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Background: Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC., Methods: In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m 2 per day intravenously on days 1-5] and cisplatin [80 mg/m 2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m 2 per day on days 1-5], cisplatin [70 mg/m 2 per day on day 1], and docetaxel [70 mg/m 2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m 2 per day on days 1-4] and cisplatin [75 mg/m 2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete., Findings: A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group., Interpretation: Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy., Funding: Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund., Competing Interests: Declaration of interests KK reports funding to their institution from Merck Sharp & Dohme, Ono Pharmaceuticals, Bristol Myers Squibb, Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. HH reports funding to their institution form ALX Oncology, Amgen, AstraZeneca, Astellas Pharma, Bayel, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Janssen, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; and honoraria from Bayer, Chugai, Merck Biopharma, Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD, Takeda, Asahi Kasei, and Yakult. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Reports of radiation therapy for prostate cancer using dose fractions between moderate hypofractionation and ultrahypofractionation are limited. This pilot study involved the application of highly hypofractionated intensity modulated radiation therapy (IMRT) in 15 fractions for 3 weeks and the number of fractions was intermediate between the 2 previously mentioned dose fractions. The long-term outcomes are reported., Methods and Materials: From April 2014 to September 2015, patients with low- to intermediate-risk prostate cancer received 54 Gy in 15 fractions (3.6 Gy per fraction) for 3 weeks using IMRT without intraprostatic fiducial markers or a rectal hydrogel spacer. Neoadjuvant hormone therapy (HT) was administered for 4 to 8 months. Adjuvant HT was not administered to any patients. Rates of biochemical relapse-free survival, clinical relapse-free survival, overall survival, and the cumulative incidence of late grade ≥2 toxicities were analyzed., Results: Twenty-five patients were enrolled in this prospective study; 24 of them were treated with highly hypofractionated IMRT (17% had low-risk and 83% had intermediate-risk disease). The median neoadjuvant HT duration was 5.3 months. The median follow-up period was 77 months (range, 57-87 months). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival rates were 91.7%, 95.8%, and 95.8% at 5 years, and 87.5%, 86.3%, and 95.8% at 7 years, respectively. Neither grade ≥2 late gastrointestinal toxicity nor grade ≥3 late genitourinary toxicity was observed. The cumulative incidence rates of grade 2 genitourinary toxicity were 8.5% and 18.3% at 5 and 7 years, respectively., Conclusions: Highly hypofractionated IMRT delivering 54 Gy in 15 fractions for 3 weeks for prostate cancer without intraprostatic fiducial markers facilitated favorable oncological outcomes without severe complications. This treatment approach may be a possible alternative to moderate hypofractionation, but further validation is needed., Competing Interests: Disclosures Shusuke Akamatsu reports receiving research grants from AstraZeneca, Astellas Pharma, and Tosoh and honoraria from Janssen, AstraZeneca, Astellas, Bayer, Sanofi, and Takeda. Takashi Kobayashi reports receiving honoraria from Janssen and Astellas. Takashi Mizowaki reports receiving research grants from Varian Medical Systems, Hitachi Ltd, and Brainlab AG and honoraria from Varian Medical Systems, Hitachi Ltd, Elekta KK, and BrainLab AG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The recommended first-line chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is bevacizumab (BEV)-containing therapy for right-sided colon cancer (R) and antiepidermal growth factor receptor antibody (anti-EGFR)-containing therapy for left-sided colon cancer (L) or rectal cancer (RE). However, anatomical or biological heterogeneity reportedly exists between L and RE. Therefore, we aimed to compare the efficacies of anti-EGFR and BEV therapies for L and RE, respectively., Methods: We retrospectively reviewed 265 patients with KRAS (RAS)/BRAF wild-type mCRC treated with fluoropyrimidine-based doublet chemotherapy plus anti-EGFR or BEV as the first-line treatment at a single institution. They were divided into 3 groups: R, L, and RE. Overall survival (OS), progression-free survival (PFS), objective response rate, and conversion surgery rate were analyzed., Results: Forty-five patients had R (anti-EGFR/BEV: 6/39), 137 patients had L (45/92), and 83 patients had RE (25/58). In patients with R, both median (m) PFS and OS were superior with BEV therapy (mPFS, anti-EGFR vs. BEV: 8.7 vs. 13.0 months, hazard ratio [HR]: 3.90, P = .01; mOS, 17.1 vs. 33.9 months, HR: 1.54, P = .38). In patients with L, better mPFS and comparable mOS with anti-EGFR therapy were observed (mPFS, 20.0 vs. 13.4 months, HR: 0.68, P = .08; mOS, 44.8 vs. 36.0 months, HR: 0.87, P = .53), whereas, in patients with RE, comparable mPFS and worse mOS with anti-EGFR therapy were observed (mPFS, 17.2 vs. 17.8 months, HR: 1.08, P = .81; mOS, 29.1 vs. 42.2 months, HR: 1.53, P = .17)., Conclusions: Efficacies of anti-EGFR and BEV therapies may differ between patients with L and RE., Competing Interests: Disclosure Yukiya Narita has received grants and personal fees from Ono, BMS, AstraZeneca and Daiichi Sankyo, honoraria for lectures, presentations, and speakers bureaus from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, Ono, and BMS, and participation on an advisory board from Daiichi Sankyo. Hiroya Taniguchi has received grants and personal fees from Daiichi Sankyo, and Takeda and honoraria for lectures, presentations, and speakers bureaus from Takeda, Chugai, Eli Lilly, Merck Biopharma and Ono. Kei Muro has received grants and personal fees from Chugai, MSD, Amgen, Ono, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, and Pfizer, consulting fees from AstraZeneca, Ono and Amgen, and Honoraria for lectures from Ono, Taiho, BMS, Eli Lilly, MSD and Daichi Sankyo, and advisory board from Ono, Amgen, AstraZeneca, Eli Lilly, and Takeda. Shigenori Kadowaki has received research funding from Taiho, Eli Lilly, MSD, Chugai, Nobelpharma, Ono, Daiichi Sankyo, and Yansen, honoraria for lectures from Eli Lilly, Taiho Ono, BMS, Chugai, Bayer, Merck KGaA, Daichi Sankyo, and Eisai. Yuki Matsubara has received honoraria for lectures from BMS, Takeda, MSD, Taiho and Eli Lilly. Kazunori Honda has received grants from Pfizer to the NPOs to which he belongs. Toshiki Masuishi has received MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Healthe Clinical, Boehringer-Ingelheim, Pfizer, Cimic Shift Zero, and Eli Lilly, and honoraria for lectures from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Eli Lilly, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and BMS. Other authors have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The differential diagnosis of neuropathic pain, especially discrimination between neuropathic pain caused by spinal canal stenosis (SCS) and neuropathic pain associated with causes other than SCS, is sometimes difficult; however, it is important for surgical application., Methods: We established a reliable method for measuring lysophosphatidylcholine (LPC), a precursor of lysophosphatidic acids which are known as being pain initiators, using a liquid chromatography-tandem mass spectrometry method, and measured the LPC concentrations in the cerebrospinal fluid (CSF) in patients with SCS (SCS group; n = 76), patients with neuropathic pain caused by non-SCS diseases (Others group; n = 49), and control subjects without pain (control group; n = 92)., Results: Both within-run and between-run CV(%) were almost < 10 %, suggesting an enough performance for clinical introduction. The CSF concentrations of LPC (16:0) and LPC (18:0) were higher in the SCS group than those in the Control or Others group; the concentrations of LPC (18:1), LPC (18:2), LPC (20:4), LPC (22:6) levels were higher in the SCS group than those in the control or others group, but they were also higher in the Others group than those in the control group. The areas under the curve in the ROC curve analyses of LPC (18:1) for discriminating between the SCS and control groups, others and control groups, and SCS and others groups were 0.994, 0.860, and 0.869, respectively., Conclusions: LPC measurement in the CSF is useful for the differential diagnosis of neuropathic pain, especially for surgical decision-making, which is expected for clinical introduction., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Splenic hilar lymphadenectomy is not recommended for advanced proximal gastric cancer that does not invade the greater curvature according to the results of the previous studies. The efficacy of splenic hilar lymphadenectomy for type II and type III adenocarcinomas of the esophagogastric junction and easy spread to the greater curvature of the stomach remains unclear. This study aimed to investigate the efficacy of splenic hilar lymphadenectomy and identify the risk factors for metastasis to splenic hilar nodes., Methods: We examined patients who underwent R0/1 gastrectomy for Siewert types II and III at a single high-volume center in Japan. We analyzed the metastatic incidence, therapeutic value index, and risk factors for splenic hilar lymph node metastasis., Results: We examined 126 patients (74, type II; 52, type III). Splenectomy was performed in 76 patients. Metastatic incidence and the therapeutic value index of splenic hilar lymph nodes in patients with type II and type III tumors were 4.5% and 0, and 21.9% and 9.4, respectively. In the patients who underwent splenectomy, we identified Siewert type III tumors (odds ratio: 6.93, 95% confidence interval: 1.24-38.8, p = 0.027) and tumor location other than the lesser curvature (odds ratio: 7.36, 95% confidence interval: 1.32-41.1, p = 0.023) to be independent risk factors. The metastatic incidence (46.2%) and therapeutic value index (15.4) were high in patients with both risk factors., Conclusions: Splenic hilar lymphadenectomy may contribute to the survival of patients with Siewert type III tumors, especially when the predominant location is not the lesser curvature., Competing Interests: Declaration of competing interest Yasushi Rino has received speaker honorariums and research grants from Daiichi Sankyo, Johnson & Johnson, Otsuka, Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Abbott Nutrition, Asahi Kasei, Tsumura & Co., Covidien, Zeria Pharmaceutical and EA Pharma. The other authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects., Methods: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated., Results: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments., Conclusion: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Autonomic dysfunction has been occasionally described in varicella-zoster virus (VZV) infection, while few systematic reviews are available. We systematically review autonomic dysfunction due to VZV infection., Methods: This study followed the PRISMA guideline, and three databases were researched and included cross-sectional studies in full-length publications in the English language using appropriate search keywords., Results: A total of 102 articles were identified initially; finally 45 studies were used for review, comprising pupillomotor dysfunction in 4, sudomotor dysfunction in 2, cardiovascular dysfunction in 2, gastrointestinal dysfunction in 14, and urogenital dysfunction in 23. They can be summarized as (1) VZV infection rarely produces orthostatic hypotension, which involves diffuse sympathetic dysfunction by polyneuropathy. (2) In contrast, VZV infection produces dysfunction of the bladder and the bowel, which involves segmental parasympathetic or sympathetic dysfunction by dorsal root ganglionopathy., Conclusions: Awareness of VZV-related autonomic dysfunction is important, because such patients may first visit a gastroenterology or urology clinic. Close collaboration among neurologists, dermatologists, gastroenterologists, and urologists is important to start early antiviral agents and maximize bowel and bladder care in such patients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Sphingobacterium is an aerobic, glucose non-fermenting, Gram-negative rod bacterium that has been isolated from soil, plants, food, and water sources, including in hospitals. Reports of systemic infections caused by Sphingobacterium multivorum (S. multivorum) are rare, and their clinical and microbiological characteristics remain unclear. Moreover, conventional microbiological methods have limited ability to identify S. multivorum. We report the first case of obstructive cholangitis with bacteremia caused by S. multivorum in a patient with gastric cancer., Case Report: A 68-year-old woman with advanced gastric cancer, hypertension, and hyperlipidemia was admitted with obstructive jaundice, and subsequently developed obstructive cholangitis during the hospital stay. S. multivorum were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S ribosomal RNA sequencing of the patient's blood samples. Based on the antibiotic susceptibility results of the isolates, cefepime was administered intravenously for 14 days, with good therapeutic outcomes., Conclusions: S. multivorum infection is rare, and its microbiology and pathogenicity in humans is mostly unknown. Therefore, multiple diagnostic approaches should be used to identify S. multivorum, and antimicrobial therapy should be selected based on the in vitro susceptibility. This report provides clinicians with novel information on the clinical manifestations and diagnostic methods for an accurate diagnosis of S. multivorum., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Schizophrenia is a devastating mental disease that affects approximately 1% of the world's population. Breast cancer is the second most common type of cancer in the world that causes death in women. It is often unclear whether patients with schizophrenia receive recommended cancer treatment that met the guideline. This study characterized breast cancer treatment disruptions in schizophrenia patients and sought to identify and resolve correctable predictors of those disruptions., Materials and Methods: A retrospective cohort study was conducted on 55 primary breast cancer patients diagnosed with schizophrenia and treated for breast cancer. We evaluated the characteristics of the breast cancer patients with schizophrenia compared to those of 610 breast cancer patients without schizophrenia., Results: Compared to the control group, the schizophrenia group had significantly advanced T and N factors and disease stage. Significantly fewer patients in the schizophrenia group than in the control group received chemotherapy (P < .0001) or recommended cancer treatment (P = .0004). Within the schizophrenia group, the patients in need of ADL support were significantly less likely to receive recommended cancer treatment., Conclusion: Patients with schizophrenia are often diagnosed with breast cancer in advanced stages. In addition, patients with schizophrenia with reduced ADL are less likely to receive chemotherapy or recommended cancer treatment. It is highly recommended that patients with schizophrenia undergo breast cancer screening so that they can be diagnosed early and treated adequately., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine., Methods: The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members., Results: Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature., Conclusions: The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain., Competing Interests: Conflict of interest All guideline formulation committee members confirmed the COI through self-reporting. No companies or any other organizations were directly involved in any text pertaining to the guideline, including the recommendations for all CQs and BQs., (Copyright © 2021. Published by Elsevier B.V.)

Estrogens regulate pubertal development and reproductive function in women, spermatogenesis in men, and bone turnover and metabolic conditions in individuals of both sexes. Estradiol, the major estrogen in humans, is synthesized from testosterone by the action of aromatase and exerts its effects though binding to estrogen receptors. Germline loss- and gain-of-function variants in CYP19A1, the gene encoding aromatase, lead to aromatase deficiency and aromatase excess syndrome, respectively. Germline loss-of-function variants in ESR1, the gene encoding estrogen receptor α, are known to cause of estrogen insensitivity/resistance. In addition, rare variants in ESR1 and ESR2 have been implicated in various disease phenotypes. Clinical studies on these rare endocrine disorders provided clues to understand the biological functions of estrogens in the human body. This review introduces the genetic basis, phenotypes, and current management procedures of congenital disorders in estrogen biosynthesis and action., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To elucidate the incidence rate of enlargement of vertebral artery dissecting aneurysms (VADAs) during the acute phase and factors associated with enlargement., Methods: Of 115 patients with unilateral intracranial vertebral artery dissection who did not experience subarachnoid hemorrhage, 64 with the pearl sign of vertebral artery dissection (VADA without stenosis) participated in the study. We performed initial magnetic resonance imaging to diagnose VADA and subsequent magnetic resonance imaging to evaluate VADA enlargement. The presence of a hyperintense intramural signal was confirmed using T1-weighted three-dimensional turbo spin-echo imaging. Enlargement of VADAs between the initial and subsequent examinations was evaluated via magnetic resonance angiography and defined as the end point. We studied the rate of VADA enlargement using Kaplan-Meier curve analysis. After independent variables were determined, the Cox proportional hazards model was applied in multivariable analysis to identify the factors significantly associated with VADA enlargement., Results: Of 64 patients (mean age, 55.7 ± 13.0 years; 44 men and 20 women), 15 exhibited VADA enlargement. Kaplan-Meier curve analysis indicated that 24.8% of VADA enlargements were detected 30 days after initial magnetic resonance imaging. The Cox proportional hazards model revealed that young age (hazard ratio 0.953, P = 0.043) and the presence of hyperintense intramural signal (hazard ratio 2.841, P = 0.033) were significantly associated with VADA enlargement., Conclusions: VADAs enlarged by approximately 25% until day 30 after the initial examination. Younger age and the presence of hyperintense intramural signal were significantly associated with VADA enlargement., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Congenital limb deficiency is a rare anomaly that impairs limb function. Transverse deficiency accounts for approximately half of congenital limb deficiency cases. In Japan, there have been no detailed data of clinical features, especially treatment approaches, of this disorder. The present study aimed to investigate the status of treatment approaches of congenital transverse limb deficiency in Japan., Methods: From the national epidemiological survey of congenital limb deficiency undertaken in Japan in 2016, all the data of 200 patients with congenital transverse limb deficiencies were extracted. These data were analysed to reveal the treatment approaches of congenital transverse limb deficiency and its basic clinical features., Results: Surgical treatments and prosthetic or orthotic intervention had been implemented or planned for about one-quarter of patients, respectively. In the upper limb deficiencies, prosthetic or orthotic intervention was likely chosen in cases of deficiency at the metacarpal or proximal to metacarpal level. Surgical treatment was chosen only in cases of deficiency at the carpal or distal to carpal level. Although the number of patients with transverse lower limb deficiencies was small, prosthetic or orthotic intervention was likely chosen in proximal deficiencies, and surgical treatment was likely chosen in distal deficiencies., Conclusions: Herein, we revealed the status of treatment approaches for congenital transverse limb deficiency in Japan. Approximately half of the patients had no history of-and no plans for-surgical, prosthetic, or orthotic interventions. Further treatment advances may enable patients with congenital limb deficiencies to increase their participation in daily activities., Study Design: Cross-sectional survey., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: Parkinson's disease (PD) is the most common degenerative cause of movement disorder, and autonomic dysfunction has been recognized in this disorder. PD patients' lower urinary tract (LUT) function is not established. We investigated LUT function in PD by single-photon emission computerized tomography (SPECT) imaging of the dopamine transporter with 123 I-ioflupane and clinical-urodynamic observations., Patients and Methods: We retrospectively analyzed the cases of 30 patients diagnosed with PD based on published criteria who completed a systematized lower urinary tract symptoms (LUTS) questionnaire and a urodynamics examination irrespective of the presence of LUTS. None of the patients were taking anti-parkinsonian medication during the study., Results: The questionnaire revealed that all 30 patients had LUTS: night-time urinary frequency (in 70%), urinary incontinence (40%), and daytime urinary frequency (80%). A urodynamic study revealed a mean volume at the first sensation at 92.3 ml, bladder capacity at 200.9 ml, and detrusor overactivity in 50%. Sphincter electromyography revealed neurogenic change in 13.6% of those for whom the test was performed. The average SBR showed a significant correlation with bladder capacity (Spearman's correlation coefficient p = 0.0076) and Hoehn Yahr motor stage (Spearman's correlation coefficient p = 0.012)., Conclusion: Our findings demonstrate that the striatum is relevant to the higher control of storage in micturition function in PD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Young-onset stroke has a greater social impact than does stroke in older persons, indicating the importance of its prevention. Although there have been studies comparing stroke risk factors in young versus older individuals, no definition of young-onset ischemic stroke has been established. Large extracranial and intracranial atheroma, small vessel disease and atrial fibrillation have a major role in cases of stroke in the elderly, while these disorders are much less frequent in young adults. The purpose of this study was to determine the optimal cut-off point for defining young-onset ischemic stroke according to its cause., Methods: We identified 203 patients aged 65 years or less who had been admitted to our hospital between 2010 and 2017 with ischemic stroke, and we divided them into two groups according to the causes of the stroke. We allocated patients with strokes caused by small vessel occlusion, large artery atherosclerosis, atrial fibrillation, or aortic atheroma to Group A and those with strokes of other causes to Group B which included dissection, Trousseau syndrome and cerebral sinus thrombosis. We then used receiver operating characteristics curve analysis by the above groups and by sex to determine the cut-off age for defining young-onset., Results: Group A comprised 131 patients (58 ± 7 years, 92 men, 39 women) and Group B 72 (45 ± 15 years, 47 men, 25 women). Receiver operating characteristics curve analysis to differentiate Group B from Group A in all participants indicated a cut-off value of 53 years of age (area under curve: 0.78 [0.71-0.85], P < 0.001), which we therefore considered should define young-onset ischemic stroke. After dividing all patients by their sex, ROC analyses identified a cut-off for age of between 53 and 54 years for men (AUC: 0.75, 95% CI: 0.65-0.85, P < 0.001). In comparison, ≤ 48 years was the cut-off for young ischemic stroke in women (AUC: 0.83, 95% CI: 0.71-0.94, P < 0.001)., Conclusions: The age of 53 years may be the optimal cut-off point for young-onset ischemic stroke. Of note, the cut-off point between young- and non-young-onset stroke was 48 years for women, whereas it was 53 years for men. It is therefore important to carefully examine and treat female patients with this sex difference in mind., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: In clinical practice, whether cirrhotic livers in patients with hepatocellular carcinoma (HCC) can withstand repeated stereotactic body radiation therapy (SBRT) remains unclear. This study aimed to evaluate the outcomes and toxicities in these patients., Methods and Materials: This retrospective study included patients with HCC who were treated with SBRT at least twice between January 2012 and June 2019. Local control and overall survival rates were calculated. Liver function before and after irradiation was evaluated using the Child-Pugh score and modified albumin-bilirubin grade. All toxicities were assessed using the Common Terminology Criteria for Adverse Events (version 4.0)., Results: Fifty-two patients underwent 136 courses (148 lesions) of SBRT, which was mostly performed for out-of-field tumors but 3 in-field recurrences. The median follow-up duration from the first SBRT was 52.6 months (range, 15.7-89.3 months). The median gross tumor volume was 4.6 cm 3 (range, 0.8-55.2 cm 3 ) at the second SBRT. The 3-year local control rate was 94.5% (95% confidence interval, 88.0%-97.5%). The 3-year overall survival rate after the second course was 62.8% (95% confidence interval, 45.1%-76.2%). Although the Child-Pugh score did not deteriorate after the second course, deterioration of the modified albumin-bilirubin grade at 6, 12, and 24 months was statistically significant compared with that before the second course. One patient (1.9%) experienced grade 3 hypoalbuminemia and 2 patients (3.8%) had grade 3 thrombocytopenia 6 months after the second course. Mild fatigue and nausea were reported in 9 (17.3%) and 6 (11.5%) patients, respectively. One instance of grade 5 toxicity was observed. Two patients (1.5%) had grade 2 gastric ulcers. No other grade ≥3 gastrointestinal toxicities occurred., Conclusions: Repeated SBRT is feasible and produces minimal toxicity in patients with HCC and Child-Pugh scores of ≤7 and a low normal liver dose., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Author Disclosures All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by non-cancerous tumors in multiple organs including the brain, kidney, lung, heart, and skin. We encountered a Japanese family consisting of two siblings (a four-year-old boy and a one-year-old girl) with multiple cardiac rhabdomyomas conveying a high risk of TSC and apparently unaffected sibling (a two-year-old girl) and parents. Whole exome sequencing and application of Integrative Genomic Viewer revealed an identical intragenic TSC1 deletion with the breakpoints on intron 15 and exon 19 in the affected siblings, but not in the apparently unaffected sibling and parents. Subsequently, PCR-based analyses were performed using primers flanking the deletion, showing that the deletion was also present in the father and that the deletion occurred between chr9:135,777,038 (bp) and chr9:135,780,540 (bp) in association with a one bp overlap. Furthermore, RT-PCR analyses were carried out using lymphoblastoid cell lines, revealing a major in-frame insertion/deletion transcript produced by aberrant splicing using a cryptic ″ag″ splice acceptor motif at intron 15 (r.1998&#95;2438delinsTTCATTAGGTGG) and a minor frameshift transcript generated by aberrant splicing between exon 15 and exon 20 (r.1998&#95;2502del, p.Lys666Asnfs*15) in the affected siblings. These findings imply that the intragenic deletion producing two aberrant transcripts was generated as a somatic pathogenic variant involving the germline in the father and was transmitted to the affected siblings., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Heterotrimeric G proteins are composed of α, β, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gβ proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: The purpose of this study was to elucidate the association of cerebral large artery disease (CLAD) with cerebral blood flow (CBF) in the posterior cerebral artery (PCA) territory and cognitive performance., Method: We prospectively registered patients with CLAD who had internal carotid or middle cerebral artery (MCA) with the degree of stenosis ≥50%. Automated brain segmentation was used to quantify CBF in the thalamus, hippocampus, and PCA and MCA territories. We measured cognitive function of patients using the Wechsler Memory Scale Revised (WMS-R), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment. Patients were divided into 3 groups according to CBF of the cortical and subcortical PCA territory., Results: There were 60 patients included in this study. The degree of stenosis was significantly correlated with CBF in the PCA territory (Γ = 0.35, P = .006) and hippocampus (Γ = 0.34, P = .008). Verbal memory, general memory, and reproduction on WMS-R and MMSE were significantly reduced areas with low CBF in the PCA territory compared with areas with middle and high CBF., Conclusions: CBF of the PCA territory was significantly inversely correlated with the degree of stenosis in CLAD patients. Low CBF of the PCA territory was significantly associated with reduced cognitive and memory functions., (Copyright © 2019. Published by Elsevier B.V.)

Whole-exome sequencing (WES) can comprehensively detect both pathogenic single nucleotide variants and copy number variants, enabling identification of a coexistence of two or more genetic etiologies. Here we report a family consisting of individuals with Becker muscular dystrophy and rippling muscle disease. The proband, a 12-year-old boy, was diagnosed with Becker muscular dystrophy with exon 45-55 DMD deletions at age 4. He had myalgia and muscle stiffness. Interestingly, percussion-induced muscle mounding (PIMM), which is a characteristic of rippling muscle disease, was also observed. The father also showed muscle stiffness, myalgia, fatigability, muscle rippling and PIMM. WES revealed a missense CAV3 mutation (NM&#95;033337.2:c.80G>A) in the proband, the father, the oldest sister and the grandmother, who had an elevated serum creatine kinase (CK) level. The c.80G>A mutation was considered pathogenic according to ACMG guidelines. The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation and had normal CK. Using two programs for copy number analysis with WES data, we successfully identified the DMD deletion in the proband, the older sister and the mother. We revealed the coexistence of the CAV3 mutation and the DMD deletion in a family with complex muscular diseases and confirmed the usefulness of WES for elucidating such etiology., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan., Methods: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma., Results: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01)., Conclusions: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved., Methods: We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain., Results: In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice., Conclusions: These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Body weight loss (BWL) is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. The risk factors for severe BWL after gastrectomy remain unclear., Methods: The present study retrospectively examined patients who underwent curative gastrectomy for gastric cancer between January 2012 and June 2014 at Kanagawa Cancer Center. All patients received perioperative care based on the enhanced recovery after surgery protocol. The %BWL value was calculated based on the percentage of body weight at 1 month after surgery in comparison to the preoperative body weight. Severe BWL was defined as %BWL > 10%. The risk factors for severe BWL were determined by both univariate and multivariate logistic regression analyses., Results: There were 278 patients examined. The median age of the patients was 68 years. The operative procedures included total gastrectomy [n=97; open (n=61) and laparoscopic {n=36)] and distal gastrectomy (n=181). Surgical complications of grade ≥ 2 (as defined by the Clavien-Dindo classification) were observed in 37 patients, these included: pancreatic fistula (n=9), anastomotic leakage (n=5), and abdominal abscess (n=3). There were no cases of surgery-associated mortality. Both univariate and multivariate logistic analyses demonstrated that surgical complications, and total gastrectomy were significant risk factors for severe BWL., Conclusions: Surgical complications and total gastrectomy were identified as being significant risk factors for severe BWL in the 1 st month after gastrectomy. To maintain body weight after gastrectomy, physicians should pay careful attention to patients who undergo total gastrectomy and those who develop surgical complications., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week-old apoE deficient (apoE -/- ) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-β1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-β1 concentration, which was inversely correlated with the suprarenal lesion area (r = -0.63, P = 0.012). Treatment with neutralizing TGF-β antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-β-positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-β1-mediated anti-inflammatory response, which may involve alternatively activated macrophages., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitate depressive-like behaviors, and investigated the effects on atherosclerosis. Eight-week-old male apoE -/- mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days and fed a high-cholesterol diet (HCD) for 6 weeks. The social interaction ratio and immobility time showed dramatic social avoidance before and after HCD feeding. Defeated mice showed higher increase in atherosclerotic lesion areas in the aortic root and entire aorta than control mice. Mean blood pressure and lipid profile were equivalent in both groups. While Ly-6G- and Mac3-positive areas in the aortic root were comparable between the groups, citrullinated histone H3 (Cit-H3)- and myeloperoxidase (MPO)-positive areas, markers of neutrophil extracellular traps (NETs), were significantly increased in the defeated mice. Treatment with DNase I completely diminished the exaggerated atherosclerosis. The proportion of peripheral blood polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), but not of inflammatory monocytes, was markedly increased. Moreover, in vitro NETs formation from bone marrow (BM) PMN-MDSC was markedly augmented, accompanied by higher expression of Nox2 gene and reactive oxygen species. Our findings demonstrate that exposure to RSD promotes atherosclerosis by augmenting NETs formation within the plaque. This provides new insight into the underlying mechanism of depression-related CVD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Shellfish aquaculture in Ofunato Bay, Northeast Japan, was seriously damaged by a tsunami generated by the Great East Japan Earthquake, March 11th, 2011, accompanied by paralytic shellfish poisoning (PSP) outbreaks caused by Alexandrium tamarense (Dinophyceae). To understand longer future trends of PSP, an investigation was made of the historical occurrence and causes of Alexandrium outbreaks after the tsunami. Vertical distributions of Alexandrium cysts in two sediment-cores from Ofunato Bay revealed that the sediments above ca. 25 cm were eroded, re-suspended and re-deposited, and they included unusually abundant Alexandrium cysts. This abundance of cysts was due to re-deposition of older sediments by the tsunami. The first Ofunato Bay PSP incident was in 1961 after the Chilean Earthquake tsunami and was probably caused by similar unusual blooms of Alexandrium germinated from older sediments as the Great East Japan tsunami, together with nutrient enrichment because of population increase at the start of shellfish aquaculture., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE -/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE -/- mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.

Objective: The ultrasonography findings in the superficial temporal artery (STA) in Moyamoya disease patients treated with indirect bypass remain unclear. We evaluated the time-related changes in ultrasonography findings of the STA main trunk and branches in patients with Moyamoya disease who underwent encephalo-duro-arterio-synangiosis (EDAS)., Patients and Methods: Patients (n=21, 30 sides) with Moyamoya disease who underwent EDAS at Fukuoka University Hospital were prospectively registered between 2008 and 2015. EDAS using the frontal and parietal branches of the STA was adopted in an indirect bypass procedure. Mean velocity (MV) and resistance index (RI) were used as ultrasonography markers, and their changes over time in the STA main trunk and branches were assessed., Results: There was a significant increase in MV in both the STA main trunk (p=0.001) and branches (frontal: p=0.005, parietal: p=0.003) at 3 months after EDAS, whereas there was a decrease in RI at 14days after EDAS (main trunk: p <0.001, frontal: p <0.001, parietal: p=0.014). In subgroup analysis of patients divided by EDAS outcome, compared with before EDAS, there were significant differences at 3 months after EDAS in MV (responders: main trunk: p=0.002, frontal: p=0.001, parietal: p=0.001; non-responders: main trunk: p=0.093, frontal: p=0.24, parietal: p=0.96) and RI (responders: main trunk: p<0.001, frontal: p<0.001, parietal: p=0.006; non-responders: main trunk: p=0.17, frontal: p=0.12, parietal: p=0.17)., Conclusions: Measurement of MV may be useful for predicting outcome at 3 months after EDAS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC -/- ) mice subjected to periaortic application of CaCl 2 developed AAAs. Six weeks after CaCl 2 treatment, internal and external aortic diameters were significantly increased in MURC -/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC -/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC -/- AAAs compared with WT AAAs at 5 days after CaCl 2 treatment. At 6 weeks after CaCl 2 treatment, MURC -/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl 2 treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC -/- , apolipoprotein E -/- (ApoE -/- ), and MURC/Cavin-4 and ApoE double-knockout (MURC -/- ApoE -/- ) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE -/- and MURC -/- ApoE -/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC -/- ApoE -/- mice compared with Ang II-infused ApoE -/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In an embryonic developmental stage of the peripheral nervous system (PNS), Schwann cell precursors migrate along neuronal axons to their final destinations. After birth, they eventually wrap around individual axons to form myelin sheaths, which insulate axons to increase the nerve conduction velocity. Some growth factors and adhesion molecules are known to control these developmental stages from in the fish to in the mammal. Neuregulin-1 (NRG1), which is composed of many alternative splicing variants, is such a growth factor. Among these variants, the type III isoform of NRG1, interacting with ErbB2 and ErbB3 receptors on Schwann cells, plays an essential role in myelination in the fish and the mammal. NRG1 type III is also known to promote migration of fish Schwann cell precursors; however, it still remains to be clarified whether mammalian type III isoform does it. We have therefore generated type III isoform-specific knockout mice in inbred strain. The mice result in delayed migration of the precursors from the dorsal to ventral root via a peripheral ganglion, comparing littermate controls. Similar results are observed in an in vitro migration assay using reaggregated Schwann cell precursors. Furthermore, the knockout mice exhibit reduced myelin thickness, consistent with the established role of NRG1 type III in myelination. These results indicate that in mice, NRG1 type III plays a key role not only in myelination but also in migration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Recent studies have identified multilocus imprinting disturbances (MLIDs) in a subset of patients with imprinting diseases (IDs) caused by epimutations. We examined MLIDs in patients with Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14)., Methods: We studied four TS14 patients (patients 1-4) and five KOS14 patients (patients 5-9) with epimutations. We performed HumanMethylation450 BeadChip (HM450k) analysis for 43 differentially methylated regions (DMRs) (753 CpG sites) and pyrosequencing for 12 DMRs (62 CpG sites) using leukocyte genomic DNA (Leu-gDNA) of patients 1-9, and performed HM450k analysis for 43 DMRs (a slightly different set of 753 CpG sites) using buccal cell gDNA (Buc-gDNA) of patients 1, 3, and 4. We also performed mutation analysis for six causative and candidate genes for MLIDs and quantitative expression analysis using immortalized lymphocytes in MLID-positive patients., Results: Methylation analysis showed hypermethylated ZDBF2-DMR and ZNF597/NAA60-DMR, hypomethylated ZNF597-DMR in both Leu-gDNA and Buc-gDNA, and hypomethylated PPIEL-DMR in Buc-gDNA of patient 1, and hypermethylated GNAS-A/B-DMR in Leu-gDNA of patient 3. No mutations were detected in the six genes for MLIDs. Expression patterns of ZDBF2, ZNF597, and GNAS-A/B were consistent with the identified MLIDs., Conclusion: This study indicates the presence of MLIDs in TS14 patients but not in KOS14 patients.Genet Med 19 4, 476-482.

Introduction: Levetiracetam has a high tolerability and is effective against various seizure types and epilepsy syndromes. However, no study has specifically evaluated the efficacy of levetiracetam in children with refractory epilepsy based on magnetic resonance imaging (MRI) findings and the presence of intellectual disability (ID)., Methods: We retrospectively evaluated levetiracetam efficacy and safety in 49 pediatric patients who met the following inclusion criteria: (1) diagnosis of refractory epilepsy with first-line antiepileptic (AED) treatment ⩾2years, (2) younger than 20years old, and (3) received oral levetiracetam treatment for ⩾6months. We assessed the relationships of these outcomes with MRI findings and ID status., Results: Eighteen (37%) patients achieved a ⩾50% reduction in seizure frequency, and the majority (78%) had no remarkable side effects. Twenty-two (45%) patients had previously been treated with more than seven antiepileptic drugs prior to levetiracetam. Among 18 patients who achieved a ⩾50% reduction in seizure frequency, 13 and 5 had negative and positive MRI findings, and 9 and 9 had and did not have ID, respectively., Conclusions: Our findings suggest that even for intractable pediatric cases with symptomatic etiology (i.e., MRI lesion and ID), levetiracetam has favorable efficacy for refractory epilepsy with tolerable adverse effects., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We report a case of thoracic empyema caused by Campylobacter rectus, an organism considered as a periodontal pathogen but rarely recovered from extraoral specimens. The patient fully recovered through drainage of purulent pleural fluid and administration of antibiotics. The present case illustrates that C. rectus can be a cause of not only periodontal disease but also pulmonary infection., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The Japanese Society for Spine Surgery and Related Research (JSSR) performed a third study on complications in spinal surgery in 2011. The purpose was to present information about surgery and complications in a large amount of elderly patients aged 65 years with lumbar spinal stenosis (LSS) without coexisting spondylolisthesis, spondylolysis, or scoliosis, and to compare patients aged ≥80 years to those aged 65-79 years., Methods: A recordable optical disc for data storage was sent by JSSR in January 2012 to 1105 surgeons certified by the JSSR in order to collect surgical data. Data were returned by the end of May 2012., Results: Data were accumulated for 8033 patients aged 65 years. The incidence of surgical complications was 10.8%, and did not differ significantly between age groups. The incidence of general complications was 2.7%, and differed significantly between age groups (p < 0.005). The highest incidence of surgical complications was for dural tear (DT) (3.6%), followed by deep wound infection (DWI) (1.4%), neurological complications (1.3%), and epidural hematoma (1.3%). Spinal instrumentation was applied in 30.3%. Incidences of surgical complications in instrumented and noninstrumented surgery were 17.3% and 8.8%. In instrumented surgery, incidences of surgical and general complications were higher in the ≥80 year age group than in the 65-79 year age group. Logistic regression analyses showed patients with microendoscopic surgery at increased risk of DT. Patients with diabetes mellitus and instrumented surgery showed increased risks of DWI., Conclusions: Incidences of surgical complications did not differ significantly between age groups. Attention should be paid to both surgical and general complications, particularly for postoperative mental disease in instrumented surgery for patients≥80 years old., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Six fluorescein-nitroxide radical hybrid-compounds (2ab, 3ab, 4, and 5) were synthesized by the condensation of 5- or 6-carboxy-fluorescein and 4-amino-TEMPO (2ab), 5- or 6-aminofluorescein and 4-carboxy-TEMPO (3ab), and fluorescein and 4-carboxy-TEMPO (4), or by reaction of the 3-hydroxyl group of fluorescein with DPROXYL-3-ylmethyl methanesulfonate (5). Fluorescence intensities (around 520nm) after reduction of the radical increased to 1.43-, 1.38-, and 1.61-folds for 2a, 2b and 3b respectively; 3a alone exhibited a decrease in intensity on reduction. Since 4 was readily solvolyzed in PBS or even methanol to afford fluorescein and 4-carboxy-TEMPO, its fluorescence change could not be measured. Hybrid compound 5 containing an ether-linkage between the fluorescein phenol and 3-hydroxymethyl-DPROXYL hydroxyl centers, was stable and on reduction, showed a maximum increase (3.21-fold) in relative fluorescence intensity in PBS (pH5.0), despite its remarkably low absolute fluorescence intensity., (Copyright © 2016. Published by Elsevier B.V.)