An Overview of the Clinical Characteristics of Japanese Patients with Spinal Muscular Atrophy: Data from SMART Consortium

Background: Patient registries play an important role in rare disease, particularly for recruitment of clinical trials and clinical research.Methods: In 2012, we launched a registry for the purpose of clarifying the clinical characteristics of spinal muscular atrophy (SMA) in Japan and with the goal of enrolling patients with SMA into newly started clinical trials. In order to document the current status of SMA in Japan, we conducted a survey based on the data of 277 SMA patients enrolled in the registry from October 2012 to July 2020.Results: Genetic testing was performed in 95% of patients. Patients with type III SMA experienced the longest onset to genetic diagnosis times, while those with type I had the shortest times. Tongue fasciculation was more common in types I and II SMA, while finger fasciculation was more common in types II and III. The site of fasciculation was thought to be the key to predicting the disease type. Over-the-counter or investigational drugs were administered to 76% of patients as of June 2019.Conclusion: Our registry is useful for understanding the current status of SMA patients in Japan, and can provide accurate and up-to-date information on the clinical course of patients over their lifetime

Developmental Changes in Conditioned Taste Aversion in Lymnaea stagnalis

As the first step to study relationships between development and learning in the molluscan central nervous system,we examined developmental changes in acquisition and retention of a conditioned taste aversion (CTA) in the pond snail, Lymnaea stagnalis. We found that snails developed ability of a CTA as a long-term memory through three critical stages. Embryos in veliconcha started to respond to appetitive sucrose at the first critical stage. This response was in good agreement with morphological observations that embryos at this developmental stage seemed to be physically ready to eat. However, they could not associate this appetitive stimulus (conditioned stimulus: CS) with an aversive stimulus of KCI (unconditioned stimulus: UCS). At the second critical stage, embryos just before hatching acquired the CTA, but the conditioned response did not persist. Through this stage, they may acquire learning ability to safely seek out food in an external environment. At the third critical stage, immature snails with a 10 mm shell could use a long-term memory to maintain the conditioned response. This memory persisted for at least a month, showing that now they are able to maintain a long-term memory so that they can safely eat a variety of food when they cover wide territory to search for a mate. The present findings indicate that the development of learning ability in snails, which secures acquisition of better survival ability, is coincident with the major changes in their life cycle

自閉症におけるメチルコバラミン療法の予備的検討

我々は13例の自閉症患者でビタミンB_<12>(メチルコバラミン:Me-B_<12>)の治療効果をオープン試験で試みた.Me-B_<12>の治療開始時期は2歳3ヵ月から18歳で,Me-B_<12>を25～30μg/kg/day,6～25ヵ月間投与した.IQ/DQによる評価では,治療前は45±5.3(平均±標準誤差)であったが,治療後は52±6.0と有意な上昇が認められた(p=0.0199).CARS検査(小児自閉症評定尺度)では,治療前は35.9±1.6であったが,治療後は33.0±1.7(p=0.0008)と改善した.自然経過による改善とMe-B_<12>効果を鑑別するため,患者を年齢,知能でそれぞれ2群に分類し検討したところ,思春期群と低IQ群のCARSスコアーが,幼児・早期学童期群,高IQ群と同様に改善した.自閉症児において思春期は一般に症状改善に乏しく,症状の自然改善は高機能自閉症児に見られることから,この結果は, Me-B_<12>効果は自然経過とは異なると考えられた.検討はまだ予備的段階であるが,自閉症においてMe-B_<12>は治療薬として試みる価値があると考えられた.We conducted an open trial on the effect of methylcobalamin (Me-B_<12>) in 13 patients with autism. The patients' ages at the start of treatment ranged from 2 years and 3 months to 18 years. Me-B_<12> was administered at a dosage of 25-30 g/kg/day for 6-25 months. The intelligence and developmental quotient (IQ/DQ) after Me-B_<12>treatment was 52±6.0 (mean ± SE), which was significantly higher than before treatment (45±5.3) (p<0.05). The childhood autism rating scale (CARS) score improved significantly, from 35.9±1.6 before to 33.0±1.7 after treatment (p<0.001). To distinguish the effects of Me-B_<12> from natural developmental factors, the patients were divided into two subgroups, both according to age and according to intelligence. The CARS scores of the teenage and the low-IQ groups improved as much as those of the pre-early school age and the high-IQ groups. As adolescent autism patients usually show a decline in their condition, while some high function autism patients exhibit positive development, the improvement of CARS scores with Me-B_<12> treatment in the teenage and the low-IQ groups suggests that the Me-B_<12> effect is distinct from developmental factors. Although these data are very preliminary, Me-B_<12> is potentially beneficial in autism as an additional or alternative treatment

自閉症におけるメチルコバラミン療法の予備的検討

我々は13例の自閉症患者でビタミンB_(メチルコバラミン:Me-B_)の治療効果をオープン試験で試みた.Me-B_の治療開始時期は2歳3ヵ月から18歳で,Me-B_を25～30μg/kg/day,6～25ヵ月間投与した.IQ/DQによる評価では,治療前は45±5.3(平均±標準誤差)であったが,治療後は52±6.0と有意な上昇が認められた(p=0.0199).CARS検査(小児自閉症評定尺度)では,治療前は35.9±1.6であったが,治療後は33.0±1.7(p=0.0008)と改善した.自然経過による改善とMe-B_効果を鑑別するため,患者を年齢,知能でそれぞれ2群に分類し検討したところ,思春期群と低IQ群のCARSスコアーが,幼児・早期学童期群,高IQ群と同様に改善した.自閉症児において思春期は一般に症状改善に乏しく,症状の自然改善は高機能自閉症児に見られることから,この結果は, Me-B_効果は自然経過とは異なると考えられた.検討はまだ予備的段階であるが,自閉症においてMe-B_は治療薬として試みる価値があると考えられた.We conducted an open trial on the effect of methylcobalamin (Me-B_) in 13 patients with autism. The patients\u27 ages at the start of treatment ranged from 2 years and 3 months to 18 years. Me-B_ was administered at a dosage of 25-30 g/kg/day for 6-25 months. The intelligence and developmental quotient (IQ/DQ) after Me-B_treatment was 52±6.0 (mean ± SE), which was significantly higher than before treatment (45±5.3) (p from natural developmental factors, the patients were divided into two subgroups, both according to age and according to intelligence. The CARS scores of the teenage and the low-IQ groups improved as much as those of the pre-early school age and the high-IQ groups. As adolescent autism patients usually show a decline in their condition, while some high function autism patients exhibit positive development, the improvement of CARS scores with Me-B_ treatment in the teenage and the low-IQ groups suggests that the Me-B_ effect is distinct from developmental factors. Although these data are very preliminary, Me-B_ is potentially beneficial in autism as an additional or alternative treatment

Dual IRE1 RNase functions dictate glioblastoma development

Abstract Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression