Genki Horitsugi

Cell-sheet Therapy With Omentopexy Promotes Arteriogenesis and Improves Coronary Circulation Physiology in Failing Heart

Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insufficient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into four groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiography revealed that the combined procedure increased vascularization in resistance arterial vessels with better dilatory responses to endothelium-dependent agents. Serial (13)N-ammonia PET showed better global coronary flow reserve in the combined group, mainly attributed to improvement in the basal left ventricle. Consequently, the combined group had sustained improvements in cardiac function parameters and better functional capacity. Cell-sheet transplantation with an omentum-flap better promoted arteriogenesis and improved coronary microcirculation physiology in ischemic myocardium, leading to potent functional recovery in the failing heart.

Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study

Objective(s): It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP. Methods: We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 µg of DNP, respectively, while one patient was scanned following the oral administration of 30 µg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT. Results: In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 µg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 µg of DNP, or no DNP. Conclusion: The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP.

Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

Purpose Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimers disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. Results The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. Conclusions We demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

A prostacyclin agonist and an omental flap increased myocardial blood flow in a porcine chronic ischemia model

Objective: We hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO‐1301SR, a slow‐release synthetic prostacyclin agonist‐inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart. Methods: A minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO‐1301SR only, and ONO‐1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting. Results: In an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a 13N‐ammonia positron emission tomography study, the combined group displayed a prominent increase in myocardial blood flow and myocardial flow reserve in the left circumflex territory, particularly at the infarct‐border region. Consequently, the combined group showed greater regional cardiac function in the left circumflex territory particularly at the infarct‐border region, contributing to a greater global ejection fraction with a smaller left ventricular endosystolic volume. Pathologically, attenuated fibrosis, nonswollen myocytes, and upgraded capillary density and proangiogenic cytokines were prominent in the combined group. Conclusions: ONO‐1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model.

Assessing the Effectiveness of Risk Communication for Maintenance Workers Who Deal With Induced Radioactivity Management of Medical Linear Accelerators.

AbstractIn Japan, an amended law that mandates levels of unintended induced radioactivity has been in effect since 1 April 2012. According to the new regulation, if the concentration of induced radioactivity in affected parts is above the clearance level, the parts must be regarded as radioactive even if they weigh less than 1 kg. This regulation reform raises several new issues concerning medical linear accelerators, including how to determine the decay period for induced radioactivity before maintenance can be performed and how to identify what parts should be considered radioactive waste. The authors performed several risk communication (RC) activities aimed at improving the understanding of maintenance workers at medical accelerator manufacturers and establishing good guidelines by involving stakeholders. For this purpose, a working group was established and conducted RC activities, such as holding opinion exchange meetings between medical staff and maintenance workers and creating a booklet to answer questions from maintenance workers. To evaluate these activities, three questionnaire surveys were conducted between 2011 and 2014. According to the results of this study, the ratio of maintenance workers who accepted “The decay period is within one week” was approximately 60% at the third survey and significantly increased (P < 0.0001) during the survey period. Approximately 25% of the maintenance workers felt that not enough information was provided about the decay period, and approximately 63% thought that the information provided on the health effects of radiation was sufficient. These results suggest that the present RC was successful.

172 A Slow-Releasing Synthetic Prostacyclin Agonist “Ono 1301-sr†Combined with Omental Flap Increases Myocardial Blood Flow and Reduces Microvascular Resistance, Associated with Functional Recovery, in a Porcine Chronic Myocardial Infarction Model

Introduction Coronary microvascular dysfunction (MVD) has been shown to be the major cause of persistent myocardial ischaemia and progressive left ventricular (LV) remodelling in the chronic myocardial infarction (MI) heart. ONO-1301SR is a slow-releasing synthetic prostacyclin agonist, being developed to induce angiogenesis by upregulating a variety of proangiogenic cytokines in the targeted region. In addition, pedicle omental flap covering over the LV surface reportedly yields proangiogenic effects on chronic MI heart. We herein hypothesised pedicle omental flap covering, combined with ONO-1301SR placement. over the LV surface may be effective on the MVD and related functional deterioration in a chronic MI heart. To test this hypothesis, clinically latest imaging studies were applied in a porcine chronic MI model. Methods A mini-pig chronic MI model was generated by placing an ameroid constrictor around the left anterior descending artery for 4 weeks. The mini-pigs were then randomly assigned into the following 4 groups; sham group, omental flap alone (OM group), ONO-1301SR alone (ONO group), ONO-1301SR plus omental flap (ONO+OM group, n = 6 each). Results At 4 weeks after the treatment, 13N-ammonia PET study showed that the ONO+OM group, but not the other groups, displayed a significantly increase in myocardial blood flow (189 ± 89% increase, P < 0.05) and coronary flow reserve (179 ± 121% increase, P < 0.05) under the stress compared to those under the rest. This trend was predominated in the left circumflex territory. In addition, coronary angiogram and pressure-temperature sensor wire study showed that the ONO+OM and the ONO groups, but not the OM group, showed a significantly greater number of collateral arteries and smaller indexed of microvascular resistance, in particular, in the left circumflex territory, compared to the sham group. Moreover, echocardiographical EF was significantly greater in the ONO+OM group (50 ± 7%) and the ONO group (48 ± 3%), compared to the OM group (41 ± 3%) and the sham group (38 ± 5%) at 4 weeks. Furthermore, histological density of CD31-positive capillaries and CD31SMA-double positive arterioles were significantly greater in the ONO+OM group than the sham group or the OM group, in association with a significantly smaller myocyte size and interstitial fibrous area in the ONO+OM and the ONO group compared to those in the other groups. However, expression of proangiogenic cytokines, such as vascular endothelial growth factor, hepatocyte growth factor or stem cell-derived factor-1, were not significantly different among the groups, indicating that angiogenic process might have been completed at the 4 weeks after the treatment. Conclusions ONO-1301SR combined with omental flap therapy promoted myocardial angiogenesis with collateral artery growth, leading to recovery of the cardiac function in a porcine ICM model. This combined therapy may be useful in regenerating myocardial microvasculature.

[Current status on storage, processing and risk communication of medical radioactive waste in Japan].

Decay-in-storage for radioactive waste including that of nuclear medicine has not been implemented in Japan. Therefore, all medical radioactive waste is collected and stored at the Japan Radioisotope Association Takizawa laboratory, even if the radioactivity has already decayed out. To clarify the current situation between Takizawa village and Takizawa laboratory, we investigated the radiation management status and risk communication activities at the laboratory via a questionnaire and site visiting survey in June 2010. Takizawa laboratory continues to maintain an interactive relationship with local residents. As a result, Takizawa village permitted the acceptance of new medical radioactive waste containing Sr-89 and Y-90. However, the village did not accept any non-medical radioactive waste such as waste from research laboratories. To implement decay-in-storage in Japan, it is important to obtain agreement with all stakeholders. We must continue to exert sincere efforts to acquire the trust of all stakeholders.