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Biomedical subjects

H Shinkai

Publications and source records attributed to H Shinkai.

At least 55 records · Page 3Linked to original sources
PubMed1999

Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma.

We have established a mouse model for scleroderma induced by repeated local injections of bleomycin (BLM). Daily injection of BLM at a dose of >10 microg per ml for 4 wk induced histologic changes of dermal sclerosis, but not fibrosis, with thickened and homogenous collagen bundles and cellular infiltrates in BALB/C mice, whereas clinical signs of scleroderma were not apparent. In addition, lung fibrosis was also induced preceding the cutaneous changes. Sclerotic changes were not found in other sites of the skin distant from the injection site. Dermal sclerosis could also be induced by injecting BLM only every other day. The sclerotic changes of the dermis were sustained after ceasing BLM applications for at least 6 wk. Mast cells gradually increased in number as the sclerotic changes developed. Marked degranulation of mast cells was observed with elevated histamine release. The amount of hydroxyproline in skin was significantly increased at 4 wk of BLM treatment as compared with that in untreated or phosphate-buffered saline-treated mice. Anti-nuclear antibody was detected in serum of BLM-treated mice. Transforming growth factor-beta1 mRNA was detected at an early phase, while transforming growth factor-beta2 mRNA was strongly expressed at 4 wk when the sclerotic features were prominent. These results suggest that dermal sclerosis induced by BLM closely resembles systemic sclerosis both histologically and biochemically. Our mouse model can provide a powerful tool of inducing dermal sclerosis to examine the pathogenesis and the therapeutic approach of scleroderma.

Animals↗
PubMed1999

Dermatopontin expression is decreased in hypertrophic scar and systemic sclerosis skin fibroblasts and is regulated by transforming growth factor-beta1, interleukin-4, and matrix collagen.

Dermatopontin is a recently discovered extracellular matrix protein with proteoglycan and cell-binding properties and is assumed to play important roles in cell-matrix interactions and matrix assembly. In this study we examined the expression of dermatopontin mRNA and protein in skin fibroblast cultures from patients with hypertrophic scar and patients with systemic sclerosis. Dermatopontin mRNA and protein levels were reduced in fibroblast cultures from hypertrophic scar lesional skin compared with fibroblasts from normal skin of the same hypertrophic scar patient. Fibroblast cultures from systemic sclerosis patient involved skin also showed significantly reduced expression of dermatopontin compared with normal skin fibroblasts from healthy individuals. We also investigated the effects of cytokines and matrix collagen on dermatopontin expression in normal cultured fibroblasts. Transforming growth factor-beta1 increased dermatopontin mRNA and protein levels, while interleukin-4 reduced dermatopontin expression. Substrate coated with type I collagen reduced dermatopontin mRNA levels, the reduction being more prominent in three-dimensional collagen matrices. Our results suggest that the decreased expression of dermatopontin is associated with the pathogenesis of fibrosis in hypertrophic scar and systemic sclerosis, and that the effect of the cytokines and matrix collagen on dermatopontin may have important implications for skin fibrosis.

Adolescent↗
PubMed1999

Encapsulated necrosis associated with Behçet's syndrome.

We reported a case of a 45-year-old woman with encapsulated necrosis associated with Behçet's syndrome. The lesions were characterized by multiple, small subcutaneous nodules on the extremities. Histologically, a nodule consisted of degenerative adipocytes encapsulated by fibrous tissue. A membranocystic lesion was also observed in the cavity of the nodule. The patient had a long-term history of Behçet's syndrome and suffered from erythematous subcutaneous nodules, resembling erythema nodosum on the extremities with a tendency to recurrence. These observations indicate that Behçet's syndrome could be implicated in the development of encapsulated necrosis as an underlying disease.

Behcet Syndrome↗
PubMed1999

A case of Werner's syndrome associated with osteosarcoma.

We described a case of Werner's syndrome associated with osteosarcoma. A 37-year-old Japanese man was diagnosed as having Werner's syndrome by the presence of juvenile cataracts, skin sclerosis and hyperpigmentation of the feet, high-pitched voice, characteristic bird-like appearance of the face with beak-shaped nose, thinning of the entire skin and hyperkeratoses on soles, hyperlipemia, hyperuricemia, diabetes melitus, and the mutated responsible gene (WRN). He had a 3-month history of a tumor on his left forearm. Histologically, the tumor included four histological patterns; a malignant fibrous histiocytoma-like, a desmoid-like, a dermatofibrosarcoma protuberans-like, and a chondrosarcoma-like pattern. Tumoral osteoid formation was also found in the tumor. Therefore, the tumor was diagnosed as osteosarcoma.

Adult↗
PubMed1998

4-(trans-4-Methylcyclohexyl)-4-oxobutyric acid (JTT-608). A new class of antidiabetic agent.

During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.

Animals↗
PubMed1998

Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents.

Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.

3T3 Cells↗
PubMed1998

A miniature probe enables clear demonstration of the cystic duct during laparoscopic cholecystectomy.

We performed intraoperative ultrasonography with a miniature probe to explore the biliary anatomy, especially the cystic duct, during laparoscopic cholecystectomy. By using this radial-type probe introduced into a hard metal sheath with a balloon at the end, the plane containing Calot's triangle can be scanned easily when the gallbladder is extracted to the right side, thereby facilitating the identification of the cystic duct as well as the common ducts. In 30 cases, no common duct stone was found and the cystic duct was clearly identified. This radial-type miniature probe can be used to locate the cystic duct and avoid inadvertant incision or division of the common ducts.

Catheterization↗
PubMed1998

Surgical indications for small polypoid lesions of the gallbladder.

BACKGROUND: To determine which polyps of the gallbladder should be operated upon, we investigated the size and number of polyps in resected gallbladders, and studied changes in gallbladder polyps using ultrasonography (US). METHODS: We studied 74 resected gallbladders with small polypoid lesions less than 20 mm in diameter, and 60 patients with gallbladder polyps by US. The polyps in resected gallbladders were classified into four groups histologically, and clinical features, maximum diameter, and number of lesions were compared among the groups. In the followed-up cases with gallbladder polyps, the size and number of polyps were examined by US, and changes during the observation period were studied. RESULTS: The mean diameter of adenoma was 6.00 +/- 3.39 mm (mean +/- SD) and that of cancer 10.8 +/- 4.16 mm; 97% of cholesterol polyps were less than 10 mm in diameter (3.66 +/- 2.68 mm). Neoplastic polyps tended to be single (adenoma, n = 1.40 +/- 0.89; cancer, n = 1.16 +/- 0.40), whereas half of the cholesterol polyps were multiple (n = 3.09 +/- 3.31). However, when there were fewer than 3 lesions, the incidence of neoplasm was 37% among polyps 5 to 10 mm in diameter. A low incidence (6%) of neoplasm was also observed among polyps less than 5 mm in diameter. CONCLUSIONS: These data indicate that an aggressive surgical approach for small gallbladder polyps is warranted when there are fewer than 3 polyps, regardless of their size.

Adult↗
PubMed1998

Regulation of matrix metalloproteinase (MMP) expression in cutis laxa fibroblasts: upregulation of MMP-1, MMP-3 and MMP-9 genes but not of the MMP-2 gene.

A major histopathological abnormality in cutis laxa (CL) is a paucity of elastic structures. The aim of this study was to investigate the gene expression levels of the major matrix degrading factors matrix metalloproteinase (MMP) 1, MMP-2, MMP-3 and MMP-9 in CL. The gene expression levels of MMP-1, MMP-2, MMP-3 and MMP-9 in cultured CL fibroblasts were measured by northern blot, immunoblot and gelatin zymographic analysis. Markedly increased mRNA levels of MMP-1 (8.4-fold), MMP-3 (7.2-fold) and MMP-9 (more than 10-fold) were found in CL fibroblasts, whereas MMP-2 mRNA levels in these fibroblasts were unaltered. Increased protein production levels of MMP-1 (4.6-fold) and MMP-3 (5.1-fold) in CL fibroblasts were shown by immunoblot analysis. On gelatin zymographic analysis, the gelatinolytic activities of MMP-9 but not of MMP-2 were increased (2.2-fold). These results suggest that increased gene expression levels of MMP-1, MMP-3 and MMP-9 in CL fibroblasts may contribute to the histopathological abnormality in CL.

Blotting, Northern↗
PubMed1998

Annular lichen planus showing a change in metallothionein expression on immunohistochemistry.

The immunohistochemical localization of metallothioneins (MTs), low-molecular-weight metal-binding proteins, was investigated in a case of annular lichen planus (LP) that enlarged centrifugally with healing in the centre after a month. The annular lesion was found to exhibit the early, developed and late stages of LP, as judged by the clinical and histopathological findings. Immunostaining for MTs was increased around the lesion, discontinuous around the rim of the erythema and undetectable in the centre of the lesion. MT expression was examined in eight specimens of idiopathic LP. Discontinuous immunostaining for MTs was observed in six specimens and increased staining around the lesion was observed in two specimens. These results suggest that MT expression changes depending on the inflammatory stage of LP. Although the role of MTs in dermatological disease is still unknown, their expression might be related to the pathological process of LP.

Aged↗
PubMed1998

Increased expression of heat-shock protein 47 is associated with overproduction of type I procollagen in systemic sclerosis skin fibroblasts.

Heat-shock protein 47 (HSP47) is a collagen-binding stress protein that is thought to act as a collagen-specific molecular chaperon during the biosynthesis and secretion of procollagen. In this study we examined the expression of HSP47 mRNA and protein in systemic sclerosis (SSc) skin fibroblasts. HSP47 mRNA and protein levels were significantly higher in fibroblast cultures from SSc patient-involved skin samples than in fibroblasts from normal skin from healthy individuals, as assessed by northern blot and immunoblot analyses, respectively. SSc cultured fibroblasts with increased levels of HSP47 mRNA and protein showed high expression of type I procollagen. By in situ hybridization, SSc skin had a higher number of fibroblasts with high HSP47 and procollagen alpha1(I) mRNA levels than normal skin, and the distribution of HSP47 mRNA was similar to that of procollagen alpha1(I) mRNA. We also investigated the effects of cytokines on the expression of HSP47 in normal cultured fibroblasts. Transforming growth factor-beta1 and interleukin-4 increased HSP47 mRNA and protein levels, whereas interferon-gamma reduced HSP47 expression. The same pattern of cytokine-regulated expression was observed for type I procollagen levels. These results indicate that HSP47 expression is closely associated with that of type I procollagen in skin fibroblasts, and that increased expression of HSP47 may be involved in the abundant production of type I procollagen by SSc fibroblasts.

Cells, Cultured↗
PubMed1998

A case of cutaneous Ki-1 positive anaplastic large cell lymphoma in a hemodialysed patient.

A 66-year-old woman who suffered from chronic glomerulonephritis had been undergoing hemodialysis for about 10 years. A reddish papule on her waist developed gradually into a nodule (1.9 x 1.4 cm). Histopathological findings showed that the tumor cells had oval to reniform nuclei; multinucleated neoplastic cells and erythrophagocytosis were also present. Immunohistochemical analyses revealed that the membranes of the tumor cells stained for Ber-H2 (Ki-1) and epithelial membrane antigen (EMA), Vimentin was partially positive, but keratin, S-100, chromogranin, leukocyte common antigen (LCA), UCHL-1, MT-1, L-26, MB-1 and C3D-1 were all negative. Anti-human T-cell leukemia virus-1 (HTLV-1) was also negative. No gene rearrangement of the T-cell receptors beta-, gamma- and delta-chain could be detected. From these results, we diagnosed cutaneous Ki-1 anaplastic large cell lymphoma (ALCL), but the origin could not be determined. The relationship between lymphoma and chronic renal failure and/or hemodialysis was far from clear.

Aged↗
PubMed1998

A case of bullous pemphigoid in a patient on hemodialysis.

We describe a case of bullous pemphigoid (BP) in a patient with chronic renal failure maintained on hemodialysis. We diagnosed BP by histopathological and immunofluorescence studies. The relationship between BP and chronic renal failure and/or hemodialysis is not clear, but we believe that immune disarrangement due to chronic renal failure and/or hemodialysis may have influenced the pathogenesis of BP in our case.

Aged↗
PubMed1998

A case of subcutaneous cysticercosis.

We report the fourth case of subcutaneous cysticercosis infected in Japan since 1975. The patient noticed a subcutaneous nodule on his left shoulder without symptoms for three years. No remarkable changes were found in laboratory findings and physical examination after surgical excision of the subcutaneous nodule. The adult worm of Taenia solium could not be found in the intestine. Histological findings revealed a cystic structure with a fibrous capsule and a protoscolex with suckers, hooks, and calcareous corpuscula. It was identified as a Cysticercus cellulosae hominis based on morphological characteristics. The patient has been living in the Kanto area of Japan and has never been outside Japan since he was born.

Adult↗
PubMed1997

Manual and automatic extraction and high-performance liquid chromatographic determination of a spicamycin derivative, KRN5500, in rat plasma.

A sensitive reliable method for the extraction, separation and quantitation of KRN5500 (I), a spicamycin derivative, from rat plasma was developed. It involves solid-phase extraction of the drug using a Bond Elut C18 cartridge and reversed-phase HPLC on a YMC-Pack ODS column with an ultraviolet detector. The intra- and inter-assay coefficients of variation by manual (n=10) and automatic (n=5) extraction were less than 9 and 13% and 6 and 8%, respectively. The limit of quantitation of each extraction procedure was 2 ng potency/ml. This extraction method may thus be considered useful for monitoring I in animals following its administration.

Animals↗
PubMed1997

Downregulation of decorin expression in dermal fibroblasts by interleukin-4.

Decorin, a chondroitin/dermatan sulphate proteoglycan, plays an important role in the assembly of extracellular matrix components. In this study, we investigated the influence of interleukin-4 (IL-4) on the expression of decorin and sulphated glycosamino-glycans (GAGs) in cultures of human skin fibroblasts. IL-4 inhibited the expression of decorin mRNA and its core protein synthesis. IL-4 stimulated dermatan sulphate but decreased chondroitin sulphate synthesis without altering the total amount of sulphated GAGs. IL-4 had no effect on the initiation activity of the dermatan sulphate and chondroitin sulphate chains, as evaluated by the effect of exogenous beta-xyloside that acts as an artificial chain initiator for dermatan sulphate and chondroitin sulphate biosynthesis. Type I collagen mRNA levels and protein synthesis were increased by this IL-4. Therefore, the effects of IL-4 on decorin and GAGs as well as type I collagen may have important implications for wound healing and for the treatment of several fibrosing diseases.

Adult↗
PubMed1997

Decorin and glycosaminoglycan synthesis in skin fibroblasts from patients with systemic sclerosis.

We investigated the expression of decorin and the synthesis of sulphated glycosaminoglycans (GAGs) in cultured fibroblasts from patients with early-stage systemic sclerosis (SSc). Decorin mRNA levels were 1.8-fold higher in SSc fibroblasts than in control fibroblasts. SSc fibroblasts also produced 2.3-fold more decorin core protein and 2.2-fold more sulphated GAGs including dermatan sulphate and chondroitin sulphate. Newly synthesized GAGs, in the presence of p-nitrophenyl beta-xylopyranoside, which elongates dermatan sulphate and chondroitin sulphate as an initiator, were increased tenfold and were mainly composed of dermatan sulphate and chondroitin sulphate. The rate of stimulation by the beta-xyloside was similar in SSc and control fibroblasts. These results suggest that the increased amount of dermatan/chondroitin sulphate in SSc fibroblasts reflects an enhanced expression of decorin core protein. Type I collagen mRNA levels in SSc fibroblasts were also increased together with its synthesis. Therefore, our results indicate that an altered decorin and collagen production may affect the organization of collagen fibres and the fibrotic process observed in patients with SSc.

Adult↗