骨の石灰化機構におけるMEPE由来リン酸化ASARMの役割

内容の要旨 , 審査の要旨広島大学(Hiroshima University)博士(歯学)Doctor of Philosophy in Dental Sciencedoctora

Soluble Klotho causes hypomineralization in Klotho-deficient mice

The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (18592001 and 20592139 to Y Y and 21791788 to T M), and the Canadian Institutes of Health Research (MOP 83704 to J E A)

Oral hypofunction in the older population : Position paper of the Japanese Society of Gerodontology in 2016

Background: There is growing international interest in identifying the effects of ageing on oral health and on appropriate strategies for managing oral disorders. The Japanese Society of Gerodontology (JSG), as the official representative of researchers and clinicians interested in geriatric dentistry in Japan, makes several recommendations on the concept of “oral hypofunction.” Aims: This study proposes diagnostic criteria and management strategies to reduce the risk of oral hypofunction among older people. Conceptual Framework: We define oral hypofunction as a presentation of 7 oral signs or symptoms: oral uncleanness; oral dryness; decline in occlusal force; decline in motor function of tongue and lips; decline in tongue pressure; decline in chewing function; and decline in swallowing function. The criteria of each symptom were determined based on the data of previous studies, and oral hypofunction was diagnosed if the criteria for 3 or more signs or symptoms were met. Conclusions: We recommend that more evidence should be gathered from clinical studies and trials to clarify our diagnostic criteria and management strategies

Preliminary Survey to Establish Indicator for Screening of Primary School-age Children Who Require Welfare Assistance

小学校において被虐待児にみられる行動特徴から要保護児童をスクリーニングできる質問紙を作成するために，教職員にとって判断が容易で信頼性の高い回答が得られる項目を厳選するための基礎調査を行った。64名の小学校の教職員に，35項目からなる同じ内容の質問紙に2週間の間隔をあけ， 2回回答してもらった結果を照合し，質問内容の判断の容易さ回答の再現性，および文章表現について検討した。 1. 学校現場で教職員が判断するのが難しい質問項目は，「トイレの後に手を洗わない」，「行事の時の弁当が手作り弁当ではない」，「保護者と目を合わさず，おどおどする」，「家族関係に変化があった」，「年齢にそぐわない性的な言動がみられる」，「病気になっても病院に行かない」，および「過度な警戒心を持つ」であった。 2. 回答の信頼性の低い質問項目は「やせすぎている」，「行事の時の弁当が手作り弁当ではない」，「よく教室から離れる」，および「保護者と目を合わさず，おどおどする」であった。 3. 表現が不適切であると指摘された質間項目は「時々嘘をつく」，「友達をいじめる」，および「集団になじめないところがある」であった。 今後は，上記の質問項目を除いた質問項目からなる質問紙を作成し，実際に児童を対象とした調査を行い，要保護児童のスクリーニング指標としての有効性について検証する必要があると考えられる。We conducted a survey to select questions that teachers could easily and reliably answer as part of a basic research project to create a questionnaire based on characteristic behaviors exhibited by abused children at primary school for screening of those who may need welfare assistance. Questionnaires comprised of 35 items were sent to 64 primary school teachers, with the same questionnaire sent again 2 weeks later. Responses to both were compared to examine ease of assessing the contents of the questions, reproducibility of the responses, and written expressions. 1) Items that teachers found difficult to assess at school were "Does not wash hands after using the toilet," "Does not bring homemade lunch to events," "Does not meet guardian's eyes; appears apprehensive," "Has experienced a change in familial relations," "Uses sexual speech and behavior that is not age appropriate," "Does not see a doctor despite being sick," and "Is excessively wary." 2) Items that showed responses with low reliability were "ls too thin," "Does not bring homemade lunch to events," "Is often absent from the classroom," and "Does not meet guardian's eyes; appears apprehensive." 3) Items indicated to use inappropriate expressions were "Sometimes tells lies," "ls bullied by friends," and "Does not fit in with group in some ways." Next, use of a questionnaire that does not include the above items should be done with actual children to examine its effectiveness as an indicator for screening children who require welfare assistance

Orchestrated ensemble activities constitute a hippocampal memory engram

The brain stores and recalls memories through a set of neurons, termed engram cells. However, it is unclear how these cells are organized to constitute a corresponding memory trace. We established a unique imaging system that combines Ca2+ imaging and engram identification to extract the characteristics of engram activity by visualizing and discriminating between engram and non-engram cells. Here, we show that engram cells detected in the hippocampus display higher repetitive activity than non-engram cells during novel context learning. The total activity pattern of the engram cells during learning is stable across post-learning memory processing. Within a single engram population, we detected several sub-ensembles composed of neurons collectively activated during learning. Some sub-ensembles preferentially reappear during post-learning sleep, and these replayed sub-ensembles are more likely to be reactivated during retrieval. These results indicate that sub-ensembles represent distinct pieces of information, which are then orchestrated to constitute an entire memory

最大酸素摂取量と身体組成の関係からみた年少者スイマーの特性

Purposes of this study were to investigate how maximal oxygen uptake (VO_2max) relates to body weight and lean body weight in male swimmers, and to clarify characteristics of prepubertal male swimmers. 17 prepubertal male swimmers with a mean age of 11.3±0.6 years and 19 college male swimmers of 20.4±0.9 years old were measured for lean body weight by underwater-weighing method and VO_2max by flume swimming. They all were well trained swimmers. Correlation between VO_2max and lean body weight for prepubertal swimmers was found to be higher (r=0.898, p<0.001) than for college swimmers (r=0.604, p<0.01). In addition, correlation between VO_2max and body weight for prepubertal swimmers was found to be higher (r=0.825, p<0.001) than for college swimmers (r=0.588, p<0.01). It was also shown that prepubertal swimmers had a significantly smaller VO_2max per 1 kg of lean body weight than college swimmers. Therefore, it was concluded that the respiratory-cardiovascular system of prepubertal male swimmers was not matured or improved enough for VO_2max measurement even when they were well trained for their age

Learning of Phonetic Language in Autistic Children

藤井稔　編事例1 井関香・櫻井聖子 著事例2 若栄花恵・岸和田谷真弓　

Impact of Chronic Kidney Disease on the Presence and Severity of Aortic Stenosis in Patients at High Risk for Coronary Artery Disease

<p>Abstract</p> <p>Objective</p> <p>We evaluated the impact of chronic kidney disease (CKD) on the presence and severity of aortic stenosis (AS) in patients at high risk for coronary artery disease (CAD).</p> <p>Methods</p> <p>One hundred and twenty consecutive patients who underwent invasive coronary angiography were enrolled. Aortic valve area (AVA) was calculated by the continuity equation using transthoracic echocardiography, and was normalized by body surface area (AVA index).</p> <p>Results</p> <p>Among all 120 patients, 78% had CAD, 55% had CKD (stage 3: 81%; stage 4: 19%), and 34% had AS (AVA < 2.0cm²). Patients with AS were older, more often female, and had a higher frequency of CKD than those without AS, but the prevalence of CAD and most other coexisting conventional risk factors was similar between patients with and without AS. Multivariate linear regression analysis indicated that only CKD and CAD were independent determinants of AVA index with standardized coefficients of -0.37 and -0.28, respectively. When patients were divided into 3 groups (group 1: absence of CKD and CAD, n = 16; group 2: presence of either CKD or CAD, n = 51; and group 3: presence of both CKD and CAD, n = 53), group 3 had the smallest AVA index (1.19 ± 0.30*# cm²/m², *p < 0.05 vs. group 1: 1.65 ± 0.32 cm²/m², and #p < 0.05 vs. group 2: 1.43 ± 0.29* cm²/m²) and the highest peak velocity across the aortic valve (1.53 ± 0.41*# m/sec; *p < 0.05 vs. group 1: 1.28 ± 0.29 m/sec, and #p < 0.05 vs. group 2: 1.35 ± 0.27 m/sec).</p> <p>Conclusion</p> <p>CKD, even pre-stage 5 CKD, has a more powerful impact on the presence and severity of AS than other conventional risk factors for atherosclerosis in patients at high risk for CAD.</p

Evaluation of Pax6 Mutant Rat as a Model for Autism

Autism is a highly variable brain developmental disorder and has a strong genetic basis. Pax6 is a pivotal player in brain development and maintenance. It is expressed in embryonic and adult neural stem cells, in astrocytes in the entire central nervous system, and in neurons in the olfactory bulb, amygdala, thalamus, and cerebellum, functioning in highly context-dependent manners. We have recently reported that Pax6 heterozygous mutant (rSey2/+) rats with a spontaneous mutation in the Pax6 gene, show impaired prepulse inhibition (PPI). In the present study, we further examined behaviors of rSey2/+ rats and revealed that they exhibited abnormality in social interaction (more aggression and withdrawal) in addition to impairment in rearing activity and in fear-conditioned memory. Ultrasonic vocalization (USV) in rSey2+ rat pups was normal in male but abnormal in female. Moreover, treatment with clozapine successfully recovered the defects in sensorimotor gating function, but not in fear-conditioned memory. Taken together with our prior human genetic data and results in other literatures, rSey2/+ rats likely have some phenotypic components of autism