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Few studies have examined whether objective or subjective economic status (ES) has a greater association with the happiness of older adults, despite concerns regarding the growing economic cost of morbidity and their functional dependence in developing countries with aging populations. Thus, this study examined whether objective/subjective ES was associated with happiness in older adults in two Myanmar regions. A multistage random sampling procedure and face-to-face interviews were conducted in the urban and rural areas of Myanmar. The happiness of 1200 participants aged >60 years was evaluated using a single happiness score ranging from 0 (very unhappy) to 10 (very happy). The wealth index, used as an objective ES, was calculated from 17 household asset items, such as radio, washing machines, and television. Subjective ES was assessed by asking “Which of the following best describes your current financial situation in light of general economic conditions?” Responses ranged from “very difficult” to “very comfortable”. Both low objective and subjective ES were negatively associated with happiness, after adjusting for confounding variables and stratification by region (urban and rural areas). Although objective and subjective ES had similar associations with happiness in urban areas, subjective ES had a stronger association in rural areas.

Introduction: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the factors related to high care burden after completing the discharge-support program., Methods: A questionnaire-based cross-sectional study was conducted on all primary caregivers whose children received the program in our center and moved from hospital to home (30 children and 29 families) from May 2011 to May 2018. Fifteen children came from the neonatal intensive care unit. The questionnaire consisted of three parts: characteristics of children and families and life after the program; the Zarit Burden Interview (ZBI); and the Positive and Negative Affect Schedule (PANAS)., Results: Twenty-three primary caregivers responded (79% response rate). All children received tracheostomy and 71% received home mechanical ventilation. Primary caregivers were all mothers. High ZBI score was not related to the severity and type of medical equipment. There were relationships between high ZBI score and following factors: 'unimproved relationship between patients and family members without primary caregivers' and 'additional medical equipment after discharge'. The result of PANAS showed that positive attitude was not different between those with high and low ZBI scores., Conclusion: It is crucial to reach out to family members without a primary caregiver. Additional medical care/equipment after the program is related to the care burden of primary caregivers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Craniosynostosis is caused by abnormalities of multiple signaling pathways, including excessive RAS signaling. Recently, a truncating variant in ETS2 repressor factor (ERF), a negative transcriptional regulator of the RAS pathway, was shown to be associated with craniosynostosis. Here, we report a 10-year-old male patient with a heterozygous nonsense mutation, p.Arg183*, in ERF who exhibited craniosynostosis with Noonan syndrome-like phenotypes. In consideration that loss-of-function variants in ERF would result in excessive RAS signaling and RASopathy phenotypes, we propose that ERF may represent a causative gene for Noonan syndrome. Since preceding studies on ERF mutations dealt with patients who were ascertained because of craniosynostosis, further studies are needed to evaluate whether patients with variants in ERF can present with Noonan syndrome-like features without craniosynostosis., (© 2021 Japanese Teratology Society.)

Vaccine hesitancy is a growing concern in global public health, and illustrates serious problems arising from loss of social trust. Japan is experiencing a human papillomavirus (HPV) vaccine crisis that started with a rapid decline in the vaccination rate in 2013 from approximately 70% to less than 1% and lasting for 7 years. We analyze Japan's case of vaccine hesitancy for HPV vaccine, using a framework for examining barriers to access and use of health technologies according to four categories: architecture, availability, affordability, and adoption. Significant problems were identified in the architecture of the decision-making body, public information availability, adoption of evidence in policy-making process, knowledge and confidence among providers, education to the public, and communication with end-users. We propose a series of actions to address these barriers. The national government should diversify the advisory committee to include broader scientific evidence and various viewpoints. Municipalities should actively distribute information cooperating with local providers. Professional associations should create an alliance to influence policy makers and deliver education to health care providers and end-users. Politicians should integrate opinions from citizens and scientists to implement an up-to-date policy. Civil society should share individual stories from cervical cancer patients and positive experiences of vaccinated girls. Mass media should use more diverse sources of information to report more comprehensive and science-based views. These actions would help build mutual trust among stakeholders, which is required to increase social trust in the HPV vaccine in Japan and thereby regain vaccine confidence and reduce preventable deaths and complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest regarding this study., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.

To elucidate the microscopic origin of the thermal droop, a blue-emitting indium gallium nitride (InGaN) quantum well grown on epitaxially laterally overgrown gallium nitride was investigated using temperature-dependent microphotoluminescence spectroscopy. Below 300 K, the sample exhibited a well-known dislocation-tolerant luminescence behavior. However, as temperature increases from 300 K to 500 K, the near band-edge emission at the wing region (with lower threading dislocation densities) was stronger than that at the seed region (with higher threading dislocation densities), indicating that threading dislocations are the microscopic origin of the thermal droop. Considering the carrier diffusion length, edge-type threading dislocations should play a major role in the thermal droop of heteroepitaxially grown InGaN-based LEDs.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large-scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA-binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison to those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan., (This article is protected by copyright. All rights reserved.)

Background: Recent treatment for food allergies involves the intake of allergy-causing foods at doses lower than the threshold dose determined by the oral food challenge (OFC). For a more successful treatment, it is necessary to identify a biomarker to establish safer doses of allergens in foods consumed at home., Objective: In this study, we aim to investigate whether the pattern of sensitization to cow's milk (CM) is related to the threshold dose of CM., Methods: Fifty patients with sensitization to casein (casein-specific IgE titer ≥ 0.7 UA/ml) and who have undergone the CM OFC test from July 2013 to July 2015 were enrolled. They were examined for the presence or absence of sensitization to β-lactoglobulin (BLG) (BLG-specific IgE ≥ 0.7 UA/ml). They were divided into two groups, namely, the only-casein-specific IgE-positive (C) group, and both casein- and BLG-specific IgE-positive (C + B) group., Results: The C group had 26 patients and the C + B group had 24. Both the CM- and casein-specific IgE titers were higher in the C + B group than in the C group. The positivity rates determined from OFC test results were 53.8 and 87.5%, and the threshold doses of CM were 88.7 and 31.1 ml in the C and C + B groups, respectively. In patients with low casein-specific IgE titers (≤ 10 UA/ml), the C + B group showed a significantly lower threshold dose of CM than the C group., Conclusions: Our results suggest that children with CM allergy sensitized to casein alone have a higher threshold dose than those sensitized to both casein and BLG.

The aim of the study was to investigate rural-urban differences in depressive symptoms in terms of the risk factors among older adults of two regions in Myanmar to provide appropriate intervention for depression depending on local characteristics. This cross-sectional study, conducted between September and December, 2018, used a multistage sampling method to recruit participants from the two regions, for face-to-face interviews. Depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale (GDS). Depressive symptoms were positively associated with living in rural areas (B = 0.42; 95% confidence interval (CI): 0.12,0.72), female (B = 0.55; 95% CI: 0.31,0.79), illness during the preceding year (B = 0.68; 95% CI: 0.45,0.91) and non-Buddhist religion (B = 0.57; 95% CI: 0.001,1.15) and protectively associated with education to middle school level or higher (B = -0.61; 95% CI: -0.94, -0.28) and the frequency of visits to religious facilities (B = -0.20; 95% CI: -0.30, -0.10). In women in urban areas, depressive symptoms were positively associated with illness during the preceding year (B = 0.78; 95% CI: 0.36, 1.20) and protectively associated with education to middle school level or higher (B = -0.67; 95% CI: -1.23, -0.11), middle or high wealth index (B = -0.92; 95% CI: -1.59, -0.25) and the frequency of visits to religious facilities (B = -0.20; 95% CI: -0.38, -0.03). In men in rural areas, illness during the preceding year was positively associated with depressive symptoms (B = 0.87; 95% CI: 0.33, 1.42). In women in rural areas, depressive symptoms were positively associated with illness during the preceding year (B = 0.83; 95% CI: 0.36, 1.30) and protectively associated with primary education (B = -0.62; 95% CI: -1.12, -0.12) and the frequency of visits to religious facilities (B = -0.44; 95% CI: -0.68, -0.21). Religion and wealth could have different levels of association with depression between older adults in the urban and rural areas and men and women. Interventions for depression in older adults should consider regional and gender differences in the roles of religion and wealth in Myanmar.

Low objective socioeconomic status (SES) has been correlated with poor physical and mental health among older adults. Some studies suggest that subjective SES is also important for ensuring sound physical and mental health among older adults. However, few studies have been conducted on the impact of both objective and subjective SES on mental health among older adults. This study examines whether objective or subjective SES is associated with depressive symptoms in older adults in Myanmar. This cross-sectional study, conducted between September and December, 2018, used a multistage sampling method to recruit participants from two regions of Myanmar, for face-to-face interviews. The Geriatric Depression Scale (GDS) was used to evaluate the depressive symptoms. Participants were classified as having no depressive symptom (GDS score <5) and having depressive symptoms (GDS score ≥5). Objective and subjective SES were assessed using the wealth index and asking participants a multiple-choice question about their current financial situation, respectively. The relationship between objective/subjective SES and depressive symptoms was examined using a multivariable logistic regression analysis. The mean age of the 1,186 participants aged 60 years and above was 69.7 (SD: 7.3), and 706 (59.5%) were female. Among them, 265 (22.3%) had depressive symptoms. After adjusting for objective SES and other covariates, only low subjective SES was positively associated with depressive symptoms (adjusted odds ratio, AOR: 4.18, 95% confidence interval, CI: 2.98-5.87). This association was stronger among participants in the rural areas (urban areas, AOR: 2.10, 95% CI: 1.08-4.05; rural areas, AOR: 5.65, 95% CI: 3.69-8.64). Subjective SES has a stronger association with depressive symptoms than objective SES, among older adults of the two regions in Myanmar, especially in the rural areas. Interventions for depression in older adults should consider regional differences in the context of subjective SES by reducing socioeconomic disparities among the communities., Competing Interests: The authors have declared that no competing interests exist.

Objective: The novel morpholino antisense oligonucleotide viltolarsen targets exon 53 of the dystrophin gene, and could be an effective treatment for patients with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to induce dystrophin expression and examined its safety in DMD patients., Methods: In this open-label, multicenter, parallel-group, phase 1/2, exploratory study, 16 ambulant and nonambulant males aged 5-12 years with DMD received viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary endpoints were dystrophin expression and exon 53 skipping levels., Results: In western blot analysis, mean changes in dystrophin expression (% normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46 (P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and 4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group (2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53 skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events were judged to be mild or moderate in intensity and none led to study discontinuation., Interpretation: Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing trend in dystrophin expression and exon 53 skipping levels, and was safe and well tolerated. The decline in motor function appeared less marked in patients with higher dystrophin levels; this may warrant further investigation. This study supports the potential clinical benefit of viltolarsen., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

We report a thorough study of InGaN quantum wells spatially modified by varying the local misorientation of the GaN substrate prior to the epitaxial growth of the structure. More than 25 nm shift of emission wavelength was obtained, which is attributed to indium content changes in the quantum wells. Such an active region is promising for broadening of the emission spectrum of (In,Al,Ga)N superluminescent diodes. We observed that the light intensity changes with misorientation, being stable around 0.5° to 2° and decreasing above 2°. This relation can be used as a base for future device designing.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration or loss of lower motor neurons. The survival of motor neuron (SMN) 1 gene, which produces the SMN protein, has been identified as a responsible gene for the disease. SMN is ubiquitously expressed in any tissue and may play an important role on the metabolism in the human body. However, no appropriate biomarkers reflecting the alteration in the metabolism in SMA have been identified., Methods: Low-molecular-weight metabolites were extracted from plasma of 20 human infants (9 SMA type 1 patients and 11 controls) and 9 infant mice (5 SMA-model mice, 4 control mice), and derivatized with N-methyl-N-trimethylsilyltrifluoroacetamide. Finally, the derivatized products were applied to Gas Chromatography/Mass Spectrometry apparatus. To confirm the metabolite abnormality in SMA type 1 patients, we performed SMN-silencing experiment using a hepatocyte-derived cell line (HepG2)., Results: We performed a comprehensive metabolomics analysis of plasma from the patients with SMA type 1 and controls, and found that phosphoethanolamine (PEA) was significantly higher in the patients than in the controls. HepG2 experiment also showed that SMN-silencing increased PEA levels. However, comprehensive metabolomics analysis of plasma from SMA-model mice and control mice showed different profile compared to human plasma; there was no increase of PEA even in the SMA-model mice plasma., Conclusion: Our data suggested that PEA was one of the possible biomarkers of human SMA reflecting metabolic abnormalities due to the SMN protein deficiency.

Objective: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D 2 (PGD 2 ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years., Methods: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24., Results: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed., Interpretation: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Oral parafunctional activities such as daytime non-functional tooth contact (nFTC) are considered aetiological factors for temporomandibular disorders (TMD)., Objectives: To evaluate the effectiveness of an email-based recording and reminding system for limiting daytime nFTC in patients with TMDs., Methods: Thirty patients with TMDs (mean age, 30.7 ± 8.7 years) were randomly assigned to three groups according to the intervention for limiting nFTC: cognitive behavioural therapy (CBT) with an email-based recording and reminding system for 20 days (e-CBT group, n = 10), CBT with a sticky note reminder for 20 days (s-CBT group, n = 10) and simple verbal instructions to avoid nFTC that were provided before the experimental period (control group, n = 10). The frequency of nFTC, range of pain-free unassisted mouth opening and pain intensity during painful unassisted maximum mouth opening was evaluated before and after the experimental period., Results: The frequency of nFTC significantly decreased after the intervention in the e-CBT and s-CBT groups. Among the three groups, the decrease in the nFTC frequency was the maximum in the e-CBT group (P < .01). In addition, the range of pain-free unassisted mouth opening showed a significant increase in all three groups, with the maximum improvement in the e-CBT group (analysis of variance, P < .01)., Conclusions: The present findings suggest that our email-based recording and reminding system may have the potential to effectively control daytime nFTC and could be an effective strategy for the management of TMDs., (© 2019 John Wiley & Sons Ltd.)

Objectives: The rate of admissions for ambulatory care sensitive conditions (ACSCs) is a key outcome indicator for primary care, and patient experience (PX) is a crucial process indicator. Studies have reported higher rates of admission for ACSCs in rural areas than in urban areas. Whether there is an association between admissions for ACSCs and PX in rural areas has not been examined. This study aimed to document admissions for ACSCs on Japanese rural islands, and assess whether there was an association between the rate of admissions for ACSCs and PX., Design: Multicentred, prospective, cohort study SETTING: This study was conducted on five rural islands in Okinawa, Japan., Participants: The study participants were all island inhabitants aged 65 years or older., Primary Outcome Measures: This study examined the association between ACSCs and PX assessed by a questionnaire, the Japanese Version of Primary Care Assessment Tool. ACSCs were classified using the International Classification of Diseases, Tenth Revision, and the rate of admissions for ACSCs in 1 year., Results: Of 1258 residents, 740 completed the questionnaire. This study documented 38 admissions for ACSCs (29 patients, males/females: 15/14, median age 81.9) that included congestive heart failure (11), pneumonia (7) and influenza (5). After adjusting for covariates and geographical clustering, admissions for ACSCs had a significant positive association with each patient's PX scores (OR per 1 SD increase=1.62, 95% CI 1.02-2.61)., Conclusions: Physicians serving rural areas need to stress the importance of preventive interventions for heart failure, pneumonia and influenza to reduce the number of admissions for ACSCs. Contrary to previous studies, our findings might be explained by close patient-doctor relationships on the rural islands., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure-activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro-d-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG ( 54 ) and 2,3,4,6-tetra-galloyl-d-glucopyranose ( 61 ) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin ( 37 ). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6- O -hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.

Spinal muscular atrophy (SMA) is an inherited disease characterized by progressive motor neuron death and subsequent muscle weakness and is caused by deletion or mutation of survival motor neuron (SMN) 1 gene. Protecting spinal motor neuron is an effective clinical strategy for SMA. The purpose of this study was to investigate the potential effect of an anti-epileptic drug levetiracetam on SMA. In the present study, we used differentiated spinal motor neurons (MNs) from SMA patient-derived induced pluripotent stem cells (SMA-iPSCs) to investigate the effect of levetiracetam. Levetiracetam promoted neurite elongation in SMA-iPSCs-MNs. TUNEL-positive spinal motor neurons were significantly reduced by levetiracetam in SMA-iPSCs-MNs. In addition, the expression level of cleaved-caspase 3 was decreased by levetiracetam in SMA-iPSCs-MNs. Furthermore, levetiracetam improved impaired mitochondrial function in SMA-iPSCs-MNs. On the other hand, levetiracetam did not affect the expression level of SMN protein in SMA-iPSCs-MNs. These findings indicate that levetiracetam has a neuroprotective effect for SMA.

Survival motor neuron (SMN) deficiency indicates that various cellular processes are impaired in spinal muscular atrophy (SMA). Previous reports have shown that SMN deficiency causes motor neuron degeneration, whereas the numbers of astrocytes and microglia are significantly increased or activated in SMA model systems. Only a few groups have studied the role of oligodendrocyte (OL) lineages such as OL precursor cell and nerve/glial antigen 2 (NG2)-glia in SMA pathology. Our aim in this study was to investigate whether OL lineages are impaired in SMA model systems. We investigated the expression of myelin basic protein (MBP) and NG2, which are OL lineage markers, using SMNΔ7 mice (mSmn, SMN2, SMNΔ7) and cell cultures derived from induced pluripotent stem cells generated from SMA patients. We showed for the first time that the OL lineages, including NG2-positive OL precursor cells and MBP-positive myelinating OLs were impaired in SMNΔ7 mice and induced pluripotent stem cells derived from SMA patients. Notch was involved in the decline of NG2 expression in the spinal cord of SMNΔ7 mice. In addition, pharmacological Notch inhibition promoted MBP-positive OL differentiation in SMNΔ7 mice. These findings indicate that OL differentiation was impaired in SMA, which might be involved in the Notch dysregulation.

Sleep disordered breathing (SDB) was more prevalent in adolescent athletes than expected, and several potential warning signs related to autonomic nerve activity appeared in SDB athletes. SDB screening may prevent associated downstream risks in the future. http://ow.ly/GQqK30nGm8r., Competing Interests: Conflict of interest: Y. Iso has nothing to disclose. Conflict of interest: H. Kitai has nothing to disclose. Conflict of interest: E. Kyuno has nothing to disclose. Conflict of interest: F. Tsunoda has nothing to disclose. Conflict of interest: N. Nishinaka has nothing to disclose. Conflict of interest: M. Funato has nothing to disclose. Conflict of interest: E. Nishimura has nothing to disclose. Conflict of interest: S. Akihiro has nothing to disclose. Conflict of interest: H. Tanuma has nothing to disclose. Conflict of interest: T. Yonechi has nothing to disclose. Conflict of interest: E. Geshi has nothing to disclose. Conflict of interest: T. Sambe has nothing to disclose. Conflict of interest: H. Suzuki has nothing to disclose.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons and muscle atrophy. The disease is mainly caused by low level of the survival motor neuron (SMN) protein, which is coded by two genes, namely SMN1 and SMN2, but leads to selective spinal motor neuron degeneration when SMN1 gene is deleted or mutated. Previous reports have shown that SMN-protein-deficient astrocytes are abnormally abundant in the spinal cords of SMA model mice. However, the mechanism of the SMN- deficient astrocyte abnormality remains unclear. The purpose of this study is to identify the cellular signaling pathways associated with the SMN-deficient astrocyte abnormality and propose a candidate therapy tool that modulates signaling. In the present study, we found that the astrocyte density was increased around the central canal of the spinal cord in a mouse SMA model and we identified the dysregulation of Notch signaling which is a known mechanism that regulates astrocyte differentiation and proliferation, in the spinal cord in both early and late stages of SMA pathogenesis. Moreover, pharmacological inhibition of Notch signaling improved the motor functional deficits in SMA model mice. These findings indicate that dysregulated Notch signaling may be an underlying cause of SMA pathology.

Among the III-nitride semiconductors, In x Ga 1-x N is a key material for visible optical devices such as light-emitting diodes (LEDs), laser diodes, and solar cells. Light emission is achieved via electron-hole recombination within the In x Ga 1-x N layer. When In x Ga 1-x N-based blue LEDs were first commercialized, the high probability of electron-hole radiative recombination despite the presence of numerous threading dislocations was a mystery. Extensive studies have proposed that carrier localization in nanoscopic potential fluctuations due, for example, to the immiscibility between InN and GaN or random alloy fluctuations is a key mechanism for the high emission efficiency. In actual LED devices, not only nanoscopic potential fluctuations but also microscopic ones exist within the In x Ga 1-x N quantum well light-emitting layers. Herein we map the synchrotron radiation microbeam X-ray fluorescence of In x Ga 1-x N blue LEDs at a sub-micron level. To acquire weak signals of In, Ar, which is in the air and has a fluorescent X-ray energy similar to that of In, is evacuated from the sample chamber by He purge. As a result, we successfully visualize the spatial In distribution of In x Ga 1-x N layer nondestructively and present good agreement with optical properties. Additionally, we demonstrate that unlike nanoscopic fluctuations, microscopic In compositional fluctuations do not necessarily have positive effects on device performance. Appropriately controlling both nanoscopic and microscopic fluctuations at the same time is necessary to achieve supreme device performance.

Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy characterized by progressive muscle degeneration. This disease is caused by the mutation or deletion of the dystrophin gene. Currently, there are no effective treatments and glucocorticoid administration is a standard care for DMD. However, the mechanism underlying prednisolone effects, which leads to increased walking, as well as decreased muscle wastage, is poorly understood. Our purpose in this study is to investigate the mechanisms of the efficacy of prednisolone for this disease. We converted fibroblasts of normal human cell line and a DMD patient sample to myotubes by MyoD transduction using a retroviral vector. In myotubes from the MyoD-transduced fibroblasts of the DMD patient, the myotube area was decreased and its apoptosis was increased. Furthermore, we confirmed that prednisolone could rescue these pathologies. Prednisolone increased the expression of not utrophin but laminin by down-regulation of MMP-2 mRNA. These results suggest that the up-regulation of laminin may be one of the mechanisms of the efficacy of prednisolone for DMD.

VGF nerve growth factor inducible (VGF) is a polypeptide that is induced by neurotrophic factors and is involved in neurite growth and neuroprotection. The mRNA of the Vgf gene has been detected in the adult rat retina, however the roles played by VGF in the retina are still undetermined. Thus, the purpose of this study was to determine the effects of VGF on the retinal ganglion cells (RGCs) of mice in the optic nerve crush (ONC) model, rat-derived primary cultured RGCs and human induced pluripotent stem cells (iPSCs)-derived RGCs. The mRNA and protein of Vgf were upregulated after the ONC. Immunostaining showed that the VGF was located in glial cells including Müller glia and astrocytes but not in the retinal neurons and their axons. AQEE-30, a VGF peptide, suppressed the loss of RGCs induced by the ONC, and it increased survival rat-derived RGCs and promoted the outgrowth of neurites of rat and human iPSCs derived RGCs in vitro. These findings indicate that VGF plays important roles in neuronal degeneration and has protective effects against the ONC on RGCs. Thus, VGF should be considered as a treatment of RGCs degeneration.

Background/aim: Polaprezinc suspension in sodium alginate (PZ-AG) reduces the incidence and severity of oral mucositis in adult patients receiving radiotherapy or high-dose chemotherapy. In the present study, the prophylactic effect of PZ-AG against oral mucositis was assessed in pediatric patients with hematological malignancies receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT)., Patients and Methods: Data of 16 children who underwent HSCT during a period between January 2010 and December 2017 were obtained from medical records and they were retrospectively analyzed. Oral mucositis was evaluated by the WHO scale., Results: Six (37.5%) of 16 children refused to take PZ-AG in a preliminary assessment and they were pretreated with azulene gargle. The remaining 10 (62.5%) patients were pretreated with PZ-AG for prevention of oral mucositis. Grade≥ 3 oral mucositis occurred in 5 (83.3%) of 6 patients receiving azulene gargle, but in 2 (20%) patients who took PZ-AG (p=0.035). The prevalence for the use of opioid analgesics was also significantly lower (30% vs. 100%, p=0.011), while the average duration of total parenteral nutrition use was significantly shorter (11.1 days vs. 24.3 days, p=0.016), in PZ-AG group than in azulene group. On the other hand, PZ-AG had no significant influence on the incidence of other adverse events, mean time to engraftment, or overall survival., Conclusion: PZ-AG was found to be highly effective in preventing oral mucositis in pediatric patients with hematological malignancies receiving high-dose chemotherapy followed by HSCT, as in adult patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Maresin 1 is a novel pro-resolving mediator derived from docosahexaenoic acid (DHA), with potent anti-inflammation effects against several animal models, including brain ischemia, sepsis, and lung fibrosis. However, its effect against motor neuron cell death is still not investigated. Therefore, we investigated the effects of maresin 1 on several stress-induced motor neuron cell death. Maresin 1 suppressed combinatorial stress which was evoked by superoxide dismutase 1 (SOD1) G93A and serum-free, -induced motor neuron cells death in a concentration-dependent manner, and had a stronger neuroprotective effective than DHA. Maresin 1 also had neuroprotective effects against transactivation response DNA-binding protein (TDP)-43 A315T and serum-free stress, H 2 O 2 , and tunicamycin-induced cell death. Maresin 1 reduced the reactive oxygen species (ROS) production caused by SOD1 G93A or TDP-43 A315T . Moreover, maresin 1 suppressed the NF-κB activation induced by SOD1 G93A and serum-free stress. These data indicate that maresin 1 has motor neuron protective effects against several stresses by reduction of ROS production or attenuation of the NF-κB activation. Maresin 1 also had neuroprotective effects against H 2 O 2 , and tunicamycin-induced cell death in a concentration-dependent manner. Finally, maresin 1 ameliorated the motor function deficits of spinal muscular atrophy model in which endoplasmic reticulum stress was upregulated. Thus, maresin 1 may be beneficial to protect against motor neuron diseases.

Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants., (© 2018 Wiley Periodicals, Inc.)

Purpose: To determine a chemical agent that can reduce the aggregation of optineurin (OPTN) in cells differentiated from induced pluripotent stem cells obtained from a patient with normal-tension glaucoma (NTG) caused by an E50K mutation in the OPTN gene (OPTNE50K-NTG)., Methods: Retinal ganglion cells (RGCs) were created from induced pluripotent stem cells derived from a healthy individual (wild-type [WT]-iPSCs) and from a patient with NTG due to OPTNE50K (E50K-iPSCs) mutation. The death of the induced RGCs was evaluated by counting the number of TUNEL- and ATH5-positive cells. Axonal growth was determined by measuring the axonal length of TUJ1-positive cells. OPTN aggregation was assessed by measuring the OPTN-positive area by immunofluorescence and by Western blotting. Autophagic flux assay was investigated by determining the light chain 3 (LC3)B-II/LC3B-I ratio and p62 expression by Western blotting., Results: The results showed OPTNE50K aggregation, activation of astrocytes, reduction in the number of RGCs, and enhancement of apoptotic cell death in the in vitro OPTNE50K model of NTG. Timolol was found to reduce the OPTNE50K-positive area and decreased the insoluble OPTNE50K, suggesting that it has the potential of reducing the OPTNE50K aggregation. Timolol also increased the ATH5-positive cells, decreased TUNEL-positive cells, increased the LC3B-II/LC3B-I ratio, and decreased the expression of p62. These findings suggest that timolol might enhance autophagic flux, leading to reduced OPTNE50K aggregation., Conclusions: Timolol should be considered a potential therapeutic agent specific to OPTNE50K-NTG because it can reduce the OPTNE50K aggregation in E50K-iPSCs-RGCs by enhancing autophagic flux and neuroprotective effects.

Spinal muscular atrophy (SMA) is an intractable disease characterized by a progressive loss of spinal motor neurons, which leads to skeletal muscle weakness and atrophy. Currently, there are no curative agents for SMA, although it is understood to be caused by reduced levels of survival motor neuron (SMN) protein. Additionally, why reduced SMN protein level results in selective apoptosis in spinal motor neurons is still not understood. Our purpose in this study was to evaluate the therapeutic potential of edaravone, a free radical scavenger, by using induced pluripotent stem cells from an SMA patient (SMA-iPSCs) and to address oxidative stress-induced apoptosis in spinal motor neurons. We first found that edaravone could improve impaired neural development of SMA-iPSCs-derived spinal motor neurons with limited effect on nuclear SMN protein expression. Furthermore, edaravone inhibited the generation of reactive oxygen species and mitochondrial reactive oxygen species upregulated in SMA-iPSCs-derived spinal motor neurons, and reversed oxidative-stress induced apoptosis. In this study, we suggest that oxidative stress might be partly the reason for selective apoptosis in spinal motor neurons in SMA pathology, and that oxidative stress-induced apoptosis might be the therapeutic target of SMA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims/introduction: The present study was carried out to generate induced pluripotent stem cells (iPSCs) from patients with fulminant type 1 diabetes, and evaluate the cytokine-induced apoptotic reactions of β-like insulin-producing cells differentiated from the iPSCs., Materials and Methods: iPSCs were generated from fibroblasts of patients with fulminant type 1 diabetes by inducing six reprogramming factors. Insulin-producing cells were differentiated from the iPSCs in vitro. The proportion of cleaved caspase-3-positive or terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling-positive cells among insulin (INS)-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines was evaluated under treatment with tumor necrosis factor-α, interleukin-1β and interferon-γ. Ribonucleic acid sequencing was carried out to compare gene expressions in INS-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines., Results: Two iPSC clones were established from each of three patients with fulminant type 1 diabetes. The differentiation of insulin-producing cells from fulminant type 1 diabetes iPSC was confirmed by immunofluorescence analysis and KCl-induced C-peptide secretion. After treatment with pro-inflammatory cytokines, these INS-positive cells showed higher expression of cleaved caspase-3 than those derived from control human iPSCs. Altered expression levels of several apoptosis-related genes were observed in INS-positive cells derived from the fulminant type 1 diabetes iPSCs by ribonucleic acid sequencing., Conclusions: We generated iPSCs from patients with fulminant type 1 diabetes and differentiated them into insulin-producing cells. This in vitro disease model can be used to elucidate the disease mechanisms of fulminant type 1 diabetes., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/hypothesis: Pancreatic beta-like cells generated from human induced pluripotent stem cells (hiPSCs) or human embryonic stem cells (hESCs) offer an appealing donor tissue source. However, differentiation protocols that mainly use growth factors are costly. Therefore, in this study, we aimed to establish efficient differentiation protocols to change hiPSCs/hESCs to insulin (INS) + cells using novel small-molecule inducers., Methods: We screened small molecules that increased the induction rate of INS + cells from hESC-derived pancreatic and duodenal homeobox 1 (PDX1) + pancreatic progenitor cells. The differentiation protocol to generate INS + cells from hiPSCs/hESCs was optimised using hit compounds, and INS + cells induced with the compounds were characterised for their in vitro and in vivo functions. The inducing activity of the hit compounds was also examined using mouse embryonic pancreatic tissues in an explant culture system. Finally, RNA sequencing analyses were performed on the INS + cells to elucidate the mechanisms of action by which the hit compounds induced pancreatic endocrine differentiation., Results: One hit compound, sodium cromoglicate (SCG), was identified out of approximately 1250 small molecules screened. When SCG was combined with a previously described protocol, the induction rate of INS + cells increased from a mean ± SD of 5.9 ± 1.5% (n = 3) to 16.5 ± 2.1% (n = 3). SCG induced neurogenin 3-positive cells at a mean ± SD of 32.6 ± 4.6% (n = 3) compared with 14.2 ± 3.6% (n = 3) for control treatment without SCG, resulting in an increased generation of endocrine cells including insulin-producing cells. Similar induction by SCG was confirmed using mouse embryonic pancreatic explants. We also confirmed that the mechanisms of action by which SCG induced pancreatic endocrine differentiation included the inhibition of bone morphogenetic protein 4 signalling., Conclusions/interpretation: SCG improves the generation of pancreatic endocrine cells from multiple hiPSC/hESC lines and mouse embryonic pancreatic explants by facilitating the differentiation of endocrine precursors. This discovery will contribute to elucidating the mechanisms of pancreatic endocrine development and facilitate cost-effective generation of INS + cells from hiPSCs/hESCs., Data Availability: The RNA sequencing data generated during the current study are available in the Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo ) with series accession number GSE89973.

Baller-Gerold syndrome (BGS) is a rare autosomal genetic disorder characterized by radial aplasia/hypoplasia and craniosynostosis. The causative gene for BGS encodes RECQL4, which belongs to the RecQ helicase family. To understand BGS patients in Japan, a nationwide survey was conducted, which identified 2 families and 3 patients affected by the syndrome. All the three patients showed radial defects and craniosynostosis. In one patient who showed a dislocated joint of the hip and flexion contracture of both the elbow joints and wrists at birth, a homozygous large deletion in the RECQL4 gene was identified. This is the first reported case of BGS in Japan caused by RECQL4 gene mutation.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance: Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was established, which showed that the thyrotropin releasing hormone (TRH) analog promoted transcriptional activation of the SMN2 gene and inhibition of GSK-3β activity, resulting in the increase and stabilization of the SMN protein and axon elongation of spinal motor neurons. These results reveal the potential efficacy of TRH analog treatment for SMA., (©AlphaMed Press.)

Background: Very-low-birthweight infants (VLBWIs) are at high risk for suboptimal bone mineral density (BMD) and bone mineral content (BMC). Small-for-gestational-age (SGA) status also causes reduced bone mineralization in full-term infants. However, the impact of intrauterine and postnatal extrauterine growth on BMD and BMC in VLBWIs is inconclusive., Methods: We retrospectively investigated n=68 VLBWIs, comprising 45 appropriate-for-gestational-age (AGA) and 23 SGA infants who underwent lumbar spine dual-energy X-ray absorptiometry at term-equivalent age., Results: BMD and BMC did not differ between AGA and SGA VLBWIs. Subgroup analyses of infants with birthweight<1000 g vs 1000-1500 g, and GA<27 weeks vs ≥ 27 weeks also showed no differences in BMD and BMC between AGA and SGA infants. In contrast, infants with extrauterine growth restriction (EUGR) showed significantly lower values than those without (BMD: 0.124 ± 0.023 vs 0.141 ± 0.032 g/cm(2), P=0.02; BMC: 0.80 ± 0.26 vs 0.94 ± 0.23 g, P=0.04). There were no differences between AGA and SGA infants with EUGR. However, in the AGA cohort, infants with EUGR showed significantly lower values than those without (BMD: 0.121 ± 0.022; 0.141 ± 0.03 g/cm(2), P=0.02; BMC: 0.73 ± 0.23 vs 0.94 ± 0.23 g, P=0.005). Multiple regression analyses showed GA, weight and head circumference at birth, and weight percentile at term correlated with term BMD. Conversely, only weight percentile at term significantly correlated with term BMC., Conclusion: EUGR, rather than IUGR, is a risk factor for reduced BMD and BMC in the neonatal period in VLBWIs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aluminum nitride (AlN) has attracted increasing interest as an optoelectronic material in the deep ultraviolet spectral range due to its wide bandgap of 6.0 eV (207 nm wavelength) at room temperature. Because AlN bulk single crystals are ideal device substrates for such applications, the crystal growth of bulky AlN has been extensively studied. Two growth methods seem especially promising: hydride vapor phase epitaxy (HVPE) and sublimation. However, the former requires hazardous gases such as hydrochloric acid and ammonia, while the latter needs extremely high growth temperatures around 2000 °C. Herein we propose a novel vapor-phase-epitaxy-based growth method for AlN that does not use toxic materials; the source precursors are elementary aluminum and nitrogen gas. To prepare our AlN, we constructed a new growth apparatus, which realizes growth of AlN single crystals at a rate of ~18 μm/h at 1550 °C using argon as the source transfer via the simple reaction Al + 1/2N2 → AlN. This growth rate is comparable to that by HVPE, and the growth temperature is much lower than that in sublimation. Thus, this study opens up a novel route to achieve environmentally friendly growth of AlN.

Background: This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy., Design/subjects: For this multicenter retrospective study, 18 Japanese extremely low birth weight (ELBW) infants with clinical KI were included. Clinical KI was diagnosed based on the presence of motor developmental impairment with/without athetosis, and abnormal magnetic resonance imaging or brainstem auditory evoked potential findings during infancy. High and low TB or UB levels were defined as serum TB levels ⩾ and <15 mg/dL or serum UB levels ⩾ and <0.8 μg/dL, respectively. The clinical characteristics of KI preterm infants were analyzed. The proportion of infants with high or low serum TB levels and with high or low serum UB levels was then investigated. Sensitivity and specificity were calculated., Results: In 18 KI infants, the median age when serum TB levels peaked was 28 days after birth. In eight KI infants with low serum TB levels, 88% of them had high serum UB levels. For comparison of the number of infants who had high or low serum TB and UB levels, the sensitivity was 90% and specificity was 13%., Conclusions: Serum TB and UB levels peak at a later age than expected. Chronic serum UB monitoring may be helpful for identifying ELBW infants at risk for developing KI, even when they do not have high serum TB levels., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Clinical kernicterus in preterm infants has recently been reported in Japan, diagnosed on the basis of clinical findings during the neonatal and infancy periods. We investigated the incidence of clinical kernicterus in preterm infants <30 weeks gestational age (GA) based on a nationwide survey conducted in 233 certified educational facilities for neonatologists. The numbers of infants admitted and infants who died within 14 days after birth during 2011, and the number of infants who subsequently developed clinical kernicterus, were recorded. A total of 2720 infants were analyzed, representing 59% (2720/4623) of all preterm live births <30 weeks GA in Japan in 2011. Of these, 159 (5.8%) died within 14 days after birth, similar to the national rate. Five infants developed clinical kernicterus in infancy (5/2720, 0.18%). The current incidence of clinical kernicterus in Japan is therefore estimated at 1.8 per 1000 live births <30 weeks GA., (© 2015 Japan Pediatric Society.)

Embryonic pancreatic bud cells, the earliest pancreas-committed cells, generated from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been shown to differentiate into mature pancreatic β-cells in vivo, indicating the feasibility of hESC/iPSC-based cell therapy for diabetes. However, the key factors required for the differentiation of these cells into pancreatic bud cells are incompletely understood. The purpose of this study was to establish culture conditions that efficiently induce PDX1(+)NKX6.1(+) pancreatic bud cells from hESCs/iPSCs. We differentiated a hESC line, KhES-3, into pancreatic lineages with a stepwise protocol recapitulating developmental process. The induction rate of PDX1(+)NKX6.1(+) cells was correlated with cell density in adherent cultures, and markedly improved with cell aggregation cultures. The positive effects of cell aggregation cultures on the differentiation of pancreatic bud cells were reproduced in multiple hESC/iPSC lines. The human PDX1(+)NKX6.1(+) cells developed into pancreatic epithelia after implantation into immunocompromised mice. Moreover, human C-peptide secretion into mouse bloodstream was stimulated by glucose challenges after in vivo maturation. Taken together, these results suggest that cultures with high cell density are crucial for the differentiation of pancreas-committed progenitor cells from hESCs/iPSCs. Our findings may be applicable for the development of hESC/iPSC-based cell therapy for diabetes., (Copyright © 2015. Published by Elsevier B.V.)

No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1(+) "ventralized" anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM(+) cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM(+) cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Extramedullary infiltration is common in acute myeloid leukemia (AML) patients. Although AML can cause neurological symptoms, especially when associated with extramedullary infiltration, a presenting manifestation of facial palsy is rare. We report on a 1-year-old boy who developed right facial palsy. Detailed examination led to a diagnosis of AML (French-American-British classification M1). Magnetic resonance imaging enhanced with gadolinium-diethylenetriamine penta-acetic acid showed abnormal enhancement of the right facial nerve, which disappeared after chemotherapy. AML should be considered as a differential diagnosis of facial palsy. Enhanced magnetic resonance imaging may be useful for diagnosing facial palsy associated with AML and for evaluating treatment outcome., (© 2014 Japan Pediatric Society.)

Purpose: Gain-of-function mutations in complement factor B (CFB) were recently identified in patients with atypical hemolytic uremic syndrome (aHUS), but are extremely rare. Our purpose is to describe a large kindred with aHUS associated with a CFB mutation and to further understand CFB-mutated aHUS patients., Methods and Results: We report a large kindred in which 3 members had aHUS. This kindred revealed that 9 of 12 members, including 2 affected patients, had persistent activation of the alternative pathway with low complement component 3 and that those 9 members showed a CFB mutation (c.1050G > C, p.Lys350Asn) in exon 8. This missense mutation was heterozygous in 8 of them and homozygous in only one. From structural studies, this mutation is shown to be located in close proximity to the Mg2-binding site within a von Willebrand factor type A domain of CFB, resulting in a gain-of-function effect of CFB and predisposition to aHUS. At present, 2 of the 3 members with aHUS have maintained normal renal function for a long-term period., Conclusions: This kindred illustrates that a CFB mutation (c.1050G > C, p.Lys350Asn) can result in aHUS. In the future, phenotype-genotype correlations and outcome in CFB-mutated aHUS patients need to be further investigated by accumulation of a number of cases.

Background: Preterm infants show transient hypothyroxinemia without thyroid-stimulating hormone (TSH) elevation. In addition, the degree of neurodevelopmental delay in preterm infants become severe according to the decreasing gestational age (GA). Because of the crucial role of thyroid hormones in brain development, hypothyroxinemia has the potential to cause developmental delay; however, the effectiveness of thyroxine (T4) supplementation on developmental outcomes remains controversial. To resolve these issues, we evaluated the clinical course of transient hypothyroxinemia and the effects of levothyroxine (LT4) supplementation in extremely low birth weight (ELBW) infants., Methods: Serum levels of free T4 (FT4) and TSH were examined in 36 ELBW infants from 7 days after birth. LT4 (5-10 microg/kg/day) was orally administered to 18 of 36 infants with a low serum FT4 level (< 0.4 ng/dL) or normal serum FT4 levels and a clinical manifestation of hypothyroidism, whereas remaining 18 patients without a low serum FT4 level or clinical hypothyroidism were not given LT4 supplementation as control subjects. Infants were followed-up at a corrected age of 12 months, and clinical outcome was compared between infants that received LT4 and those that did not., Results: ELBW infants showed low serum FT4 levels without TSH elevation. During hospitalization and at follow-up, LT4-administered infants with low serum FT4 levels showed a shorter GA compared with the control group. There were no other statistically significant differences in clinical outcomes at 12 months of corrected age between LT4-administered and control groups., Conclusions: Our results show that shorter GA is associated with lower serum FT4 levels. Shorter GA is known to cause developmental delay, however, LT4 supplementation prevents the developmental delay of ELBW infants with transient hypothyroxinemia.

Background: Raised nucleated red blood cell (NRBC) counts in neonates may indicate in utero hypoxia and brain damage., Objective: The study aimed to examine the use of NRBC counts as a predictor of brain injury and neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) treated under current cooling-based strategy., Methods: Forty-three neonates with asphyxia between 2004 and 2010 were retrospectively investigated. Twenty neonates with moderate/severe HIE underwent hypothermia (HT), and 23 with mild HIE were treated in normothermia (NT). Neonates were divided into groups according to the presence of cerebral parenchymal lesions on magnetic resonance imaging (MRI) at 2 weeks after birth. All patients were followed-up neurologically for ⩾ 24 months. NRBC counts during the first 3 days were compared between groups., Results: Eleven HT (HT-N) and 21 NT (NT-N) neonates had normal MRI, and 9 HT (HT-L) and 2 NT (NT-L) neonates had parenchymal lesions. NRBC counts, both absolute and /100 white blood cells (WBC) counts, during the first 3 days in HT-L and NT-L were significantly higher than those in HT-N and NT-N, particularly within 6 hours after birth (HT-N: 502 [0-3060]/mm(3) vs HT-L: 2765 [496-6192]; 0 [0-3417] vs NT-L: 4384 [3978-4789], median [range]). Neonates with /100 white blood cells ⩾ 6/mm(3) and absolute NRBC counts ⩾ 1324/mm(3) within 6 hours of birth had high risks of abnormal MRIs and 2-year outcomes., Conclusions: NRBC counts can predict brain injury and neurological outcomes in cooled and non-cooled asphyxiated neonates., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The aims of this study were to introduce a novel electronic system for reliable evaluation of the non-functional tooth contact in patients with temporomandibular disorders (TMDs) and investigate the possible associations between the non-functional tooth contact and some characteristics of the patients with TMD. We designed and installed a software program to send emails regarding the non-functional tooth contact to the subjects' preregistered cellular phones at intervals of 20 ± 9 min daily for 10 consecutive days. Twelve patients with TMD and 12 gender- and age-matched healthy subjects responded via emails to one of 3 choices: no tooth contact, tooth contact during oral functions or tooth contact not associated with oral functions. The influence of subjective stress, anxiety, depression, personality and daily activities on tooth contact was then assessed. The frequency of the non-functional tooth contact was significantly higher in the patients with TMD than in the healthy subjects (35·0% vs. 9·6%, P < 0·001), while no significant group difference was found for the frequency of functional tooth contact, the stress, anxiety, depression and personality., (© 2014 The Authors. Journal of Oral Rehabilitation Published by John Wiley & Sons Ltd.)

Allogeneic peripheral blood stem cell transplantation (PBSCT) is becoming a common transplantation procedure in children. However, few benefits have been reported, in particular in regard to the choice of small children as donors for larger recipients. We report a case of relapsed acute myeloid leukemia (body weight 52 kg and blood type O) who underwent allogeneic PBSCT from his smaller human leukocyte antigen-matched brother (body weight 29.9 kg and blood type A)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)