A Liver Model of Infantile-Onset Pompe Disease Using Patient-Specific Induced Pluripotent Stem Cells

Infantile-onset Pompe disease (IOPD) is a life-threatening multi-organ disease caused by an inborn defect of lysosomal acid α-glucosidase (GAA), which can degrade glycogen into glucose. Lack of GAA causes abnormal accumulation of glycogen in the lysosomes, particularly in the skeletal muscle, liver, and heart. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is the only available treatment; however, its effect varies by organ. Thus, to fully understand the pathomechanism of IOPD, organ-specific disease models are necessary. We previously generated induced pluripotent stem cells (iPSCs) from three unrelated patients with IOPD and establish a skeletal muscle model of IOPD. Here, we used the same iPSC lines as the previous study and differentiated them into hepatocytes. As a result, hepatocytes differentiated from iPSC of IOPD patients showed abnormal accumulation of lysosomal glycogen, the hallmark of Pompe disease. Using this model, we also demonstrated that glycogen accumulation was dose-dependently restored by rhGAA treatment. In conclusion, we have successfully established an in vitro liver model of IOPD using patient-specific iPSCs. This model can be a platform to elucidate the underlying disease mechanism or to be applied to drug-screening. Moreover, our study also suggest that an iPSC-based approach is suitable for modeling of diseases that affect multiple organs like Pompe disease

Reducing nitrogen footprints of consumer-level food loss and protein overconsumption in Japan, considering gender and age differences

The agro-food system perturbs the nitrogen (N) cycle through its N loads to the environment. The present study focused on food-related consumer-level N loads in Japan from 1961–2015, with a particular focus on food loss and protein overconsumption. Gender and age differences were also analyzed. Consumer-level food loss was negligible until the 1970s, when it began to slowly increase, accounting for an average of 13.2% of the annual net supply during 2011–2015. Japanese people have consumed more protein than the World Health Organization’s recommended intake since 1961. Protein overconsumption increased until the mid-1990s, when it began to decrease, but it still accounted for an average of 32.3% of total annual protein consumption during 2011–2015. The national mean of food N footprints (total release of reactive N into the environment related to individual food consumption) in the same period was 18.3 kg N capita ^–1 yr ^–1 , of which food loss accounted for 4% and protein overconsumption for 37%. The food N footprint of each sex/age class varied from 16.0–21.6 kg N capita ^–1 yr ^–1 , males had a larger footprint in each age class. Seven scenarios to reduce the N footprints were evaluated; a scenario that included halving protein overconsumption, livestock meat consumption, and food loss was estimated to reduce the food N footprint by 31%. Thus, there is room for reducing consumer-induced N loads to the environment. Campaigns aimed at boosting healthy and environmentally friendly diets should consider the diverse consumption patterns of different sex and age classes

Feasibility of Pilates for Late-Stage Frail Older Adults to Minimize Falls and Enhance Cognitive Functions

Globally, we are facing the tendency of aging, and demands for health enhancement among the older population have been steadily increasing. Among various exercise interventions, Pilates has been popularly utilized in rehabilitation; therefore, it is considered suitable for vulnerable populations. In this study, frail late-stage older adults (>75 years) participated in a modified Pilates program (30 min per session, once a week for eight weeks). Age-and condition-matched Controls were also involved as the benchmark to reveal the effect of Pilates. While only the Pilates group participated in the exercise intervention, both groups undertook the health assessments twice (before and after the intervention period). Assessments included: (i) falling risk based on 3D motion capture systems and (ii) overall cognitive functions utilizing Mini-Mental State Examination and executive function with the use of Trail Making Test-A (TMT-A). Two-dimensional mood state was also used to measure changes in mood due to Pilates intervention. An 8-week Pilates intervention was effective in achieving higher and symmetrical swing foot control. Dynamic balance at heel contact was also improved by extending the spatial margin in case of slipping. Despite the trend of positive Pilates effects on executive functions (29% improvement) confirmed by TMT-A, no significant effects were observed for cognitive functions. Positive mood changes were achieved by Pilates intervention, which may be the key for late-stage seniors to continue their participation in exercise programs. While further studies with a larger sample size are essential, Pilates appears to provide adequate exercise for the frail late-stage older population to minimize frailty

Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells

Development of factor VIII (fVIII)-neutralizing antibodies, called inhibitors, is a challenging problem in the management of hemophilia A patients. We explored the possibility of pretreatment with apoptotic fVIII-expressing embryonic stem (ES) cells to prevent the development of fVIII inhibitors. Murine ES cells integrated with the human F8 gene were differentiated into embryoid bodies, dissociated to a single cell suspension, subjected to hypo-osmotic shock to induce apoptosis, and intraperitoneally injected into hemophilia A mice. Inhibitors were induced by periodic intraperitoneal injections of recombinant human fVIII (rhfVIII). In the groups in which intraperitoneal injections of rhfVIII began at 1-3 weeks after pretreatment, the titers of inhibitors were significantly lower after the third administration of rhfVIII compared with that in the control group in which apoptotic Ainv18 ES cells (without the human F8 gene) were used for pretreatment, and continued to show lower levels until the sixth administration of rhfVIII. These results suggest that pretreatment with apoptotic hfVIII-expressing ES cells might be promising for the prevention of fVIII inhibitor development in hemophilia A patients

CLDジ ノ フクスウ ゲンゴ ノウリョク ノ カンケイ ニ ツイテ オオサカフカ ノ コウリツ ショウガッコウ デノ チョウサ ケンキュウ ヨリ

This article presents some of the findings of a longitudinal study conducted during last eight years supported by the KAKEN Grants-in-Aid for Scientific Research. Current study has been carried out for the last five years, based on the previous three-year-study at public elementary schools in Osaka, where more than twenty percent of the pupils are from China. Those Culturally Linguistically Diverse (CLD) Children are prospective bilingual speakers of their home language, Chinese, and the local language, Japanese in our society. As increasing number of CLD children have been accepted and facing difficulties at Japanese public schools, the authors and their research group believe it important to assess not only their Japanese but their Chinese language proficiency as well, so that "additive bilingualism" is taken into consideration, as the standpoint of promoting JSL education, rather than "subtractive bilingualism" which leads children to monolingual Japanese. The subjects of the assessment for this article were 110 in total, among whom fifty pupils were assessed in both Japanese and Chinese language, using assessment tools of the Oral Proficiency Interview for Bilingual Children (OBC) and the Dialogic Reading Assessment (DRA) in the two languages separately and individually. Our research questions are two folds: (1) how speaking and reading skills in Japanese are improving among those Chinese pupils, and (2) how their L1 Chinese proficiency is related to their Japanese literacy. The results indicated as follows: (1) their Japanese speaking and reading skills improved yearly, and (2) their Japanese literacy showed mild correlation with their Chinese proficiency. Their Japanese literacy showed highest when they are literate in L1 Chinese. It was higher if they can communicate in Chinese, compared to those who have only L1 listening skill. These results support Cummins'Interdependence Hypothesis, and can be interpreted to encourage additive bilingualism in such public schools in Japan.研究論文Article

A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud

AbstractMammal–fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS1: M101116, M101117, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M101117 and M101192 show no marked abnormalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and M100081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgene driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCS1, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements

QOL after RT or OP for uterine cervix cancer

This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important