Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs.

The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc (QTc) interval and its integration from 1 to 21 h (AUC1-21h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1-21h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation.

Nuclear medicine practice in Japan: a report of the sixth nationwide survey in 2007.

OBJECTIVE: The Subcommittee on the Survey of Nuclear Medicine Practice in Japan has performed a nationwide survey of nuclear medicine practice every 5 years since 1982 to provide detailed information on its present status. METHODS: Questionnaires were sent to all institutions known to the Japan Radioisotope Association to conduct nuclear medicine examinations. The questionnaires addressed the number and kind of nuclear medicine examinations performed as well as the kind and dose of the radiopharmaceuticals used during the month of June 2007. The annual number of total or specific examinations was then estimated. RESULTS: Of the institutions sent questionnaires, 1219 were for in vivo study, 49 for in vitro study, and 212 for positron emission tomography (PET) study. Of these, 92.2% provided answers. A total of 1569 gamma cameras were installed in 1119 institutions, of which 70% were dual-head cameras. The estimated total annual number of in vivo examinations expressed by the number of administered radiopharmaceuticals was 1.41 million, representing a decrease of 11.5% when compared with that of the previous survey (2002). The frequency of study with respect to single-photon emission computed tomography (SPECT) slightly increased to 42.3% from 39.9% in the previous survey. The most frequently performed scintigraphy was bone (38.3%), followed by myocardium (26.2%) and brain perfusion (14.1%). Brain perfusion scintigraphy slightly increased, whereas tumor scintigraphy decreased by one-half when compared with the previous survey. The most commonly used radiopharmaceutical for each scintigraphy was (99m)Tc-HMDP for bone, thallium-201 ((201)Tl)-chloride for myocardium, gallium-67 ((67)Ga)-citrate for tumor, and technetium-99m-ethylcysteinate dimmer ((99m)Tc-ECD) for brain. The number of PET institutes increased from 36 to 212. (18)F-fluorodeoxyglucose ((18)F-FDG)-PET dramatically increased 14.8-fold during the past 5 years. Radionuclide therapy also increased. (131)I therapy for thyroid cancer and hyperthyroidism was conducted yearly in 2373 and 4146 patients, respectively. A total of 13.1 million in vitro radioassays were carried out yearly, the number of which has been decreasing continuously since 1992. CONCLUSIONS: It was proved that the content of nuclear medicine practice in Japan has changed considerably in the past 5 years. Namely, (18)F-FDG-PET and radionuclide therapy increased. This report might be useful for understanding the present trends of nuclear medicine practice in Japan.

The death effector domain-containing DEDD supports S6K1 activity via preventing Cdk1-dependent inhibitory phosphorylation.

Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the death effector domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD(-/-) cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD(-/-) cells and tissues. Consequently, as in S6K1(-/-) mice, the insulin mass within pancreatic islets was reduced in DEDD(-/-) mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.

Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.

Port site recurrence diagnosed by positron emission tomography after laparoscopic surgery for colon cancer.

Port site recurrence after laparoscopic surgery for colorectal cancer patients is a rare complication. We report a case of port site recurrence in a 46-year-old woman that was detected by positron emission tomography (PET) using 18[F]-fluoro-deoxyglucose (FDG). Surgical treatment consisted of laparoscopic ileo-cecal resection and lymph node dissection. At her nine months postoperative follow-up examination, her serum carcinoembryonic antigen (CEA) levels had raised to 15.8ng/mL. Although computed tomography and colonoscopic examination were performed, lung, liver and local recurrence in the colon were not detected. FDG-PET was then performed and detected a higher concentration of FDG at the port site in the abdominal wall. Port site recurrence was diagnosed clinically and surgical resection of tumor at the port site was performed. Pathology revealed a moderately differentiated adenocarcinoma diagnosed as port site recurrence. This case suggests that FDG-PET is an important examination for the detection of port site recurrence when serum CEA levels are rising and routinely radiographic examinations are unable to detect the site of recurrence.

Early colon cancers detected by FDG-pet: a report of two cases with immunohistochemical investigation.

Increased glucose uptake is one of the metabolic characteristics of tumor cells. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET), a technique that is used widely to study this altered glucose metabolism in tumors, allows the detection of various types of malignancy. We present herein two cases of early colon cancers detected incidentally by FDG-PET. The technique was used as part of the screening examinations for preoperative staging, and for postoperative follow-up. In both cases, the lesions were removed by colonoscopic polypectomy, with no complications. Moreover, we confirmed the existence of altered glucose metabolism in the resected specimen by immunohistochemical staining using an antibody raised against Glut1. Immunohistochemically, Glut1 was expressed in vitro in both of the lesions, supporting the positive FDG-PET result obtained in vivo. To our knowledge, this is the first report to describe in vitro Glut1 expression and in vivo tumor detection using FDG-PET in colorectal carcinoma.