SummaryNeural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) are considered to be a promising cell source for cell-based interventions that target CNS disorders. We previously reported that transplanting certain hiPSC-NS/PCs in the spinal cord results in tumor-like overgrowth of hiPSC-NS/PCs and subsequent deterioration of motor function. Remnant immature cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC transplantation. Because Notch signaling plays a role in maintaining NS/PCs, we evaluated the effects of γ-secretase inhibitor (GSI) and found that pretreating hiPSC-NS/PCs with GSI promoted neuronal differentiation and maturation in vitro, and GSI pretreatment also reduced the overgrowth of transplanted hiPSC-NS/PCs and inhibited the deterioration of motor function in vivo. These results indicate that pretreatment with hiPSC-NS/PCs decreases the proliferative capacity of transplanted hiPSC-NS/PCs, triggers neuronal commitment, and improves the safety of hiPSC-based approaches in regenerative medicine.

The increase of proportion of return to work after stroke was nonlinear, and this trend was referable to the social security systems available to the patients included in this study. Normal muscle strength and absence of apraxia were significant predictors of return to work after stroke. White-collar occupation showed a tendency to promote return to work.

Introduction Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI. Setting NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models. Methods The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 10 6 cells will be transplanted into the injured spinal cord parenchyma 14–28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000035074; Japan Registry of Clinical Trials [jRCT] number, jRCTa031190228). Discussion/conclusion We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.

Few studies have identified factors that predict return to work after stroke in Japan. Our aim in this study was to determine the predictors of return to work after stroke in Japan. We performed a retrospective cohort study on the association between patients' characteristics at admission and return to work in 230 first-stroke patients, adjusting for potential confounding factors. The patients were all aged younger than 65 years and were working, students, or housewives at the time of their stroke. Return to work was evaluated by a follow-up questionnaire. Data were analyzed using forward logistic regression analysis to compute odds ratios of return to work. The adjusted odds ratios (and 95% confidence intervals) for patients with normal muscle strength vs severe muscle weakness, without apraxia vs with apraxia, and with white-collar vs blue-collar occupation were 4.50 (1.04 to 19.42), 4.87 (1.28 to 18.54), and 3.33 (1.34 to 8.30), respectively. Significant predictors of return to work after stroke were no muscle weakness, absence of apraxia, and white-collar occupation.

SummaryTreatment involving regenerative medicine for chronic spinal cord injury (SCI) is difficult due to phase-dependent changes in the intraspinal environment. We previously reported that treatment with a gamma-secretase inhibitor (GSI), which inhibits Notch signaling, promotes the differentiation into mature neurons in human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for subacute SCI. Here, we evaluated the efficacy of GSI-treated hiPSC-NS/PC transplantation in treating chronic SCI, which resulted in significantly enhanced axonal regrowth, remyelination, inhibitory synapse formation with the host neural circuitry, and reticulo spinal tract fiber formation. Interestingly, inhibiting Notch signaling with GSI caused phosphorylation of p38 MAPK, which is a key molecule required to promote axonal regeneration. These favorable outcomes contributed to motor function improvement. Therefore, treating cells with GSI provides a beneficial effect after transplantation, even in the chronic phase following SCI.

There are many reports of reduction of zinc level and rise of copper level in serum of patients with liver disease. However, there are a few reports that compare the trace elements in tumor tissues and nontumor tissues of the liver with hepatoma. We studied trace element distribution in tumor tissues and nontumor tissues of liver with hepatoma and compared them with data from normal liver tissues. Zinc (Zn), copper (Cu), selenium (Se), cadmium (Cd), mercury (Hg), and iron (Fe) were chosen as the trace elements to be observed. We observed falls of Zn, Cd, and Hg levels in tumor tissues and the rise of Cu level as a result of this investigation. Zn, Cd, and Hg levels in tumor tissues were significantly lower than those in nontumor tissues and Zn, Cd, and Hg levels in nontumor tissues were significantly lower than in normal liver tissues. This tendency was clearer for Cd and Hg than for Zn. Although the distribution of Cu was not significant, a distribution contrary to that of Zn was shown. These findings indicate that the distribution of Zn, Cd, and Hg can serve as supportive evidence that could be useful as a tumor marker. Selenium showed almost the same accumulation tendency among tumor tissues, nontumor tissues, and normal livers. Although correlation was observed among most metals in the normal liver, there was almost no correlation in tumor tissues.

and Environmental Health-The objective of the present study was to evaluate the ecological relationship between mesothelioma incidence/mortality and per capita asbestos consumption in ten Western countries and Japan. The two national indices used to assess the geographical correlation were the most recent incidence/mortality rate of mesothelioma for the population over 15 years of age, and the per capita asbestos consumption rate of approximately 10-25 years ago for the population of all ages at that time. Among the ten Western countries, a clear linear relationship was shown between the mesothelioma incidence/mortality rate and the preceding per capita asbestos consumption rate with the Spearman correlation coefficient at 0.70 (p=0.03), and R2-value at 66%. However, the data-point for Japan was situated apart from the linear relationship due to the lower mesothelioma mortality rate, and when combined with other Western countries, the significant relationship diminished.It is possible that the asbestos consumption curve for Japan in past years lagged behind that for the Western countries and the cumulative exposure effect has not yet reached the level that can be expected from other Western countries. (J Occup Health 1999; 41: 8-11)

The optimal cut off point of the new immunological method of FOBT was estimated to be about 200 ng/ml, a value which, more than the current cut off value, favours specificity over sensitivity.