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Watanabe N.,Kanazawa Medical University | Yokoyama K.,Public Central Hospital of Matto Ishikawa | Kinuya S.,Kanazawa University | Tonami H.,Kanazawa Medical University
Annals of Nuclear Medicine | Year: 2016

Objective: The purpose of this study was to evaluate the degree of cytological radiation damage to lymphocytes occurring after I-131 metaiodobenzylguanidine (MIBG) therapy as determined by the cytokinesis-blocked micronucleus assay. The chromosomal damage to lymphocytes induced by I-131 in vivo should result in augmentation of the number of cells with micronuclei. Methods: We studied 15 patients with pheochromocytoma (14/15) or ganglioneuroma (1/15), who were treated initially with 7.4 GBq of I-131-MIBG. Isolated lymphocytes collected from patients 10 days after the therapy were harvested and treated according to the cytokinesis-blocked method of Fenech and Morley. Serial blood samples were obtained periodically only from two patients for 2 years after therapy. Micronucleus number of micronuclei per 500 binucleated cells was scored by visual inspection. As controls, lymphocytes from the same patients before the therapy were also studied. In an in vitro study, lymphocytes from eight normal volunteers were exposed to doses varying from 0.5 to 2 Gy and studied with the same method. Results: The mean number (mean ± SD) of micronuclei after treatment was significantly increased (p < 0.001) as compared to control subjects (49.4 ± 8.2 vs. 11.3 ± 6.4). Internal radiation absorbed doses estimated for the 15 patients were 1.6 ± 0.3 Gy in this external irradiation study. The frequency of micronuclei post-administration of I-131-MIBG gradually decreased to near baseline (i.e., pre-therapy) levels by 2 years. Conclusions: The relatively low frequency of lymphocyte micronuclei induced by I-131-MIBG in vivo and reversal of the increasing frequency of lymphocyte micronuclei after therapy suggest that the short-term non-stochastic damage induced by this therapy with 7.4 GBq of I-131-MIBG in pheochromocytoma or ganglioneuroma patients is limited and reversible. © 2016 The Japanese Society of Nuclear Medicine

Ueda N.,Public Central Hospital of Matto Ishikawa
International Journal of Molecular Sciences | Year: 2015

Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Aim: Our goal was to compare the effects of thrice-daily lispro 50/50 and twice-daily aspart 70/30 on blood glucose fluctuation and postprandial hyperglycemia in type 2 diabetes mellitus patients. Methods: Thirty-nine type 2 diabetes patients hospitalized at our hospital for poorly controlled disease (26 men, 13 women; mean age 62.5 years, mean BMI 24.1) received either thrice-daily lispro 50/50 (50/50 group, n = 19) or twice-daily aspart 70/30 (70/30 group, n = 20) after 1 week of multiple-daily injection insulin regimen. Efficacy measurements included HbA1c, diurnal variation in blood glucose levels and total daily insulin doses. Despite a small number of subjects, we also explored the potent effect in prevention of progression of atherosclerosis. Ultrasound examination of bilateral carotid arteries (n = 22) and the cardio-ankle vascular index (CAVI) (n = 12) were performed before and after 48 weeks of treatment. Results: Mean HbA1c levels improved significantly in each treatment group, and HbA1c at 48 weeks was significantly lower in the 50/50 group than the 70/30 group (7.0 ± 1.0 vs. 7.3 ± 1.1 %, P = 0.03), whereas mean fasting blood glucose levels did not differ significantly between the two groups at 48 weeks (127.4 ± 30.9 vs. 132.6 ± 20.6 mg/dL, P = 0.47). A significantly greater percentage of subjects in the 50/50 group achieved the target HbA1c value of ≤ 6.9 %compared to the 70/30 group [57.9 % (11/19 patients) vs. 25.0 % (5/20 patients), P = 0.01). The 50/50 group tended to have less daily plasma glucose fluctuation than the 70/30 group. Although there was a significant difference in the degrees of change in CAVI between the subsets of each group, there were no significant differences in the maximum thickness of the intima-media layers of the carotid arteries (IMT) and plaque scores. Conclusions: Thrice-daily lispro 50/50 injection reduces the postprandial blood glucose level and stabilizes the diurnal fluctuations of blood glucose levels more efficiently than twice-daily aspart 70/30 in type 2 diabetes mellitus patients. © 2014, The Japan Diabetes Society.

We describe a 64-year-old woman with a cystic pituitary mass presenting with central diabetes insipidus. Brain magnetic resonance imaging (MRI) with enhancement showed enlargement of the pituitary gland with cystic portions and thickening of the pituitary stalk with homogeneous enhancement. Combined anterior pituitary stimulation test and insulininduced hypoglycemic test confirmed the diagnosis of panhypopituitarism, including adrenocortical insufficiency due to pituitary and hypothalamic dysfunction by stalk compression. Interestingly, the response of serum cortisol to CRH was low and delayed, in contrast to the marked increase in plasma ACTH. Molecular analysis of her plasma ACTH by Sephadex G75 gel exclusion chromatography coupled with radioimmunoassay (RIA) indicated a peak for high molecular weight ACTH, i.e., proACTH, in addition to that for 1-39 ACTH. Three years later, enlargement of the pituitary gland with cystic portions and thickening of the pituitary stalk disappeared completely, followed by the decrease in plasma proACTH level. By the results of endocrinological study and the change of pituitary MRI findings, lymphocytic hypophysitis was suggested. Synthesis of immature ACTH is generally thought to be due to impaired processing of the precursor proopiomelanocortin (POMC) through activation of prohormone convertase (PC)-1 by CRH. It is possible that the immature ACTH in this case was produced by impaired processing of the precursor POMC due to decreased CRH, dysfunction of corticotrophs in the anterior pituitary by compression of the normal pituitary, or antibodies targeting hypothalamic and/or pituitary cells. This report suggested that impaired processing of POMC may unusually play a role in adrenocortical insufficiency exhibited in lymphocytic hypophysitis. © The Japan Endocrine Society.

Yamada A.,Social Insurance Chukyo Hospital | Tashiro A.,Social Insurance Chukyo Hospital | Hiraiwa T.,Social Insurance Chukyo Hospital | Komatsu T.,Social Insurance Chukyo Hospital | And 2 more authors.
Pediatric Transplantation | Year: 2014

Little is known about the risk factors for long-term poor outcome in pediatric renal transplantation. Between 1973 and 2010, 111 renal transplants (92 living donations) were performed in 104 children (56 males, mean age, 12.5 yr) at the Social Insurance Chukyo Hospital, and followed-up for a mean period of 13.6 yr. The patient survival at 1, 5, 10, 15, 20 (living- and deceased-donor transplants), and 30 yr (living-donor transplants only) was 98.1%, 92.8%, 87.8%, 84.9%, 82.6%, and 79.3%. The graft survival at 1, 5, 10, 15, 20, and 30 yr was 92.0%, 77.3%, 58.4%, 50.8%, 38.5%, and 33.3%. The most common cause of graft loss was CAI, AR, death with functioning, recurrent primary disease, ATN, and malignancy. Donor gender, ATN, malignancy/cardiovascular events, and eras affected patient survival. AR and CAI were the risk factors for graft loss. The evolved immunosuppression protocols improved the outcome by reducing AR episodes and ATN but not CAI, suggesting CAI as the major risk factor for graft loss. CAI was correlated with AR episodes, CMV infection, and post-transplant hypertension. Strategies for preventing the risk factors for malignancy/cardiovascular events and CAI, including hypertension/infection, are crucial for better outcomes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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