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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

A 16-year-old male adolescent with a history of retractile testes fell in the bath and hit his scrotum against the bathtub. The following day, he presented to the primary care clinic with severe right testicular pain and nausea 2 hours after the onset. Physical examination showed a tender right

To evaluate the toxicity of Amphotericin B (AmB) in Optisol™-GS Corneal Storage Media (BauschLomb) on corneal epithelial cell (CEC) morphology and migration ability.Sclerocorneal strips were removed from male Japanese white rabbits, and then stored at 4 °C in Optisol™-GS containing 0 µg/ml of AmB (control group) and 2.5, 5, 25, and 50 µg/ml of AmB (AmB groups; four eyes per group). After 7 days of storage, CEC morphology was evaluated by hematoxylin-eosin staining, immunohistochemical staining (ZO-1), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Moreover, to evaluate CEC migration ability, three corneal blocks (6-8 × 3 mm each) from one preserved cornea were cultured for 24 h, and the area of CEC migration (2 mm at the central region) onto the stromal surface was then measured.At 5, 25, and 50 µg/ml of AmB, deformation and vacuolation of CECs were observed in all preserved corneas. ZO-1 expression was significantly reduced in corneas preserved at AmB concentrations of 25 and 50 µg/ml. TUNEL Labeling Index was significantly increased at AmB concentrations of ≥5 µg/ml. CEC migration was inhibited in a dose-dependent manner at AmB concentrations of 25 and 50 µg/ml compared to the control group.The addition of AmB to Optisol™-GS can be toxic to CECs and inhibit their migration at a concentration of ≥5 µg/ml. AmB at a concentration of 2.5 µg/ml can be considered safe for the preservation of donor corneal tissue used in corneal epithelial transplantation surgery.

To determine the characteristics of balance bike injuries.This study retrospectively identified patients injured while riding a balance bike and treated at one paediatric emergency department in urban Japan, from February 2015 to July 2020. Data extracted were patient age and sex, circumstances and location of the injury occurrence, helmet use, adult supervision, injury type and body site, treatment and emergency department disposition. Based on these data and the balance bike manual instructions, cases were classified as correct and incorrect balance bike use.The study assessed 78 patients, age 2-6 years (median 3 years; 73% male). Of these 78 patients, 63 did not follow balance bike manual instructions (80.8%); 34 (43.6%) were injured while riding in prohibited places of use; 45 (57.7%) were injured in prohibited situations of use; and 37 (47.4%) were injured despite adult supervision. A total of 124 injuries were noted; the most common injured body site was the face (49 injuries, 39.5%), followed by the head (40 injuries, 32.3%). Most injuries were contusions and abrasions (65 injuries, 52.4%). More serious injuries were intensive care unit admission with intracerebral haemorrhage (1 patient) and lateral condyle fracture with surgical repair (1 patient).Most of the 78 balance bike injuries (76 patients) were mild; 2 were more severe and required intensive care unit admission or operation. Parents must be aware of the rules and instructions for balance bike use and ensure that their children can use the balance bike correctly.

Recovery time after corpus callosotomy (CC) is known to be longer in elderly than in younger patients.To evaluate the relationship between patient age and recovery time of activities of daily living (ADL) after 1-stage complete CC.This study included 41 patients (22 women; aged 13 months-34 years, median 7 years) who underwent 1-stage complete CC for medically intractable seizures with drop attacks, infantile spasms, and/or bilaterally synchronized electroencephalographic discharges between August 2009 and April 2019. The timing of restart of competence in 5 ADL categories and surgical outcomes were recorded.Patients (1) restarted speech at 2.2 ± 1.3 (mean ± 2 standard deviations; range 1-5) days, (2) restarted replying with their own name on request at 5.5 ± 8.6 (2-33) days, (3) restarted oral intake at 1.6 ± 1.7 (1-11) days, (5) discontinued intravenous feeding at 6.0 ± 3.0 (2-16) days, and (5) restarted ambulation or wheelchair movement at 5.8 ± 3.4 (2-10) days. Younger patients showed significantly (P.0223) earlier recovery of ambulation or wheelchair movement, but no age difference was found in the other 4 ADL categories. Overall seizure freedom was achieved in 5 patients, excellent (80%) seizure reduction in 11, good (50%-80%) seizure reduction in 5, and poor (50%) seizure reduction in 20.Early ADL recovery after 1-stage complete CC is favorable in both young and adult patients. These findings, with good surgical outcomes, will encourage more positive consideration of 1-stage complete CC in both pediatric and adult patients.

Background/Aim: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E(2) (PGE(2)) synthesis. PGE(2) in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE(2) axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. Materials and Methods: The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1(−/−)) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues. Results: Angiogenesis was suppressed in mPGES-1(−/−) mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3(+) Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1(−/−) mice than in WT mice. Neutralizing Tregs with antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice, but not in mPGES-1(−/−) mice. The topical application of PGE(2) into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1(−/−) mice. Conclusion: Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE(2). mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.

Aim To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD). Methods We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (＜5.5%) and increased baPWV (＞1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for ＜60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs. Results During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Conclusions The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

Summary Background There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. Methods We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001. Findings Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20–40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3). Interpretation Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings. Funding Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyo

Aim Schizophrenia is considered to be a disorder of progressive structural brain abnormalities. Previous studies have indicated that the cerebellar Crus I/II plays a critical role in schizophrenia. We aimed to investigate how specific morphological features in the Crus I/II at different critical stages of the schizophrenia spectrum contribute to the disease. Methods The study involved 73 participants on the schizophrenia spectrum (28 with ultra-high risk for psychosis [UHR], 17 with first-episode schizophrenia [FES], and 28 with chronic schizophrenia), and 79 healthy controls. We undertook a detailed investigation into differences in Crus I/II volume using a semi-automated segmentation method optimized for the cerebellum. We analyzed the effects of group and sex, as well as their interaction, on Crus I/II volume in gray matter (GM) and white matter (WM). Results Significant group × sex interactions were found in WM volumes of the bilateral Crus I/II; the UHR males demonstrated significantly larger WM volumes compared to the other male groups, whereas no significant group differences were found in the female groups. Additionally, WM and GM volumes of the Crus I/II had positive associations with symptom severity in the UHR group, whereas, in contrast, GM volumes in the FES group were negatively associated with symptom severity. Conclusions The present findings provide evidence that the morphology of Crus I/II is involved in schizophrenia in a sex- and disease stage-dependent manner. Additionally, alterations of WM volumes of Crus I/II may have potential as a biological marker of early detection and treatment for UHR individuals. This article is protected by copyright. All rights reserved.

Aims Frailty is associated with prognosis of cardiovascular diseases. However, the significance of frailty in patients with heart failure with preserved ejection fraction (HFpEF) remains to be elucidated. The purpose of this study was to examine the prognostic significance of the Clinical Frailty Scale (CFS) in real‐world patients with HFpEF using data from a prospective multicentre observational study of patients with HFpEF (PURSUIT‐HFpEF study). Method and Results We classified 842 patients with HFpEF enrolled in the PURSUIT‐HFpEF study into two groups using CFS. The registry enrolled patients hospitalized with a diagnosis of decompensated heart failure. Median age was 82 [interquartile range: 77, 87], and 45% of the patients were male. Of 842 patients, 406 were classified as high CFS (CFS ≥ 4, 48%) and 436 as low CFS (CFS ≤ 3, 52%). The primary endpoint was the composite of all‐cause mortality and heart failure admission. Secondary endpoints were all‐cause mortality and heart failure admission. Patients with high CFS were older (85 vs. 79 years, P

Background The length of hospital stay in community-acquired pneumonia patients is closely associated with medical costs, the burden of which is increasing in aging societies. Herein, we developed and validated models for predicting prolonged length of stay in community-acquired pneumonia patients to support efficient care in these patients. Methods We obtained data of 32,916 patients hospitalized for pneumonia who were discharged between 2012 and 2013 from 304 acute care hospitals in Japan. Logistic regression models were developed with prolonged length of stay as the outcome and patient characteristics as predictors. The models were internally validated using bootstrapping and externally validated using pneumonia patients discharged in 2014. Results The median length of stay was 11 (interquartile range, 8–17) days. The following were significant predictors of prolonged length of stay (odds ratio >1.6): age ≥75 years, Barthel index score ≤6, fraction of inspired oxygen ≥35%, Japan Coma Scale score of 100–300, anemia, muscle wasting and atrophy, bedsores, dysphasia, and methicillin-resistant Staphylococcus aureus infection. Our validation models had a c-statistic of 0.78 (95% confidence interval, 0.77–0.79) and a calibration slope of 0.98. Conclusions Our prediction models may help policymakers in developing strategies for the optimal management of community-acquired pneumonia patients with a focus on patients at a high risk of prolonged length of stay.

We herein report a case of severe coronavirus disease 2019 (COVID-19) in which high-dose intravenous immunoglobulin (IVIg) treatment achieved significant clinical improvement of deterioration of pulmonary inflammation after temporary clinical improvement. In the present case, clinical and radiological deterioration occurred despite a decrease in viral load, suggesting that deterioration was caused by reactivation of proinflammatory factors, such as tumor necrosis factor-α and interleukin-6, rather than direct viral effects. IVIg treatment may provide not only immunosuppressive effects but also inhibition of proinflammatory cytokines, indicating that treatment including IVIg may be effective by inhibiting cytokine storm in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection.

OBJECTIVEThere is disagreement about the occurrence of severe traumatic brain injury, especially subdural hematoma, caused by short falls in very young children. To verify intracranial injury due to these falls and examine its characteristics, the authors compared infants and toddlers with head trauma witnessed by a nonrelative with those whose injuries were not witnessed by a nonrelative.METHODSThe authors retrospectively reviewed clinical records of children younger than 2 years with head trauma due to a short fall who visited the emergency department of the National Center for Child Health and Development in Japan between April 2015 and March 2018. Patients were classified into two groups: falls that were witnessed by a nonrelative and falls not witnessed by a nonrelative. The authors compared the age in months, sex, mechanism of injury, fall height, prevalence rate of intracranial injury, skull fracture, type of traumatic brain injury, retinal hemorrhage, rib or long-bone fracture, and outcomes between patients whose fall was witnessed by a nonrelative and those whose fall was not witnessed by a nonrelative.RESULTSAmong 1494 patients included in the present analysis, 392 patients were classified into the group of falls witnessed by a nonrelative, and 1102 patients were classified into the group of falls that were not witnessed by a nonrelative. The prevalence rates of intracranial injury, skull fracture, epidural hematoma, and subarachnoid hemorrhage were equal between the groups. The prevalence rate of subdural hematoma in the group whose falls were witnessed by a nonrelative was significantly lower than that of the other group (p = 0.027). There were no patients with subdural hematoma, retinal hemorrhage, or neurological sequelae in the group whose fall was witnessed by a nonrelative.CONCLUSIONSSubdural hematoma, retinal hemorrhage, and neurological sequelae due to short falls were not seen after witnessed falls in the present study.

Numerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population., Ishida et al. investigated genome-wide associations between 1068 healthy Japanese adults and their gut microbiota. They find that five loci account for a small variation of the human gut microbiota composition and that six genera are heritable. This study suggests that human gut microbiota composition is likely to be affected by multiple genetic loci.

Background Pheochromocytomas (PCC) and paragangliomas (PGL) are catecholamine-producing neuroendocrine tumors. According to the World Health Organization Classification 2017, all PCC/PGL are considered to have malignant potential. There is growing evidence that PCC/PGL represent a metabolic disease that leads to aerobic glycolysis. Cellular energy metabolism involves both transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) subtypes, but the association of these substances with PCC/PGL is largely unknown. Methods We investigated SDHB gene mutation and protein expressions for SDHB and Nrf2 in surgical specimens from 29 PCC/PGL. We also assessed preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography and mRNA levels for Nrf2. Results Among 5 PCC/PGL with a PASS Score ≥ 4 or with a moderately to poorly differentiated type in the GAPP Score, 4 were metastatic and found to be SDHB mutants with homogeneous deletion of SDHB protein. SDHB mutants showed a higher expression of Nrf2 protein and a higher preoperative SUVmax than non-SDHB mutants with a PASS Nrf2 mRNA level positively correlated with malignant phenotype, higher expression for Nrf2 protein and SDHB gene mutant, but negatively correlated with expression for SDHB protein. There was also a positive correlation between Nrf2 mRNA level and SUVmax. Conclusion These results suggest that activation of Nrf2 and elevated metabolism play roles in PCC/PGL with malignant potential that have SDHB gene mutation and SDHB deficiency.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma and other organ involvement is very rare. A rare case of MEITL involving the lung and brain is herein reported. The patient developed panperitonitis with a small intestinal perforation, and emergency surgery was performed. The pathological findings from the surgical specimens demonstrated atypical lymphoid cells which were positive for CD3, CD8, and CD56. Moreover, the pathological findings of lung specimens taken by bronchoscopy were consistent with those of the small intestine. It is therefore important to include the possibility of MEITL in the differential diagnosis of cancer patients.

Sudden cardiac arrest is a serious complication of acute myocardial infarction (MI). Although in-hospital mortality from MI has decreased, the mortality of MI patients complicated with out-of-hospital cardiac arrest (OHCA) remains high. However, the features of acute MI patients with OHCA have not been well known.We sought to characterize the clinical and angiographic features of acute MI patients with OHCA comparing with those without OHCA.We retrospectively analyzed 480 consecutive patients with acute MI undergoing percutaneous coronary intervention. Patients complicated with OHCA were compared with patients without OHCA.Of the patients, 141 (29%) were complicated with OHCA. Multivariate analysis revealed that age (odds ratio [OR]: 0.8; 95% confidence interval [CI]: 0.7 to 0.9 per 5 years; p 0.001), estimated glomerular filtration rate (OR: 0.8; 95% CI: 0.7 to 0.8 per 10 ml/min/1.73 mYounger age, no use of calcium-channel antagonists, worse renal function, larger infarct size, culprit lesion in the left main coronary artery, and having chronic total occlusion were associated with OHCA.

Background Head trauma in children is one of the most common causes for emergency department visits. Although most trauma cases are minor, identifying those patients who have clinically important traumatic brain injury (ciTBI) is challenging. The Pediatric Emergency Care Applied Research Network (PECARN) head trauma prediction rules identifying children who do not require cranial computed tomography (CT) were validated and are used all over the world. However, these rules have not been validated with large cohort multicenter studies in Asia. Objectives To investigate whether the PECARN rules can be safely applied to Japanese children. Methods We conducted a multicenter, prospective, observational cohort study. We included children younger than 16 with minor head trauma (Glasgow Coma Scale ≥14) who presented to the six participating centers within 24 h of their injuries between June 2016 and September 2017. The primary analysis was set to calculate the negative predictive value of the patients with very low risk by the PECARN rules, compared with a preset threshold of 99.85%. Results We included 6585 children of which 463 (7.0%) had head CT scans performed and 23 (0.35%) had ciTBI. There were two patients with ciTBI who were classified as very low risk. The negative predictive value, calculated as 99.96% (95%CI: 99.86–100.00; P = .019), was significantly superior compared with the preset threshold of 99.85%. Conclusions The PECARN head trauma prediction rules seemed to be safely applicable to Japanese children. Further studies are needed to determine safety in hospitals where physicians do not have expertise in managing children.

Background The efficacy of anti‐programmed cell death‐1/ligand 1 antibody monotherapy (anti‐PD‐1/PD‐L1 monotherapy) in patients with active brain metastases (BMs) is not established. Here, we aimed to evaluate the efficacy of anti‐PD‐1/PD‐L1 monotherapy in non‐small cell lung cancer (NSCLC) patients with active BMs. Methods This retrospective study included NSCLC patients treated with second‐line or later‐line anti‐PD‐1/PD‐L1 monotherapy between December 2015 and August 2019. Patients were classified into those with or without active BMs, including symptomatic BMs requiring systemic steroids and untreated BMs. The progression‐free survival (PFS) and overall survival (OS) of the patients with and without active BMs were compared. Intracranial and extracranial tumor responses were evaluated in patients with active BMs. Results We analyzed 197 patients who had received anti‐PD‐1/PD‐L1 monotherapy. Among them, 24 had active BMs. Among those without active BMs, 145 had no BMs and 28 had treated asymptomatic BMs. The PFS and OS of patients with active BMs were significantly shorter than those of patients without active BMs (1.3 vs. 2.7 months; P, The present study showed that anti‐PD‐1/PD‐L1antibody monotherapy was not effective for non‐small cell lung cancer patients with active brain metastases. Intracranial and extracranial response rates were 13.3% and 26.7% respectively. Further studies on immunotherapy are needed for patients with active BMs.

Dry powder inhalers (DPI) are frequently used by asthmatic patients, and the usage rate increases every year. The pharmacists at our hospital provided initial inhalation instructions on how the inhaler must be used but did not elaborate on the cleaning of the device. Therefore, the cleaning status of the inhaler is unknown, and there is a possibility of bacterial growth. This study investigated the cleaning status and hygiene of steroid drug inhalers used by elderly asthma patients. We administered a questionnaire to investigate the inhaler cleaning status after inhalation, and conducted a cross-sectional survey on hygiene using ATP measurement and bacterial culture examination. Considering the responses by 53 patients, it became clear that the ATP values of patients who answered "never cleaned" after inhalation were significantly higher than those who answered "cleaned every time". Moreover, some bacteria were detected in 62% of inhalers; 4 patients' inhalers contained bacteria other than normal oral microbial flora. In conclusion, because the inhalers used by elderly patients are in poor hygienic conditions, we must give cleaning instructions accordingly. We believe that it is necessary to give proper medical instructions along with instructions on the cleaning method with dry cloth.

Purpose: Latanoprost ophthalmic solution is highly effective as a therapeutic agent for glaucoma and is applied worldwide. However, harmful effects on the corneal surface have been reported regardi...

Background This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. Methods HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose. Results Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. Conclusions This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

A 26-year and 6-month-old male sika deer that was kept at the Showa Park, Tokyo, Japan, collapsed and died of severe disease wasting and severe tabefaction. Grossly, numerous masses, 0.3-1.0 cm diameter, were dispersed throughout the liver. The multiple masses were composed of tumor cells, which had hypochromatic nuclei and abundant faintly eosinophilic cytoplasm, arranged in nests of various sizes. Immunohistochemically, tumor cells were positive for cytokeratin, chromogranin A, synaptophysin and gastrin. Ultrastructurally, the cytoplasm of the tumor cells contained abundant membrane-bound electron-dense granules. A metastatic lesion was observed in the renal, hepatic and pancreatic lymph nodes. On the basis of these findings, this tumor was diagnosed as a neuroendocrine carcinoma with metastases to the lymph nodes.

Background Withdrawal syndromes can occur after dose reduction or discontinuation of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Few measurement instruments are available to assess them: Diagnostic Clinical Interview for Drug Withdrawal 1-New Symptoms of SSRI and SNRI (DID-W1) and Discontinuation Emergent Signs and Symptoms (DESS) checklist. We assessed their interrater reliability, verified the percent agreement between the two, and tested DESS sensitivity and specificity on the basis of the diagnoses formulated via the DID-W1. Methods One-hundred thirty-four subjects who referred for withdrawal at 3 outpatient facilities were enrolled and assessed via the DESS and the DID-W1. Percent agreement and Cohen kappa were calculated to measure DID-W1 and DESS interrater reliability, as well as the agreement between DID-W1 and DESS items. Sensitivity and specificity of DESS were derived from the identification of true-positive, false-negative, true-negative, and false-positive on the DID-W1. Results Both tools showed excellent interrater reliability (DID-W1 Cohen kappa = 0.958; DESS Cohen kappa = 0.81-1). The degree of agreement between DID-W1 and DESS items was poor or fair (Cohen kappa < 0.40) for some items and moderate (Cohen kappa = 0.41-0.60) for others. Sensitivity and specificity of DESS were 0.937 (true-positive = 60, false-negative = 4) and 0.285 (true-negative = 20, false-positive = 50), respectively. Conclusions DID-W1 was a reliable method to identify and diagnose withdrawal syndromes. The DESS checklist showed to be a useful tool for detecting withdrawal SSRI/SNRI symptoms when the aim is to achieve high sensitivity to identify true positives.

Background Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. Methods Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. Results Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. Conclusions Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Anemia is a major complication of chronic renal failure. To treat this anemia, prolylhydroxylase domain enzyme (PHD) inhibitors as well as erythropoiesis-stimulating agents (ESAs) have been used. Although PHD inhibitors rapidly stimulate erythropoietin (Epo) production, the precise sites of Epo production following the administration of these drugs have not been identified. We developed a novel method for the detection of the Epo protein that employs deglycosylation-coupled Western blotting. With protein deglycosylation, tissue Epo contents can be quantified over an extremely wide range. Using this method, we examined the effects of the PHD inhibitor, Roxadustat (ROX), and severe hypoxia on Epo production in various tissues in rats. We observed that ROX increased Epo mRNA expression in both the kidneys and liver. However, Epo protein was detected in the kidneys but not in the liver. Epo protein was also detected in the salivary glands, spleen, epididymis and ovaries. However, both PHD inhibitors (ROX) and severe hypoxia increased the Epo protein abundance only in the kidneys. These data show that, while Epo is produced in many tissues, PHD inhibitors as well as severe hypoxia regulate Epo production only in the kidneys.

A-68-year-old man, who has allergic rhinitis with peripheral blood eosinophilia, hospitalized because of fever of unknown origin in May 2020. Five days after antibiotics were given, itchy exanthema occurred, followed by gland glass opacity on both lungs with bilateral pleural effusions. Since acute respiratory failure developed, bronchoscopy was hard to carry out. However, this case was considered acute eosinophilic pneumonia induced by antibiotics, based on radiological findings and laboratory data. Therefore, steroid pulse therapy using intravenous administration of methylprednisolone started, and this therapy was effective. Since these chest shadows and hypoxia were disappeared in two weeks, the amount of steroid was gradually reduced, however, eosinophilic pneumonia recurred once during this course. After discharge in June 2020, this patient came to the outpatient department. When oral administration of prednisolone was decreased less than 2.5mg/day, redness and swelling with slight itch were appeared in the left forearm in September 2020. Histological findings from shin biopsy showed that eosinophils excessively invade to the dermis without angiitis. Although flame figure was not observed in the specimen, we considered that this case has developed eosinophilic cellulitis, based on the clinical manifestation and pathological findings. When prednisolone was increased to 30mg/day, these symptoms were improved, and then prednisolone was gradually reduced. After that, recurrences of these diseases did not occur during the observation period. This case may be diagnosed as hypereosinophilic syndrome since eosinophilic pneumonia and eosinophilic cellulitis caused continuously by recruitment of eosinophils to lung and skin.

Characterization of brain networks by diffusion MRI (dMRI) has rapidly evolved, and there are ongoing movements toward data sharing and multi-center studies. To extract meaningful information from multi-center data, methods to correct for the bias caused by scanner differences, that is, harmonization, are urgently needed. In this work, we report the cross-scanner differences in structural network analyses using data from nine traveling subjects (four males and five females, 21–49 years-old) who underwent scanning using four 3T scanners (public database available from the Brain/MINDS Beyond Human Brain MRI project (http://mriportal.umin.jp/)). The reliability and reproducibility were compared to those of data from another set of four subjects (all males, 29–42 years-old) who underwent scan-rescan (interval, 105–147 days) with the same scanner as well as scan-rescan data from the Human Connectome Project database. The results demonstrated that the reliability of the edge weights and graph theory metrics was lower for data including different scanners, compared to the scan-rescan with the same scanner. Besides, systematic differences between scanners were observed, indicating the risk of bias in comparing networks obtained from different scanners directly. We further demonstrate that it is feasible to reduce inter-scanner variabilities while preserving the inter-subject differences among healthy individuals by modeling the scanner effects at the level of network matrices, when traveling-subject data are available for calibration between scanners. The present data and results are expected to serve as a basis for developing and evaluating novel harmonization methods.

Calf mortality severely affects productivity in the beef industry. The present study was conducted to assess the calf mortality risk (CMR) in Japanese Black calves and investigate potential associations between calf/cow information and the CMR. Records for calves born between April 2006 and March 2010 were extracted from an existing database, which included production data on commercial cow-calf operations in Miyazaki, Japan. The study group comprised 40,462 calves born to 15,600 cows on 908 farms. Because calves on the studied farms were weaned at approximately 4 months of age, the calf records were collected from birth to 120 days. The CMR was calculated as the number of dead calves divided by the number of surviving calves. Mixed-effect multivariable logistic regression modeling was used to determine potential associations between the CMR and the factors hypothesized to influence that risk. CMR analyses were performed separately for the following production stages: days 0-30, days 31-60, days 61-90 and days 91-120 after birth. Of the 40,462 calves, 1465 died during days 0-120 after birth, and the CMR was 3.6 %. Of the 1465 dead calves, 35.9 % died within 10 days after birth. During the 0-30-day period, the CMR was associated with dam parity, calving status, gestation length, sex, birth season and twin births (P 0.05), but not with the number of inseminations to conception. Low parity, dystocia, gestation lengths 280 days and 301 days, male calves, calves born in autumn and winter and twin births yielded higher CMRs. Low dam parity also yielded higher CMRs during the 31-60-day, 61-90-day and 91-120-day periods (P 0.05), but no other factors were associated with the CMR during these periods. Thus, various cow and calf factors were shown to be associated with CMRs in Japanese Black calves, and calves with these factors should be considered high-risk calves.

Introduction In male patients with low rectal cancer undergoing abdominoperineal resection (APR), successful dissection of the anterior anorectum is key to reducing the risk of circumferential resection margin involvement, intraoperative bowel perforation, and local recurrence, but it is challenging. To overcome difficulties dissecting the anterior anorectum, we present a safe and feasible procedure using a transperineal endoscopic approach during APR (TpAPR). Materials and surgical technique The male patient is placed in the prone jackknife position. TpAPR precedes the procedure from an abdominal approach. We use some pelvic tissues as clear anatomical landmarks to dissect the anterior anorectum. The key steps of this procedure are shown in the video. Discussion The identification of a clear anatomical dissection plane of the anterior anorectum is difficult because of the complex surgical anatomy of the region. Clear anatomical landmarks for dissection of the anterior anorectum are necessary for safe implementation of this procedure. Therefore, TpAPR in the prone jackknife position can be performed to obtain better visualization of each anatomical landmark at a glance.

ObjectivesThe severity of diastolic dysfunction is assessed using a combination of several indices of left atrial (LA) volume overload and LA pressure overload. We aimed to clarify which overload is more associated with the prognosis in patients with heart failure and preserved ejection fraction (HFpEF).SettingA prospective, multicenter observational registry of collaborating hospitals in Osaka, Japan.ParticipantsWe enrolled hospitalised patients with HFpEF showing sinus rhythm (men, 79; women, 113). Blood tests and transthoracic echocardiography were performed before discharge. The ratio of diastolic elastance (Ed) to arterial elastance (Ea) was used as a relative index of LA pressure overload.Primary outcome measuresAll-cause mortality and admission for heart failure were evaluated at >1 year after discharge.ResultsIn the multivariable Cox regression analysis, Ed/Ea, but not LA volume index, was significantly associated with all-cause mortality or admission for heart failure (HR 2.034, 95% CI 1.059 to 3.907, p=0.032), independent of age, sex, and the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level. In patients with a higher NT-proBNP level, the effect of higher Ed/Ea on prognosis was prominent (p=0.015).ConclusionsEd/Ea, an index of LA pressure overload, was significantly associated with the prognosis in elderly patients with HFpEF showing sinus rhythm.Trial registration numberUMIN000021831.

The impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0–4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470–34.600] and 55.803 [12.761–244.015] (P P

Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud

Cardiovascular disease is a leading cause of death in the Kingdom of Bhutan, and early detection of hypertension is critical for preventing cardiovascular disease. However, health-seeking behavior, including blood pressure measurement, is infrequently investigated in Bhutan. Therefore, this study investigated factors related to blood pressure measurement in Bhutan. We performed a secondary data analysis of a target population of 1,962 individuals using data from the “2014 Bhutan STEPS survey data”as a cross-sectional study. Approximately 26% of those with hypertension who were detected during the STEPS survey had never had their blood pressure measured. Previous blood pressure measurement was significantly associated with age and working status in men (self-employed [odds ratio (OR): 0.219, 95% CI: 0.133–0.361], non-working [OR: 0.114, 95% CI: 0.050–0.263], employee [OR: 1.000]). Previous blood pressure measurement was significantly associated with higher income in women (Quartile-2 [OR: 1.984, 95% CI: 1.209–3.255], Quartile-1 [OR: 2.161, 95% CI: 1.415–3.299], Quartile-4 [OR: 1.000]). A family history of hypertension (OR: 2.019, 95% CI: 1.549–2.243) increased the likelihood of having experienced a blood pressure measurement in both men and women. Multivariate logistic regression showed that people with unhealthy lifestyles (high salt intake [adjusted odds ratio (AOR): 0.247, 95% confidence interval (CI): 0.068–0.893], tobacco use [AOR: 0.538, 95% CI: 0.380–0.761]) had a decreased likelihood of previous blood pressure measurement. To promote the early detection of hypertension in Bhutan, we suggest that more attention be paid to low-income women, non-working, self-employed, and low-income men, and a reduction of barriers to blood pressure measurement. Before the STEPS survey, a substantial number of hypertensive people had never had their blood pressure measured or were unconcerned about their health. As a result, we propose that early blood pressure monitoring and treatment for people with hypertension or at higher risk of hypertension be given increased emphasis.

Background Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported. Aim The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment. Method The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale–2nd edition (SRS-2). Results All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score. Conclusion Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest “TAND impact” on families.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Recently, anti-PD-1 antibody therapy became a key treatment for stage IV NSCLC as the combination of immune checkpoint inhibitors (ICIs) and platinum doublet chemotherapy. However, the efficacy and toxicity of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC are not well examined. Patients who received anti-PD-1 therapy for recurrence after CRT were identified in our clinical database. The safety and efficacy of anti-PD-1 therapy were retrospectively analyzed. From March 1, 2013 to April 30, 2018, there were 20 patients who received anti-PD-1 therapy for recurrence after CRT. The median duration from CRT to initial anti-PD-1 therapy was 9.3 months. 12 patients (60%) were alive and 7 patients (35%) were still receiving anti-PD-1 therapy at the data cutoff point (median follow-up, 13.5 months). The ORR for anti-PD-1 therapy was 45.0%. Median progression-free survival (PFS) and overall survival (OS) from initiation of anti-PD-1 therapy was 8.4 months and 26.2 months, respectively. PFS in patients who had a short interval from last CRT to initial anti-PD-1 therapy seemed to have better outcomes (duration from last CRT to initial anti-PD-1 therapy

Type III collagen is the major protein in the walls of blood vessels and hollow organs; it is decreased in patients with vascular Ehlers-Danlos syndrome (EDS). A 52-year-old man was admitted for severe back pain, and right hemothorax was suspected by chest computed tomography. Immediately after embolization for bleeding bronchial artery, aortic dissection occurred and was treated conservatively in the intensive-care unit. Vascular EDS with a mutation of COL3A1 cDNA (c.3175G>A) was diagnosed. When vascular EDS is suspected, the patient should be treated prophylactically, and a genetic examination should be performed to confirm the diagnosis.

Objective: Fractional exhaled nitric oxide (FeNO) is widely used as a biomarker of allergic airway inflammation. At present, both stationary chemiluminescence and portable electrochemical analyzers...

To evaluate volume-outcome relationship in paediatric out-of-hospital cardiac arrest (OHCA).This post hoc analysis of the SOS-KANTO 2012 study included data of paediatric OHCA patients18 years old who were transported to the 53 emergency hospitals in the Kanto region of Japan between January 2012 and March 2013. Based on the paediatric OHCA case volume, the higher one-third of institutions (more than 10 paediatric OHCA cases during the study period) were defined as high-volume centres, the middle one-third institutions (6-10 cases) were defined as middle-volume centres and the lower one-third of institutions (less than 6 cases) were defined as low-volume centres. The primary outcome measurement was survival at 1 month after cardiac arrest. Multivariate logistic regression analysis for 1-month survival and paediatric OHCA case volume were performed after adjusting for multiple propensity scores. To estimate the multiple propensity score, we fitted a multinomial logistic regression model, which fell into one of the three groups as patient demographics and prehospital factors.Among the eligible 282 children, 112, 82 and 88 patients were transported to the low-volume (36 institutions), middle-volume (11 institutions) and high-volume (6 institutions) centres, respectively. Transport to a high-volume centre was significantly associated with a better 1-month survival after adjusting for multiple propensity score (adjusted odds ratio, 2.55; 95% confidence interval, 1.05-6.17).There may be a relationship between institutional case volume and survival outcomes in paediatric OHCA.

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Although increased production of prostaglandin E2 (PGE2) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE2 production but also inhibited 6-OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type (WT) mice, but not in mPGES-1 knockout (KO) mice. Furthermore, in cultured primary mesencephalic neurons, addition of PGE2 to compensate for the deficiency of 6-OHDA-induced PGE2 production in mPGES-1 KO neurons recovered 6-OHDA toxicity to almost the same extent as that seen in WT neurons. These results suggest that induction of mPGES-1 enhances 6-OHDA-induced dopaminergic neuronal death through excessive PGE2 production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD.

Stromal cell-derived factor-1α (SDF-1α) is an inflammatory chemokine that plays a critical role in cardiovascular disease. Although persistent inflammation causes renal dysfunction, it remains unclear whether SDF-1α is related to progression of chronic kidney disease. This study examined whether high levels of SDF-1α are associated with future declines in renal function in patients with coronary artery disease (CAD). Plasma levels of SDF-1α in the peripheral blood were measured by enzyme-linked immunosorbent assay in 344 patients with CAD. All patients were followed for 24 months or until the occurrence of renal dysfunction, defined as ≥ 25% decrease in estimated glomerular filtration rate (eGFR) from baseline. During the follow-up period, 36 patients developed renal dysfunction. Multivariate logistic regression analysis showed that high plasma levels of SDF-1α were significantly associated with progression of renal dysfunction (odds ratio 1.65; 95% confidence intervals 1.07–2.35, p = 0.03). In addition, high plasma levels of SDF-1α had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.58 [0.07–1.02], p

In this study, we investigated the effects of commercially available multi-dose sodium hyaluronate 0.1% (HyaleinJapanese white male rabbits were divided into four groups. The corneas of each group exposed to one of the following solutions: sodium hyaluronate 0.1%, C12-BAC, C12, 14, 16-BAC Mixture, and Hank's Balanced Salt Solution (HBSS) (as control), respectively. Corneal transepithelial electrical resistance (TER) changes after 60 s of exposure to the above solutions were measured in living rabbits. TER reflects the barrier function of the epithelium. In addition, scanning electron microscopy was used to examine the acute effects of the above solutions on the integrity of the corneal epithelium of four groups.There was no significant decrease in the corneal TER after exposure of the cornea to HyaleinThis study confirms that Hyalein

Background and aim Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. Methods We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. Results Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. Conclusions Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

Severe papillomatosis occasionally causes astasia leading to euthanizing cattle. There are currently a limited number of reports on virologic approach in severe bovine papillomatosis. Here we report a full genome characterization of bovine papillomavirus type 1 (BPV-1) from the case of severe papillomatosis. A calf developed numerous papillomas on the skin and some nodules in the upper gastrointestinal tract at seven months old. The skin lesion was diagnosed as the epithelial papilloma with BPV antigen expression, while the gastrointestinal lesions were diagnosed as the fibropapilloma without BPV antigen. Full genome analysis revealed that BPV-1s detected in all the lesions were exactly the same. Compared with the reference BPV-1 sequence, there was a single nucleotide insertion in the upstream regulatory region.

Previous studies have demonstrated that use of intravascular ultrasound (IVUS) during percutaneous coronary intervention (PCI) was associated with lower incidence of death, myocardial infarction, and target vessel revascularization. Recently, optical coherence tomography (OCT) has emerged as an alternative intravascular imaging device with better resolution. The aim of this study was to investigate frequency and prognostic impact of IVUS or OCT-guided PCI during urgent revascularization for acute myocardial infarction diagnosed by the universal definition. A total of 2788 patients who underwent urgent PCI were selected from a multicenter, Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET). Frequency, clinical characteristics and prognostic impact of the IVUS-, or OCT- guided PCI were investigated. Clinical endpoint was in-hospital death. Angiography-, IVUS-, and OCT-guided urgent PCI were performed in 689 (24.7%), 1947 (69.8%), and 152 (5.5%) patients. In-hospital death in each group was 10.4%, 5.1%, and 3.3%, respectively (P

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P

BACKGROUND Although patients with poor ability to perform activities of daily living, such as those with high Clinical Frailty Score (CFS), will often receive a cardiac implantable electric device (CIED), the indications for implantation in these patients have not been clearly defined. We investigated the association between CFS and prognosis in patients with a CIED.Methods and Results:We retrospectively enrolled 323 consecutive patients who underwent initial device implantation (age, 77 (70-83) years; male, 181 [56%] patients; high-voltage device, 49 [15%] patients), and the CFS was retrospectively estimated. Primary outcome was all-cause death, and the secondary outcome was hospitalization due to heart failure (HF). Median CFS was 4 (3-5) points. During 2 years' follow-up, all-cause death occurred in 32 patients (10%). Freedom from all-cause death was significantly lower in patients with a high CFS than in those with a low score (1-2 points: 100%, 3-4 points: 92.9%, 5-9 points: 77.3%, P

Cell culture media influence the characteristics of human osteogenic periosteal sheets. We have previously found that a stem cell medium facilitates growth and collagen matrix formation in vitro and osteogenesis in vivo. However, it has not yet been demonstrated which culture medium is superior for osteoclastogenesis, a prerequisite for reconstruction of normal bone metabolic basis. To address this question, we compared chemotaxis and osteoclastogenesis in tissue-engineered periosteal sheets (TPSs) prepared with two types of culture media. Periosteal tissues obtained from adult volunteers were expanded with the conventional Medium 199 or with the stem cell medium, MesenPRO. Hematopoietic enhanced-green-fluorescent-protein (EGFP)-nude mice were prepared by γ-irradiation of Balb/c nu/nu mice and subsequent transplantation of bone marrow cells from CAG-EGFP C57BL/6 mice. TPSs were implanted subcutaneously into the chimeric mice and retrieved after intervals for immunohistopathological examination. EGFP+ cells were similarly recruited to the implantation site in both the TPSs prepared, whereas the distribution of CD11b+ cells was significantly lower in the TPS prepared with the stem cell medium. Instead, osteoclastogenesis was higher in the TPS prepared with the stem cell medium than in the one prepared with the conventional medium. These findings suggest that the stem cell medium is preferable for the preparation of more functional TPSs.