Kimio Fujii

Roles of E- and P-cadherin in the human skin.

The Ca2+‐dependent cell‐cell adhesion molecules, termed cadherins, are subdivided into several subclasses. E (epithelial)‐ and P (placental)‐cadherins are involved in the selective adhesion of epidermal cells.

Expression of cadherin cell adhesion molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts

SummaryExpression of E (epithelia) and P (placental) cadherin cell adhesion molecules was examined immunohistochemically using human developing skin. In adult skin, E-cadherin was expressed on cell surfaces of whole epidermal layers including skin appendages, whereas P-cadherin was expressed only on those of basal layers and the outer layers of skin appendages, which was consistent with the compartment of proliferating cells. In fetal skin, while the patterns of E- and P-cadherin expression were generally similar to those in the adult, P-cadherin temporarily showed a unique spatiotemporal expression pattern in developing sweat ducts. During this stage, the expression of P-cadherin accumulated in the epidermal ridges and showed a discrepancy with the compartment of proliferating cells. These results suggest that the expression of P-cadherin is spatiotemporally controlled, and may be closely related to the segregation of basal layers as well as to the arrangement of epidermal cells into eccrine sweat ducts, but is not closely related to cell proliferation.

Acute urticaria with elevated circulating interleukin-6 is resistant to anti-histamine treatment.

Histamine released from dermal mast cells plays a central role in the increased vascular permeability in acute urticaria, and administration of anti‐histamines usually suppresses development of wheals. Acute idiopathic urticaria, particularly a severe case, occasionally presents with acute inflammatory reactions such as low‐grade fever and leukocytosis and is resistant to anti‐histamines. Considering the wide spectrum of proinflammatory cytokines and chemokines that can be released from activated mast cells, some of them might be involved in the pathogenesis of urticaria. We measured plasma levels of interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), and tumor necrosis factor‐α (TNF‐α) in 16 cases of severe acute urticaria. None of them showed elevated plasma levels of IL‐8 or TNF‐α. Nine out of 16 acute urticaria patients showed elevated circulating IL‐6 with concomitant increases in serum CRP levels. All such patients were resistant to conventional anti‐histamine treatment and required systemic steroids for complete suppression of wheal development. After subsidence of the urticaria, their elevated IL‐6 and CRP levels dropped to their normal ranges. In contrast, all but one patient without elevated circulating IL‐6 was successfully treated with a H1 receptor antagonist, cetirizine. The data suggest involvement of IL‐6 in the pathogenesis of severe acute urticaria that is resistant to anti‐histamines.

Elevation of circulating thrombin–antithrombin III complex and fibrin degradation products in urticaria: A laboratory finding unrelated to intravascular coagulopathy

Dear Editor, Voluminous exudation of plasma components into the dermis through the hyperpermeable cutaneous vasculature marks a pathophysiological feature of urticaria. When skin mast cells are stimulated to degranulate by injection of recombinant human stem cell factor, fibrin is shown to be deposited in the perivascular area at the injected sites. Fibrin formation, therefore, originating from extravasated plasma fibrinogen could likewise occur in urticarial skin lesion. Massive fibrin formation in the dermis may well affect the plasma levels of coagulation/ fibrinolysis parameters. As shown in Table 1, a large proportion of urticaria patients showed elevated circulating thrombin–antithrombin III complex (TAT) and/or D-dimer. Nobody showed a drop in plasma antithrombin III (AT III) activity, or a detectable level of plasma soluble fibrin monomer complex (SFMC). All the patients showed normal levels or ranges of platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma protein C and S activities, serum compliment C3 and C4,

Eosinophilic cellulitis as a cutaneous manifestation of idiopathic hypereosinophilic syndrome

Three patients with eosinophilic cellulitis associated with sustained peripheral blood eosinophilia of unidentified cause are reported. They also presented with diversities of extracutaneous symptoms such as bronchospasm, sensory polyneuropathies, epigastralgia, and gangrenous eosinophilic enteritis. These cases suggest that eosinophilic cellulitis can develop as a cutaneous manifestation of idiopathic hypereosinophilic syndrome.

Subungual hyperkeratosis due to sarcoidosis

A 30‐year‐old Japanese woman presented to our clinic for evaluation and treatment of subungual hyperkeratotic lesions of the toenails. Five years previously the bilateral parotid glands and hilar lymph nodes became enlarged, and tender subcutaneous nodules developed in the lower extremities. Transbronchial lung biopsies showed epithelioid granulomas and systemic sarcoidosis was diagnosed. A skin biopsy showed nonspecific septal panniculitis, a finding compatible with erythema nodosum. Since then the patient had experienced intermittent episodes of low grade fever, general malaise, dyspnea, diarrhea, and superficial lymphadenopathy, and systemic steroid was administered when the disease was aggravated. The initial erythema nodosum subsided in a couple of months and was replaced by a large number of slightly scaly, erythematous papules and nodules in the lower extremities and in the face. The biopsy specimens of these lesions showed noncaseating epithelioid granulomas in the dermls. These cutaneous lesions waxed and waned along with the systemic symptoms. The patient had never had uveitis or lupus pernio. A few months previously new erythematous papules and nodules had developed in the face and in the lower extremities. Hyperkeratotic verrucous lesions also developed at the hyponychium and beneath the distal portion of the nail plates in all the toenails (Fig. 1a). The proximal and lateral nail folds and the nail plates appeared normal. Repeated potassium hydroxide stain and culture of the subungual hyperkeratotic materials were negative for fungus. Roentgenogram of the toe phalanges was normal. Interestingly, none of the fingernails were affected. A biopsy specimen of the nail bed showed orthokeratotic hyperkeratosis and acanthosis of the epidermis, but no papillomatosis or vacuolated keratinocytes (not shown). There were discrete epithelioid granulomas in the superficial dermis (Fig. 2). Systemic steroid, 30 mg/day, was administered because the patients lung parenchymal lesions were aggravated. The subungual hyperkeratosis rapidly improved after administrating steroid for 2 weeks (Fig. 1b).

A Case of Autoimmune Bullous Dermatosis with Features of Pemphigus Vulgaris and Bullous Pemphigoid

Pleomorphic blisters, including tense bullae and annularly arranged vesicles around the erythema as well as erosive eruptions in the oral cavity, appeared on a 61-year-old woman 5 years after surgery for cholangiocellular carcinoma. A biopsy specimen from the oral cavity showed intraepidermal blisters, and those from skin lesions showed subepidermal blisters with infiltrates of eosino-phils and neutrophils. The early-stage vesicles showed infiltrates along the epidermal-dermal junction, where electron microscopy disclosed disruption of the lamina densa, basal cells remaining on the dermis, and acan-tholytic keratinocytes among the infiltrates, but there was no cleavage of the epidermal-dermal junction at the lamina lucida. Direct immunofluorescence studies showed immune deposition at the intercellular space (ICS) and along the basement membrane zone (BMZ). Indirect immunofluorescence studies confirmed coexistence of IgG class anti-ICS and anti-BMZ antibodies. Although this case showed immunohistochemical features of bullous pemphigoid, the presence of suprabasal cleavage in the oral mucosa, acantholytic cells in the blister cavity, the deposition of IgG at the ICS of the perilesional epidermis, and circulating anti-ICS antibodies strongly suggested that this case was primarily pemphigus. The strong inflammation along the epidermal-dermal junction due to unknown factors may have modified the clinical appearance and the histopathology.

Survival period of tumor-bearing mice is prolonged after the interferon-γ-producing gene transfer

A highly tumorigenic keratinocyte-derived carcinoma cell line, designated as Pam-T, was established from a Pam212 line. The intradermal injection of more than 10(5) of these cells into syngeneic BALB/c mice induced substantial tumors. The tumors progressively enlarged and then invaded the peritoneal cavity leading to the death of the host mice. To comprehensively investigate the effects of interferon-gamma on tumorigenicity, we manufactured interferon-gamma-producing PamT cells by interferon-gamma gene transfer and examined the characteristics of the tumors induced by these cells in syngeneic mice. Interferon-gamma producing cells exhibited an apparently similar in vitro cell growth pattern and in vivo tumor formation to control cells, but the mean survival of the mice with the interferon-gamma-producing cells was significantly longer compared with control mice.

Interrelationship between Ca2+-dependent phospholipid base-exchange reaction and phospholipase D-like activity in bovine retina

Endogenous substrates (phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine) for the Ca2+-dependent base-exchange reaction were investigated using bovine retinal microsomes. The amounts of the three bases, serine, ethanolamine and choline, released from the membranes and the amount of phosphatidic acid generated in the membranes were measured in the presence of Ca2+ with or without exogenous bases. When the membranes were incubated with Ca2+ alone, the three bases were liberated into the water-soluble fractions accompanied by accumulation of phosphatidic acid, suggesting the presence of Ca2+-dependent phospholipase D-like activity. When an exogenous base was added to the reaction mixture, the liberation of the other two bases increased slightly and the formation of phosphatidic acid decreased markedly. The exogenous base also stimulated the liberation of the same base from prelabeled phospholipids. Accompanying these changes, the exogenous base was incorporated into the membrane phospholipid. With respect to pH profile, time course and metal requirements, both the base incorporation and phospholipase D-like activity were quite similar. The amount of base incorporated generally agreed with both the decreased amount of phosphatidic acid formed and the increased amount of base released. These results suggest that, beside the base-exchange reaction, phospholipase D-like activity plays an important role in Ca2+-dependent base incorporation into bovine retinal membranes.

Giant Metastatic Malignant Melanoma with an Unknown Primary Site

We report a case of malignant melanoma of unknown primary origin which presented with a giant metastatic tumor in his right inguinal region. A 94‐year‐old man noticed a small subcutaneous tumor in the right inguinal region 3 years earlier, which eventually became as large as 9 cm in diameter without treatment. Although a histological examination of the lesion showed malignant melanoma, extensive examination did not reveal its primary lesion or any metastasis other than that to the right inguinal area. Our case took an interesting course in that this well‐growing metastatic tumor was localized in only one region and supported a previous report indicating that malignant melanoma with unknown primary origin has a low tendency to metastasize and a relatively good prognosis.