Vascular amyloid of unknown origin and senile transthyretin amyloid in the lung and gastrointestinal tract of old age: Histological and immunohistochemical studies

The histological and immunohistochemical characteristics and the incidence of amyloid deposits in the tissues of the lung and gastrointestinal tract were investigated in 64 autopsied individuals who were 80 years and older (age range: 80-92 years; mean: 83.3 years). Immunohistochemical examination was performed with antibodies against amyloid A, transthyretin, immunoglobulin lambda and kappa light chain amyloid fibril proteins, beta2-microglobulin, beta protein, apolipoprotein AI, apolipoprotein AII, atrial natriuretic peptide, apolipoprotein E, and amyloid P component. Transthyretin amyloid fibril protein (ATTR) deposits were observed in five cases (7.8%). Gastrointestinal amyloid deposits of unknown origin were observed in the veins of the gastrointestinal tract in 26 cases (40.6%). This amyloid was regarded as portal amyloid with respect to distribution pattern. Pulmonary vascular amyloid deposits of unknown origin were observed in 12 cases (18.8%). These amyloid deposits were found mainly in medium-sized veins in the lungs and did not react with any antibodies against amyloid fibril proteins except apolipoprotein E and amyloid P component. Eleven of the 26 cases (42.3%) showing portal amyloid also showed pulmonary vascular amyloid of unknown origin. The pulmonary vascular amyloid deposits were similar to the portal amyloid deposits with respect to their morphological features and their relation to elastic fibers in the vessels. Further morphological investigation and biochemical analysis of the pulmonary vascular amyloid and portal amyloid will resolve questions of their origins and relation.     

Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma

Gonadotropin releasing hormone (GnRH) analogs can cause regression of hormone-dependent breast carcinomas via the specific GnRH receptor (GnRH-R). In an attempt to obtain a better understanding of GnRH actions in human breast carcinoma, the expression of GnRH-R was examined immunohistochemically in 58 invasive ductal carcinomas and correlated with various clinicopathological parameters. GnRH-R was immunolocalized in the cytoplasm of carcinoma cells in 37 of 58 invasive ductal carcinoma cases (64%). Immunoreactivity for GnRH-R was also detected focally in the cytoplasm of morphologically normal glandular epithelia adjacent to the carcinoma. A significant correlation was observed between the immunohistochemical expression of GnRH-R and estrogen receptor labeling index (LI; P = 0.030) or progesterone receptor LI (P = 0.0074). There was a significant inverse correlation between GnRH-R immunoreactivity and Ki-67 LI (P = 0.012). No significant correlations were detected between GnRH-R and other clinicopathological parameters, including patient age, menopausal status, stage, tumor size, lymph node status, histological grade and prognosis. This study indicates that GnRH-R is widely distributed in human breast carcinoma cells and regulates GnRH actions locally. Breast carcinomas positive for GnRH-R maintain some hormonal regulatory mechanisms, and GnRH actions may lead to a low proliferative rate in human breast carcinoma.     

Positron Emission Tomography with F-Fluorodeoxyglucose of Uterine Sarcoma: A Comparison with Magnetic Resonance Imaging and Power Doppler Imaging

Objective. The effectiveness of positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) for diagnosis of uterine sarcoma was evaluated in comparison to the effectiveness of magnetic resonance (MR) imaging and power Doppler imaging.Method. The cases of five Osaka City University Hospital patients diagnosed with uterine sarcoma based on histopathological examination, in whom FDG-PET, MR imaging, and power Doppler imaging studies had been performed preoperatively, were reviewed. A comparative study of the usefulness of these three imaging modalities for diagnosis of sarcoma was conducted. Tumors comprised three leiomyosarcomas, one endometrial stromal sarcoma, and one carcinosarcoma.Results.FDG-PET examinations were 100% positive for the five sarcomas; MR imagings were 80% positive (four of five cases), and US was 40% positive (two of five cases). The mean strandardized uptake value of the sarcomas was 4.5 ± 1.3.Conclusion. The sarcoma lesions were clearly imaged by FDG-PET. FDG-PET may be a most useful diagnostic method for uterine sarcoma.     

Comparison of remnant-like lipoprotein particles in postmenopausal women with and without coronary artery disease and in men with coronary artery disease

It is known that hypertriglyceridemia is a risk factor of coronary artery disease (CAD) in postmenopausal women. This study prospectively examined whether remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, may have a significant risk and prognostic values in postmenopausal women with angiographically verified CAD. Remnant-like lipoprotein particles cholesterol (RLP cholesterol) levels in fasting serum were measured in 134 consecutive postmenopausal women with (n = 56) or without (n = 78) CAD by an immunoseparation method. The women with CAD were followed for ≤24 months until occurrence of the following clinical coronary events: readmission or coronary revascularization due to recurrent or refractory angina pectoris, nonfatal myocardial infarction, and cardiac death. Multivariate logistic regression analysis showed that high RLP cholesterol levels (>5.7 mg/dl cholesterol; 90th percentile of the distribution of RLP cholesterol levels in controls) were a significant risk factor for the presence of CAD independent of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and other traditional risk factors. Kaplan-Meier analysis demonstrated that women with CAD and higher RLP cholesterol levels had a significantly higher probability of developing coronary events (p <0.001). In multivariate Cox hazard analysis, high RLP cholesterol levels as well as diabetes and hypercholesterolemia were a significant predictor of future coronary events independent of other risk factors in women with CAD (odds ratio 9.7, 95% confidence intervals 1.3 to 20.3, P = 0.02). In conclusion, increased levels of RLP cholesterol are a significant and independent risk factor of CAD and predict future coronary events in postmenopausal women with CAD.     

Neuroreceptors and Ion Channels as Targets of Alcohol

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Kinya Kuriyama. The presentations were (1) Modulation of neuroreceptors and ion channels by alcohol, by T. Narahashi; (2) Inhibition by ethanol of NMDA and AMPA receptor-channels, by P. Illes, K. Wirkner, W. Fischer, K. Mühlberg, P. Scheibler, and C. Allgaier; (3) Effects of ethanol on metabotropic glutamate receptors, by K. Minami; (4) Acute alcohol actions on the 5-HT3 ligand-gated ion channel, by D. Lovinger; (5) Inhibition of NMDA receptors by MK801 attenuates ethanol-induced taurine release from the hippocampus, by F. Lallemand, R.J. Ward, and P. DeWitte; and (6) Effect of ethanol on voltage-operated Ca²⁺ channels in hepatic stellate cells, by T. Itatsu, Y. Takei, H. Oide, M. Hirose, X. E. Wang, S. Watanabe, M. Tateyama, R. Ochi, and N. Sato.     

Phosphodiesterase 3B gene expression is enhanced in the liver but reduced in the adipose tissue of obese insulin resistant db/db mouse.

Phosphodiesterase (PDE) 3B, when activated by insulin, causes a decrease in intracellular cAMP concentration. The activation of this enzyme results in the reduced output of free fatty acids (FFA) from adipocytes, and an increased lipogenesis in liver. We have recently shown that PDE3B gene expression is reduced in adipose tissues of KKAy mice. We intend to further elucidate the regulation of PDE3B in liver as well as adipose tissues in relation to the insulin resistant state. We examined PDE3B gene expression in liver and adipose tissues of obese, insulin-resistant diabetic db/db mice and also checked the effect of an insulin-sensitizing drug, troglitazone, on this gene expression. In the liver of db/db mice, PDE3B mRNA, its corresponding protein, and the associated catalytic activity were all increased by 2.1, 1.9 and 1.6-fold, respectively, over those in db/+ control mice. Histological examination revealed substantial triglyceride storage in the liver of db/db mice. Conversely, in the adipose tissue of db/db mice, PDE3B mRNA, protein, and its associated activity were all decreased by 0.38, 0.33 and 0.36-fold, respectively. Troglitazone, which has no effect on PDE3B in liver, increased the expression of this gene in adipocytes. This increase is associated with a reduction in the elevated levels of serum insulin, glucose, FFA and triglycerides. The reduced PDE3B gene expression in adipose tissues, which results in the elevation of serum FFA, could be the primary event in the development of insulin resistance in db/db mice. The enhanced PDE3B gene expression may correlate with changes in triglyceride storage in the liver of these mice.     

Usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose for predicting outcome in patients with hepatocellular carcinoma

OBJECTIVES: The present study was designed to assess the usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) for predicting outcome in patients with hepatocellular carcinoma. METHODS: FDG-PET was performed in 48 patients with hepatocellular carcinoma. For quantitative evaluation, a region of interest (ROI) was placed over the area of maximum activity within the lesion. A background ROI was then placed over the nontumor region of the liver. The average activity within each ROI was subsequently corrected for radioactive decay, and the standardized uptake value (SUV) was calculated by dividing the tissue activity by the injected dose of radioactivity per unit body weight. SUV ratio was expressed as the tumor-to-nontumor ratio of the SUV. RESULTS: The tumor-volume doubling time, as index of the growth rate of hepatocellular carcinoma, correlated significantly with SUV ratio but did not correlate with SUV. On the basis of the SUV ratio, the patients were divided into two groups of similar size: group A, SUV ratio of < or = 1.5; and group B, SUV ratio > 1.5. The cumulative survival rate was significantly lower in group B than in group A. On the basis of the SUV, the patients were divided into two groups of roughly equal size: group C, < or = SUV 2.6; and group D, > SUV 2.6. The cumulative survival rate was similar in these groups. On regression analysis with the Cox proportional hazards model, the SUV ratio and tumor number were significantly related to survival. CONCLUSIONS: These results suggest that FDG-PET is useful not only for the evaluation of the malignancy of hepatocellular carcinoma but also for the prediction of outcome in patients with hepatocellular carcinoma.     

Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma

Abstract:  Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor β. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.     

Vasohibin-1 in human breast carcinoma: A potential negative feedback regulator of angiogenesis

Vasohibin-1 is a recently identified negative feedback inhibitor or suppressor of angiogenesis induced by vascular endothelial growth factor (VEGF)-A. The status of vasohibin-1 in human breast carcinoma has not been examined. We examined 151 breast specimens including 98 cases of invasive ductal carcinoma (IDC), 12 of ductal carcinoma in situ (DCIS), 16 of fibroadenoma (FA), six of inflammatory lesion, nine of fibrocystic change and seven of non-pathological breast tissue. We immunolocalized vasohibin-1 and compared its immunoreactivity to that of VEGF-A, basic fibroblastic growth factor (bFGF), VEGF receptor 2 (Flk-1), CD31, CD34 and Ki-67/MIB-1. The correlation of vasohibin-1 immunoreactivity with overall survival (OS), and disease-free survival (DFS) of the patients with breast carcinoma was also evaluated. In addition, we evaluated Ki-67 and CD31, and Ki-67 and vasohibin-1 double-immunostaining for further characterization of neovascularization. Vasohibin-1 was detected in endothelial cells of human breast and its immunodensity was significantly higher in IDC and inflammatory lesions than the other types ( P <  0.001). In addition, a significant positive correlation was detected between vasohibin-1 and VEGF-A, bFGF or Flk-1 ( P <  0.001). There was also positive association s between vasohibin-1 and OS ( P  = 0.004) and between vasohibin-1 and DFS ( P ≤ 0.001 ) in carcinoma cases. Results of double-immunostaining demonstrated the ratio of Ki-67-positive cells among vasohibin-1-positive endothelial cells (46.5%) was significantly higher than those among CD31-positive cells (23.5%). This is the first study demonstrating the status of vasohibin-1 in human breast lesions, which indicates that vasohibin-1 is associated with neovascularization and may especially play important roles in the regulation of intratumoral angiogenesis in human breast cancer. ( Cancer Sci 2009; 100: 88–94)