Pathological findings from synovium of early osteoarthritic knee joints with persistent hydrarthrosis.

AIM: Nonspecific chronic synovitis of the knee joint was reported by Pollard in 1962 and its pathogenesis is considered to be a physiological reaction to intra-articular disease. In this study, we evaluated the pathological findings of the synovium of early osteoarthritis (OA)-affected knee joints with hydrarthrosis in comparison to typical OA. METHODS: Synovial tissues were harvested from early OA knee joints with hydrarthrosis graded 0-2 according to the Kellgren and Lawrence classification and examined by histopathology. RESULTS: The synovial tissues showed proliferation of fibroblast-like synoviocytes (FLS) as if in rheumatoid arthritis (RA), and were immunohistochemically positive for matrix metalloproteinase 3, tumor necrosis factor α and interleukin 6. CONCLUSIONS: The histology of RA is characterized by marked proliferation of FLS. In this study, the synovial tissues of early OA with hydrarthrosis showed moderate FLS proliferation. They also expressed the cytokines that are detected in the synovial tissues of RA. We suggest long-term follow-up is needed because early OA with hydrarthrosis might progress to overt RA.

Adenomyoepithelioma with carcinoma of the breast: A report of two cases and a review of the literature.

We herein described two cases of adenomyoepithelioma (AME) with carcinoma of the breast. Both of them were Japanese women, and they presented with a mass in their breast. Post-operative specimens revealed encapsulated and well-circumscribed tumors with local invasion, necrosis, cytological atypia, and a high mitotic rate. In immunohistochemistry, coincidentally with the loose adhesion pattern of myoepithelial cells in both cases, the intensities of E-cadherin and beta-catenin were much weaker in myoepithelial than luminal epithelial cells, with almost negative finding of beta-catenin in one case. We first found deletion of CDH1 and polysomy of CEP16 in myoepithelial cells by double color-fluorescence in situ hybridization. The two cases have been followed up for 5-8 years, and both remained free from local recurrence and distant metastases. We also presented an overview of 47 cases of AME with carcinoma in English-language literatures.

Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes.

PURPOSE: The recent FIELD study demonstrated that the lipid-lowering agent fenofibrate significantly reduces the development and progression of diabetic retinopathy (DR). These results suggest that lipids may play a causal role in DR. They also suggest that AMP-activated protein kinase (AMPK) activation could account for these findings given that fenofibrate is an AMPK activator. The authors previously demonstrated that free fatty acids, in addition to hyperglycemia, can induce apoptosis in retinal pericytes (PCs), the first cells lost in the diabetic retina. Incubation with the saturated fatty acid palmitate, but not the monounsaturated fatty acid oleate, elicited cytotoxicity in a manner dependent on oxidative stress, NF-κB activation, and ceramide accumulation. In this study, the authors explored whether AMPK can downregulate these pathways and, in doing so, protect PCs from apoptosis. METHODS: PCs were incubated with palmitate or oleate to determine whether the factors previously linked to lipotoxicity were uniquely increased by palmitate. The effects of AMPK activation on these parameters and on apoptosis were concurrently examined. RESULTS: Only palmitate increased NF-κB activation, ceramide and diacylglycerol mass, and apoptosis. Activation of AMPK with AICAR or, where used, expression of a constitutively active AMPK prevented all these effects. In contrast, both palmitate and oleate markedly increased oxidative stress, and the activation of AMPK did not prevent this. CONCLUSIONS: AMPK activation prevents the metabolic abnormalities and apoptosis specifically caused by palmitate in cultured PCs. Pharmacologic agents that activate AMPK in the diabetic retina may warrant consideration as a therapeutic option to avert PC apoptosis and to maintain microvascular homeostasis.

Incipient intranuclear inclusion body disease in a 78-year-old woman.

We report an incipient case of intranuclear inclusion body disease (INIBD) in a 78-year-old woman. No apparent neurological symptoms were noticed during the clinical course. Post mortem examination revealed widespread occurrence of eosinophilic intranuclear inclusions in neuronal and glial cells of the central and peripheral nervous systems, as well as in parenchymal cells of the visceral organs. The inclusions were observed more frequently in glial cells than in neuronal cells. Ultrastructurally, the inclusions consisted of granular and filamentous material. Immunohistochemically, the inclusions were positive for ubiquitin, ubiquitin-related proteins (NEDD8 ultimate buster 1, small ubiquitin modifier-1, small ubiquitin modifier-2 and p62), promyelocytic leukemia protein and abnormally expanded polyglutamine. Consistent with previous studies, the vast majority of inclusion-bearing glial cells were astrocytes. Furthermore, p25α-positive oligodendrocytes rarely contained intranuclear inclusions. These findings suggest that INIBD may occur in non-demented elderly individuals and that oligodendrocyte is also involved in the disease process of INIBD.

Development of tumor-induced osteomalacia in a subcutaneous tumor, defined by venous blood sampling of fibroblast growth factor-23.

A 25-year-old man with severe lumbago was referred to our department for further evaluation. Serum phosphate and TmP/GFR levels were decreased. Physical examination revealed an elastic tumor in the instep of the right foot, which the patient reported having since the age of 10 years. He had no symptoms of osteomalacia at that time. Within the recent years, the tumor had grown in size and the patient developed lumbago. To examine the existence of a fibroblast growth factor-23 (FGF-23)-producing tumor, venous blood was collected from four main veins. FGF-23 levels were significantly increased in the right femoral vein, compared with other veins. After the resection of the tumor, the histopathology was consistent with a phosphaturic mesenchymal tumor (mixed connective tissue variant). Taken together, these results indicated that the development of osteomalacia in this patient was associated with the production of FGF-23 in the subcutaneous tumor.

Expression of retinoic acid-inducible gene-I (RIG-I) in macrophages: possible involvement of RIG-I in atherosclerosis.

AIM: Retinoic acid-inducible gene-I (RIG-I) is one of the genes induced by interferon (IFN)-gamma which plays an important role in atherosclerosis. The aim of this study is to examine if RIG-I is involved in atherosclerosis. METHODS: The expression of RIG-I in atherosclerotic lesions in human aorta was examined by immunohistochemical analysis. The expression of RIG-I in THP-1 monocytic cell line or human monocyte-derived macrophages was studied by western blot and RT-PCR analyses. RESULTS: Intense immunoreactivity for RIG-I was detected in intimal macrophages in atherosclerotic lesions. IFN-gamma slightly enhanced the RIG-I expression in THP-1 cells. Treatment of the cells with phorbol 12-myristate 13-acetate, which induces the differentiation of the cells into macrophage-like cells, significantly enhanced the IFN-gamma -induced RIG-I expression. IFN-gamma also stimulated the expression of RIG-I in monocyte-derived macrophages. CONCLUSION: These results suggest that RIG-I may be involved in differentiation and activation of macrophages, playing a role in atherosclerosis.

AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells.

The fuel sensing enzyme AMP-activated protein kinase (AMPK) enhances processes that generate ATP when stresses such as exercise or glucose deprivation make cells energy deficient. We report here a novel role of AMPK, to prevent the activation of NF-kappaB in endothelial cells exposed to the fatty acid palmitate or the cytokine TNF-alpha. Incubation of cultured human umbilical vein endothelial cells (HUVEC) with elevated levels of palmitate (0.4mM) increased NF-kappaB reporter gene expression by 2- to 4-fold within 8h and caused a 7-fold increase in VCAM-1 mRNA expression at 24h. In contrast, no increase in reporter gene expression was detected for AP-1, glucocorticoid-, cyclic AMP-, or serum response elements. Similar increases in NF-kappaB activation and VCAM-1 expression were not observed in cells incubated with an elevated concentration of glucose (25mM). The increases in NF-kappaB activation and VCAM-1 expression caused by palmitate were markedly inhibited by co-incubation with the AMPK activator AICAR and, where studied, by expression of a constitutively active AMPK. Likewise, AMPK activation inhibited the increase in NF-kappaB reporter gene expression observed in HUVEC incubated with TNF-alpha. The results suggest that AMPK inhibits the activation of NF-kappaB caused by both palmitate and TNF-alpha. The mechanism responsible for this action, as well as its relevance to the reported anti-atherogenic actions of exercise, metformin, thiazolidinediones, and adiponectin, all of which have been shown to activate AMPK, remains to be determined.

Upregulation of retinoic acid-inducible gene-I in T24 urinary bladder carcinoma cells stimulated with interferon-gamma.

Urinary bladder epithelial cells play an important role in the host defense against urinary tract infections. Interferon-gamma (IFN-gamma) is a potent cytokine that regulates immune responses by inducing multiple genes in many types of cells including urinary bladder epithelial cells. Retinoic acid-inducible gene-I (RIG-I) is a member of the DExH-box family, which is involved in various reactions related to RNA metabolism, and is induced in leukemic cells by retinoic acid or in endothelial cells by lipopolysaccharide. We have studied the expression of RIG-I in T24 cells, a cell line derived from human urinary bladder epithelial carcinoma cells. IFN-gamma stimulated T24 cells to express RIG-I mRNA and protein in concentration- and time-dependent manners. Immunohistochemical analysis revealed the expression of RIG-I in the urinary bladder epithelium from a patient with chronic urinary tract infection and in a bladder epithelial carcinoma. We conclude that RIG-I may play some role in inflammatory reactions in the urinary tract epithelium.

Expression of retinoic acid-inducible gene-I in vascular smooth muscle cells stimulated with interferon-gamma.

Vascular smooth muscle cells (SMC) play an important role in atherogenesis and vasospasm. Interferon-gamma (IFN-gamma) is a potent cytokine that regulates immune and inflammatory responses by inducing multiple genes in many types of cells including SMC. Retinoic acid-inducible gene-I (RIG-I) is a putative RNA helicase, but its physiological function is not known. RIG-I is induced in leukemic cells by retinoic acid or in endothelial cells by lipopolysaccharide. We have studied the expression of RIG-I in cultured SMC from human umbilical artery. IFN-gamma stimulated SMC to express RIG-I mRNA and protein in concentration- and time-dependent manners. Immunohistochemical analysis revealed the expression of RIG-I in SMC in vivo. We conclude that RIG-I may play some pathophysiological role in immune and inflammatory reactions in SMC.