filamentous material, and no collagen fibres were seen in the matrix. The matrix appeared to be secreted by oral epithelial cells of the inner fold surrounding the surface of the tooth plate, and deposited in the area between the cell membrane and basal lamina-like structure of these epithelial cells. Therefore, it is suggested that the hypermineralized surface layer of lungfish plates is enamel of ectodermal origin.

The taste buds and their nerves in the guinea pig were immunocytochemically investigated with regard to the localization of spot 35 protein, neuron-specific enolase (NSE), neurofilament protein (NFP), and S-100 protein. The spot 35 protein-like immunoreactivity was confined to slender cells comprising half the number of taste bud cells. NSE-like immunoreactivity was recognized in some taste bud cells as well as nerve fibers both within the taste bud and in the subepithelial connective tissue. The NSE-immunoreactive cells were divided into two cell populations: one weakly and the other intensely immunoreactive. The former cells proved to be spot 35 protein-immunoreactive. Moreover, the cells immunoreactive for both spot 35 protein and NSE were frequently associated with nerve fibers immunostained intensely for NSE. The NFP- and S-100 protein-like immunoreactivities were found in none of cells in the taste bud, but exclusively in the subepithelial neural elements.

The taste buds and associated nerves in the guinea pig, rat, cat, and mouse were investigated by immunocytochemistry and formaldehyde-induced fluorescence histochemistry. The antisera used were against spot 35 protein, neuron-specific enolase (NSE), neurofilament protein (NFP), and substance P. The spot 35 protein immunoreactivity was confined to taste bud cells in the guinea pig and rat; the immunoreactive cells, slender in shape, comprised half the number of the total taste bud cells in the guinea pig but were fewer in the rat. For NSE, on the other hand, taste bud cells as well as neural elements localized in both the taste bud and the subepithelial connective tissue were immunoreactive in all the species investigated. Furthermore, all of the spot 35 protein-immunoreactive cells proved to be NSE-immunoreactive in the guinea pig and rat. For NFP, neither the bud cells nor the nerves in the taste bud were reactive, whereas a part of nerves in the connective tissue was immunostained in all the species. The antiserum against substance P exclusively detected some parts of nerves in and out of the taste buds in the cat, rat, and mouse. The aminergic innervation was rather meager and appeared in the nerve fibers localized in the taste buds and connective tissue of the cat and mouse.

The duct-like structures present in 7 cases of benign and malignant eccrine poroma were examined by immunohistochemical staining for carcinoembryonic antigen (CEA), involucrin, and S-100 protein. The demonstration of CEA and involucrin was helpful in the recognition of these structures. The overt immunopositivity precedes morphological evidence for duct formation. On the basis of the CEA immunostaining, the duct-like structures were divided into 4 types: 1) mature acrosyringeal structure, 2) cystic luminal structure lined by elongated cells, 3) immature acrosyringeal structure, and 4) vacuole- or dot-like potential lumen in a single cell. Involucrine was observed in the lining cells of 1) and 2). None of the 4 types showed positive reactivity for S-100 protein, suggesting the irrelevance of these structures to the secretory element of sweat gland. The polymorphism of the ductal formation tended to be more remarkably observed in malignant eccrine poromas than in the cases of benign eccrine poroma and poroepithelioma tested.

Differences by routes of administration of the effects of prostaglandins and vasoactive substances on blood pressure, peripheral blood flow and respiration were investigated. Intravenous prostaglandins evoked respiratory excitation in rabbits, and lowered blood pressure more prominently and longer after intracarotid injection than after the intrajugular administration. The effects of prostaglandins were apparently more conspicuous after vertebral artery than via carotid artery. In rats, 1 microgram/kg i.v. of PGE1 and PGE2 caused a fall of blood pressure but 1 microgram/kg i.v. of PGF2 alpha caused a rise. PGF2 alpha produce a decrease of blood pressure when injected 10 micrograms/kg i.v.. A remarkable elevation of blood pressure occurred in rats following injection into the lateral cerebral ventricle of 0.1 microgram/kg of PGE1 or PGF2 alpha or of the same dose of 5-hydroxytryptamine (5-HT). Intra-arterial injection of PGE1 gave rise to an increase in blood flow of rabbit dorsal skeletal muscle whereas that of PGF2 alpha resulted in blood flows. The above results indicate that the effects of prostaglandins on these parameters essentially vary to slight extents with the species of animals and differ in intensity with routes of administration.

Morphological observations were made of the behavior of biogenic amines in the gastric wall of rats with acetic acid-induced ulcer. In the normal rat stomach, abundant adrenergic fibers were seen in the adventitia of arteries and arterioles, with frequently distributed mast cells in their environs, in all gastric wall layers. Mast cells had a more frequent distribution in the antral region than in the corpus ventriculi while enterochromaffin-like cells (EC-like cells) were found with greater frequencies in the latter region of gastric wall. Adrenergic fibers were abundant around blood vessels in perilesional area of the gastric wall of rats with acetic acid ulcer. Mast cells, seen more frequently in the antral region as in the normal rats, showed degranulation in these rats. The population of PAS-positive mucous cells reached its peak in 10 days after injection of acetic acid and subsequently declined with healing of the ulcer, thus remarkably concordant with the ulcer index. Local administration of serotonin produced angiospasm in the greater omentum. The finding indicates a possible participation of arteriospasm by adrenergic nerve fibers in the pathogenesis of gastric ulcer. The results of the present study strongly suggest that biogenic amines have bearing as an aggressive factor upon the angiospasm theory of ulcerogenesis.