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Miloradovic V.,Clinical Center Kragujevac | Jagic N.,Center for Cardiology | Petrovic D.,Center for Urology and Nephrology | Popovic M.,Clinical Center Kragujevac
Serbian Journal of Experimental and Clinical Research

Introduction: The prediction of improvements in left ventricular ejection fraction (EF) after revascularisation in patients with ischemic cardiomyopathy relies only on the extent of viable myocardium. The amounts of viable tissue and scar tissue are important but their relationship is different in diabetic and non-diabetic patients. Design and Methods: This study included 50 patients with a low EF (EF<40% by the Simsons method) divided into two groups. The first group consisted of 30 patients with registered coronary artery disease and normal glycoregulation, and the second group consisted of 20 patients with diabetes mellitus and registered coronary artery disease. All patients underwent Dobutamine stress echocardiography before surgical revascularisation and 8 weeks after surgery (2-5 months). Dobutamine infusion was terminated at 15 μg/kg/min. Results: The mean number of hypokinetic segments was 4.32±2.9 before testing, 1.9±2.07 at a 15 μg/kg/min dose of Dobutamine, 2.5±2.12 after revascularisation in the group with diabetes mellitus type II and 4.77±2.11, 1.87±2.18, and 2.97±2.28, respectively, in the group without diabetes mellitus type II. The mean number of akinetic segments was 5.95±2.63, 5.45±2.65 and 5.35±2.62 in the group with diabetes mellitus type II and 4.57±1.68, 3.5±2.26, 3.2±2.16 in the group without diabetes mellitus type II. The wall motion score index (WMSI) was 1.99±0.32 before and 1.86±,031 after revascularisation in the first group and 1.85±0.27 and 1.58±0.24, respectively, in the second group. The sensitivity for the detection of viable myocardium was 100% CI (93%-100%) in both groups, and the specificity was 96% CI (93%-98%) in the group with diabetes mellitus type II and 91% (89%-95%) in the group without diabetes mellitus type II. Conclusions: Our study shows that recovery of function occurs in a sizeable number of revascularised dysfunctional segments. This method was very helpful for the assessment of truly "viable" segments in patients with a poor prognosis. Source

Hatashita M.,Wakasa - Wan Energy Research Center | Taniguchi M.,Osaka University of Pharmaceutical Sciences | Baba K.,Osaka University of Pharmaceutical Sciences | Koshiba K.,Center for Urology and Nephrology | And 4 more authors.
International Journal of Molecular Medicine

Sinodielide A (SA) is a naturally occurring guaianolide, which is isolated from the root of Sinodielsia yunnanensis. This root, commonly found in Yunnan province, is used in traditional Chinese medicine as an antipyretic, analgesic and diaphoretic agent. A number of studies have reported that agents isolated from a species of Umbelliferae (Apiaceae) have antitumor activities. We previously reported, using combined treatments with this medicinal herb and hyperthermia at various temperatures, an enhanced cytotoxicity in the human prostate cancer androgen-independent cell lines, PC3 and DU145, and analyzed the related mechanisms. In the present study, we investigated the effects of treatment with SA prior to hyperthermia on the thermosensitivity of DU145 cells, and the mechanisms related to the induction of apoptosis and G2/M cell cycle arrest via the activation of extracellular-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, as well as the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. Cells were exposed to hyperthermia alone (40-44°C) or hyperthermia in combination with SA. Lethal damage to cells treated with mild hyperthermia (40 or 42°C) for up to 6 h was slight; however, hyperthermia in combination with SA synergistically enhanced thermosensivity. Lethal damage to cells treated with acute hyperthermia (43 or 44°C) was more severe, but these effects were also enhanced and were more significant by the combined treatment with SA. The kinetics of apoptosis induction and cell cycle distribution were analyzed by flow cytometry. In addition, the levels of ERK1/2, JNK and Akt were determined by western blot analysis. The incidence of apoptotic cells after treatment with SA (20.0 μM) at 37°C for 4 h, hyperthermia (44°C) alone for 30 min, and the combination in sequence were examined. The sub-G1 division (%) in the diagram obtained by flow cytometry was applied to that assay. The percentage of apoptotic cells (10.53±5.02%) was higher at 48 h as compared to 0, 12 and 24 h after treatment. The distribution of DU145 cells in the G2/M cell cycle phase was markedly increased after 24 h of heating at 44°C and after the combined treatment with heating and SA. The phosphorylation of ERK1/2 was reduced following treatment with heating and SA, while the levels of phosphorylated JNK (p-JNK) were markedly increased immediately after heating at 44°C and when heating was combined with SA. By contrast, the levels of phosphorylated Akt (p-Akt) were immediately increased only after heating at 44°C. Thus, we concluded that SA exerts its thermosensitizing effects on DU145 cells by inhibiting the activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways. Source

Hayashi S.,University of Fukui | Koshiba K.,Center for Urology and Nephrology | Hatashita M.,Wakasa - Wan Energy Research Center | Sato T.,Kitasato University | And 4 more authors.
International Journal of Molecular Medicine

Parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G 2/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK signaling on mitogen-activated protein kinase (MAPK). Lethal damage caused by mild hyperthermia at 41.0°C or 42.0°C in both cell lines resulted in a low level of thermosensitivity, while sequential combination with PTL showed significant thermosensitization. Step-up hyperthermia (SUH) (42°C for 30 min, 43.0°C or 43.5°C for various periods) reduced the thermosensitivity of the cells to second heating. However, PTL given as pre-treatment prior to SUH prevented SUH-induced thermal tolerance and resulted in significant thermosensitization. Induction of apoptosis by the combination of PTL and hyperthermia at 44.0°C was determined by the ratio of sub-G 1 division cells using flow cytometry, which was increased significantly in comparison with single treatment, and was more effective in PC3 than DU145 cells. The behavior of ERK1/2, p38, and SAPK/JNK signaling in the MAPK cascade by treatment with PTL and hyperthermia were examined by Western blotting. As for PC3 cells, ras-downstream p-ERK1/2 was activated and p-p38 slightly activated by combined treatment with PTL and hyperthermia in comparison with each alone. As for DU145 cells, ERK1/2 was not changed, while p38 and SAPK/JNK were slightly activated by combination treatment. These results were related to increases in the induction of apoptosis, G 2/M cell cycle arrest, and lethal damage of cells via the MAPK cascade. Together, our findings demonstrate that PTL is an effective thermosensitizing agent for multidisciplinary therapy for human prostate cancer. Source

Labudovic T.,Center for Urology and Nephrology | Labudovic T.,University of Kragujevac | Nedeljkovic B.,Center for Urology and Nephrology | Petrovic D.,Center for Urology and Nephrology | And 3 more authors.
Medicinski Casopis

Cardiorenal syndrome is a psychophysical disorder of the functions of the heart and kidneys, where the acute or chronic disorder of the functioning of one organ causes the acute or chronic disorder of the functioning of the other organ. In the type 4 of the cardiorenal syndrome (chronic renocardial syndrome), the deficiency of the vitamin D and the secondary hyperparathyroidism cause a disorder of the functioning of the heart and kidneys. The goal of this work is to analyze the risk factors, pathogenetic mechanisms of the development of the secondary hyperparathyroidism and to point out the clinical importance of its early detection and timely treatment. Works written by experts have been examined, as well as the clinical studies researching etiopathogenesis, diagnostics and treatment of secondary hyperparathyroidism. In the chronic kidney disease (stadiums 2 and 3), adaptation mechanisms are activated, while the concentration of FGF-23 and the concentration of parathyroid in the serum both increase. These hormones increase the fractional excretion of the phosphates within the kidney, while parathyroid releases the calcium from the bone tissue, therefore maintaining the concentration of calcium and phosphates in the serum within the normal range. The kidneys' loss of ability to create active vitamin D metabolites and excrete phosphate out of the organism significantly contributes to the development and progress of type 4 cardiorenal syndrome. The main clinical consequences of the secondary hyperparathyroidism are the high turnover bone disease, vascular and valvular calcification and the development of heart diseases. Modern treatment includes the use of phosphate binders that not contain calcium, new vitamin D metabolites and the use of calcimimetics. The early diagnosis and optimal control of secondary hyperparathyroidism prevent the progress of the chronic kidney disease and the development of cardiovascular diseases, reduce the rate of cardiovascular morbidity and mortality and improve the patients' quality of life. © 2014, Serbian Medical Society. All rights reserved. Source

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