Effects of a novel anti-hyperlipidemic agent, S-2E, on blood lipid levels in rats with fructose-induced hypertriglyceridemia

Using rats with fructose-induced hypertriglyceridemia, an animal model of human hypertriglyceridemia, we investigated whether (+)-(S)-p-[1-(p-tert-butylphenyl)-2-oxo-4-pyrrolidinyl]-methoxybenzoic acid (S-2E), a novel anti-hyperlipidemic agent, reduced the elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C), and then whether it elevated HDL-C levels. At doses of 3-30 mg/kg, S-2E reduced elevated TG levels and non-HDL-C levels simultaneously in a dose-dependent manner after a week. Furthermore, S-2E treatment at 10 mg/kg for 4 weeks showed similar effects, while the elongation of intervals between feeding periods led to further increases in these levels. Interestingly, S-2E increased blood HDL-C levels after 4 weeks of treatment. It is therefore reasonable to assume that S-2E may be useful to improve dyslipidemia such as hypertriglyceridemia and low levels of HDL-C.     

Biochemical comparison between radon effects and thermal effects on humans in radon hot spring therapy

The radioactive and thermal effects of radon hot spring were biochemically compared under a sauna room or hot spring conditions with a similar chemical component, using the parameters that are closely involved in the clinic for radon therapy. The results showed that the radon and thermal therapy enhanced the antioxidation functions, such as the activities of superoxide dismutase (SOD) and catalase, which inhibit lipid peroxidation and total cholesterol produced in the body. Moreover the therapy enhanced concanavalin A (ConA)-induced mitogen response and increased the percentage of CD4 positive cells, which is the marker of helper T cells, and decreased the percentage of CD8 positive cells, which is the common marker of killer T cells and suppressor T cells, in the white blood cell differentiation antigen (CD8/CD4) assay. Furthermore, the therapy increased the levels of alpha atrial natriuretic polypeptide (alpha ANP), beta endorphin, adrenocorticotropic hormone (ACTH), insulin and glucose-6-phosphate dehydrogenase (G-6-PDH), and it decreased the vasopression level. The results were on the whole larger in the radon group than in the thermal group. The findings suggest that radon therapy contributes more to the prevention of life-style-related diseases related to peroxidation reactions and immune suppression than to thermal therapy. Moreover, these indicate what may be a part of the mechanism for the alleviation of hypertension, osteoarthritis (pain), and diabetes mellitus brought about more by radon therapy than by thermal therapy.     

Individual background factors for "cannot go out alone to distant places" among medium elderly persons living alone in a metropolitan suburb

OBJECTIVE: To verify whether the statement "cannot go out alone to distant places" should be considered a risk factor for disability among medium elderly persons living alone autonomously in a metropolitan suburban environment, the present cross-sectional study was performed. METHODS: Self-rated mobility levels in elderly persons living alone were surveyed by questionnaire in 1,216 elderly people (209 male, 1007 female) aged 65 to 74 years, living in a metropolitan suburb, who had autonomy and ambulation competence. Two categories were used for evaluation of the self-rated mobility level: the A group were those who were able to go out alone to distant places and the B group were those who were able to do so in the locality, but not to distant places without help (cannot go out alone to distant places). Factors such as everyday lifestyle, self-rated health, and psychological, functional, physical and social items were investigated. RESULTS: Although the frequency of going out was nearly the same between the A and B groups, the B group showed the lower hobby and association activity in social communities. Individual factors such as self-rated health, instrumental activities of daily living (Tokyo Metropolitan Institute of Gerontology), eyesight, masticatory ability, 1 km continuous walking, pedestrian crossing walking on a green light, and fracture history, medicine intake, cerebrovascular disorder related subjective symptoms, intermittent claudication related subjective symptoms, physical pain, symptoms of depression, daytime sleep, number of meals, and no regular walking and light gymnastic exercises demonstrated significant differences in levels between the A and B groups. The B group had characteristics of lower social activities in social communities, deterioration of physical functions, subjective symptoms of sickness and depression, and a worse self-rated level of health. On stepwise multiple logistic regression analysis, individual frailty-risk factors related to "cannot go out alone to distant places", were "inability to continuously walk a distance of 1 km", "lower masticatory ability", "having depressive symptoms", and "having symptoms of intermittent claudication". CONCLUSIONS: The findings from this study show that with autonomous medium elderly persons, those who "cannot go out alone to distant places" have risk factors for a trend toward disability.     

Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disorders (LPD) of children and young adults are sometimes termed as severe chronic active EBV infection (CAEBV), and are associated with an aggressive clinical course. However, these clinicopathological states and the role of EBV have not been clarified. A retrospective study was performed on 43 children and adult patients, who manifested EBV-associated T/NK-cell lymphoproliferative disorders (EBV-T/NK-LPD) and most of whom had experienced general illness with CAEBV for several months or years. Clinicopathologically, 43 patients were classified into four groups: group A (smoldering state) (n=7), morphological non-neoplastic LPD with chronic clinical course (several years); group B (chronic state) (n=10), non-neoplastic LPD with clonal EBV-infected cells and a chronic course; group C (leukemia/lymphoma state) (n=22), neoplastic LPD with a subacute course (years to months); group D (fulminant state) (n=4), neoplastic LPD with a fulminant course (weeks to days). The 43 patients comprised 21 males and 22 females. The median age of group A was 14 years, group B 12 years, group C 17 years, and group D 1 year. Four of 7 patients in group A, 3 of 10 in group B, 12 of 22 in group C, and all 4 in group D have died. Causes of death included hemophagocytic syndrome and/or tumor death. Genotypically and phenotypically, group C was composed of peripheral T-cell lymphoma (PTCL), and NK-cell leukemia/lymphoma (NKLL), and group D comprised cases of PTCL. Groups A and B exhibited increased NK- or T-cells (CD8>CD4), and rare B-cells. Serologic titers of EBV were only modestly elevated or not elevated in almost all cases. EBV early RNA-1 (EBER-1)-expressing EBV-infected cells were frequently encountered in each group, but the number of infected cells varied between the cases. The EBV genotype did not differ between the groups. Our findings support an important pathogenic role for EBV-infected T/NK-cell infection, rather than the EBV state, in CAEBV and consequent EBV-associated NK/T-neoplasia.     

A Case of Breast Cholesterol Granuloma Accompanied by Cancer

Cholesterol granuloma of the breast is a very rare benign disease with clinical and imaging features that are often indistinguishable from cancer preoperatively. We report a case of breast cholesterol granuloma accompanied by cancer. The patient was a 78-year-old woman who complained of a lump in her right breast. Mammography and ultrasonography showed a well-circumscribed mass. Fine needle aspiration cytology showed many cholesterol crystals and inflammatory cells without malignancy. With a diagnosis of cholesterol granuloma, tumor extirpation was performed. Histopathologic examination revealed cholesterol granuloma together with breast cancer, and additional partial mastectomy was subsequently performed. It is noted that breast cholesterol granuloma could be accompanied by cancer.     

Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer

In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR-3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR-3 and other specific lymphatic markers, LYVE-1 and prox-1. Then we systemically administered anti-VEGFR-3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.     

Expression of RCAS1 in human gastric carcinoma: a potential mechanism of immune escape

RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) inhibits the in vitro growth of receptor-expressing cells and induces apoptosis, which may contribute to the ability of tumor cells to evade host immune surveillance. In this study, we investigated RCAS1 expression in gastric cancer and precancerous lesions by immunohistochemical means. We then analyzed the relationship between RCAS1 expression and clinicopathological variables, and examined whether RCAS1 expression is associated with infiltration of tumor-infiltrating lymphocytes (TILs) and apoptosis of TILs. Of 54 gastric cancers analyzed, RCAS1 expression was positive in 52 (96%) of them. The expression pattern of RCAS1 in gastric cancer cells could be classified as granular staining either enriched in the glandular side of the cytoplasm with polarity (P pattern) or scattered diffusely in the cytoplasm and on the cell membranes (D pattern). Nineteen of 39 intestinal-type carcinomas (49%) showed the P pattern, and all of 13 diffuse type carcinomas (100%) showed the D pattern. In contrast, all RCAS1-positive specimens of gastric adenoma and metaplastic mucosa were of the P pattern. The D pattern of gastric cancers was more frequently recognized in carcinomas with large size (P<0.01), in those with regional lymph node metastasis (P<0.05) and in those that had invaded beyond the submucosa (P<0.01), compared with the P pattern. On the same sections, significantly less TILs were identified in RCAS1-positive areas than RCAS1-negative areas. Furthermore, the rate of apoptosis of TILs was significantly higher in RCAS1-positive areas than in RCAS1-negative areas. The expression and distribution of RCAS1 may be involved in malignant transformation, tumor progression, histological type and tumor escape from host immune surveillance in gastric cancer.     

Generation of a transgenic animal model of hyperthyroid Graves' disease

Graves' disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (thyroid-stimulating antibodies, TSAb), which mimic the thyrotropin (TSH) action, are thought to cause GD. The precise immunological mechanism of TSAb production, however, remains elusive. Previous immunization approaches using TSH receptor led to transient hyperthyroidism, but did not seem sufficient for comprehensive understanding of the development of autoimmune responses. To create GD-related autoimmunity in mice, we here generated TSAb-transgenic mice in which a patient-derived TSAb is expressed in B cells. Expression of the human TSAb in mice resulted in various manifestations of hyperthyroidism including increased free thyroxine levels with concomitantly decreased TSH levels, increased thyroid uptake of technetium pertechnetate, hyperthermia and thyroid hyperplasia. We found a correlation between the serum levels of human TSAb immunoglobulin and free thyroxine. In addition, conventional B cells expressing the TSAb were partially deleted in the periphery while B1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous demonstrations that the maintenance of B1 cells plays an important role in the development of autoimmune diseases. Thus, our transgenic mouse may provide a novel and useful animal model for elucidating the pathogenesis and pathophysiology of GD.