The self-organizing tissue-based approach coupled with induced pluripotent stem (iPS) cell technology is evolving as a promising field for designing organoids in culture; it is expected to achieve valuable practical outcomes in regenerative medicine and drug development. Organoids show properties of functional organs and represent an alternative to cell models in conventional two-dimensional differentiation platforms; moreover, organoids can be used to investigate mechanisms of development and disease, drug discovery and toxicity assessment. Here we review characters of emerging organoid technology focusing on liver bud as an example, and discuss their promise and challenges for the use regenerative medicine.

The study of kidney regeneration has progressed more slowly than that of the other organs. This is not only because the kidney is composed of a wide variety of cells, but also because developmental processes of the kidney were not clarified in detail. We proved that "nephron progenitors" originate from posterior nascent mesoderm and differentiate by way of posterior intermediate mesoderm. We also found that long-term exposure to Wnt signal is the key to these processes.
We established a method, based on these embryologic findings, to reconstruct the 3-D kidney structures via nephron progenitors from mouse embryonic stem cells and human induced pluripotent stem cells. Many groups have now reported the induction of nephron progenitors, progenitor expansion, generation of kidney organoids, and gene manipulations, as well as the trials to generate the kidney in chimeric animals. Although many problems remain to be solved, the reciprocal interactions between embryology and regeneration research will lead to the realization of regenerative medicine of the kidney.

Pancreas transplantation and islet transplantation are performed all over the world. However, the number of donor is lacking. Recently pluripotent stem cells such as iPS (induced Pluripotent Stem) cells and ES (Embryonic Stem) cells are thought to be promising cell sources for regenerative medicine. Although it is not easy to make artificial pancreas from them in vitro, it is possible to induce functional islets from them. We succeeded in generating human islet-like spheroids from human iPS cells and confirmed that transplanted cells functioned in vivo. Moreover, we are aiming at the next generation islet transplantation by encapsulating induced human islets for type 1 diabetic patients.

Organ transplantation is a promising therapy for organ failure and defects of organ specific functions. However, the transplantation of a small or large intestine is difficult to perform partly because of the shortage of donor organs. Alternatively, organoid transplantation is becoming another choice for restoring organ-specific functions. For example, the recent development of 3-D-culture technique for intestinal stem cells has opened up our way to apply those cultured cells to tissue-regenerative therapies. Here we present a short review of studies regarding intestinal organoids established from somatic stem cells or otherwise from pluripotent stem cells. Also, we wish to discuss the possibility of using intestinal organoids as a novel tool for regenerative medicine.

The respiratory system is a highly branched organ composed of trachea, bronchioles, and alveoli. Because its main function is the exchange of oxygen and carbon dioxide, respiratory dysfunction can be life threatening. In fact, respiratory disease is a leading cause of death worldwide. Therefore regenerative medicine of the respiratory system is getting more attention, and many researches to reconstitute the respiratory system using pluripotent stem cells or somatic stem cells have been reported. This review summarizes the development of the respiratory system and advances in the tracheal/bronchiolar/lung stem cells and cell culture technology, including 3-D organoids. In conclusion, we also discuss challenges to make regenerative medicine suitable for practical use.

Although public opinion polls reported that over 40% of Japanese people want to donate their organs at death, the number of organs remains low (=< 1 donor/million population). This low donation rate is supposed to be due to the lack of an in-hospital system to confirm patient desires to donate organs to patients at hospitals. The purpose of this study is to develop and evaluate the educational program to improve the quality of terminal care at acute care hospitals in the form of a QM (quality management) seminar at emergency departments, focusing on management methods and quality management to facilitate and establish an in-hospital system.
From 2013 to 2015, there were 94 participants. Pre- and post-program test showed that the improvement rate was 15.9% for transplantation medical care, 6.9% for skills, and 10.5% for the management method. By the educational method, the improvement rate was 10.1% for lecture and 10.2% for group-work exercise (+ lecture). Compared with doctors, nurses had a lower improvement rate in the domain of management methods. A questionnaire survey showed that the participants evaluated that management method was difficult and their understanding level was low, but they highly recommended participation.
To improve the quality terminal care, the role of nurses is important because they are the major players in patient care, and revision to improve the educational program is necessary to provide outcomes similar to those doctors produce. Other supporting methods, such as the provision of educational tools and sharing success cases, should be considered to facilitate in-hospital system development.

【Objective】In pediatric liver transplants, not only will the continuous monitoring of physical status/growth catch-up/patient survival be necessary, but also the lifelong psychomotor development/quality of life will be essential in the recipients' long-term follow-up. The aim of the present study was to evaluate posttransplant school activities (nursery, preschool, and elementary) and validate the psychosocial support in each life stage of the recipients.
【Methods】During the study period, 262 liver transplant recipients and their parents in the National Center for Child Health and Development, except for those patients aged over 18 and living abroad, were enrolled and participated in a survey assay using several modules, which measured general, disease-related, and family functions, including research in each school status.
【Results】Responses from 173 among the 262 recipients and their parents (66.0%) were obtained. A total of 106 patients experienced entering school (nursery, 41, preschool, 71), though 38% of nursery students and 18% of preschool patients were denied entry to school because of their lack of knowledge about liver transplants and infectious complications with immunosuppression. Seventy-one patients experienced elementary school life, although 73% of them had general education, and 24% required special needs education because of developmental delay. The patients in special needs education class and 58% of the patients received liver transplants for metabolic liver disease. Regarding school activities during the field day, 72% of the patients needed no special assistance. However, 71% of the patients had impairment of activites during the school trip. Most parents described difficulties in regard to understanding patient conditions, including immunosuppression and the restriction of foods and of some school activities.
【Conclusion】Our results also suggest that the necessity of long-term social support reduces social isolation to improve the health care of children who have had liver transplants.

【Objective】Cyclosporin A is one of the calcineurin inhibitors and used as a potent immunosuppressive drug. However, it is also known to have toxic effects by causing mitochondrial stress or cell senescence in renal tubular cells. Recently, magnesium supplementation was discovered to help maintain mitochondria membrane potential under stress-inducing environments. In this study, we confirm whether citrate, a magnesium chelator in mitochondria, can attenuate cyclosporine A-induced mitochondrial stress.
【Methods】We evaluated mitochondrial membrane potential, reactive oxygen species generated from mitochondria, and cell senescence by measuring relative fluorescent intensity of Tetramethylrhodamine ethyl ester, MitoSOX, and H4K16ac staining in human renal tubular cells (HK-2) with or without cyclosporine A or citrate.
【Results】Citrate helped maintain mitochondria membrane potential under cyclosporine A- inducing metabolic stress in a dose-dependent manner. Interestingly, citrate did not affect quantity of reactive oxygen species generated from mitochondria, though it attenuated cyclosporine A-inducing cell senescence in HK-2 cells.
【Conclusion】A magnesium chelator in mitochondria, citrate possibly could attenuate cyclosporine A-induced mitochondria stress and resulting cell senescence in human renal tubular cells.

【Objective】Ganciclovir (GCV) and valganciclovir (VGCV) are used for the treatment and preemptive therapy of cytomegalovirus infection in pediatric liver transplantation patients. A GCV 24-hour area under the time-concentration curve (AUC_0-24) of 40 – 60 μg/mL⋅hr is related to efficacy. The primary objective was to compare systemic exposures of GCV in patients administered GCV or VGCV using AUC_0-24. Secondary objectives were the evaluation of causal relationships between AUC_0-24 and efficacy or adverse effects.
【Study Design】Retrospective case series study.
【Methods】A limited sampling strategy was used to estimate AUC_0-24. The time to a clearance of pp65 antigenemia was used as an efficacy, and incidences of renal and hematological toxicity were used as a safety.
【Results】Twenty-two pediatric liver transplantation patients were enrolled in the study. Estimated AUC_0-24 using 2 sampling times (2 – 3 and 6 – 8 hours after administration) showed a good predictive performance by the Bayesian approaches. Ten patients were included in the AUC_0-24 equivalence study and the mean AUC_0-24 ratio (VGCV/GCV) was 1.04. In this study, a higher inter-individual variability in AUC_0-24 was observed after VGCV administration. In efficacy evaluation, a slower clearance of pp65 antigenemia was observed in patients with AUC_0-24 of less than 40. Incidences of renal and hematological toxicity tend to be higher in patients with AUC_0-24 more than 60, although not significant differences were noted between AUC_0-24 groups.
【Conclusions】In this study, the systemic exposure of GCV following VGCV and GCV administration was equivalent. Lower exposure may cause prolongation of the dosing period, and long-term administration threatens patients with renal and hematological toxicity.

【Objective】We aimed to clarify the usefulness of nursing intervention by exploring psychological experiences of adult living-donor liver transplant recipients during their hospitalization period in this study.
【Design】This was a category study.
【Methods】We interviewed living-donor liver transplant recipients with their consent. In a semi-structured format, we asked about their psychological experiences during hospitalization, and then analyzed the meaning of their experiences.
【Results】The recipients (n=11) had postoperative feelings of "escape from intolerable confusion," "reassurance provided by the obligatory situation," "complicated emotions when thinking of donors" before the operation and "hallucinations and trouble discerning reality," and "greater suffering than expected." Prior to hospital discharge, the recipients had felt "elevated motivation resulting from the pleasure derived from improved recovery and receiving support". These six feeling categories consisted of 19 subcategories.
【Conclusion】The present results suggest the need, for postoperative recovery to widely accept the postoperative difficulties and suffering that recipients face. Nurses evidently can help the recipients acquire self-care abilities by understanding their suffering and facilitating their ability to speak their mind.

【Objective】Therapeutic drug monitoring (TDM) of everolimus is essential to maintain safety and efficacy in personalized immunosuppressive therapy. Several methodologies to measure the blood levels of everolimus are available. In this study, we aimed to evaluate a new automated electrochemiluminescence immunoassay (ECLIA) for measuring blood concentrations of everolimus in clinical practice.
【Methods】Spiked whole-blood samples were used to evaluate the performance of ECLIA. Residual EDTA whole-blood concentrations of everolimus in transplant patients were measured by ECLIA, liquid chromatography with tandem mass spectrometry (LC-MS/MS, n = 126), and latex agglutination (LA, n = 116). We also examined whether the simultaneous measurement of everolimus and tacrolimus was feasible.
【Results】The lower limitation of quantification of 0.22 ng/mL at 20% coefficient of variation was determined. Imprecision testing gave coefficients of variation less than 6% for both within-run and intermediate imprecisions. Values obtained by ECLIA were highly correlated with those of LC-MS/MS (ECLIA=1.128×LC-MS/MS+0.993; r=0.946), and LA (ECLIA= 0.981×LA + 1.245; r=0.964). A high correlation between the results of simultaneous measurement and independent measurement was observed for blood concentrations of everolimus and tacrolimus, respectively (r > 0.99).
【Conclusion】The ECLIA is a sensitive and useful method for routine TDM of everolimus.

Hepatitis E identified as a zoonosis with a natural reservoir in pigs.
Hepatitis E virus (HEV) infection attracted close attention in Japan after the fatal case of a patient with hepatitis E was reported in 2002, and after that reports of clinical HEV infection had increased rapidly. Infection via blood transfusion leads to further increased medical concerns. Subclinical infection is the most common situation, and rare cases of HEV infection develop acute hepatitis, which results in complete recovery. There were no data on chronic hepatitis E until recently. However, in organ-transplanted patients receiving immunosuppression therapy chronicity is a possibility, and these patients need close attention.
Here we report four cases that developed hepatitis E after kidney transplantation and were diagnosed in our institution. We investigated the potential route of HEV infection and present a detailed clinical course in our cases.

We report a case of deceased donor liver transplantation (DDLT) using a deceased liver graft from a marginal donor (MD) to the patient with decompensated liver cirrhosis coexisting with hepatocellular carcinoma (HCC). A 57-year-old man with decompensated liver cirrhosis whose medical urgency score was estimated at six points was registered on waiting lists. He had been suffering from HCC for one year when he received a donor call. The deceased donor was also a man over 50 years old who had histories of diabetes mellitus and acute myocardial infarction with morbid obesity. Furthermore, the deceased donor had about 60 minutes of cardiopulmonary arrest time. However, that information suggested that the harvested graft might be a marginal liver graft owing to morbid obesity and long cardiopulmonary arrest time. We harvested the liver graft until receiving the confirmation of histopathological infelicity. A histopathological evaluation revealed that the deceased liver graft was appropriate as a whole liver graft because no steatosis and hepatocellular necrosis were observed. He underwent DDLT using this graft and recovered from decompensated liver cirrhosis. Although the harvested grafts from MDs are usually considered marginal grafts, MDs do not always have marginal grafts. The liver pool is strictly limited owing to a lack of deceased donors and an increase of patients on waiting lists; therefore, transplant surgeons must remember the use of extended criteria liver grafts from MDs to help remedy organ shortages.