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Objective: Magnetic resonance imaging (MRI) is commonly used to evaluate cervical spinal canal stenosis; however, some patients are ineligible for MRI. We aimed to assess the effect of deep learning reconstruction (DLR) in evaluating cervical spinal canal stenosis using computed tomography (CT) compared with hybrid iterative reconstruction (hybrid IR)., Methods: This retrospective study included 33 patients (16 male patients; mean age, 57.7 ± 18.4 years) who underwent cervical spine CT. Images were reconstructed using DLR and hybrid IR. In the quantitative analyses, noise was recorded by placing the regions of interest on the trapezius muscle. In the qualitative analyses, 2 radiologists evaluated the depiction of structures, image noise, overall image quality, and degree of cervical canal stenosis. We additionally evaluated the agreement between MRI and CT in 15 patients for whom preoperative cervical MRI was available., Results: Image noise was less with DLR than hybrid IR in the quantitative ( P ≤ 0.0395) and subjective analyses ( P ≤ 0.0023), and the depiction of most structures was improved ( P ≤ 0.0052), which resulted in better overall quality ( P ≤ 0.0118). Interobserver agreement in the assessment of spinal canal stenosis with DLR (0.7390; 95% confidence interval [CI], 0.7189-0.7592) was superior to that with hybrid IR (0.7038; 96% CI, 0.6846-0.7229). As for the agreement between MRI and CT, significant improvement was observed for 1 reader with DLR (0.7910; 96% CI, 0.7762-0.8057) than hybrid IR (0.7536; 96% CI, 0.7383-0.7688)., Conclusions: Deep learning reconstruction provided better quality cervical spine CT images in the evaluation of cervical spinal stenosis than hybrid IR., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Some genera of Rubiaceae in South-eastern Asia are known as typical ant plants. They have large domatia, which form in well-developed hypocotyls in which ants nest. Previously, cavity formation processes were described; however, these reports were dependent on tissue sections of different individuals of different ages. No continuous time-course analyses were done because cavity formation occurs inside the thick tissues of highly swollen domatia. Here we observed cavity formation processes in ant plants by using X-ray computed tomography (CT) imaging and revealed previously overlooked features of cavity formation. Firstly, the cavity pore occurs at the hypocotyl base in not only gravity-dependent but also basal position-dependent manner. Secondly, the cavity forms prior to the start of short tunnel formation between the cavity and the pore. The cavity axis is parallel to the longitudinal axis of the hypocotyl; however, the short tunnel axis between the pore and cavity depends on gravity. Non-invasive CT scanning is a very powerful method to analyze deeply hidden morphogenic processes in organs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsukaya and Ohtake.)

We propose a dynamic-spectral-broadness Littman/Metcalf external cavity diode laser, which replaces the flat end mirror of the external cavity with a curved one with a tunable radius of curvature (RoC). The concept was verified via simulation; first, the frequency selectivity of the cavity was calculated for each RoC using Gaussian-beam optics combined with ray tracing, and second, laser oscillation and amplified spontaneous-emission (ASE) spectra were obtained using the transmission-line laser model. The simulation revealed a tuning range with spectral broadness: 250 kHz for single-mode operation, 1.2-47 GHz for multi-mode operation, and 50 GHz-3.9 THz for ASE.

There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase ( COMT ) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 ( CCL11 ; rs17809012), histamine N-methyltransferase ( HNMT ; rs1050891) and transient receptor potential V1 ( TRPV1 ; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain., Competing Interests: Dr Tsurutani reports research fundings from Daiichi Sankyo, Eisai, Taiho, Chugai, Nihonkayaku, Eli Lilly, Pfizer and MSD outside the submitted work. Dr Hayashi reports honoraria from Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd., and research funding from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Merck Serono Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., SymBio Pharmaceuticals Ltd., AbbVie Inc., inVentiv Health Japan, ICON Japan K.K., Gritstone Oncology Inc., Parexel International Corp., Kissei Pharmaceutical Co. Ltd., EPS Corp., Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services Japan K.K., EP-CRSU Co. Ltd., Linical Co. Ltd., Eisai Co. Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co. Ltd., Bayer Yakuhin Ltd., EPS International Co. Ltd. and Otsuka Pharmaceutical Co. Ltd. Dr Takeda reports honoraria from Ono Pharmaceutical Co., Boehringer Ingelheim Japan Inc. and Novartis Pharma K.K. outside the submitted work. Dr Haratani reports grants from AS ONE Corporation outside the submitted work. Dr Takahama reports research funding from Takeda and Pfizer outside the submitted work. Dr. Nishio reports grants from Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Ignyta Inc., Astellas Pharma Inc., Thoracic Oncology Research Group, and North East Japan Study Group outside the submitted work. Dr Nakagawa reports grants from Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., AbbVie Inc., inVentiv Health Japan, ICON Japan K.K., Gritstone Oncology Inc., Parexel International Co., Kissei Pharmaceutical Co., Ltd., EPS Co., Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Co., Quintiles Inc./IQVIA Services JAPAN K.K., EP-CRSU Co., Ltd., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd., Bayer Yakuhin, Ltd., EPS International Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb Co., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd. and Merck Serono Co., Ltd./Merck Biopharma Co., Ltd. outside the submitted work. Drs Fujita, Matsuoka, Chiba, Sakai, Yoshida, Nakura, Sakamoto, Makimura, Ohtake, Tanaka, Okuno, Takegawa, Tanizaki and Koyama have nothing to disclose., (Copyright: © Fujita et al.)

Background: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain., Methods: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype., Results: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098)., Conclusion: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief., (© The Author(s) 2022. Published by Oxford University Press.)

Conventionally, ultrasound (US) diagnosis is performed using hand-held rigid probes. Such devices are difficult to be used for long-term monitoring because they need to be continuously pressed against the body to remove the air between the probe and body. Flexible probes, which can deform and effectively adhere to the body, are a promising technology for long-term monitoring applications. However, owing to the flexible element array geometry, the reconstructed image becomes blurred and distorted. In this study, we propose a flexible probe U.S. imaging method based on element array geometry estimation from radio frequency (RF) data using a deep neural network (DNN). The input and output of the DNN are the RF data and parameters that determine the element array geometry, respectively. The DNN was first trained from scratch with simulation data and then fine-tuned with in vivo data. The DNN performance was evaluated according to the element position mean absolute error (MAE) and the reconstructed image quality. The reconstructed image quality was evaluated with peak-signal-to-noise ratio (PSNR) and mean structural similarity (MSSIM). In the test conducted with simulation data, the average element position MAE was 0.86 mm, and the average reconstructed image PSNR and MSSIM were 20.6 and 0.791, respectively. In the test conducted with in vivo data, the average element position MAE was 1.11 mm, and the average reconstructed image PSNR and MSSIM were 19.4 and 0.798, respectively. The average estimation time was 0.045 s. These results demonstrate the feasibility of the proposed method for long-term real-time monitoring using flexible probes.

Purpose: To compare image quality and interobserver agreement in evaluations of neuroforaminal stenosis between 1.5T cervical spine magnetic resonance imaging (MRI) with deep learning reconstruction (DLR) and 3T MRI without DLR., Methods: In this prospective study, 21 volunteers (mean age: 42.4 ± 11.9 years; 17 males) underwent cervical spine T2-weighted sagittal 1.5T and 3T MRI on the same day. The 1.5T and 3T MRI data were used to reconstruct images with (1.5T-DLR) and without (3T-nonDLR) DLR, respectively. Regions of interest were marked on the spinal cord to calculate non-uniformity (NU; standard deviation/signal intensity × 100), as an indicator of image noise. Two blinded radiologists evaluated the images in terms of the depiction of structures, artifacts, noise, overall image quality, and neuroforaminal stenosis. The NU value and the subjective image quality scores were compared between 1.5T-DLR and 3T-nonDLR using the Wilcoxon signed-rank test. Interobserver agreement in evaluations of neuroforaminal stenosis for 1.5T-DLR and 3T-nonDLR was evaluated using Cohen's weighted kappa analysis., Results: The NU value for 1.5T-DLR was 8.4, which was significantly better than that for 3T-nonDLR (10.3; p < 0.001). Subjective image scores were significantly better for 1.5T-DLR than 3T-nonDLR images (p < 0.037). Interobserver agreement (95% confidence intervals) in the evaluations of neuroforaminal stenosis was significantly superior for 1.5T-DLR (0.920 [0.916-0.924]) than 3T-nonDLR (0.894 [0.889-0.898])., Conclusion: By using DLR, image quality and interobserver agreement in evaluations of neuroforaminal stenosis on 1.5T cervical spine MRI could be improved compared to 3T MRI without DLR., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To investigate whether deep learning reconstruction (DLR) provides improved cervical spine MR images using a 1.5 T unit in the evaluation of degenerative changes without increasing imaging time., Methods: This study included 21 volunteers (age 42.4 ± 11.9 years; 17 males) who underwent 1.5 T cervical spine sagittal T2-weighted MRI. From the imaging data with number of acquisitions (NAQ) of 1 or 2, images were reconstructed with DLR (NAQ1-DLR) and without DLR (NAQ1) or without DLR (NAQ2), respectively. Two readers evaluated the images for depiction of structures, artifacts, noise, overall image quality, spinal canal stenosis, and neuroforaminal stenosis. The two readers read studies blinded and randomly. Values were compared between NAQ1-DLR and NAQ1 and between NAQ1-DLR and NAQ2 using the Wilcoxon signed-rank test., Results: The analyses showed significantly better results for NAQ1-DLR compared with NAQ1 and NAQ2 (p < 0.023), except for depiction of disc and foramina by one reader and artifacts by both readers in the comparison between NAQ1-DLR and NAQ2. Interobserver agreements (Cohen's weighted kappa [97.5% confidence interval]) in the evaluation of spinal canal stenosis for NAQ1-DLR/NAQ1/NAQ2 were 0.874 (0.866-0.883)/0.778 (0.767-0.789)/0.818 (0.809-0.827), respectively, and those in the evaluation of neuroforaminal stenosis were 0.878 (0.872-0.883)/0.855 (0.849-0.860)/0.852 (0.845-0.860), respectively., Conclusions: DLR improved the 1.5 T cervical spine MR images in the evaluation of degenerative spine changes., Key Points: • Two radiologists demonstrated that deep learning reconstruction reduced the noise in cervical spine sagittal T2-weighted MR images obtained using a 1.5 T unit. • Reduced noise in deep learning reconstruction images resulted in a clearer depiction of structures, such as the spinal cord, vertebrae, and zygapophyseal joint. • Interobserver agreement in the evaluation of spinal canal stenosis and foraminal stenosis on cervical spine MR images was significantly improved using deep learning reconstruction (0.874 and 0.878, respectively) versus without deep learning (0.778-0.818 and 0.852-0.855, respectively)., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

The Japanese Psycho-Oncology Society and the Japanese Association of Supportive Care in Cancer developed evidence-based clinical practice guidelines for the care of psychologically distressed bereaved families who have lost members to physical illness including cancer. The guideline development group formulated two clinical questions. A systematic literature review was conducted. The level of evidence and the strength of the recommendations were graded and recommendation statements validated using the modified Delphi method. The recommendations were as follows: non-pharmacological interventions were indicated for serious psychological distress (depression and grief); antidepressants were indicated for depression; however, psychotropic medications including antidepressants were not recommended for 'complicated' grief. These guidelines will facilitate the provision of appropriate care to distressed bereaved family members and highlight areas where further research is needed., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The COVID-19 pandemic has affected the mental health of health care workers. This study aimed to investigate the stress factors that cause burnout in Japanese physicians and their coping methods during the COVID-19 pandemic., Methods: We conducted a sequential explanatory mixed-method study to investigate the psychological responses of physicians in the early stages of the pandemic. A cross-sectional, web-based, anonymous survey was conducted among members of the American College of Physicians Japan Chapter to quantitatively investigate the stress factors and prevalence of burnout. An open-ended questionnaire with questions about stress factors and coping methods was additionally administered. The qualitative data were analyzed using qualitative content analysis., Results: Among the 1173 physicians surveyed, 214 (18.2%) responded. Among the participants, 107 (50.0%) responded "yes" to the question "I feel or have felt very stressed at work during the COVID-19 pandemic," and 68 (31.8%) reported burnout symptoms. Those who reported feeling stress (117 respondents) were asked to select 12 items of the stress factors related to COVID-19. The most significant stress factor related to COVID-19 was "Perceived risk of spreading COVID-19 to family members" ( n  = 47). Content analysis identified 12 categories for the stress factors and 7 for stress-coping methods corresponding to COVID-19 (Cohen's kappa = 0.84 and 0.95, respectively)., Conclusion: Several distinct stressors existed during the COVID-19 pandemic, which might be related to burnout among physicians. Practicing stress-coping strategies, as identified in the present study, may help reduce work-related stress and prevent burnout., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Objective To evaluate the change in the prevalence of burnout during the COVID-19 pandemic among internists and primary care physicians in Japan, and to identify factors associated with the exacerbation of burnout among these populations during this period. Methods This was a cross-sectional study based on two web-based surveys conducted in January 2020 (before the declaration of the COVID-19 pandemic) and June 2020 (during the pandemic). The participants were internists and primary care physicians of the Japanese Chapter of the American College of Physicians. The main outcome was the change in the prevalence of burnout between before and during the "first wave" of the pandemic. We also examined factors associated with the exacerbation of burnout during this period. Results Among the 283 respondents in the first survey and 322 in the second survey, 98 (34.6%) and 111 (34.5%) reported symptoms of burnout, respectively. In June 2020, 82 respondents (25.5%) reported that their level of burnout exacerbated compared to January 2020. Only the experience of self-quarantine was associated with the exacerbation of burnout [odds ratio (OR) 3.12; 95% confidence interval (CI) 1.49-6.50; p=0.002], while being a woman, being a resident physician, and an experience of having worked in a prefecture under a state of emergency were not. Conclusions No marked change in the prevalence of burnout among internists and primary care physicians in Japan was observed during the COVID-19 pandemic as a whole. However, self-quarantine was associated with the exacerbation of the burnout level.

Aims/introduction: This systematic review and meta-analysis aimed to investigate the efficacy and safety of acceptance and commitment therapy (ACT) for people with type 2 diabetes mellitus., Materials and Methods: Several electronic databases were examined on 16 January 2021, including PubMed, CENTRAL, PsycINFO, International Clinical Trials Registry Platform and ClinicalTrials.gov. Randomized controlled trials were included to compare ACT with usual treatment for people with type 2 diabetes reported in any language. Primary outcome measures were glycated hemoglobin, self-care ability assessed by the summary of diabetes self-care activities and all adverse events. The secondary outcome measure was acceptance assessed by the acceptance and action diabetes questionnaire., Results: Of 678 publications initially identified, three trials were included in the meta-analysis. ACT resulted in a reduction in glycated hemoglobin (mean difference -0.62 points lower in the intervention group; 95% confidence interval -1.07 to -0.16; I 2  = 0%; low-quality evidence). In addition, ACT increased the score of the summary of diabetes self-care activities (mean difference 8.48 points higher in the intervention group; 95% confidence interval 2.16-14.80; high-quality evidence). Adverse events were not measured in all trials. ACT increased scores of the acceptance and action diabetes questionnaire (mean difference 5.98 points higher in the intervention group; 95% confidence interval, 1.42-10.54; I 2  = 43%; low-quality evidence)., Conclusions: ACT might reduce glycated hemoglobin, and increase self-care ability and acceptance among people with type 2 diabetes., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: Synovial sarcoma (SS) predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic SS. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with SS., Methods: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic SS who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated., Results: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for >6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively., Conclusion: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with SS was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for SSs., (© 2022 S. Karger AG, Basel.)

Anterior cervical foraminotomy is a motion-preserving and precise decompressing surgery with minimal bone removal. As preserving the motion segment and maximizing decompression are contradictory concepts, proficiency is needed to balance these requirements. Anatomical knowledge and good intraoperative orientation are essential to reach the nerve roots accurately in a narrow surgical field.

Background: Idiopathic spinal cord herniation (ISCH) is very rare. Some reports have described postoperative ventral cerebrospinal fluid (CSF) collections in patients with ISCH; however, such collections are asymptomatic in most patients, and there is no consensus regarding whether they are part of the natural history or a complication., Observations: A 30-year-old man with ISCH underwent direct closure of a duplicated dura mater. Eight months postoperatively, he developed reworsening of right lower limb paresis and new severe right arm pain and paresis. Three-dimensional magnetic resonance imaging revealed ventral CSF collections, which the authors judged as the responsible lesions. The authors initially considered these collections to be present in the epidural space, extradurally compressing the dural sac and resulting in myelopathy. An epidural blood patch failed; however, a CSF drainage test resulted in dramatic improvement. The authors therefore determined that the CSF collections were located in the interdural space, not the epidural space. A lumboperitoneal (LP) shunt was performed to reduce the CSF pressure. The patient's symptoms improved immediately postoperatively. He had developed no recurrence of symptoms 6 months after surgery., Lessons: Ventral interdural CSF collections after ISCH surgery can cause reworsening of myelopathy and may be cured by a LP shunt to control CSF pressure.

Background: Research engagement contributes to the improvement of patient care. A systematic review is a suitable first scholarly activity because it entails summarization of publicly available data and usually requires neither rigorous ethical review nor research funding., Methods: This study aimed to develop a model workshop for healthcare staff to acquire skills in creating systematic review protocols based on their own clinical questions at teaching hospitals. We used an action research method to create a model workshop at four hospitals in Japan from April 2015 to March 2017. To improve the program, we solicited reflections using participant questionnaires for each lecture and examined the quality of homework submitted by participants after each lecture. We administered a revised final version of the workshop at five hospitals from April 2016 to March 2017. We evaluated the participants' scholarly productivity related to these workshops. The observation period was a minimum of 2 years following the workshops., Results: Most participants had never developed a formal clinical research protocol and voluntarily participated in the workshop. The action research was developed and implemented at nine teaching hospitals in Japan, including one university hospital. The study developed a model nine-step workshop curriculum: 1) Research question development, 2) Search strategy development, 3) Search strategy brush-up, 4) Exclusion and inclusion criteria development, 5) Risk of bias assessment planning, 6) Meta-analysis planning, 7) Subgroup and sensitivity analysis planning, 8) Planning the presentation of results, and 9) Presentation protocols. A total of 233 participants, including medical doctors and other health professionals, produced 414 research questions. Seventy-nine participants (34%) completed the workshop, and 47 review teams accomplished systematic review protocols. The participants published 13 peer-reviewed articles as a result of the workshop., Conclusions: We developed a structured scholarly productive model workshop for healthcare staff working at hospitals. We found healthcare staff with clinical subspecialties were able to develop an unexpectedly high number of research questions through this workshop. Medical teachers at hospitals with prior systematic review experience could teach how to develop systematic review protocols using this model. Further research is needed to increase the academic productivity of such workshops., Trial Registration: UMIN (https://www.umin.ac.jp/ctr/), UMIN000017107 (4/15/2015), UMIN000025580 (1/10/2017).

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48-22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99-14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies., (Copyright: © Mizuno et al.)

Anterior cervical foraminotomy (ACF) is a surgical procedure for cervical radiculopathy to avoid fusion and adjacent segment disease (ASD), but its long-term outcome has yet to be investigated. It is also unclear whether ACF enables preservation of range of motion (ROM) and decreases ASD compared with anterior cervical discectomy and fusion (ACDF). This study included nine patients who underwent ACF, and 12 who underwent ACDF and with follow-up period of at least 5 years (average follow-up: 8.7 years). Preoperative and postoperative radiological findings were investigated, comparing the changes in ACF versus ACDF. All disc height (DH) levels (C2/3-C7/Th1) were measured preoperatively and postoperatively in all 21 patients to compare with the change due to the natural history. The ACF group experienced significant loss of DH (0.6 mm, 13.5%, p <0.01) and ROM (p <0.01) at the operated level postoperatively. However, loss of DH was not significantly different from natural changes at unaffected levels, and ROM was maintained. The ACDF group experienced a significant increase in the ROM of the cranial adjacent segment from 6.46 mm to 7.45 mm (p <0.01), and the dislocation in dynamic X-ray was also significantly increased from 1.61 mm to 2.89 mm (p <0.01), indicating radiological ASD. The ACF group had no significant increase in ROM and dislocation. ACF causes significant loss of DH and ROM, but this change is not significantly different compared with natural changes at unaffected levels. Furthermore, ACF causes less ASD than ACDF in the long term.

Patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) have a poorer prognosis than those with squamous cell carcinoma (SCC). Erb-b2 receptor tyrosine kinase 3 (HER3) is a member of the epidermal growth factor receptor family and its expression is associated with unfavorable prognosis in several cancer types, including SCC of the cervix. As there is limited information on the prognostic value of HER3 for AC and ASC of the cervix, the present study aimed to evaluate the expression of HER3 and its impact on post-operative recurrence in patients with AC and ASC of the cervix. This retrospective study included 39 patients with early-stage AC and ASC who underwent primary surgery between January 1997 and December 2017. Immunohistochemical staining for HER3 was performed on formalin-fixed paraffin-embedded surgical specimens. The possible influence of HER3 expression on disease-free survival (DFS) was studied by using multivariate Cox regression with adjustment for established risk factors of post-operative recurrence. High expression of HER3 (HER3-high) was detected in 85.1% of cases of AC (23/27) and in 58.3% of cases of ASC (7/12). The median follow-up duration was 63.1 months and Kaplan-Meier analysis indicated that the 5-year DFS rates of patients with AC and ASC of the cervix were 56.7% in patients with HER3-high and 77.8% in patients with HER3-low (log rank, P=0.20). On multivariate analysis, HER3-high [hazard ratio (HR)=6.32, 95% CI: 1.10-36.26, P=0.039), pelvic lymph node metastasis (HR=7.61, 95% CI: 2.07-28.00, P=0.002) and vascular invasion (HR=4.28, 95% CI: 1.12-16.31, P=0.033) were indicated to be independent predictors of DFS. To date, the present study is the most comprehensive analysis to evaluate the expression of HER3 in patients with early-stage AC and ASC of the cervix. The results suggested that HER3 overexpression may be an independent risk factor for post-operative recurrence. However, these results and the prognostic value of HER3 should be confirmed in a larger sample., (Copyright: © Mizuno et al.)

Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including phosphatase and tensin homolog (PTEN) and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. The Lin28 gene is essential for cell development and pluripotency in worms and mammals. In this study, we evaluated the role of Lin28a in regulating regenerative capacity of diverse populations of CNS neurons in adult mammals. Using a neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple populations of projection neurons, including corticospinal tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in transgenic mice induces significant long distance regeneration of both corticospinal axons and the optic nerve in adult mice. Importantly, overexpression of Lin28a by post-injury treatment with adeno-associated virus type 2 (AAV2) vector stimulates dramatic regeneration of descending spinal tracts and optic nerve axons after lesions. Upregulation of Lin28a also enhances activity of the Akt signaling pathway in mature CNS neurons. Therefore, Lin28a is critical for regulating growth capacity of multiple CNS neurons and may become an important molecular target for treating CNS injuries., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Duloxetine has some effect against cancer neuropathic pain (CNP); however, predictors of duloxetine response are unclear. This study sought to identify predictors of duloxetine response in patients with CNP., Methods: Patients (N = 70) with CNP unresponsive to or intolerant of opioid-pregabalin combination therapy, with a brief pain inventory-short form (BPI-SF) Item 5 score (average pain) ≥ 4, and with a total hospital anxiety and depression scale score < 20, were randomized to a duloxetine or a placebo group. Multiple linear regression analysis was conducted to identify predictors of duloxetine response as a secondary analysis with the change in the average pain score on day 10 from day 0 as the dependent variable, and the following five covariates; baseline (day 0) average pain score, baseline opioid dose, continuation/discontinuation of pregabalin, and items 20 and 21 score of the short-form McGill pain questionnaire 2 (SF-MPQ-2) as independent variables., Results: Of the four domains (continuous pain, intermittent pain, neuropathic pain, and affective descriptors) score of SF-MPQ-2 on day 0, significant differences were observed in the neuropathic pain domain (p = 0.040) in change on the average pain between day 10 and day 0 in the duloxetine group. Multiple linear regression analysis revealed that patients with a high score for SF-MPQ-2 Item 21 (tingling pain) on day 0 had a significantly greater change in average pain between day 10 and day 0 (p = 0.046)., Conclusion: Patients with a high score for SF-MPQ-2 Item 21 might benefit more from duloxetine.

This clinical study was performed to evaluate the effects of continuous apple polyphenol (AP) administration on facial skin conditions and pigmentation induced by ultraviolet (UV) irradiation in healthy women participants. Participants (n = 65, age 20-39 years) were randomized to receive tablets containing AP (300 or 600 mg/day) or placebo in a double-blinded, placebo-controlled clinical trial. Continuous administration of AP for 12 weeks significantly prevented UV irradiation induced skin pigmentation (erythema value, melanin value, L value), although a dose-dependent relationship was not clearly observed. In contrast, no significant differences were detected between the groups with regard to water content and trans-epidermal water loss. Our study demonstrated that APs and their major active compounds, procyanidins, have several health benefits. Here, we report that continuous administration of AP for 12 weeks alleviated UV irradiation induced skin pigmentation, when compared with placebo, in healthy women.

Modulation of immune activation using immunotherapy has attracted considerable attention for many years as a potential therapeutic intervention for several inflammation-associated neurodegenerative diseases. However, the efficacy of single-target immunotherapy intervention has shown limited or no efficacy in alleviating disease burden and restoring functional capacity. Marked immune system activation and neuroinflammation are important features and prodromal signs in polyQ repeat disorders and α-synucleinopathies. This review describes the current status and future directions of immunotherapies in proteinopathy-induced neurodegeneration with emphasis on preclinical and clinical efficacies of several anti-inflammatory compounds and antibody-based therapies for the treatment of Huntington's disease and α-synucleinopathies. The review concludes with how disease modification and functional restoration could be achieved by using targeted multimodality therapy to target multiple factors., (Copyright © 2020 Fatoba, Ohtake, Itokazu and Yamashita.)

Aim: This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma., Methods: This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma., Results: The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death., Conclusion: IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

Context: Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails., Objectives: We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy., Methods: A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]-Item 5) ≥ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases., Results: Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P = 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 0.002)., Conclusion: Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ventral lesions of upper thoracic spinal cord due to degenerative diseases are rare and often have poor operative outcomes. Anterior decompression of the lesion is difficult because of the local anatomy. This retrospective study aimed to evaluate reproducible anatomic measurements for selecting the best surgical approach for anterior decompression of ventral lesions of upper thoracic spinal cord., Methods: Cases of anterior decompression of ventral lesions of upper thoracic spinal cord due to degenerative diseases at our institution from 2004 to 2015 were assessed. Several lines were drawn on magnetic resonance imaging and computed tomography scans of midsagittal sections of the upper thoracic spine to evaluate the most optimal approach for treating upper thoracic lesions. A line from the suprasternal notch to the vertebral body (suprasternal notch to vertebral body [SV] line) was accepted as baseline., Results: The caudal edge of the lesion was above the SV line in 10 cases, each of which was treated via an anterior approach without sternotomy. The caudal edge was below the SV line in 7 cases, 5 of which underwent surgery with the sternum-splitting or transthoracic approach. The other 2 lesions were approached via an obliquely deviated route without sternotomy. The SV line sometimes changed with patients' posture alterations., Conclusions: The SV line, a useful landmark for upper thoracic lesions, is not sufficiently reliable because it changes according to the patient's posture. By leaning in the direction of the surgical microscope, more caudal upper thoracic lesions can be reached than when using the SV line as a surgical landmark., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Liver kinase B1 (LKB1), a downstream effector of cyclic AMP (cAMP)/PKA and phosphatidylinositol 3-kinase (PI3K) pathways, is a determinant for migration and differentiation of many cells, but its role in CNS axon regeneration is unknown. Therefore, LKB1 was overexpressed in sensorimotor cortex of adult mice five days after mid-thoracic spinal cord injury, using an AAV2 vector. Regeneration of corticospinal axons was dramatically enhanced. Next, systemic injection of a mutant-AAV9 vector was used to upregulate LKB1 specifically in neurons. This promoted long-distance regeneration of injured corticospinal fibers into caudal spinal cord in adult mice and regrowth of descending serotonergic and tyrosine hydroxylase immunoreactive axons. Either intracortical or systemic viral delivery of LKB1 significantly improved recovery of locomotor functions in adult mice with spinal cord injury. Moreover, we demonstrated that LKB1 used AMPKα, NUAK1, and ERK as the downstream effectors in the cortex of adult mice. Thus, LKB1 may be a critical factor for enhancing the growth capacity of mature neurons and may be an important molecular target in the treatment of CNS injuries., (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

A 57-year-old female underwent abdominoperineal resection for rectal cancer. Although she received postoperative adjuvant chemotherapy, she had presacral recurrence with pain 26 months postoperatively. We provided palliative care in parallel with systemic chemotherapy, but she had difficulty controlling pain despite using high-dose opioids at 43 months after surgery. Multimodal therapy contributed to a reduction in opioid use for a brief time. Nevertheless, she required high-dose opioid therapy again at 50 months after the procedure. Since she used a rescue dose for relieving anticipatory anxiety for pain, we estimated that she developed chemical coping. After we tried analgesic adjuvant therapy and psychotherapy, her opioid use was reduced. For 10 months afterward, her disease worsened with time, but her pain was well-controlled. In cases where it is difficult to control pain, protection against exacerbation or opioid dose escalation should be considered. Furthermore, psychological contexts, including chemical coping, should also be considered. It may lead to the use of a proper dose of opioids and improve quality of life for patients.

A 66-year-old woman was referred to our institute for an enlarging tumor of the thyroid, and neck and chest computed tomography scan showed not only a thyroid tumor, but also an anterior mediastinal tumor and ground-glass nodules in the lung. Because of persisting symptoms, an enlarging thyroid mass, and the possibility of cancer, excision of the tumors was proposed. A 6-cm-long vertical skin incision was made in the right axilla, a mini-thoracotomy was made in the third intercostal space, and an additional port was placed in the fifth intercostal space. Thoracoscopic partial resection of the right upper lobe of the lung was performed first. Then, the da Vinci surgical system (da Vinci, Intuitive Surgical Inc., Sunnyvale, CA, USA) was introduced through the mini-thoracotomy. The mediastinal tumor was then excised circumferentially robotically. After resection of the lung and mediastinal tumors, the da Vinci was undocked, and a subcutaneous tunnel from the axillary incision to the thyroid was created using the flap dissection technique. The da Vinci was re-introduced through the axillary incision. A long camera port was used, and the skin and muscle flap was elevated to maintain adequate working space during the robot-assisted thyroidectomy. Total operating time was 277 min, and the patient's postoperative course was uneventful. The histopathological examinations of the lung, mediastinal, and thyroid tumors were adenocarcinoma, thymolipoma, and adenomatous goiter, respectively. In conclusion, single-incision robotic surgery for three lesions was achieved safely with good clinical results and excellent cosmetic results.

Objective: Computed tomography following myelography (CTM) revealed an unusual flow of contrast dye into the anterior median fissure (AMF) in a patient with cervical spondylotic myelopathy. Since then, several AMF configurations have been observed on CTM. Therefore, we evaluated morphological patterns of the AMF on CTM and investigated the significance and mechanisms of contrast dye flow into the AMF., Methods: Morphological patterns of the AMF on CTM were examined in 79 patients. Group A (24 patients) underwent surgery because of symptomatic cervical myelopathy. Group B (43 patients) had no clinical symptoms but showed spinal cord compression on CTM. Group C (12 patients), who showed neither clinical symptoms nor cord changes, underwent CTM for lumbar lesion evaluation. AMF patterns were classified into 4 types according to their configurations on CTM (reversed T, Y, V, and O types)., Results: In group B, the reversed T type and Y type appeared significantly more often near the compressed portion (p<0.001). A similar tendency was seen in group A. The V and O types were most frequently observed in group C (p<0.001)., Conclusion: On CTM, contrast dye tends to flow into the AMF of the cervical cord when the spinal cord is compressed. We speculate that there may be 3 possible mechanisms for this phenomenon: deformation of the epipial layer of the AMF due to cervical cord compression, AMF dilatation due to atrophy of the anterior funiculus or anterior horn, and temporary AMF dilatation when it becomes an alternative route for cerebrospinal fluid circulation.

Abnormal accumulation of the microtubule-associated protein tau is thought to cause neuronal cell death in a group of age-associated neurodegenerative disorders. Tau is phosphorylated at multiple sites in diseased brains, and phosphorylation of tau at Ser262 initiates tau accumulation and toxicity. In this study, we sought to identify novel factors that affect the metabolism and toxicity of tau phosphorylated at Ser262 (pSer262-tau). A biased screen using a Drosophila model of tau toxicity revealed that knockdown of S6K, the Drosophila homolog of p70S6K1, increased the level of pSer262-tau and enhanced tau toxicity. S6K can be activated by the insulin signaling, however, unlike knockdown of S6K, knockdown of insulin receptor or insulin receptor substrate nonselectively decreased total tau levels via autophagy. Importantly, activation of S6K significantly suppressed tau-mediated axon degeneration, whereas manipulation of either the insulin signaling pathway or autophagy did not. Our results suggest that activation of S6K may be an effective therapeutic strategy for selectively decreasing the levels of toxic tau species and suppressing neurodegeneration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Bone metastases from endometrial cancer are rare. To our knowledge, only 2 cases of solitary vertebral metastases from endometrial cancer presenting with osseous and/or neurologic symptoms before the diagnosis of the primary endometrial cancer have been reported; however, in both cases, the metastases were thoracic. Thus, cervical vertebral metastases are extremely rare., Case Description: We describe the case of a 55-year-old woman who presented with right C6 radicular and neck pain. Neurologic imaging showed destruction of the C6 vertebral body by an extradural mass with kyphotic changes in the cervical spine. Fluorodeoxyglucose positron emission tomography showed increased uptake in the enlarged body of the uterus as well as the C6 vertebral body. Additional pelvic magnetic resonance images and endometrial biopsy confirmed endometrial cancer. The patient underwent excision of the cervical tumor with anterior reconstruction and posterior fixation followed 1 month later by semiradical hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymph node dissection. The cervical and endometrial histopathologic findings were similar, and the final diagnosis made was cervical metastatic adenocarcinoma originating from an endometrial cancer., Conclusions: We describe an extremely rare case of a precocious solitary cervical metastasis from an endometrial cancer presenting as cervical radicular pain. In our review of published reports, we found that solitary spinal metastases are significantly associated with longer overall survival than are multiple lesions. Resection of the spinal lesion with rigid spinal reconstruction followed by radical hysterectomy may be beneficial in such patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tyrosine phosphorylation is a common means of regulating protein functions and signal transduction in multiple cells. Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes that remove phosphate groups from tyrosine residues of target proteins and change their functions. Among them, receptor-type PTPs (RPTPs) exhibit a distinct spatial pattern of expression and play essential roles in regulating neurite outgrowth, axon guidance, and synaptic organization in developmental nervous system. Some RPTPs function as essential receptors for chondroitin sulfate proteoglycans that inhibit axon regeneration following CNS injury. Interestingly, certain RPTPs are also important to regulate functions of immune cells and development of autoimmune diseases. PTPσ, a RPTP in the LAR subfamily, is expressed in various immune cells and regulates their differentiation, production of various cytokines and immune responses. In this review, we highlight the physiological and pathological significance of PTPσ and related molecules in both nervous and immune systems., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca 2+ ) oscillations at an injured site is critical for the regulation of regenerative responses. In polarized neurons, distal axonal segments contain a well-developed endoplasmic reticulum (ER) network that is responsible for Ca 2+ homeostasis. Although these characteristics implicate the relevance among injury-induced Ca 2+ dynamics, axonal ER-derived signaling, and regenerative responses propagated along the axons, the details are not fully understood. In the present study, we found that Ca 2+ release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca 2+ release from the ER activated unfolded protein response (UPR) signaling at injured sites. Inhibition of axonal UPR signaling led to fragmentation of the axonal ER and disrupted growth cone formation, suggesting that activation of axonal UPR branches following axonal injury promotes regeneration via regulation of ER reconstruction and formation of growth cones. Our studies revealed that local activation of axonal UPR signaling by injury-induced Ca 2+ release from the ER is critical for regeneration. These findings provide a new concept for the link between injury-induced signaling at a distant location and regulation of organelle and cytoskeletal formation in the orchestration of axonal regeneration., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We identified 37 ubiquitin ligases containing RING-finger and transmembrane domains. Of these, we found that RNF183 is abundantly expressed in the kidney. RNF183 predominantly localizes to the endoplasmic reticulum (ER), Golgi, and lysosome. We identified Sec16A, which is involved in coat protein complex II vesicle formation, as an RNF183-interacting protein. RNF183 colocalized with Sec16A and interacted through the central conserved domain (CCD) of Sec16A. Although Sec16A is not a substrate for RNF183, RNF183 was more rapidly degraded by the ER-associated degradation (ERAD) in the absence of Sec16A. Sec16A also stabilized the interacting ubiquitin ligase RNF152, which localizes to the lysosome and has structural similarity with RNF183. These results suggest that Sec16A appears to regulate the protein stability and localization of lysosomal ubiquitin ligases.

Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box-binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity- and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159., (© 2017 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Abnormal deposition of the microtubule-associated protein tau is a common pathological feature of multiple neurodegenerative diseases, including Alzheimer's disease (AD), and plays critical roles in their pathogenesis. Disruption of calcium homeostasis and the downstream kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) coincides with pathological phosphorylation of tau in AD brains. However, it remains unclear whether and how dysregulation of CaMKII affects tau toxicity. Using a Drosophila model, we found that CaMKII promotes neurodegeneration caused by tau phosphorylated at the AD-associated sites Ser262/356. Overexpression of CaMKII promoted, while RNA-mediated knockdown of CaMKII and inhibition of CaMKII activity by expression of an inhibitory peptide suppressed, tau-mediated neurodegeneration. Blocking tau phosphorylation at Ser262/356 by alanine substitutions suppressed promotion of tau toxicity by CaMKII, suggesting that tau phosphorylation at these sites is required for this phenomenon. However, neither knockdown nor overexpression of CaMKII affected tau phosphorylation levels at Ser262/356, suggesting that CaMKII is not directly involved in tau phosphorylation at Ser262/356 in this model. These results suggest that a pathological cascade of events, including elevated levels of tau phosphorylated at Ser262/356 and aberrant activation of CaMKII, work in concert to promote tau-mediated neurodegeneration., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Protein tyrosine phosphatases (PTPs) play essential roles in regulating signaling events in multiple cells by tyrosine dephosphorylation. One of them, PTPσ, appears important in regulating function of plasmacytoid dendritic cells (pDC). Here we report that PTPσ deletion in knockout mice and inhibition with a selective antagonist peptide exacerbated symptoms of experimental autoimmune encephalomyelitis (EAE) by enhancing axon and myelin damage in the spinal cord. PTPσ-/- mice displayed pro-inflammatory profiles in the spinal cord and lymphoid organs following MOG peptide immunization. PTPσ deletion promoted a pro-inflammatory phenotype in conventional DCs and directly regulated differentiation of CD4+ T cells. It also facilitated infiltration of T lymphocytes, activation of macrophages in the CNS and development of EAE. Therefore, PTPσ is a key negative regulator in EAE initiation and progression, which acts by regulating functions of DCs, T cells, and other immune cells. PTPσ may become an important molecular target for treating autoimmune disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Design: prospective study OBJECTIVE:To evaluate repeatability of residual urine(RU)volume measurement(RUM)in patients with lumbar degenerative disorders., Summary of Background Data: RUM by abdominal echo is a non-invasive modality to evaluate lower urinary tract disorder(LUTD), repeatability of which is not found in urological disorders. Additionally, its repeatability has not been confirmed in spinal disorders. The authors examined repeatability of RUM for evaluation of LUTD in patients with lumbar degenerative disorders., Methods: Thirty-four patients with lumbar degenerative disorders and 7 normal adult volunteers entered our study. RUM was performed at least twice(two to seven times; average 3.6 times). According to urological guidelines, RU over 50 cc is defined as abnormal. Thirty-four patients were divided into two groups:the U+group with lower urinary tract lesion(16 patients)and the U-group without such a lesion(18 patients)., Results: In normal adult volunteers:In all volunteers, there was no abnormal RU. Repeatability of RUM was 100%. Average RU volume was 1.6 cc. In patients with lumbar degenerative disorders:Repeatability of RUM was 94.4% in the U-group(average RU volume was 35.2 cc)and 50% in the U+group(average RU volume was 50.1 cc). In all patients with lumbar degenerative disorders, repeatability of RUM was 73.5%(average RU volume was 43.0 cc)., Conclusions: Repeatability of RUM in patients with lumbar degenerative disorders was 73.5%. Especially, in patients without lower urinary tract lesion, high repeatability of RUM was confirmed. According to the present study, RUM seemed to be a dependable modality to evaluate LUTD in patients with lumbar degenerative disorders.

Carnitine deficiency is reportedly associated with increased pain sensation in diabetes mellitus and fibromyalgia, but the association between serum carnitine concentration and cancer pain has not been fully elucidated. We investigated the incidence of carnitine deficiency in patients with cancer pain, and examined the effect of the patients' demographic and clinical characteristics on pain intensity and carnitine deficiency. The serum carnitine concentration was measured in 50 patients with cancer pain receiving non-steroidal anti-inflammatory drugs, but not opioids. Multivariate regression analysis was used to determine the association of carnitine concentration, pain intensity, age and gender with hemoglobin and C-reactive protein (CRP) concentrations. Carnitine deficiency was detected in 9 of the patients (18.0%) and found to be significantly correlated with an elevated CRP concentration (P=0.039). In conclusion, although there does not appear to be an association between carnitine deficiency and cancer pain, it may be affected by inflammation or infection.

Secretory and membrane proteins are synthesized in ribosomes, then mature in the endoplasmic reticulum (ER), but if ER function is impaired, immature defective proteins accumulate in the ER. This situation is called ER stress: in response, a defensive mechanism called the unfolded protein response (UPR) is activated in cells to reduce the defective proteins. During the UPR, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and RNA-dependent protein kinase (PKR)-like ER kinase (PERK) are activated, stress signals are transduced to the outside of the ER, and various cell responses, including gene induction, occur. In ER-associated degradation (ERAD), one type of UPR, defective proteins are eventually expelled from the ER and degraded in the cytoplasm through the ubiquitin proteasome system. Since ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer, it is the focus of increased attention from the perspectives of elucidating pathogenic mechanisms, and in the development of therapeutics.

Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.

Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The first complete genome sequence of Lactobacillus curvatus was determined by PacBio RS II. The single circular chromosome (1,848,756 bp, G+C content of 42.1%) of L. curvatus FBA2, isolated from fermented vegetables, contained low G+C regions (26.9% minimum) and 43 sets of >1,000-bp identical sequence pairs. No plasmids were detected., (Copyright © 2016 Nakano et al.)

Instrumented lumbar fusion can provide immediate stability and assist in satisfactory arthrodesis in patients who have pain or instability of the lumbar spine. Lumbar adjunctive fusion with decompression is often a good procedure for surgical management of degenerative spondylolisthesis (DS). Among various lumbar fusion techniques, lumbar interbody fusion (LIF) has an advantage in that it maintains favorable lumbar alignment and provides successful fusion with the added effect of indirect decompression. This technique has been widely used and represents an advancement in spinal instrumentation, although the rationale and optimal type of LIF for DS remains controversial. We evaluated the current status and role of LIF in DS treatment, mainly as a means to augment instrumentation. We addressed the basic concept of LIF, its indications, and various types including minimally invasive techniques. It also has acceptable biomechanical features, and offers reconstruction with ideal lumbar alignment. Postsurgical adverse events related to each LIF technique are also addressed.

Instrumented spinal fixation is ordinarily required in patients who present with myelopathy or cauda equina syndrome secondary to vertebral collapse following osteoporotic thoracolumbar fracture. Posterior spinal fixation is a major surgical option, and partial vertebral osteotomy (PVO) through a posterior approach is occasionally reasonable for achievement of complete neural decompression and improvement of excessive local kyphosis. However, the indications and need for PVO remain unclear. The objectives of this retrospective study were to determine the efficacy and safety of posterior spinal fixation with or without PVO for osteoporotic thoracolumbar vertebral collapse and identify patients who require neural decompression and alignment correction by PVO. We retrospectively reviewed the clinical records of 20 patients (13 females, 7 males; mean age, 67.1 years) who underwent instrumented posterior fixation for osteoporotic thoracolumbar vertebral fracture. Clinical outcomes were assessed by the Japanese Orthopedic Association score and visual analog scale scores in the lumbar and leg areas. PVO was added with posterior spinal fixation in eight patients because neural decompression was incomplete after laminectomy as indicated by intraoperative echo imaging. Neurological and functional recovery significantly improved during follow-up. Clinical outcomes in patients who underwent PVO were similar to those in patients who did not undergo PVO. However, correction of the local kyphotic angle and improvement of spinal canal compromise after surgery was significant in patients who underwent PVO. The patients who required PVO had a less local kyphotic angle in the supine position and higher occupation rate of the fractured fragment in the spinal canal in the preoperative examination.

Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states.