Recent findings abont the intracellular signaling mechanisms of epidermal keratinocytes are described in this report. Epidermal keratinocytes undergo differentiation as they leave the basement membrane and form the multilayered epidermis. Adhesion signals regulate early phase keratinocyte differentiation. These signals are transmitted to intracellular signaling cascades via integrins through integrin-linked kinase (ILK) in a phosphatidyl inosito (PI) 3 kinase-dependent manner, and PI3K regulates early phase keratinocyte differentiation. The mitogen activated protein (MAP) kinase cascade has been characterized as a core signal transduction pathway that is conserved from yeast to humans. This cascade consists of three distinct protein kinase families, MAP kinase, MAP kinase kinase (MAPKK), and MAP kinase kinase kinase (MAPKKK). MAPKKK activates MAPKK, which in turn activates MAP kinase. The MAP kinase superfamily consists of the classical MAP kinase (extracellular signal regulating kinase; ERK) family, the c-Jun N-terminal kinase (JNK, also known as stress-activated protein kinase; SAPK) family, and the p38 MAP kinase family. The cascade plays an essential role in diverse intracellular signaling processes, including cell growth, cell cycle regulation, differentiation, and apoptosis. Apoptosis signal regulating kinase-1 (ASK1) is a MAP kinase kinase kinase that activates the p38 MAP kinase cascade. During epidermal differentiation, ASK1 is expressed in the upper epidermis and regulates the late phase of keratinocyte differentiation.
A 50-year-old woman presented with a two and a half-year history of skin sclerosis and dyspnea. She was diagnosed as having systemic sclerosis with anti-topoisomerase-I antibody and interstitial pneumonia, and treated with low dose prednisolone. Her skin sclerosis improved; however, her respiratory function test values were getting worse, and a ground glass appearance was shown by high-resolution computed tomography. Elevated values of serum KL-6 and SP-D, increased numbers of neutrophils and eosinophils in the bronchoalveolar lavage fluid, and Ga-67 uptake in both lungs indicated that her interstitial pneumonia was active. We treated her with intravenous cyclophosphamide therapy at 1,000 mg/day once a mouth. After the second infusion, her elevated serum KL-6 and SP-D dropped and her Ga-67 uptake disappeared without any adverse effects of the cyclophosphamide. Because the scleroderma renal crisis occurred before the third infusion, angiotensin converting enzyme inhibitor was immediately administered. We treated her again with intravenous cyclophosphamide therapy at 500mg/day three times, because her renal function was stable and the level of serum KL-6 was worsening. After the fifth infusion, the ground glass pattern of high resolution computed tomography disappeared with decreased levels of KL-6 and SP-D, and improved an PaO2 level.
A 26 year-old Japanese woman presented with multiple cutaneous nodules exhibiting spontaneous regression and periperal blood monocytosis. Histopathology of the cutaneous nodule showed massive dermal infiltration of CD4 positive tumor cells and a granuloma formation composed of CD68 positive histiocytes and multinucleated giant cells. Southern blotting analysis for DNA extracted from nodule-infiltrating lymphocytes and peripheral blood mononuclear cells, detected monoclonal rearranged bands for T cell receptor. Although the peripheral blood findings showed massive proliferation of CD14 positive monocytes, no atypical lymphoctes were detected. The patient was diagnosed as having a slightly leukemic form of a granulomatous variant of cutaneous T cell lymphoma with peripheral monocytosis. She has been in good health with oral etretinate and PUVA therapy. It is suggested that granuloma formation, monocytosis and an indolent clinical course were closely associated in our case.
We have recently reported the first two Japanese cases of typical diabetic digital sclerosis (DDS) (Jpn Dermal 122: 1111–1114, 2002). Previously, some specialists in Europe and U. S. A. have described DDS and joint contractures (JC), which may commonly accompany diabetes mellitus (DM). However, we do not yet know how common these manifestations are in Japan. To clarify the clinical importance of such manifestations in Japan, we have precisely observed the hands of 199 patients with DM and 102 normal control individuals. The results of our studies were as follows: (1) DDS and JC occurred in 48 (24.1%) and 46 (23.1%) of 119 patients with DM, respectively, compared with 0 (0.0%) and 1 (0.1%) of 102 control individuals. These differences were statistically significant (p<0.0001). (2) The percentage of DDS and JC were significantly correlated with the duration period of illness (p<0.0001), but not with age, sex, age of onset of diabetes, or type of DM. (3) Of the 48 patients with DM, three were studied pathologically. The collagen in the dermis was not increased. Instead, collagen bundles were slightly thickened and separated by clear spaces. (4) All of the 48 patients with digital sclerosis were diagnosed as DDS. We conclude that both DDS and JC are considerably common and important dermadromes in DM, and that these two manifestations should be distinguished from SSc.
Disseminated erythmatous papular, eruptions developed in six patients within one week of completion of eradication therapy for Helicobacter pylori (HP) for peptic ulcer. Two of cases were suspected to be amoxicillin-induced drug eruption. Five of them had been treated with hypotensive drugs. The relationship between the three drugs used in HP eradication and hypotensive drugs should be considered in terms of the cause of the eruption. As eradication therapy for HP increases, cases with eruptions may also increase. Therefore, careful observation is mandatory for patients under going eradication therapy for HP, especially those being treatecl with hypotensive drugs.
Angiosarcoma, which has extremely bad consequences, occurs in the head of the elderly, and it causes pulmonary metastasis at a high rate. The therapy is not yet established. We used low dose weekly therapy with Docetaxel/Paclitaxel to treat three cases of angiosarcoma with such enlarged masses that excision was impossible. The treatment inhibited the head tumors and pulmonary metastasis lesions without serious side effects and extended the mean length of life. In addition, the QOL of the patients improved because this treatment was either ambulatory once a week or administration requiring one day of hospitalization a week.
Bullous pemphgoid (BP) is an acquired autoimmune subepidermal blistering disease which affects mainly elderly persons. Its target antigens have been proved to be hemidesmosomal cytoplasmic BP230 and transmembrane BP180 proteins. In this study, we investigated the clinical benefit of BP180 NC16a scores measured by enzyme-linked immunosorbent assay (ELISA) using bullous fluid samples and whether the diagnosis of BP might be made without taking lesional biopsies. Seventeen (89.5%) of 19 bullous fluid samples from BP patients were positive, while none of 32 bullous fluid samples from other patients exceeded the cut-off value. Thus, the sensitivity and specificity of BP180 NC16a ELISA using bullous fluid samples, which showed patterns similar to those of serum samples, were 89.5% and 100%, respectively. At the same time, the bullous/serum fluid BP180NC16a ELISA index value ratios were 0.73±0.27 (mean±SD). These findings indicate that BP180NC16a ELISA using bullous fluid samples will be a valuable tool, for diagnosis of patients with BP, because they are similar to serum samples.