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In this study, we aimed to investigate the antimicrobial susceptibility of Staphylococcus saprophyticus in Japan. Additionally, we evaluated the effectiveness of different therapeutic agents and compared the differences in their outcomes in treating S. saprophyticus-induced acute cystitis, considering that cephem antibiotics are standard treatments for acute cystitis in Japan. This retrospective study was conducted at ten hospitals housing urology departments, where urologists were dispatched from the Department of Nephro-Urology, Nagoya City University Graduate School of Medicine. Initially, we prepared a list of S. saprophyticus cases detected between January 2012 and December 2021, using the bacteriological testing system of each hospital. Subsequently, we reviewed the electronic medical records of the listed cases to investigate the causative diseases, treatments, and outcomes in patients with acute cystitis. The number of S. saprophyticus samples collected in this study was 289 from urine specimens, including 157 from women with acute cystitis. All antimicrobial agents demonstrated good therapeutic efficacy in all patients, except in those who did not return for follow-up visits (30 %). Furthermore, only one case of inadequate therapeutic efficacy was observed in a patient treated with a third-generation cephalosporin. All the other patients were cured. These findings revealed that the susceptibility of S. saprophyticus to different antimicrobials did not differ considerably between the specimens from patients with acute cystitis and those from other patients, suggesting a similar trend of therapeutic efficacies of the tested antimicrobials against S. saprophyticus-induced acute cystitis., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objective: Most reported adverse events following COVID-19 vaccination have been transient. However, persistent adverse events may occur with some frequency. This study aimed to analyze patient background characteristics and trends, with a focus on whether adverse events following COVID-19 vaccination were transient or persistent., Methods: A retrospective study was performed at a single institution in Japan., Patients: The study cohort included 47 patients who presented with symptoms after COVID-19 vaccination between May 2021 and September 2023. The patients were classified into two groups based on the duration of symptoms: transient group, less than four weeks; persistent group, greater than or equal to four weeks. Data on age, sex, body mass index, smoking history, underlying conditions, type of COVID-19 vaccination, number of doses, onset, symptoms, and treatments were collected retrospectively., Results: The median age was 51.0 years and 74.5% were females, with a particularly high proportion of women in their 40s. The use of the bivalent omicron-containing booster vaccine (BA.1) was significantly more common in the persistent group than in the transient group (p = 0.0267). Onset in the transient group was more common after the first vaccination, whereas onset in the persistent group was more common after the second and subsequent vaccinations (p = 0.003). Regarding symptoms, pain was more frequent in the persistent group than in the transient group (60% vs. 13.6%; p = 0.001)., Conclusions: This study investigated the presence of persistent symptoms, especially pain, after COVID-19 vaccination. Persistent symptoms were frequently reported after the second vaccination. It should be noted that the study does not negate the usefulness of COVID-19 vaccines., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Akita University Graduate School of Medicine issued approval 3080. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Shigeharu Ueki has received grants and honoraria for lectures from AstraZeneca, honoraria for lectures from GlaxoSmithKline and Sanofi, and grants from VIB and Maruho Co. Ltd. The other authors state that they have no conflicts of interest. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hikichi et al.)

Background: Airway obstruction caused by viscous mucus is an important pathophysiologic characteristic of persistent inflammation, which can result in organ damage., Objective: We investigated the hypothesis that the biophysical characteristics of accumulating granulocytes affect the clinical properties of mucus., Methods: Surgically acquired nasal mucus samples from patients with eosinophilic chronic rhinosinusitis and neutrophil-dominant, noneosinophilic chronic rhinosinusitis were evaluated in terms of computed tomography density, viscosity, water content, wettability, and protein composition. Isolated human eosinophils and neutrophils were stimulated to induce the formation of extracellular traps, followed by the formation of aggregates. The biophysical properties of the aggregated cells were also examined., Results: Mucus from patients with eosinophilic chronic rhinosinusitis had significantly higher computed tomography density, viscosity, dry weight, and hydrophobicity compared to mucus from patients with noneosinophilic chronic rhinosinusitis. The levels of eosinophil-specific proteins in mucus correlated with its physical properties. Eosinophil and neutrophil aggregates showed physical and pathologic characteristics resembling those of mucus. Cotreatment with deoxyribonuclease and heparin, which slenderizes the structure of eosinophil extracellular traps, efficiently induced reductions in the viscosity and hydrophobicity of both eosinophil aggregates and eosinophilic mucus., Conclusions: The present study elucidated the pathogenesis of mucus stasis in infiltrated granulocyte aggregates from a novel perspective. These findings may contribute to the development of treatment strategies for eosinophilic airway diseases., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: Ipilimumab and nivolumab treatment against advanced and metastatic renal cell carcinoma (RCC) causes severe and lethal immune-related adverse events (irAEs). Predicting irAEs might improve clinical outcomes, however no practical biomarkers exist. This study examined whether eosinophils could be effective biomarkers for ≥grade 2 irAEs in RCC., Methods: We retrospectively analyzed 75 patients with RCC treated with ipilimumab and nivolumab between August 2018 and March 2021 in a multicenter study. Eosinophils were examined before and 2 weeks after treatment, and immediately after irAEs development. The optimal cut-off value for ≥grade 2 irAEs was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were undertaken to identify predictors of ≥grade 2 irAEs., Results: Two weeks after treatment, eosinophils were significantly upregulated in patients who had experienced ≥grade 2 irAEs than in those who had not experienced irAEs (mean, 5.7% vs. 3.2%; p < 0.05). The optimal cut-off value for eosinophils against ≥grade 2 irAEs was 3.0% (area under the curve = 0.69). In multivariate analyses, an eosinophil level ≥ 3.0% was a risk factor for ≥grade 2 irAEs (odds ratio 4.18, 95% confidence interval 1.16-15.1). The eosinophil level 2 weeks after treatment was upregulated by the onset of any type of irAEs including endocrine, gastrointestinal, pulmonary and skin disorders., Conclusions: An increased eosinophil level 2 weeks after treatment might be an effective biomarker for ≥grade 2 irAEs in patients with RCC treated with ipilimumab and nivolumab., (© 2023 The Japanese Urological Association.)

Objective: To identify biomarkers associated with the effectiveness of ipilimumab plus nivolumab against advanced metastatic renal cell carcinoma., Methods: We retrospectively analyzed the data of 75 patients treated with ipilimumab plus nivolumab at seven hospitals between August 2018 and April 2021. Prognostic biomarkers were assessed prior to initiating treatment with ipilimumab plus nivolumab. Median overall survival and progression-free survival were examined using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify predictors of disease progression. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors most important for predicting disease progression were determined using classification and regression tree analysis., Results: Median overall survival and progression-free survival were longer in the intermediate IMDC risk group than in the poor IMDC risk group (overall: not reached vs. 18.3 months; progression-free: not reached vs. 13.5 months). The multivariate analysis identified poor IMDC risk as a risk factor for disease progression (hazard ratio 2.61, 95% confidence interval: 1.05-6.51). Based on the results of the classification and regression tree analysis, the cohort was divided into non-anemia, anemia + neutro-Low, and anemia + neutro-High groups. Median overall survival and progression-free survival were longer in the non-anemia and anemia + neutro-Low groups than in the anemia + neutro-High group (overall: not reached vs. 29.3 months vs. 4.3 months: progression-free: not reached vs. 29.0 months vs. 3.9 months)., Conclusion: Hemoglobin and neutrophil levels may represent crucial biomarkers for predicting the effectiveness of ipilimumab plus nivolumab therapy in patients with renal cell carcinoma., (© 2023 The Japanese Urological Association.)

Aim: Acute chest pain is a commonly encountered symptom in hospital medical/surgical units; however, almost half of nurses in their second year of clinical experience in our facility have reported struggling to care for acute chest pain patients. We developed, implemented, and examined the effectiveness of a simulation-based, mastery learning clinical nursing educational program to improve self-efficacy and performance in caring for patients with acute chest pain., Methods: The study adopted a single-site, single-cohort design using simulation-based performance assessment and self-efficacy surveys on a convenience sample of 37 second-year clinical nurse participants in multi-stage hybrid mastery learning educational intervention using asynchronous e-learning, and hands-on simulation training and assessment with feedback on caring for chest pain patients. Performance assessments and self-efficacy surveys were administered pre-, post-, and 5 months post-intervention., Results: Clinical performance on the post- and 5 months follow-up assessments were significantly higher than those for the pre-test (P < .0001). The self-efficacy scores for the post- and the 5 months follow-up assessments were significantly higher than the pre-course scores (P < .0001). Participants' self-efficacy perceptions were positively correlated with their performances at 5 months post-intervention., Conclusion: Performance and self-efficacy of novice nurses in caring for acute chest pain patients improved significantly with the multi-stage hybrid mastery learning educational intervention, with improvements retained 5 months post-intervention. The results suggest the applicability of simulation-based mastery learning in a clinical setting for novice nurses to attain specific skills, and raise their self-perception of competence to care for patients in acute settings., (© 2022 The Authors. Japan Journal of Nursing Science published by John Wiley & Sons Australia, Ltd on behalf of Japan Academy of Nursing Science.)

Introduction: This study evaluated the prognostic value of a sustained high Geriatric Nutritional Risk Index (GNRI) during first-line chemotherapy for patients with metastatic urothelial carcinoma (mUC)., Methods: Between January 2018 and February 2022, 123 patients received platinum-based chemotherapy at Nagoya City University Hospital and affiliated institutions. Of these, 118 eligible patients who showed an Eastern Cooperative Oncology Group performance status (ECOG-PS) between 0 and 2 were retrospectively examined. Based on body mass index and serum albumin levels, GNRI was calculated immediately before and after the first primary chemotherapy cycle. Patients were divided into two groups based on GNRI: GNRI sustained ≥92 in sustainable (n = 63) and GNRI <92 in unsustainable (n = 55) groups, respectively. Clinical outcomes were compared., Results: No significant differences were noted between the two groups for age, gender, cycle of first-line treatment, and type of series of sequential treatments after failure of first-line therapy. Median overall survival from the start of first-line chemotherapy was 30.2 months (95% confidence interval [CI]: 20.9-NA) for sustainable and 12.6 months (95% CI: 9.0-21.2) for unsustainable groups, respectively (p < 0.05). Multivariate analysis identified ECOG-PS:2 and fatigue, an adverse event, as independent predictors of unsustainable GNRI transition (95% CI: 1.29-90.6, odds ratio [OR]: 10.8; 95% CI: 1.06-26.9, OR: 5.34, respectively)., Conclusion: Sustaining a high level of GNRI was an important prognostic indicator in patients with mUC receiving first-line chemotherapy. Appropriate intervention for controlling adverse events, including fatigue, may enhance physical strength during cancer treatment., (© 2023 S. Karger AG, Basel.)

Introduction: Health care educators are challenged with helping clinicians develop competencies beyond their foundational training. In health care systems where continuing professional development is not integral to practice, clinicians may have few opportunities. We describe the design, implementation, and evaluation of a professional development program in patient safety for Japanese clinical educators to acquire simulation instructional skills and become Patient Safety Champions at their organizations., Methods: Mixed methods were used in a longitudinal pre/post study design. The Kirkpatrick evaluation model was used to evaluate outcomes of a workshop, overall program, on-site training experiences, and impact as Patient Safety Champions. Self-assessment data on skills and knowledge of patient safety, simulation instructional methods, interprofessional collaboration, and leadership were collected and analyzed., Results: Eighty-nine percent of participants facilitated on-site patient safety training within 6 months of workshop completion. Skills and knowledge improvement were observed immediately postworkshop in four categories: patient safety, simulation instructional methods, interprofessional collaboration and communication, and leadership as a patient safety champion. Skills and knowledge increased at 6 months after facilitation of on-site safety training. Program mean satisfaction scores ranged from 84% to 92%. Mean Patient Safety Champion in-facility evaluations were 4.2 to 4.7 on a 5-point scale., Discussion: High levels of knowledge, skill retention, and behavior change are attributed to goal setting, outcome-oriented pedagogy, and reflective sessions. The Patient Safety Champion model and experiential learning approach gave Japanese clinical educators in medicine, nursing, and pharmacy an opportunity to learn from each other in simulations reflecting the practice environment., Competing Interests: Disclosures: The authors declare no conflicts of interest. This project did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Introduction: This study had two objectives: (i) to evaluate oncological outcomes in a long-term follow-up of patients with bladder cancer after reduced-port laparoscopic radical cystectomy (RP-LRC) and (ii) to assess the effect of modified Glasgow prognostic scores (mGPS) on patient outcomes., Methods: Consecutive patients (n = 100) who received RP-LRC between March 2012 and December 2018 at our institution and affiliated hospital were retrospectively reviewed. Preoperative serum albumin and C-reactive protein levels were determined. Patients were grouped based on clinical T stage (≤cT2: n = 75, ≥cT3: n = 25) using pooled cumulative data. Oncological outcomes and mGPS as a prognostic biomarker were analyzed retrospectively. Kaplan-Meier curves displayed recurrence and survival rates. Univariate and multivariate Cox regression analyses evaluated potential prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS)., Results: Patient characteristics between the two groups were statistically similar for preoperative hematological and mGPS status, blood loss level, rate of allogeneic transfusion, and pneumoperitoneum time. After a median follow-up period of 55 months, 40/100 patients experienced disease relapse. RFS and CSS for ≤cT2 were significantly less than for ≥cT3 (p < 0.001, p < 0.05, respectively). Distant metastasis occurred in 30 patients with similar distributions of relapse sites between T-stage cohorts. Median RFS for mGPS 1/2 were 18.9 (95% confidence interval [CI]: 8.8-not assessed [NA]) and 35.0 (95% CI: 8.7-NA) months, respectively, significantly worse than for mGPS 0 (median NA, 95% CI: NA-NA); CSS was similar. Univariate and multivariate analyses revealed ≥cT3 stage, worse clinical N stage, and poor mGPS status were significant prognostic factors for short RFS and CSS., Conclusions: A large proportion of bladder cancer patients who undergo RP-LRC experience relapse, with ≥cT3 stage, worse clinical N stage or poor mGPS status identified as significant prognostic factors. Our findings may contribute to improved surgical procedures for such patients., (© 2022 S. Karger AG, Basel.)

The increase of eosinophil levels is a hallmark of type-2 inflammation. Blood eosinophil counts act as a convenient biomarker for asthma phenotyping and the selection of biologics, and they are even used as a prognostic factor for severe coronavirus disease 2019. However, the circulating eosinophil count does not always reflect tissue eosinophilia and vice versa. The mismatch of blood and tissue eosinophilia can be seen in various clinical settings. For example, blood eosinophil levels in patients with acute eosinophilic pneumonia are often within normal range despite the marked symptoms and increased number of eosinophils in bronchoalveolar lavage fluid. Histological studies using immunostaining for eosinophil granule proteins have revealed the extracellular deposition of granule proteins coincident with pathological conditions, even in the absence of a significant eosinophil infiltrate. The marked deposition of eosinophil granule proteins in tissue is often associated with cytolytic degranulation. Recent studies have indicated that extracellular trap cell death (ETosis) is a major mechanism of cytolysis. Cytolytic ETosis is a total cell degranulation in which cytoplasmic and nuclear contents, including DNA and histones that act as alarmins, are also released. In the present review, eosinophil-mediated inflammation in such mismatch conditions is discussed., Competing Interests: Conflict of interest: MF received grant support from GlaxoSmithKline Japan Research Grants 2018; PA has received research support and consultancy fees from and has been on advisory boards for AstraZeneca and GlaxoSmithKline; SU received honoraria for lectures from AstraZeneca and GlaxoSmithKline as well as grant support from AstraZeneca, Novartis, and Maruho. The rest of the authors have no conflicts of interest., (Copyright © 2021. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3 + Tregs from naïve CD4 + T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the Foxp3 locus and induces Foxp3 gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β. In vivo tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3 + Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 MaruYama, Kobayashi, Nakatsukasa, Moritoki, Taguchi, Sunagawa, Morimoto, Asao, Jin, Owada, Ishii, Iwabuchi, Yoshimura, Chen and Shibata.)

The development of handling technology for microscopic biological samples such as cells and spheroids has been required for the advancement of regenerative medicine and tissue engineering. In this study, we developed micro-tweezers with a compliant mechanism to manipulate organoids. The proposed method combines high-resolution microstereolithography that uses a blue laser and topology optimization for shape optimization of micro-tweezers. An actuation system was constructed using a linear motor stage with a force control system to operate the micro-tweezers. The deformation of the topology-optimized micro-tweezers was examined analytically and experimentally. The results verified that the displacement of the tweezer tip was proportional to the applied load; furthermore, the displacement was sufficient to grasp biological samples with an approximate diameter of several hundred micrometers. We experimentally demonstrated the manipulation of an organoid with a diameter of approximately 360 µm using the proposed micro-tweezers. Thus, combining microstereolithography and topology optimization to fabricate micro-tweezers can be potentially used in modifying tools capable of handling various biological samples.

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

Eosinophils are short-lived and comprise only a small population of circulating leukocytes; however, they play surprisingly multifunctional roles in homeostasis and various diseases including allergy and infection. Recent research has shed light on active cytolytic eosinophil cell death that releases eosinophil extracellular traps (EETs) and total cellular contents, namely eosinophil extracellular trap cell death (EETosis). The pathological contribution of EETosis was made more cogent by recent findings that a classical pathological finding of eosinophilic inflammation, that of Charcot-Leyden crystals, is closely associated with EETosis. Currently no gold standard methods to identify EETosis exist, but "an active eosinophil lysis that releases cell-free granules and net-like chromatin structure" appears to be a common feature of EETosis. In this review, we describe several approaches that visualize EETs/EETosis in clinical samples and in vitro studies using isolated human eosinophils. EETs/EETosis can be observed using simple chemical or fluorescence staining, immunostaining, and electron microscopy, although it is noteworthy that visualization of EETs is greatly changed by sample preparation including the extracellular space of EETotic cells and shear flow. Considering the multiple aspects of biological significance, further study into EETs/EETosis is warranted to give a detailed understanding of the roles played in homeostasis and disease pathogenesis., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Cryptorchidism is known to impair spermatogenesis. The blood-testis barrier (BTB) becomes defined in seminiferous tubules around puberty and provides a suitable environment for germ cells. Little is known about the BTB in undescended testes (UDT)., Objectives: To determine the role of BTB during puberty in UDT using a non-surgical cryptorchid rat model., Material and Methods: Unilateral cryptorchid male rats were intraperitoneally injected with non-steroidal antiandrogen during intrauterine development; the testes were harvested at 4, 5, and 6 weeks after birth. Testicular histology, expression levels of the BTB proteins (claudin-11, occludin, zonula occludens-1), and apoptotic cells were evaluated by immunohistochemistry, Western blotting, and TUNEL assay. The functionality of the BTB was investigated by electron microscopy using the lanthanum tracer method., Results: The testicular histology of undescended testes 6 weeks after birth showed maturation arrest at the spermatocyte level. The BTB protein distributions were altered in the UDT, with a noticeable difference in claudin-11(CLDN11) localization from 4 to 5 weeks after birth between control and UDT samples. BTB protein levels were similar. More apoptotic germ cells were detected in the adluminal compartment of tubules in the UDT than in the control testes. Electron microscopy showed that the lanthanum tracer was limited to the BTB of control testes, whereas it penetrated the BTB of UDT., Discussion: Here, loss of normal BTB function and impaired spermatogenesis were observed in UDT during puberty. CLDN11 is a pivotal tight junction protein belonging to the BTB. Tight junctions are considered as essential for normal spermatogenesis, and abnormal CLDN11 organization may cause UDT-associated male infertility., Conclusion: CLDN11 disorganization within the BTB may cause spermatogenic impairment, possibly by limiting the BTB function., (© 2020 American Society of Andrology and European Academy of Andrology.)

Aim: Detection of coagulase-negative Staphylococcus in blood culture may be a result of either bacteremia or contamination. This often leads to diagnostic uncertainly. Our objective was to develop a method for differentiating whether a coagulase-negative Staphylococcus sp. positive blood culture represents bacteremia or contamination based on positive bottle detection pattern and time to positivity (TTP)., Methods: This study included 155 and 51 adults with positive blood cultures for Staphylococcus epidermidis and Staphylococcus hominis, respectively, over a three-year period from 2016 to 2018. Positive blood culture cases were categorized as either bacteremia or contamination based on the clinically available information, and the detection pattern and TTP in each category were investigated., Results: A total of 57, 92, and 6 S. epidermidis positive blood cultures were categorized as bacteremia, contamination, and undetermined, respectively, whereas 15 and 36 S. hominis positive blood cultures were categorized as bacteremia and contamination, respectively. For positive blood cultures categorized as bacteremia, all four bottles in two sets of blood cultures were positive in 47/47 S. epidermidis and 14/14 S. hominis, respectively, whereas either one bottle in each of two sets or three bottles in two sets were positive in 10/19 S. epidermidis and 1/4 S. hominis, respectively; most of those TTPs were <48 h. Among them, the TTP in catheter-related blood stream infection was <24 h., Conclusion: Although clinical assessment is crucial to differentiate between bacteremia and contamination, a combination of positive bottle detection pattern and TTP is a valuable diagnostic auxiliary tool., Competing Interests: Declaration of Competing Interest All authors confirm that there are no conflicts of interest to declare., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH., Methods: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured., Results: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 μmol/L, P = 0.001)., Conclusions: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.

In this study, a three-dimensional (3D) micromanipulator mounted on a glass capillary is developed for handling biological samples, such as multicellular spheroids and embryos. To fabricate the micromanipulator, we developed an additive manufacturing system based on high-resolution microstereolithography using a 405-nm blue laser. The fabrication system makes it possible to fabricate 3D microstructures on a glass capillary with 2.5 µm lateral resolution and 25 µm layer thickness. We also demonstrated the capture and release of a spheroid with the micromanipulator fabricated using our additive manufacturing system. We showed that spheroids can be easily handled by a simple operation with minimal damage using a cage-like multiple finger structure. Additive manufacturing of tailor-made micromanipulators mounted on a glass capillary will be useful in biological and tissue engineering research.

Introduction: Cabazitaxel (CBZ) is used worldwide for castration-resistant prostate cancer after docetaxel treatment. In July 2014 the drug was approved in Japan with the same induction dose used for Caucasian patients. In this study, we examined and compared the results of an initial low-dose CBZ treatment in patients admitted to our hospital. Patients and Methods: Between July 2014 and August 2018, sixteen mCRPC patients were enrolled and underwent a low-dose CBZ treatment at our hospital. We compared the results with those of a Japanese metastatic docetaxel- and castration-resistant prostate cancer Phase I study. Results: The median patient age was 77 years (range, 53-84 years). Of the 16 patients, eight (50%) had a lymph node metastasis and 11 (68.8%) had a distant metastasis, 10 of whom had only a bone metastasis. The median dose of CBZ was 30 mg (range, 20-32 mg) and the median number of CBZ cycles was 2.5 (range, 1-18). The PSA level of 9 (56.3%) patients decreased after CBZ treatment, including 4 (25%) who showed a decrease to <50%. The median time interval in which the PSA level decreased was 2 months (range, 1-18 months). The observed adverse events (AE) were neutropenia (31.3%), febrile neutropenia (6.3%), fatigue (43.8%), nausea (18.8%), diarrhea (12.5%), decreased appetite (25%), dysgeusia (6.3%), white blood cell count decrease (43.8%), platelet count decrease (12.3%), and anemia (75%). However, no patient listed an AE as the reason for discontinuing the treatment. Conclusions: Even at a low dose, CBZ could improve the PSA value in patients with CRPC previously treated with docetaxel. Dose reduction and prophylactic administration of sustained G-CSF were also safe treatment options. Further studies involving an introduction period including a modulation of duration and dose are necessary, especially in Japanese patients., (©2020 The Japanese Association of Rural Medicine.)

A 76-year-old Japanese man visited a nearby medical clinic complaining of abdominal distention. He had undergone extraperitoneal laparoscopic prostatectomy at our institution 5 months before the onset of abdominal distention. An imaging study revealed a large cystic lesion, and biochemical examination of a sample obtained via cyst puncture led to a diagnosis of lymphocele. As the lymphocele was resistant to puncture, drainage, and sclerotherapy with minomycin, laparoscopic fenestration was performed. Although the patient developed an adhesive ileus postoperatively, the cyst has not recurred. Fenestration surgery is a feasible option for lymphocele refractory to various conservative therapies., Competing Interests: None declared., (©2019 The Japanese Association of Rural Medicine.)

Background: Patients with metastatic urothelial carcinoma (mUC) have an uncertain prognosis. The aim of the current study was to evaluate the prognostic potential of a skeletal muscle mass reduction index measured by computed tomography (CT) for mUC patients undergoing second-line gemcitabine and docetaxel (GD) chemotherapy., Methods: We retrospectively reviewed 44 patients with mUC who received second-line GD chemotherapy between 2006 and 2015 in our hospital. Skeletal muscle area (SMA) at the third lumbar vertebra was measured using CT images obtained from medical records, and a skeletal muscle index (SMI) was calculated for each patient as: SMI = SMA / height2. Changes in SMI across timepoints (SMI inclination) were calculated as: SMI inclination = [( SMI/SMI)/duration of the interval between imaging visits]. Patients were then divided into two groups: a "steep" group (SMI inclination < -0.01) and a "gentle" group (SMI inclination ≥ -0.01). Kaplan-Meier curves and multivariate Cox proportional hazards regression models were used to evaluate the relationship between SMI inclination and overall survival (OS)., Results: There were no differences in patient characteristics between the two groups with respect to median age, gender, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), disease control rate or first-line treatment regimen. OS from the start of second-line GD therapy group was significantly shorter in the "steep" group relative to the "gentle" group. The multivariate analysis revealed that "steep" SMI inclination and presence of anemia were strong predictors of poor prognosis., Conclusion: Higher values of SMI inclination, indicating a faster rate of skeletal muscle mass reduction, may serve as a useful predictive marker for OS in mUC patients undergoing second-line GD chemotherapy.

Background: This study of umbilical catheterization deliberate practice training compared skill and knowledge outcomes of umbilical catheterization using a tissue-hybrid simulator (REAL) versus a synthetic simulated umbilical cord task trainer (ART)., Methods: This was a prospective randomized control study. Pediatric residents were randomized to REAL or ART umbilical catheterization deliberate practice training. Pre-post-training changes in skill performance and knowledge scores for REAL and ART groups were compared. Fidelity of REAL and ART were compared by neonatologists., Results: Twenty-seven pediatric residents completed training. Post-training mean skill scores were improved compared to pre-test scores (REAL, P < 0.001; ART, P < 0.0001). Post-training skill, knowledge, and self-efficacy scores were not different between the REAL and ART groups. Fidelity of REAL was higher than ART for neonatologists (P < 0.01)., Conclusions: The face validity of REAL was superior to ART, but resident umbilical cord deliberate practice training demonstrated no difference in skill, knowledge, and self-efficacy improvements between REAL and ART. Further studies on real patients are needed to evaluate the impact of using real or simulated umbilical cords for umbilical venous catheter/umbilical arterial catheter training., (© 2019 Japan Pediatric Society.)

Primary immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia caused by IgG anti-platelet autoantibodies and represents an organ-specific autoimmune disorder. Although the glycoprotein (GP)IIb/IIIa and GPIb/IX have been shown to be targets for autoantibodies, the antigen specificity of autoantibodies is not fully elucidated. To identify the characteristics of IgG B-cell receptor (BCR) repertoires in ITP, we took advantage of adaptor-ligation PCR and high-throughput DNA sequencing methods for analyzing the clone-based repertoires of IgG-expressing peripheral blood B cells. A total of 2,009,943 in-frame and 315,469 unique reads for IGH (immunoglobulin heavy) were obtained from twenty blood samples. Comparison of the IGHV repertoires between patients and controls revealed an increased usage of IGHV4-28 in ITP patients. One hundred eighty-six distinct IGHV4-28-carrying sequences were identified in ITP patients and the majority of these clones used an IGHJ4 segment. The IGHV4-28/IGHJ4-carrying B-cell clones were found in all ITP patients. Oligoclonal expansions of IGHV4-28/IGHJ4-carrying B cells were accompanied by multiple related clones with single amino substitution in the CDR3 region suggesting somatic hypermutation. Taken together, the expansion of IGHV4-28/IGHJ4-carrying IgG-expressing B cells in ITP may be the result of certain antigenic pressure and may provide a clue for the immune pathophysiology of ITP.

Objective: Bacillus Calmette-Guèrin (BCG) intravesical therapy is currently established using a low dose because of the high incidence of side-effects. Moreover, shortening the dwell time of BCG is conducted in some facilities owing to the complications associated with a long dwell time after injection. The method of BCG administration varies in each facility and even with each doctor. We evaluated whether the dwell-time and dose differences in patients who underwent intravesical BCG therapy is related to completion rates, adverse effects, and nonrecurrence rates. Methods: From November 2006 to April 2016, a total of 173 patients who received intravesical BCG therapy after transurethral resection of bladder tumor or transurethral biopsy were evaluated retrospectively. We allocated them into 4 groups based on the dose (40 or 80 mg BCG) and the dwell time (1 or 2 hours). Completion rate, side effects, and nonrecurrence rates were evaluated. Results: No significant improvement in the completion rate or reduction in side-effects was observed in any of the regimens. Although nonrecurrence rates for the 1-hour dwell time tended to be lower than the 2-hour dwell time, the difference was not significant. Conclusion: Our study suggests that reducing the BCG dose or shortening the dwell time does not reduce adverse effects or affect the nonrecurrence rate., (Creative Commons Attribution License)

Objective: UroVysion (Abbott Molecular, Inc., Illinois, USA) is based on multicolor fluorescence in situ hybridization (FISH). It has been used successfully in the USA following its Food and Drug Administration approval in 2001. However, the technology was not approved for use in Japan until 2017. Cystoscopy and urine cytology are the most frequently used examinations to detect bladder cancer in Japan, and there are only a few reports regarding the performance of UroVysion. Therefore, the aim of this study is to examine the diagnostic accuracy of UroVysion FISH in Japanese patients whose tumors are detected by cystoscopy before transurethral resection of bladder tumor (TURBT). Methods: From April 2018 to July 2018, a total of 40 patients who were diagnosed as having bladder tumors by cystoscopy, and therefore underwent TURBT were registered in this study. One day before TURBT, urine cytology and UroVysion FISH were used in order to compare the accuracy with which they could detect bladder carcinoma, as confirmed by pathological results of TURBT. Results: The pathological results of TURBT showed urothelial carcinoma in 33 cases. Urine cytology showed positive results for 0 cases (0%), suspicious results for 10 cases (30.3%), and negative results for 23 cases (69.7%). On the other hand, UroVysion FISH indicated 9 positive cases (27.3%) and 24 negative cases (72.7%). There were 19 cases of urothelial carcinoma (57.6%) that were not detected by either method. Conclusion: We conclude that UroVysion FISH alone is insufficient to detect bladder cancer and that cystoscopy is essential for the optimum detection or follow up of bladder cancer cases in our hospital., (Creative Commons Attribution License)

There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-βRII mice expressing hCD20 and human Fcγ receptors (hFcγRs). Beginning at 4-6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks' treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8 + T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells ( r = 0.7426, p = 0.0006) and between numbers of liver memory CD8 + T cells and B cells ( r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC.

Introduction: Lichen sclerosus (LS), or balanitis xerotica obliterans, is a chronic, inflammatory disease accompanied by cicatrizing skin conditions resulting in pathologic phimosis. LS can be detected clinically by the whitish appearance of the glans or the foreskin, thickened, nonretractable foreskin, dysuria, and spraying. However, diagnosis is confirmed histopathologically., Purpose: The aim of this study was to investigate whether LS can be diagnosed on the basis of clinical manifestation and symptoms., Patients and Methods: A retrospective analysis was performed, which included boys referred to our institutions for phimosis evaluation between May 2001 and December 2016. Pediatric urologists clinically diagnosed LS preoperatively. Boys with voiding problems, recurrent balanoposthitis, or who were unresponsive to topical steroid treatment underwent surgical treatment. Patients who underwent religious circumcisions were not included., Results: Three-hundred twenty boys diagnosed with phimosis were identified, and 71 (22%) boys underwent surgery. Fifty-eight boys underwent complete or partial circumcision, and 13 boys underwent a dorsal slit or preputioplasty. Thirty foreskin samples were sent for histopathologic examination. Histopathologic evaluation showed evidence of LS in 13 of 30 (43%) circumcised boys, chronic inflammation in ten (33%), no abnormality in four (13%), dysplasia in two (7%), and acute inflammation in one (3%). In the 22 boys who were clinically diagnosed with LS, 13 patients had histopathologic evidence of LS (59%). Visually, eleven cases had whitish foreskins and 21 cases had thickened nonretractable foreskins, of which there were seven (64%) ( P >0.05) and 12 (57%) ( P <0.01) cases, respectively. These cases were histopathologically diagnosed with LS. Both whitish and thickened, nonretractable foreskin was observed in eight patients, of which seven (88%) ( P <0.01) were also histologically diagnosed with LS. There was no correlation between histopathologic diagnosis and preoperative symptoms such as dysuria, ballooning, spraying, or penile pain ( P >0.2)., Conclusion: It is difficult to reliably distinguish whether a patient has histopathological LS by clinical findings alone., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Active metabolites of vitamin A, retinoic acids (RAs), are known to play critical roles in mucosal immune responses and dramatically inhibit human eosinophil apoptosis, but the detailed mechanisms have not been elucidated. We previously screened for ICAM-1 (CD54) upregulation in RA-stimulated human eosinophils by gene microarray analysis. As ICAM-1 induction and activation were observed to have a role in maintenance of eosinophil survival, we tested the hypothesis that RAs prolong eosinophil survival through ICAM-1 outside-in signaling. Blood-derived isolated eosinophils cultured with 9-cis RA and all-trans RA showed significant upregulation of ICAM-1 mRNA and cell surface expression. TTNPB, a retinoic acid receptor agonist, also induced ICAM-1 expression, while HX630, a retinoid X receptor agonist, did not. Furthermore, an RAR antagonist, HX531, completely inhibited the effect of RAs. Upregulated ICAM-1 was associated with altered kinetics of Akt, ERK, and p38 MAP kinase phosphorylation through ICAM-1 cross-linking, but an ICAM-1-blocking antibody did not affect RA-mediated cell survival. These findings indicate that RAs induce functional ICAM-1 expression through RARs, but the induced ICAM-1 does not contribute to prolongation of eosinophil survival., (Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Background: Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism., Methods: Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes., Results: In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF., Conclusions: Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.

Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo-oligosaccharides on intestinal barrier function and steatohepatitis in methionine-choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine-choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short-chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides.

Robotic-assisted procedures are gaining traction as a viable form of minimally invasive surgery in the field of reconstructive surgery. In this article, the aim is to present our initial experience and clinical outcomes of robot-assisted laparoscopic pyeloplasty (RAL-P). We performed RAL-P in 22 patients for the management of ureteropelvic junction obstruction between December 2012 and August 2015. The da Vinci® S surgical system was utilized for all cases. All procedures were performed via a transperitoneal approach. We assessed perioperative outcomes, and furthermore, compared between pediatric and adult patients undergoing this procedure. Dismembered procedures were performed in 19 patients. Three patients underwent Y-V plasty, and two patients who experienced failure during the primary pyeloplasty had to undergo reoperation. Although the console time for pediatric patients was significantly shorter than that of adults (123.1 ± 18.3, 162.4 ± 23.9 min, respectively, p < 0.001), success rate was not significantly different between pediatric and adults (100 vs 90 %, p = 0.512). According to a comparison of surgical outcomes by age, the console time was significantly shorter in pediatric than in adult patients. This finding may be attributable to the differences in intraabdominal fatty tissues. Besides, RAL-P with Y-V plasty was applicable even for cases of failed pyeloplasty. In conclusion, the surgical outcomes of RAL-P were favorable and safe for both pediatric and adult patients, and comparable to findings of previous reports. To our knowledge, this is the first report of a case series of RAL-P in Japan.

Impacted stones frequently cause changes in the ureter, including edema of the ureteral wall, stone embedding in the ureteral mucosa or ureteral bending, which often preclude spontaneous passing of the stone and increase the risk of complications during surgery. When stone impaction is suspected preoperatively, management should be adapted accordingly. However, surgical treatment strategies remain controversial in pediatric patients because of the scarcity of cases reported. We describe the case of a 2-year-old girl with a right impacted ureteral stone who presented with gross hematuria and pyuria, but no metabolic risk factors or hematological abnormalities. Ureteroscopy was carried out in the presence of a percutaneous nephrostomy catheter. At the 7-month follow up, hydronephrosis had improved from grade 3 to grade 1, and the ureter was free from residual or recurrent stones. No complications were noted. We believe that percutaneous nephrostomy before the lithotripsy facilitates treatment for impacted stones in pediatric patients., (© 2017 The Japanese Urological Association.)

Objectives: Primary mediastinal germ cell tumors (PMGCTs) are rare, which often makes them difficult to treat. Herein, we examined patients with PMGCTs who underwent multimodal treatment., Methods: We examined 6 patients (median age: 25 years, range: 19-27 years) with PMGCTs who underwent multimodal treatment between April 2001 and March 2015. Three patients had seminomas, 2 patients had yolk sac tumors, and 1 patient had choriocarcinoma. The median observation period was 32.5 months (range: 8-84 months)., Results: Three of the 6 patients received initial operation followed by 3-4 courses of chemotherapy (bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP)). One patient developed multiple lung metastases 17 months after surgery; received salvage chemotherapy with vinblastine, ifosfamide, and cisplatin; and achieved complete remission. The remaining 3 patients received initial BEP and EP chemotherapy. Multiple lung metastases and supraclavicular lymph node metastases were detected in 2 of these patients at the initial diagnosis. The patients underwent resections to remove residual tumor after treatment, and no viable tumor cells were found., Conclusions: Reliable diagnosis and immediate multimodal treatments are necessary for patients with PMGCTs. The 6 patients treated in our hospital have never experienced recurrence after the multimodal treatment.

Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is now recognized as a humoral mediator in inflammatory and immune responses. Previous studies indicated that HGF negatively regulated allergic airway inflammation. In view of eosinophils playing a role in the pathogenesis of asthma, especially in airway remodeling as a rich source of pro-fibrogenic mediators, the effects of HGF on the different types of eosinophil secretory functions were examined in this study. We found that HGF significantly inhibited IL-5-induced secretion of TGF-β and VEGF from human eosinophils. The inhibitory effect is not associated with TGF-β transcription; rather, it is associated with ultrastructural granule emptying and loss of intracellular TGF-β contents, indicating HGF inhibits the process of piecemeal degranulation. The effect of HGF on extracellular trap cell death (ETosis) that mediates cytolytic degranulation was also investigated; however, immobilized IgG- or phorbol myristate acetate-induced ETosis was only minimally attenuated by HGF. These results reveal the effect of HGF on the distinct pathways of eosinophil secretory functions and also provide novel insights into the role of HGF in the pathogenesis of allergic inflammation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In our previous report, M2-macrophage (Mφs) deficient mice showed increased renal calcium oxalate (CaOx) crystal formation; however, the role of Mφs-related-cytokines and chemokines that affect kidney stone formation remains unknown. Here, we investigated the role of M1/M2s in crystal development by using in vitro and in vivo approaches. The crystal phagocytic rate of bone marrow-derived M2Mφs was higher than that of bone marrow-derived Mφs and M1Mφs and increased on co-culture with renal tubular cells (RTCs). However, the amount of crystal attachment on RTCs reduced on co-culture with M2Mφs. In six hyperoxaluric C57BL/6J mice, M1Mφ transfusion and induction by LPS and IFN-γ facilitated renal crystal formation, whereas M2Mφ transfusion and induction by IL-4 and IL-13 suppressed renal crystal formation compared with the control. These M2Mφ treatments reduced the expression of crystal-related genes, such as osteopontin and CD44, whereas M1Mφ treatment increased the expression of pro-inflammatory and adhesion-related genes such as IL-6, inducible NOS, TNF-α, C3, and VCAM-1. The expression of M2Mφ-related genes was lower whereas that of M1Mφ-related genes was higher in papillary tissue of CaOx stone formers. Overall, our results suggest that renal crystal development is facilitated by M1Mφs, but suppressed by M2Mφs.

Background: Activated human eosinophils, as well as neutrophils, can release extracellular chromatin to form DNA traps through cytolytic extracellular trap cell death (ETosis). Although formations of neutrophil DNA traps are recognized in patients with various inflammatory conditions, neither the presence of ETosis-derived eosinophil DNA traps in human allergic diseases nor the characteristics of these DNA traps have been studied., Objective: We investigated the presence of ETosis-derived DNA traps in eosinophil-rich sinus and ear secretions and the functional attributes of ETosis DNA traps., Methods: Eosinophil-rich secretions obtained from patients with eosinophilic chronic rhinosinusitis and eosinophilic otitis media were studied microscopically. In vitro studies of ETosis and DNA trap formation used blood-derived eosinophils and neutrophils, and studies of the binding capacities of DNA traps used labeled bacteria and fluorescent microbeads. Stabilities of DNA traps were evaluated by using fluorescence microscopy., Results: Abundant nuclear histone H1-bearing DNA traps formed in vivo in the eosinophilic secretions and contributed to their increased viscosity. In vitro, after brief shear flow, eosinophil ETosis-elicited DNA traps assembled to form stable aggregates. Eosinophil DNA traps entrapped bacteria and fungi and, through hydrophobic interactions, microbeads. In comparison with neutrophil-derived DNA traps, eosinophil DNA traps ultrastructurally exhibited thicker fibers with globular structures and were less susceptible to leukocyte-derived proteolytic degradation, likely because of the lesser protease activities of eosinophils., Conclusions: In human allergic diseases local cytolysis of eosinophils not only releases free eosinophil granules but also generates nuclear-derived DNA traps that are major extracellular structural components within eosinophil-rich secretions., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Here, we report the case of a 62-year-old man with neuroblastoma, which is extremely rare in adults. His tumor was resected, but it recurred four months later. Radiotherapy reduced tumor size, and the patient remained in good health three years after surgical tumor removal. The residual tumor and the treatments administered to this patient were evaluated. We have also reviewed the literature.

Background: To examine the steady state of hepatic myeloid-derived suppressor cells (MDSCs) and the lipid accumulation and inflammation-related changes in these cells, we analyzed the presence and functions of hepatic MDSCs in the following two non-alcoholic steatohepatitis (NASH) mouse models., Methods: Monosodium glutamate (MSG) model; MSG was subcutaneously injected into neonatal male C57BL/6J mice that were fed with normal diet up to 18 weeks of age. Methionine/choline-deficient diet (MCD) model; 16-week-old male C57BL/6J mice were fed with an MCD for 2 weeks. Those hepatic MDSCs were evaluated by flow cytometry and immunohistochemically., Results: Both MSG and MCD mice exhibited greater numbers of hepatic lipid droplets than 18-week-old male control mice. Hepatocellular ballooning was obvious in MSG, whereas inflammatory cell infiltration were apparent in MCD mice. CD11b, CD115, and Gr-1-positive hepatic MDSCs were increased in both models but higher in MCD mice, and demonstrated higher expression of an M2 macrophage marker CD206 mean fluorescence intensity (MFI) in MSG compared to MCD mice. Degree of reactive oxygen species production was evaluated using the DCFDA MFI values, which were significantly elevated in hepatic MDSCs from MCD mice. MSG mouse livers demonstrated Gr-1 positive cell accumulation around lipid droplets, mimicking crown-like structures in adipose tissues. In contrast, hepatic Gr-1 positive cells were primarily located in inflammatory cell aggregates in MCD mice., Conclusions: These results suggest that hepatic fatty changes promote MDSC accumulation, and inflammatory changes induce phenotypic and functional alteration in hepatic MDSCs in NASH mouse models.