Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.     

The prognostic value of E-cadherin, α-, β- and γ-catenin in bladder cancer patients who underwent radical cystectomy

OBJECTIVES: To determine the value of the loss of expression of E-cadherin and cadherin associated molecules as useful markers for both prognosis and chemosensitivity in bladder cancer patients who have undergone radical cystectomy. PATIENTS AND METHODS: In 55 paraffin embedded specimens of radical cystectomy at our hospital from 1982 to 2000, the expression of E-cadherin, alpha-, beta- and gamma-catenin was examined by immunohistochemical staining. To evaluate the prognostic significance of these molecules, Kaplan-Meier survival curves were constructed and a statistical analysis was calculated by a log-rank test. A multivariate test (tumor stage, tumor grade, lymph node metastasis, configuration, the expression of E-cadherin, alpha-, beta- and gamma-catenin) was performed to detect prognostic markers. RESULTS: Normal expression was found in 33 cases (60.0%) for E-cadherin, 29 (52.7%) for alpha-catenin, 31 cases (56.4%) for beta-catenin, and 31 cases (56.4%) for gamma-catenin. The expression patterns for E-cadherin, alpha-, beta- and gamma-catenin were significantly correlated with each other (P < 0.01). Survival analysis showed a significant difference between normal and aberrant expression in each staining. A multivariate analysis revealed that the expression of alpha- catenin was an independent prognostic factor (P = 0.0191). In 23 patients that received adjuvant chemotherapy, there was a significant difference in survival between the normal and aberrant expression of alpha-catenin, but not other molecules. CONCLUSION: Alpha-catenin may not only be a good prognostic marker, but also one of key molecules that determine the chemosensitivities in patients with invasive bladder cancer.     

Differentiation inducing effects of vesnarinone on human glioma cells

The effects of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (vesnarinone) on the growth of glioma cells were examined in vitro. Vesnarinone at a dose of 100 mug/ml suppressed the growth of four different glioma cell lines, U-251MG, U-373MG, U-87MG and A-172, by approximately 50%, with an elongation of the cytoplasmic process on day 5 of culture. The long-term culture of U-87MG with 10 mug/ml of vesnarinone was continued up to day 34. Although growth suppression was approximately 25% on day 5, it reached over 95% on day 34. An increase in the cyclic adenosine monophosphate content of glioma cells cultured with vesnarinone was observed by enzyme-linked immunosorbent assay (ELISA). The accumulation of glial fibrillary acidic protein was observed to occur with vesnarinone by ELISA. These findings suggest that vesnarinone suppressed the growth and induced differentiation of glioma cells in vitro.     

Skull metastasis of thyroid papillary carcinoma.

Skull metastasis of thyroid carcinoma is rare. The majority of skull metastases of thyroid carcinoma are of the follicular subtype, rather than thyroid papillary carcinoma. In this report, a 55-year-old woman with skull metastasis from thyroid papillary carcinoma is presented. The metastatic lesion of the skull was hypervascular and osteolytic, and the bleeding was profuse during resection. There have been only four reports of skull metastasis from thyroid papillary carcinoma. The mean period from the initial diagnosis of thyroid carcinoma until the detection of skull metastasis is 23.3 years, whereas in this patient, it was about 2 years. Therefore, in the clinical course of thyroid papillary carcinoma, skull metastasis should be considered, and the patient should be meticulously followed up.     

Leukotriene B4 production in children with steroid-responsive nephrotic syndrome

Leukotriene B₄ (LTB₄) production in polymorphonuclear leucocytes (PMN) was examined in ten children with steroid-responsive nephrotic syndrome (SRNS) before, during, and after steroid administration. Comparison of LTB₄ production was made in 14 children with non-inflammatory disease who were not receiving steroid therapy. No significant change was noted in PMN LTB₄ biosynthesis in children with SRNS throughout any phase of the disease. Furthermore, there was no significant difference in LTB₄ biosynthesis in PMN between SRNS patients before steroid therapy and patients with non-inflammatory disease. These findings suggest that inhibition of LTB₄ production is not involved in the mechanism underlying steroid action in SRNS.     

Immunohistochemical study of fibronectin, lysozyme, and alpha-fetoprotein (AFP) in human hepatocellular carcinoma

We have immunohistochemically localized fibronectin, lysozyme and alpha-fetoprotein (AFP) in 21 human hepatocellular carcinoma (HCC) tissues obtained by surgical resection at both light and electron microscopic levels. Three distinct distribution patterns of fibronectin (sinusoidal, periacinar, and pericellular patterns) were observed. The sinusoidal and periacinar patterns were mainly observed in HCC of pseudoglandular or trabecular patterns and of Edmondson's grade I or II, whereas the pericellular pattern was observed in HCC of compact or trabecular patterns and of Edmondson's III grade, suggesting that the pericellular fibronectin was rather associated with undifferentiated HCC. Electron microscopic observation of the pericellular fibronectin showed fibronectin to be present in the dilated intercellular spaces where microvilli were moderately developed. We observed intracytoplasmic staining of fibronectin in 2 of the 21 HCC cases. By immunoelectron microscopy, fibronectin was observed in the endoplasmic reticulum (ER) of some HCC cells. In the 21 HCC cases, lysozyme-positive cancer cells were observed in 10 cases, and AFP in 6 cases. At the ultrastructural level, lysozyme was identified in the ER and the perinuclear spaces of HCC cells, suggesting that lysozyme was synthesized by these cells. Lysozyme-positive cases tended to be more frequently observed in cases with the pericellular pattern of fibronectin rather than those with sinusoidal or periacinar patterns.     

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Clinical evaluation of autoantibodies to liver cell membrane specific antigen, liver specific lipoprotein, and Tamm-Horsfall glycoprotein in autoimmune chronic active hepatitis

An enzyme-linked immunosorbent assay was developed to detect circulating autoantibodies to three liver cell membrane surface antigens, i.e., liver cell membrane specific antigen (LCM), liver specific lipoprotein (LSP), and Tamm-Horsfall glycoprotein (THGP). In autoimmune chronic active hepatitis (autoimmune CAH), the positive rate and mean titer (normal range, less than 5.5 units) for anti-LCM were 100% and 13.5 units before corticosteroid treatment and 100% and 9.9 units during the treatment. The corresponding values for anti-LSP were 84% and 11.8 units, and 81% and 8.9 units, and those for anti-THGP were 84% and 12.3 units, and 81% and 7.9 units. In an autoimmune CAH patient, elevation of the plasma levels of autoantibodies during the treatment apparently preceded the elevation of alanine aminotransferase (ALT). However, the ALT elevation induced by transcatheter arterial embolization was not associated with the elevation of these autoantibodies in an autoimmune CAH patient with hepatocellular carcinoma. In primary biliary cirrhosis, drug-induced hepatitis, and non-hepatic immunological disorders, the production of the three autoantibodies did not directly correlate with liver cell damage. These findings suggest that the elevation of autoantibodies against LCM, LSP, and THGP can be a useful guide for the prednisolone treatment of autoimmune CAH.