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Objective: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice., Methods: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients)., Results: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure., Conclusions: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study., Methods: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses., Results: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection., Conclusions: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months., Study Identifier: NCT01932372., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

The quantification of stomatal pore size has long been a fundamental approach to understand the physiological response of plants in the context of environmental adaptation. Automation of such methodologies not only alleviates human labor and bias but also realizes new experimental research methods through massive analysis. Here, we present an image analysis pipeline that automatically quantifies stomatal aperture of Arabidopsis thaliana leaves from bright-field microscopy images containing mesophyll tissue as noisy backgrounds. By combining a You Only Look Once X-based stomatal detection submodule and a U-Net-based pore segmentation submodule, we achieved a mean average precision with an intersection of union (IoU) threshold of 50% value of 0.875 (stomata detection performance) and an IoU of 0.745 (pore segmentation performance) against images of leaf discs taken with a bright-field microscope. Moreover, we designed a portable imaging device that allows easy acquisition of stomatal images from detached/undetached intact leaves on-site. We demonstrated that this device in combination with fine-tuned models of the pipeline we generated here provides robust measurements that can substitute for manual measurement of stomatal responses against pathogen inoculation. Utilization of our hardware and pipeline for automated stomatal aperture measurements is expected to accelerate research on stomatal biology of model dicots., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To assess the safety and effectiveness of baricitinib treatment for rheumatoid arthritis (RA) in real-world clinical practice., Methods: This ongoing all-case post-marketing surveillance study (starting September 2017) includes all patients with RA treated with baricitinib in Japan. Safety and effectiveness (disease activity) were assessed for 24 weeks., Results: Safety analyses to February 2021 included 4731 patients (initial baricitinib dose: 4 mg/day, n = 3058; 2 mg/day, n = 1661; other, n = 12); 1059 (22.38%) were ≥75 years and 3362 (71.06%) previously received biologic therapy. The overall observational period was 1863.14 patient-years; 1174 (24.82%) patients discontinued baricitinib before Week 24, mostly for lack of effectiveness (n = 478; 10.10%). Adverse events occurred in 1271 (26.87%) patients [serious: 203 (4.29%); death: 18 (0.38%)]. The incidence of herpes zoster, hepatic function disorder, and serious infection was 3.09%, 2.77%, and 1.90%, respectively. Malignancy occurred in 17 patients (0.36%) and major adverse cardiovascular events in seven patients (0.15%). Among patients with effectiveness data, at least 26.57% (Boolean) achieved remission at Week 24., Conclusions: This large nationwide surveillance study evaluated the safety and effectiveness of 24 weeks of baricitinib for RA in real-world clinical practice. Continued surveillance of long-term safety is ongoing., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Patients with secondary adrenal insufficiency can present with impaired free water excretion and hyponatremia, which is due to the enhanced secretion of vasopressin (AVP) despite increased total body water. AVP is produced in magnocellular neurons in the paraventricular nucleus of the hypothalamus (PVH) and supraoptic nucleus and in parvocellular corticotropin-releasing factor (CRF) neurons in the PVH. This study aimed to elucidate whether magnocellular AVP neurons or parvocellular CRF neurons coexpressing AVP are responsible for the pathogenesis of hyponatremia in secondary adrenal insufficiency. The number of CRF neurons expressing copeptin, an AVP gene product, was significantly higher in adrenalectomized AVP-floxed mice (AVPfl/fl) than in sham-operated controls. Adrenalectomized AVPfl/fl mice supplemented with aldosterone showed impaired water diuresis under ad libitum access to water or after acute water loading. They became hyponatremic after acute water loading, and it was revealed under such conditions that aquaporin-2 (AQP2) protein levels were increased in the kidney. Furthermore, translocation of AQP2 to the apical membrane was markedly enhanced in renal collecting duct epithelial cells. Remarkably, all these abnormalities observed in the mouse model for secondary adrenal insufficiency were ameliorated in CRF-AVP-/- mice that lacked AVP in CRF neurons. Our study demonstrates that CRF neurons in the PVH are responsible for the pathogenesis of impaired water excretion in secondary adrenal insufficiency., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40-41.4 Gy (relative biological effectiveness (RBE) delivered in 20-23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8-36.3 Gy (RBE) delivered in 10-14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57-84.8% in OS, 39-78% in PFS and 51-68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objectives: We have hypothesized that an endoscopically assisted transaxillary approach in the zero position would be able to improve visualization and allow safe surgery for thoracic outlet syndrome., Methods: We performed surgery only for patients with certain objective findings, including blood flow disruption, low blood flow and accelerated blood flow in the subclavian artery demonstrated using Doppler sonography, narrowing of the scalene interval width between the anterior and middle interscalene muscles (interscalene base) or costoclavicular space demonstrated using Duplex ultrasonography or computed tomography angiography. The present study included 45 consecutive patients (50 limbs) who underwent endoscopic transaxillary first rib resection with scalenotomy and brachial plexus neurolysis. We assessed the intraoperative parameters, including the interscalene base, blood loss, operation time, patient satisfaction, preoperative and postoperative Quick Disability of the Arm, Shoulder and Hand and complications., Results: The mean intraoperatively measured interscalene base width was 6.4 mm. All patients showed improvement after surgery. The outcome was excellent in 40% of cases, good in 48%, fair in 12% and poor in none. Pneumothorax was present in 6%. There were no other complications and no recurrences. Among patients who had been followed up for at least 2 years, the Quick Disability of the Arm, Shoulder and Hand score was significantly improved (42 before surgery vs 12 at final follow-up), especially in athletes relative to non-athletes (0.2 vs 16). The present approach achieved complete relief in 43% of cases overall (91% in athletes and 16% in non-athletes)., Conclusions: Endoscopically assisted transaxillary first rib resection and brachial plexus neurolysis in the zero position are useful and safe for thoracic outlet syndrome, especially in athletes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objective: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-ax SpA), and the positivity rate of human leukocyte antigen (HLA) among such patients in Japan., Methods: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September 2018, where the patients with AS/nr-ax SpA were taken care of from January to December 2017. We estimated the total number of these patients using response and extraction rates. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B27 positivity rate and clinical features., Results: The estimated total numbers of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence values of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5% (76/137) of patients with AS were HLA-B27-positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing., Conclusion: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Aims: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability., Methods and Results: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves., Conclusion: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex., Methods: The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by an in situ proximity ligation assay (PLA) with immunofluorescence. HO-1 mRNA was investigated by reverse transcription-polymerase chain reaction., Results: The number of HO-1 + cells from the RA synovium is higher than that from OA synovium. The double positive cells of HO-1 and IgG-Fc/HLA-DR complex were detected by the in situ PLA with immunofluorescence in RA synovium. HO-1 mRNA was detected in both RA and OA synovium., Conclusion: A portion of HO-1 + cells with IgG-Fc/HLA-DR complex in lining layer of RA may be concluded as one of antigen presenting cells in RA and may be involved in production of RF.

A mutant lager strain resistant to the cell wall-perturbing agent Congo red (CR) was isolated and the genetic alterations underlying CR resistance were investigated by whole genome sequencing. The parental lager strain was found to contain three distinct Saccharomyces cerevisiae (Sc)-type CHS6 (CHitin Synthase-related 6) alleles, two of which have one or two nonsense mutations in the open reading frame, leaving only one functional allele, whereas the functional allele was missing in the isolated CR-resistant strain. On the other hand, the Saccharomyces eubayanus-type CHS6 alleles shared by both the parental and mutant strains appeared to contribute poorly to chitin synthase-activating function. Therefore, the CR resistance of the mutant strain was attributable to the overall compromised activity of CHS6 gene products. The CR-resistant mutant cells exhibited less chitin production on the cell surface and smaller amounts of mannoprotein release into the medium. All these traits, in addition to the CR resistance, were complemented by the functional ScCHS6 gene. It is of great interest whether the frequent nonsense mutations found in ScCHS6 open reading frame in lager yeast strains are a consequence of the domestication process of lager yeast., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

The molecular mechanism regulating sleep largely remains to be elucidated. In humans, families that carry mutations in TFAP2B , which encodes the transcription factor AP-2β, self-reported sleep abnormalities such as short-sleep and parasomnia. Notably, AP-2 transcription factors play essential roles in sleep regulation in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster Thus, AP-2 transcription factors might have a conserved role in sleep regulation across the animal phyla. However, direct evidence supporting the involvement of TFAP2B in mammalian sleep was lacking. In this study, by using the CRISPR/Cas9 technology, we generated two Tfap2b mutant mouse strains, Tfap2b K144 and Tfap2b K145 , each harboring a single-nucleotide mutation within the introns of Tfap2b mimicking the mutations in two human kindreds that self-reported sleep abnormalities. The effects of these mutations were compared with those of a Tfap2b knockout allele ( Tfap2b - ). The protein expression level of TFAP2B in the embryonic brain was reduced to about half in Tfap2b +/- mice and was further reduced in Tfap2b -/- mice. By contrast, the protein expression level was normal in Tfap2b K145/+ mice but was reduced in Tfap2b K145/K145 mice to a similar extent as Tfap2b -/- mice. Tfap2b K144/+ and Tfap2b K144/K144 showed normal protein expression levels. Tfap2b +/- female mice showed increased wakefulness time and decreased nonrapid eye movement sleep (NREMS) time. By contrast, Tfap2b K145/+ female mice showed an apparently normal amount of sleep but instead exhibited fragmented NREMS, whereas Tfap2b K144/+ male mice showed reduced NREMS time specifically in the dark phase. Finally, in the adult brain, Tfap2b-LacZ expression was detected in the superior colliculus, locus coeruleus, cerebellum, and the nucleus of solitary tract. These findings provide direct evidence that TFAP2B influences NREMS amounts in mice and also show that different mutations in Tfap2b can lead to diverse effects on sleep architecture., (Copyright © 2020 by the Genetics Society of America.)

In Arabidopsis thaliana, a mitogen-activated protein kinase pathway, MEKK1-MKK1/MKK2-MPK4, is important for basal resistance and disruption of this pathway results in dwarf, autoimmune phenotypes. To elucidate the complex mechanisms activated by the disruption of this pathway, we have previously developed a mutant screening system based on a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Here, we report that the second group of mutants, smn2, had defects in the SMN2 gene, encoding a DEAD-box RNA helicase. SMN2 is identical to HEN2, whose function is vital for the nuclear RNA exosome because it provides non-ribosomal RNA specificity for RNA turnover, RNA quality control and RNA processing. Aberrant SMN1/RPS6 transcripts were detected in smn2 and hen2 mutants. Disease resistance against Pseudomonas syringae pv. tomato DC3000 (hopA1), which is conferred by SMN1/RPS6, was decreased in smn2 mutants, suggesting a functional connection between SMN1/RPS6 and SMN2/HEN2. We produced double mutants mekk1smn2 and mpk4smn2 to determine whether the smn2 mutations suppress the dwarf, autoimmune phenotypes of the mekk1 and mpk4 mutants, as the smn1 mutations do. As expected, the mekk1 and mpk4 phenotypes were suppressed by the smn2 mutations. These results suggested that SMN2 is involved in the proper function of SMN1/RPS6. The Gene Ontology enrichment analysis using RNA-seq data showed that defense genes were downregulated in smn2, suggesting a positive contribution of SMN2 to the genome-wide expression of defense genes. In conclusion, this study provides novel insight into plant immunity via SMN2/HEN2, an essential component of the nuclear RNA exosome., (© The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most radiation protection items made from modern lead contain 210Pb. This study estimated the impact on eye lens of radiation derived from the 210Pb in three types of radiation protection glasses. The counts from the glasses were measured using a Geiger-Müeller survey meter. The net count rate was 92 ± 1 cpm at a distance of 0.5 cm for one type of glasses. Additionally, we conducted a qualitative γ-ray spectrum analysis using a high-purity germanium semiconductor detector. The absorbed dose in the eye lens was related to 210Pb and its daughter radionuclide, 210Bi; this dose was calculated by applying dose conversion coefficients provided by the International Commission on Radiological Protection. The absorbed dose rate in eye lens was conservatively calculated to be on the order of 10 nGy/h for the type of glasses containing the most 210Pb. The dose from β-rays accounted for >99%. In addition, we investigated the dose-reduction effect using a thin acrylic plate. The count rate approximately decreased to background level by inserting a plate with a thickness of 1 mm. We conclude that the impact of 210Pb contained in radiation protection glasses is negligibly small, particularly considering the usefulness of the significant external exposure reduction., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Gouty tophi occur less frequently and disappear only with modern medication therapy for symptomatic or asymptomatic hyperuricaemia. However, the medication may require a long time to take effect due to the systemic urate pool associated with massive gouty tophi. We present the case of a 37-year-old woman who suffered from massive gouty tophi of both feet due to hyperuricaemia. After resection of the massive gouty tophi from her right foot and treatment with uricemia medication, the gouty tophi of her opposite foot disappeared rapidly due to reducing the patient's systemic urate pool with intensification of drug medication.

Prosthetic joint surgeries, total hip arthroplasty (THA) or bipolar hemiarthroplasty (BHA) and joint preservation surgeries can be performed for avascular osteonecrosis of femoral head (ONFH) with collapse. Although excellent surgical results have been reported, long-term survivorship and postoperative complications are a great concern. The purpose of this study was to report a case of bilateral disassembly of bipolar heads within 10 years after BHA for ONFH. A 61-year-old man, whose occupation was carpenter, underwent bilateral BHA for ONFH at another hospital when he was 57 years old. He had acute right hip pain during working and visited our institute. Radiographs revealed intra-articular (outer and inner head) disassembly of the right bipolar head, and conversion to THA was performed. Five years later, he had contralateral (left) hip pain. Radiographs revealed disassembly of bipolar head, as had occurred with the right hip, and similar conversion surgery was performed for the left hip. Marked wear and detachment of the polyethylene bearings of the outer head and failure of the locking mechanism between a skirted 22-mm-diameter inner head and polyethylene insert were observed in both hips at each revision surgery. Degeneration of the acetabulum were also observed in both hips. The failure of the self-centering mechanism because of degenerative change of the acetabulum, impingement of the outer head and neck, and high activity seemed to be the causes of disassembly of the bilateral bipolar heads. Therefore, it is important to select the type of prostheses depending on the age, activity and occupation of each patient.

Alpha-defensin (αD), an antimicrobial peptide released by neutrophils in response to bacterial pathogens, was proposed as a novel diagnostic biomarker in synovial fluid. Several reports have shown that αD can serve as a reliable biomarker in the diagnosis of periprosthetic joint infection (PJI). We assessed whether αD could also serve to diagnosis of septic arthritis, a similarly difficult to diagnose PJI. To our knowledge, besides PJI, few reports exist assessing the utility of αD for septic arthritis. We have attempted to diagnose several cases of suspected septic arthritis using the Synovasure ® αD detection lateral flow device. We report a false-positive case and a false-negative case. The false-negative case we experienced was caused by Staphylococcus capitis , which is coagulase-negative, and possibly represents a low virulence micro-organism infection. The false-positive case was ultimately diagnosed as seronegative rheumatoid arthritis and possessed calcium pyrophosphate depositions. False positives have been suggested to occur in conditions where neutrophils are mobilised. As for PJI, in cases where diagnosis is difficult, αD can be an additional diagnostic indicator. However, making a definitive diagnosis using the αD lateral flow device alone was found to be difficult. The utility of αD in assessing septic arthritis is inconclusive; therefore, larger prospective clinical studies should be considered for a better assessment.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce., Methods and Results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built., Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Mitogen-activated protein kinase (MAPK) pathways have a pivotal role in innate immunity signaling in plants. In Arabidopsis, the MAPK pathway that consists of MEKK1, MKK1/MKK2 and MPK4 is involved in pattern-triggered immunity signaling upstream of defense gene expression. This pathway is partly guarded by SUMM2, a nucleotide-binding domain leucine-rich repeat (NLR) protein, which is activated by disruption of the MAPK pathway. To identify other components required for the guard mechanism, here we developed a new mutant screening system utilizing a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Mutants with suppression of the dwarf, autoimmune phenotypes were identified, and one locus responsible for the phenotype was designated as suppressor of MEKK1N overexpression-induced dwarf 1 (SMN1). MutMap analysis revealed that SMN1 encodes the Toll/Interleukin-1 receptor (TIR)-class NLR protein RPS6, a previously identified resistant protein against bacterial pathogen Pseudomonas syringae pv. tomato expressing the HopA1 effector. Importantly, mutations in SMN1/RPS6 also partially suppressed the dwarf, autoimmune phenotypes of mekk1 and mpk4 plants. Our results suggest that the two structurally distinct NLR proteins, SMN1/RPS6 and SUMM2, monitor integrity of the MEKK1-MKK1/MKK2-MPK4 pathway., (� The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Although right ventricular septal pacing is thought to be more effective in minimizing pacing-induced left ventricular dysfunction, the accurate way to anchor the lead to the right ventricular septum (RVS) has not been established. Our aim was to clarify the usefulness of right ventriculography (RVG) to aid accurate anchoring of the lead to the RVS., Methods and Results: Eighty-four patients who underwent pacemaker implantation were enrolled. We anchored the lead to the RVS by using an RVG image obtained at a 30° right anterior oblique view as a reference. We confirmed the actual lead position by performing computed tomography after the procedure and examined the characteristics of the paced QRS complex. Of the 81 patients, except 3 patients whose leads were anchored to the apex due to high pacing thresholds in the RVS, the leads were successfully anchored to the RVS in the 79 (98%) patients, and the number of leads placed in the high-, mid-, and low-RVS was 3 (4%), 58 (73%), and 18 (23%), respectively. The paced QRS duration in these 79 patients was 140 ± 13 ms. The paced QRS duration from mid-RVS was considerably narrower than that from high- or low-RVS (137 ± 12 ms vs. 146 ± 12 ms; P = 0.012)., Conclusion: Right ventriculography was very useful in aiding accurate anchoring of the lead to the RVS. Further, pacing from mid-RVS may be more effective in minimizing the QRS duration than pacing from other RVS sites.

Aims: The prognostic value of programmed electrical stimulation (PES) in Brugada syndrome (BrS) remains controversial. One of the reasons for discrepant results may be due to the selection of stimulation protocol. We evaluated the prognostic value of a positive PES result (PES+) according to the inducible pacing sites and the number of extra-stimuli in BrS patients without previous cardiac arrest (CA)., Methods and Results: We enrolled 224 consecutive BrS patients without previous CA (mean age 51 ± 14 years, 209 males), who underwent PES with the identical protocol. Clinical outcomes of development of CA were explored in the patients with and without PES+ according to sites and number of extra-stimuli. During a mean follow-up period of 76 months, 12 cardiac events (CE: sudden cardiac death or documented VF) occurred (8 with and 4 without PES+). The incidence of CE was not different in patients with and without PES+, those with PES+ from RVA (n = 72) or RVOT (n = 60), and those with and without PES+ by up to 2 extra-stimuli (n = 58). However, in patients that were PES+ by a single extra-stimulus (n = 8) the incidence of CE was significantly higher than in those without PES+ (8.8 vs. 0.6%/year, P < 0.0001). On univariate analysis, syncope, spontaneous type 1 ECG, and PES+ by a single extra-stimulus were associated with CE., Conclusion: Details of the stimulation protocol may be important for risk assessment in BrS patients without previous CA. A single extra-stimulus may be useful in stratifying risk in patients with spontaneous type 1 ECG and syncope.

Aims: Patients with the Brugada type 1 ECG (Br type 1) without previous aborted sudden death (aSD) who do not have a prophylactic ICD constitute a very large population whose outcome is little known. The objective of this study was to evaluate the risk of SD or aborted SD (aSD) in these patients., Methods and Results: We conducted a meta-analysis and cumulative analysis of seven large prospective studies involving 1568 patients who had not received a prophylactic ICD in primary prevention. Patients proved to be heterogeneous. Many were theoretically at low risk, in that they had a drug-induced Br type 1 (48%) and/or were asymptomatic (87%), Others, in contrast, had one or more risk factors. During a mean/median follow-up ranging from 30 to 48 months, 23 patients suffered SD and 1 had aSD. The annual incidence of SD/aSD was 0.5% in the total population, 0.9% in patients with spontaneous Br type 1 and 0.08% in those with drug-induced Br type 1 (P = 0.0001). The paper by Brugada et al. reported an incidence of SD more than six times higher than the other studies, probably as a result of selection bias. On excluding this paper, the annual incidence of SD/aSD in the remaining 1198 patients fell to 0.22% in the total population and to 0.38 and 0.06% in spontaneous and drug-induced Br type 1, respectively. Of the 24 patients with SD/aSD, 96% were males, the mean age was 39 ± 15 years, 92% had spontaneous Br type 1, 61% had familial SD (f-SD), and only 18.2% had a previous syncope; 43% had a positive electrophysiological study. Multiple meta-analysis of individual trials showed that spontaneous Br type 1, f-SD, and previous syncope increased the risk of SD/aSD (RR 2.83, 2.49, and 3.03, respectively). However, each of these three risk factors had a very low positive predictive value (PPV) (1.9-3.3%), while negative predictive values (NPV) were high (98.5-99.7%). The incidence of SD/aSD was only slightly higher in patients with syncope than in asymptomatic patients (2% vs. 1.5%, P = 0.6124). Patients with SD/aSD when compared with the others had a mean of 1.74 vs. 0.95 risk factors (P = 0.026)., Conclusion: (i) In patients with Br type 1 ECG without an ICD in primary prevention, the risk of SD/aSD is low, particularly in those with drug-induced Br type 1; (ii) spontaneous Br type 1, f-SD, and syncope increase the risk. However, each of these risk factors individually has limited clinical usefulness, owing to their very low PPV; (iii) patients at highest risk are those with more than one risk factor.

Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern., Methods and Results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%)., Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Neuroblastoma (NB) is the most common solid tumor found in children, and deletions within the 11q region are observed in 11% to 48% of these tumors. Notably, such tumors are associated with poor prognosis; however, little is known regarding the molecular targets located in 11q., Methods: Genomic alterations of ATM , DNA damage response (DDR)-associated genes located in 11q ( MRE11A, H2AFX , and CHEK1 ), and BRCA1, BARD1, CHEK2, MDM2 , and TP53 were investigated in 45 NB-derived cell lines and 237 fresh tumor samples. PARP (poly [ADP-ribose] polymerase) inhibitor sensitivity of NB was investigated in in vitro and invivo xenograft models. All statistical tests were two-sided., Results: Among 237 fresh tumor samples, ATM, MRE11A, H2AFX , and/or CHEK1 loss or imbalance in 11q was detected in 20.7% of NBs, 89.8% of which were stage III or IV. An additional 7.2% contained ATM rare single nucleotide variants (SNVs). Rare SNVs in DDR-associated genes other than ATM were detected in 26.4% and were mutually exclusive. Overall, samples with SNVs and/or copy number alterations in these genes accounted for 48.4%. ATM-defective cells are known to exhibit dysfunctions in homologous recombination repair, suggesting a potential for synthetic lethality by PARP inhibition. Indeed, 83.3% NB-derived cell lines exhibited sensitivity to PARP inhibition. In addition, NB growth was markedly attenuated in the xenograft group receiving PARP inhibitors (sham-treated vs olaprib-treated group; mean [SD] tumor volume of sham-treated vs olaprib-treated groups = 7377 [1451] m 3 vs 298 [312] m 3 , P = .001, n = 4)., Conclusions: Genomic alterations of DDR-associated genes including ATM, which regulates homologous recombination repair, were observed in almost half of NBs, suggesting that synthetic lethality could be induced by treatment with a PARP inhibitor. Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aims: Left ventricular (LV) diastolic function assessed by tissue Doppler imaging (TDI) is reported to be associated with left atrial (LA) blood stasis in patients with non-valvular atrial fibrillation (AF). This study aimed to evaluate the relationship of diastolic TDI parameters with silent brain infarction (SBI) on brain magnetic resonance imaging (MRI), and in turn the risks of subsequent stroke or dementia, in non-valvular AF patients., Methods and Results: The study population consisted of 171 neurologically asymptomatic patients with non-valvular AF who underwent transoesophageal echocardiography (TOE) (128 men; mean age, 63 ± 11 years). We measured diastolic TDI parameters by transthoracic echocardiography, and also screened for SBI employing brain MRI. Early transmitral flow velocity (E) and mitral annular velocity by TDI (e') were measured, and E/e' ratios were calculated. An increased tertile of the E/e' ratio was significantly related to high prevalences of LA abnormalities detected by TOE (32% vs. 12% vs. 9%; P =0.002) and SBI on brain MRI (46% vs. 23% vs. 14%; P < 0.001). In multivariate logistic regression analyses after adjustment for age, hypertension, chronic kidney disease, and CHA2DS2-VASc score ≥2, the E/e' ratio ≥12.4 was found to be an independent predictor of the presence of SBI (OR 3.98, 95% CI 1.74-9.07; P = 0.001)., Conclusions: Impaired LV diastolic function evaluated by increased E/e' ratio was closely associated with the presence of SBI independent of CHA2DS2-VASc score. TDI measurements are non-invasive and useful for risk stratification of the early stage of cerebral damages in patients with non-valvular AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Context: Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings., Objective: To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients., Methods: We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics., Results: We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency., Conclusions: Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients., (© 2017 European Society of Endocrinology.)

With the aim to increase type II collagen content in the scaffold-free cartilage-like cell sheet using human bone marrow mesenchymal stem cells, we examined the effect of epigallocatechin-3-gallate (EGCG) addition to the chondrogenic medium for the cell sheet culture. The addition of EGCG (10 μM) increased the content of type II collagen 2-fold, while the addition did not markedly change the expression level of the genes encoding type II collagen and Sox 9. The reactive oxygen species level in the cells in cell sheets was thought to be too low to suppress the accumulation of type II collagen. On the other hand, the addition of EGCG markedly decreased both the matrix metalloproteinase-13 concentration in the supernatant of cell sheet culture and the type II collagen degradation activity in that supernatant. Taken together, EGCG may enhance the accumulation of type II collagen by suppressing type II collagen degradation.

The effects of epigallocatechin-3-o-gallate (EGCG) and quercetin on the contents of extracellular matrix (ECM) in porcine cartilage at 4 °C were investigated. The addition of quercetin at 0.01 mM for the incubation of porcine cartilage disks at 4 °C for 2 week could suppress the decrease in ECM and the compliance of the disks, markedly greater than those of EGCG (1.0 mM).

Japanese encephalitis virus (JEV) is the most frequent cause of mosquito-borne encephalitis in Asian countries. Several culicine species are potential vectors. The primary JEV vectors feed mainly on cows (a dead-end host for JEV), pigs (an amplifying host), and, occasionally, humans (a dead-end host). It is essential to determine blood-feeding patterns to understand the transmission cycle of the disease. Here we review blood-feeding characteristics of the primary JEV vectors Culex tritaeniorhynchus, Culex vishnui, and Culex gelidus based on experimental works and field surveys conducted in Asian countries. Several studies showed that these JEV vectors have an innate preference for cows; however, the former two species often showed higher rates of blood-feeding on pigs than on cows, probably because pigs are more abundant than cows. On the other hand, the latter species Cx. gelidus fed mostly on cows. Thus, the first two species showed higher plasticity to compromise host availability than the last. By reviewing the available articles and based on our relevant studies, it may be deduced that JEV transmission cannot be reduced by zooprophylaxis. We emphasize the need of keeping cows away from the human residences to dampen the human risk of JEV. These primary JEV vector species exhibit pre-biting resting. The adaptive significance of this behavior remains to be unexplored, but it may have a function to avoid defensive attack of host animals. Application of recent quantitative analysis of gene expression in this phase may enable us to come up with novel vector control strategies., (© The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA)., Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients., Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes., Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

A 78-year-old man had fatigue and appetite loss for 5 months. He had been receiving low-dose methotrexate for rheumatoid arthritis. Computed tomography revealed multiple pulmonary infiltrations and muddiness of the fatty tissue surrounding the right kidney, ureter wall thickening, and hydroureter/nephrosis, which were suspected retroperitoneal fibrosis. Lung biopsy revealed polymorphic/lymphoplasmacytic lymphoproliferative disorder. Methotrexate withdrawal resulted in spontaneous regression. Therefore, retroperitoneal lesion may account for the diagnosis as having retroperitoneal lymphoproliferative disorder, not retroperitoneal fibrosis.

We studied the winter activity of Aedes albopictus (Skuse) from November 2008 to April 2009 in Bat Trang village of Hanoi, Vietnam. We selected 12 houses and collected: 1) adults with BG sentinel traps, 2) pupae from household water containers, and 3) eggs with ovitraps. Aedes albopictus adults, pupae, and eggs were not collected from early January to early February. Though the egg hatching probability tended to be initially high at longer day length, the maximum probability gradually shifted to shorter day length, as the observation period elapsed. When females were reared under long day length and their eggs were immersed 1 or 5 wk after oviposition, >50% of eggs hatched within 20 days. However, when females were reared under short day length and their eggs were immersed after 1 wk, hatching was suppressed for 60 days. When females were reared under short day length, the median hatching day occurred earlier in eggs kept dry for 5 and 10 wk after oviposition than in those dried for only 1 wk. This indicates that the extended dry periods accelerate egg hatching. Our results showed that hatchability gradually changed with day length, suggesting that selection for overwintering is not as strong relative to Ae. albopictus living in the temperate zone, where winter conditions are less favorable than in tropical and subtropical areas., (© The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The female flower of hop (Humulus lupulus var. lupulus) is an essential ingredient that gives characteristic aroma, bitterness and durability/stability to beer. However, the molecular genetic basis for identifying DNA markers in hop for breeding and to study its domestication has been poorly established. Here, we provide draft genomes for two hop cultivars [cv. Saazer (SZ) and cv. Shinshu Wase (SW)] and a Japanese wild hop [H. lupulus var. cordifolius; also known as Karahanasou (KR)]. Sequencing and de novo assembly of genomic DNA from heterozygous SW plants generated scaffolds with a total size of 2.05 Gb, corresponding to approximately 80% of the estimated genome size of hop (2.57 Gb). The scaffolds contained 41,228 putative protein-encoding genes. The genome sequences for SZ and KR were constructed by aligning their short sequence reads to the SW reference genome and then replacing the nucleotides at single nucleotide polymorphism (SNP) sites. De novo RNA sequencing (RNA-Seq) analysis of SW revealed the developmental regulation of genes involved in specialized metabolic processes that impact taste and flavor in beer. Application of a novel bioinformatics tool, phylogenetic comparative RNA-Seq (PCP-Seq), which is based on read depth of genomic DNAs and RNAs, enabled the identification of genes related to the biosynthesis of aromas and flavors that are enriched in SW compared to KR. Our results not only suggest the significance of historical human selection process for enhancing aroma and bitterness biosyntheses in hop cultivars, but also serve as crucial information for breeding varieties with high quality and yield., (© The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The oleaginous yeast, Lipomyces starkeyi, is an excellent lipid producer with great industrial potential. However, methods for molecular breeding have not been established for L. starkeyi. We describe the development of a system for targeted rDNA integration of multiple copies of a gene into L. starkeyi genome by spheroplast-polyethylene glycol transformation.

In patients undergoing radiotherapy for localized prostate cancer, dose-volume histograms and clinical variables were examined to search for correlations between radiation treatment planning parameters and late rectal bleeding. We analyzed 129 patients with localized prostate cancer who were managed from 2002 to 2010 at our institution. They were treated with 3D conformal radiation therapy (3D-CRT, 70 Gy/35 fractions, 55 patients) or intensity-modulated radiation therapy (IMRT, 76 Gy/38 fractions, 74 patients). All radiation treatment plans were retrospectively reconstructed, dose-volume histograms of the rectum were generated, and the doses delivered to the rectum were calculated. Time to rectal bleeding ranged from 9-53 months, with a median of 18.7 months. Of the 129 patients, 33 patients had Grade 1 bleeding and were treated with steroid suppositories, while 25 patients with Grade 2 bleeding received argon plasma laser coagulation therapy (APC). Three patients with Grade 3 bleeding required both APC and blood transfusion. The 5-year incidence rate of Grade 2 or 3 rectal bleeding was 21.8% for the 3D-CRT group and 21.6% for the IMRT group. Univariate analysis showed significant differences in the average values from V65 to V10 between Grades 0-1 and Grades 2-3. Multivariate analysis demonstrated that patients with V65 ≥ 17% had a significantly increased risk (P = 0.032) of Grade 2 or 3 rectal bleeding. Of the 28 patients of Grade 2 or 3 rectal bleeding, 17 patients (60.7%) were cured by a single session of APC, while the other 11 patients required two sessions. Thus, none of the patients had any further rectal bleeding after the second APC session., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases., Objective: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH., Subjects and Methods: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing., Results: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements., Conclusions: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients., (© 2015 European Society of Endocrinology.)

This study sought to demonstrate the feasibility of estimating the source strength during implantation in brachytherapy. The requirement for measuring the strengths of the linked sources was investigated. The utilized sources were (125)I with air kerma strengths of 8.38-8.63 U (μGy m(2) h(-1)). Measurements were performed with a plastic scintillator (80 mm × 50 mm × 20 mm in thickness). For a source-to-source distance of 10.5 mm and at source speeds of up to 200 mm s(-1), a counting time of 10 ms and a detector-to-needle distance of 5 mm were found to be the appropriate measurement conditions. The combined standard uncertainty (CSU) with the coverage factor of 1 (k = 1) was ∼15% when using a grid to decrease the interference by the neighboring sources. Without the grid, the CSU (k = 1) was ∼5%, and an 8% overestimation due to the neighboring sources was found to potentially cause additional uncertainty. In order to improve the accuracy in estimating source strength, it is recommended that the measurment conditions should be optimized by considering the tradeoff between the overestimation due to the neighboring sources and the intensity of the measured value, which influences the random error., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

It has been unclear whether chromosomally integrated human herpesvirus 6 (ciHHV-6) can be activated with pathogenic effects on the human body. We present molecular and virological evidence of ciHHV-6A activation in a patient with X-linked severe combined immunodeficiency. These findings have significant implications for the management of patients with ciHHV-6., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The post-implantation dosimetry for brachytherapy using Monte Carlo calculation by EGS5 code combined with the source strength regression was investigated with respect to its validity. In this method, the source strength for the EGS5 calculation was adjusted with the regression, so that the calculation would reproduce the dose monitored with the glass rod dosimeters (GRDs) on a water phantom. The experiments were performed, simulating the case where one of two (125)I sources of Oncoseed 6711 was lacking strength by 4-48%. As a result, the calculation without regression was in agreement with the GRD measurement within 26-62%. In this case, the shortage in strength of a source was neglected. By the regression, in order to reflect the strength shortage, the agreement was improved up to 17-24%. This agreement was also comparable with accuracy of the dose calculation for single source geometry reported previously. These results suggest the validity of the dosimetry method proposed in this study.

The aim of this study is to demonstrate the feasibility of estimating the strength of the moving radiation source during patient implantation. The requirement for the counting time was investigated by comparing the results of the measurements for the static source with those for the source moving at 2, 5, 10 and 20 cm s(-1). The utilized source was (125)I with an air-kerma strength of 0.432 U (μGym(2)h(-1)). The detector utilized was a plastic scintillation detector (8 cm × 5 cm × 2 cm in thickness) set at 8 cm away from the needle to guide the source. Experiments were conducted in order to determine the most desirable counting time. Analysis using the maximum of the measured values while the source passed through the needle indicated that the results for the moving source increased more than those for the static source as the counting time decreased. The combined standard uncertainty, with the coverage factor of 1, was within 4% at the counting time of 100 ms. This investigation supported the feasibility of the method proposed for estimating the source strength during the implantation procedure, regardless of the source speed. The method proposed is a potential option for reducing the risk of accidental replacements of sources with those of incorrect strengths.

This study investigated the maximum tolerated dose (MTD) of S-1 with concurrent radiotherapy in patients with head and neck cancer, based on the frequency of dose-limiting toxicities (DLT). S-1 was administered orally at escalating doses from 40 mg/m(2) b.i.d. on the days of delivering radiotherapy, which was given at a total dose of 64-70 Gy in 32-35 fractions over 6-7 weeks. A total of 12 patients (3 patients at 40 mg/m(2), 6 patients at 60 mg/m(2), and 3 patients at 80 mg/m(2)) were enrolled in this trial. At the dose of 80 mg/m(2), two of the three patients developed DLT (Grade 3 anorexia and rhabdomyolysis) due to S-1, so the MTD was determined to be 80 mg/m(2). Among the 12 enrolled patients, 9 (75%) showed a complete response and 3 (25%) showed a partial response. The overall response rate was 100%. The recommended dose of S-1 with concurrent radiotherapy is 60 mg/m(2).

Background: It has been reported that podocytopenia has been occurring with increasing disease severity in patients with IgA nephropathy (IgAN). Dendrin is localized at the slit diaphragm (SD) in podocytes. We showed that dendrin translocates to the nucleus of injured podocytes in experimental nephritis and the nuclear dendrin promotes podocyte apoptosis. It is still unknown whether dendrin translocates from the SD to podocyte nucleus in IgAN. We investigated the presence of nuclear dendrin in patients with IgAN and the association between the translocated dendrin to the podocyte nucleus and disease activity., Methods: Fourteen adult patients with IgAN were enrolled. The pathological parameters were analyzed. Immunostaining of renal biopsy specimens and urinary sediments from IgAN or minimal change nephrotic syndrome (MCNS) as the control was performed., Results: A positive correlation was observed between an acute extracapillary change and the number of dendrin-positive nuclei. The location of dendrin in the nuclei was found in urinary podocytes of IgAN. The number of dendrin-positive nuclei in urinary podocytes of IgAN was significantly higher than that of MCNS. Urinary podocytes, which expressed the apoptosis marker annexin V, were also detected in IgAN. The translocation of dendrin to the podocyte nucleus as well as strong cathepsin L staining were detected in the glomeruli of IgAN., Conclusion: An increasing number of dendrin-positive nuclei in the glomeruli suggest acute glomerular injury in IgAN. Apoptotic podocytes were detectable in the urine of IgAN. It appears that the translocation of dendrin to the podocyte nuclei enhances podocyte apoptosis in acute glomerular injury and leads to podocytopenia in patients with IgAN.

A Phase III study was started in Japan to evaluate the non-inferiority of overall survival of laparoscopy-assisted distal gastrectomy with open distal gastrectomy in patients with clinical IA (T1N0) or IB [T1N1 or T2(MP)N0] gastric cancer. This study followed the previous Phase II study to confirm the safety of laparoscopy-assisted distal gastrectomy (JCOG0703) and began in March 2010. A total of 920 patients will be accrued from 33 institutions within 5 years. The primary endpoint is overall survival. The secondary endpoints are relapse-free survival, proportion of laparoscopy-assisted distal gastrectomy completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, postoperative quality of life. Only a credentialed surgeon can be responsible for both open distal gastrectomy and laparoscopy-assisted distal gastrectomy.

As part of our chemical screening program for new microbial secondary metabolites, we discovered a new compound, JBIR-107 (1), from the culture of Streptomyces tateyamensis NBRC 105047 isolated from a marine sponge sample. Extensive NMR and MS spectroscopic data enabled the structure of 1 to be determined as 5-acetamido-6-(4-(methyl(2-oxo-3-phenylpropyl)amino)phenyl)-4-oxohexanoic acid.

Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The aim of this study was to examine axonal fibre pathways across the brain for evidence of microstructural alterations associated with long-term cannabis use and to test whether age of regular cannabis use is associated with severity of any microstructural change. To this end, diffusion-weighted magnetic resonance imaging and brain connectivity mapping techniques were performed in 59 cannabis users with longstanding histories of heavy use and 33 matched controls. Axonal connectivity was found to be impaired in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum and commissural fibres. Radial and axial diffusivity in these pathways were associated with the age at which regular cannabis use commenced. Our findings indicate long-term cannabis use is hazardous to the white matter of the developing brain. Delaying the age at which regular use begins may minimize the severity of microstructural impairment.

To investigate the biological activity of a novel 24-membered macrolide compound, JBIR-19, isolated from the culture broth of the entomopathogenic fungus Metarhizium sp. fE61, morphological changes in yeast cells were examined using the automated image-processing program CalMorph. Principal components analysis was used to elucidate dynamic changes in the phenotypes, revealing two independent effects of JBIR-19 in yeast cells: bud elongation and increased size of the actin region. Using a fitness assay, we identified the genes required for robust growth in the presence of JBIR-19. Among these were CCW12, YLR111W, and DHH1, which are also involved in abnormal bud morphology. Based on these results and others, we predict intracellular targets of JBIR-19 and its functional interactions., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)