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Abstract Objective To evaluate whether patients with COVID-19 who have tested re-positive with the PCR test for the SARS-CoV-2 virus are infectious is a challenge in the current circumstances. A follow-up survey was conducted with healthcare personnel (HCP) who were exposed to a patient whose PCR test results for SARS-CoV-2 were re-positive 18 days after the initial confirmation of negative PCR results. Results We studied a total of 15 HCP who had contact exposures (15/15) and aerosol exposures (7/15). None of them tested positive for IgG against SARS-CoV-2 on blood examination. None of them had any symptoms during 10 days of active isolation. All PCR tests conducted using the nasopharyngeal swabs collected from the HCP on day 10 were negative. No apparent infection was found in any of the HCP who had contact exposure with and/or aerosol exposure to the patient whose PCR test results for SARS-CoV-2 were re-positive 18 days after the initial confirmation of negative results of PCR tests for SARS-CoV-2. Clinical trial: Trial Registration: No. 170, approved June 10th, 2020 by the ethics committee of Sakai City Medical Center.

Abstract Background IgE reactivity to fish allergens in atopic dogs, which are used as models for food allergy, has not been elucidated to date. We investigated IgE reactivity to crude extracts and purified allergens derived from the Pacific cod (Gadus macrocephalus) in atopic dogs to identify the allergenic proteins of cod. Results The levels of specific IgE to crude cod extracts were measured in the sera of 179 atopic dogs, including 27 dogs with cod allergy, using enzyme-linked immunosorbent assay (ELISA). Specific IgE to crude cod extracts were present in 36 (20%) of the 179 atopic dogs and in 12 (44%) of the 27 dogs with cod allergy. The allergens in crude cod extracts were analyzed by ELISA, immunoblotting, and liquid chromatography-tandem mass spectrometry. In allergen component analysis, IgE reactivity to tropomyosin and enolase was observed in the sera of dogs with cod allergy. IgE reactivity to parvalbumin, collagen, and tropomyosin was evaluated using the sera of atopic dogs that tested positive for specific IgE to crude cod extracts. Among the 36 dogs with IgE reactivity to crude cod extracts, 9 (25%), 14 (39%), and 18 (50%) dogs tested positive for specific IgE to parvalbumin, collagen, and tropomyosin, respectively. Conclusions The IgE reactivity to cod allergens observed in dogs was similar to that in humans, and this finding further supports the use of atopic dogs with fish allergy as a model for fish allergy in humans.

Objectives: In recent years, CapeOX therapy for patients with colorectal cancer is widely used. We previously reported that a multidisciplinary approach decreases the worsening of adverse events and increases patient satisfaction. In this study, we conducted a multicenter, prospective, observational study to evaluate the incidence of adverse events, health-related quality of life (HRQOL) of the patient, and efficacy of a management (intervention) according to the support system (SMILE study). Methods: As the interventional method, the following more than one method was carried out in each institute, 1: support with telephone, 2: dosing instruction by a pharmacist, 3: skin care instruction by a nurse, and 4: patient instruction by a doctor. The primary endpoint was the incidence of hand-foot syndrome (HFS) of more than grade 2. The secondary endpoint was the HRQOL evaluation and efficacy. The questionnaire (HADS) was administered before the start of the chemotherapy and in 1, 2, 4, 5, and 8 courses to evaluate quality of life (QOL). Results: From April 2011 to September 2012, 80 patients were enrolled from 14 sites, and all patients were the subjects of analysis. The demographic background was as follows: man/woman: 46/34, age median: 63 (36-75), and management interventional method 1/2/3/4: 36/68/73/78. The overall percentage of HFS that exceeded grade 2 within 6 months was 16.3%. It was 11.1% with the telephone support group and 20.5% without the telephone support group (p = 0.26). Conclusions: A multi-professional telephone support may reduce the deterioration of HFS. Further study which includes larger cohort is needed in the future.

Abstract Background Interferon and ribavirin have been used as therapeutic agents for chronic hepatitis C infection or C-compensated cirrhosis in the conventional treatment. Hepatitis C virus (HCV) -specific direct-acting antiviral agents that directly inhibit the growth process of HCV have been approved since 2011. However, in the early post-marketing vigilance phase of ledipasvir acetonate/sofosbuvir (LDV/SOF), there were reports of interstitial lung disease in 4 out of 32,700 cases with death in 1 case; the onset mechanism is unknown. Case presentation Treatment for hepatitis C was deemed to be necessary, and the patient was referred to our hospital. Oral administration of LDV/SOF was started. On day 8 of administration, a fever of 38–39 °C and coughing were observed followed by the gradual appearance of shortness of breath. As there was no improvement, the patient visited her primary care physician on day 16 of administration and the patient was brought urgently to our hospital on the same day. Blood tests and imaging tests were conducted at our hospital on the day of emergency transport; inflammatory response markers showed abnormal values, and sialylated carbohydrate antigen Krebs von den Lungen-6 was within the normal value range at 303 U/mL. Because the possibility of infection was low based on results of imaging and bronchoalveolar lavage, drug-induced lung disease was suspected, LDV/SOF administration was discontinued, and steroid administration was started. Following steroid pulse therapy, treatment with oral prednisolone tablets was gradually tapered. The patient’s symptoms were relieved and she was discharged. Conclusions The patient’s medication history in this case indicated that there were no drugs taken before or after administration of LDV/SOF until the adverse reaction occurred, and there were no supplements or dietary supplements taken. Therefore, LDV/SOF has been proposed as the cause of the suspected adverse effect. Pharmacists should try to collect adverse effect reports to identify adverse effects early.

The Polar Environment Data Science Center (PEDSC) is one of the centers of the Joint Support-Center for Data Science Research (DS) of the Research Organization of Information and Systems (ROIS), which was established in 2017. The purpose of the PEDSC is to promote the opening and sharing of the scientific data obtained by research activities in the polar region led by the National Institute of Polar Research (NIPR). Activities of the PEDSC have been carried out along a five year plan with the following seven specific tasks since 2017: (1) construction of an integrated database; (2) upgrade and interoperable use of the three existing database systems (NIPR Science Database, Arctic Data archive System (ADS), and Inter-university Upper atmosphere Global Observation NETwork system (IUGONET)); (3) processing of the time-series digital data; (4) processing of the sample data; (5) data publication in the Polar Data Journal; (6) collaboration with external communities; and (7) promoting data science using the database and database system.

The aims of this study were to investigate otolith dysfunction, especially isolated otolith dysfunction (with preserved semicircular canal function) in persistent postural-perceptual dizziness (PPPD) patients. Twenty-one patients who had been diagnosed with PPPD were enrolled in this study. The subjects filled out questionnaires [the Dizziness Handicap Inventory (DHI) and the Niigata PPPD Questionnaire (NPQ)] and underwent vestibular evoked myogenic potential (VEMP) tests, video head-impulse tests (vHIT), and stabilometry. Among the 21 subjects with PPPD, 9 showed isolated otolith dysfunction, 4 exhibited both otolith dysfunction and semicircular canal dysfunction, and 2 demonstrated isolated semicircular canal dysfunction. Six subjects exhibited normal VEMP and vHIT results. Concerning the subjects' questionnaire scores and stabilometric parameters, there were no significant differences among subgroups when the subjects were classified according to their VEMP and vHIT results while stabilometric parameters obtained in PPPD subjects were significantly increased than published data of healthy subjects. As precipitating conditions for PPPD, vestibular neuritis was the most frequent and the second most was idiopathic otolithic vertigo. In conclusion, the majority of PPPD patients had otolith dysfunction, and most of them showed isolated otolith dysfunction. Idiopathic otolithic vertigo can be a precipitating factor of PPPD. While otolith dysfunction may be associated with initiation of PPPD symptoms, PPPD symptoms are also considered to be associated with other dysfunctions of the sensory processing system.

Anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies are two major myositis-specific autoantibodies with distinct clinical features. However, the clinical course remains unclear in patients with clinically amyopathic dermatomyositis (CADM)-interstitial lung disease (ILD) who have co-existing anti-MDA5 and anti-ARS antibodies. Here, we describe the case of a 32-year-old woman with CADM-ILD who had anti-MDA5 and anti-PL12 antibodies. Her serum ferritin level was within the normal range. However, chest computed tomography revealed bilateral lower-lobe consolidation and ground-glass opacities. Treatment with prednisolone and immunosuppressants was successful in improving the skin lesion and ILD, but relapse occurred on reducing the dose of prednisolone. These clinical features match those of anti-ARS antibody-positive dermatomyositis-ILD. Because these two conditions show significantly different clinical features and require different intensities of treatment, clinicians should carefully follow-up these patients throughout the course of the disease.

Proliferating trichilemmal tumor (PTT) is a rare adnexal neoplasm of the hair follicle, which is usually detected on the scalp. We herein present a case of a PTT-like neoplasm arising in the external auditory canal (EAC). A man in his early sixties visited our hospital with a chief complaint of prolonged otorrhea. He underwent tympanoplasty on the basis of EAC cholesteatoma diagnosed at a local hospital, but otorrhea and debris recurred after the operation. Sixteen months after the first operation he was referred to our hospital. His EAC was filled with white debris, and computed tomography showed increased soft tissue density in the EAC and the middle ear. We performed a second operation, removing the entire circumference of EAC skin. Histopathological evaluation showed trichilemmal keratinization, which is characteristic of PTT. We concluded the patient had a PTT-like neoplasm. The tumor unfortunately became malignant fifteen months after the second operation. It is important to keep this clinical entity in mind when treating a patient with abnormal skin lesions in the EAC, as in this case presentation.

The origin of the stapes footplate has been controversial for decades, especially regarding involvement of the otic capsule in the development of the footplate. We report two cases of stapes malformation in which the stapes footplate was absent, while the oval window was formed but was covered with mucosal membrane. Both the patients visited our department for long-standing hearing loss, which was due to congenital ossicular anomalies of rare variation, as suggested by intraoperative findings. Through two operated cases, we have also discussed the origin and the mechanisms in the development of the stapes and the oval window. The findings suggest that the formation of the oval window is independent from the development of the stapes footplate. Further reports and accumulation of cases with ossicular malformation are required to develop an appropriate classification of congenital ossicular anomalies based on both developmental mechanisms and analyses of the surgical outcomes.

Abstract Background Malignant peritoneal mesothelioma is a rare aggressive tumor of the peritoneum. We report a rare case of resection of multiple localized malignant peritoneal mesotheliomas. Case presentation A 55-year-old Japanese woman was admitted to our hospital because liver tumors were detected by abdominal ultrasonography during a screening examination. Blood examination findings, including tumor makers, were within normal ranges. She had no evidence of exposure to asbestos. Computed tomography showed four hypervascular, round liver tumors, one in the lateral liver segment adjacent to the hepatic hilus, and the other three on the liver surface. Computed tomography angiography revealed that the tumor in the lateral segment had strong enhancement and was fed from the left gastric artery. In contrast, the other tumors showed no enhancement, and were fed from the right inferior phrenic artery. Abnormal accumulation was identified in the four tumors only with 18F-fluorodeoxyglucose positron emission tomography. It was very difficult to obtain a definitive preoperative diagnosis, but surgical resection was performed because we considered potential malignancy. Laparotomy revealed the principal site of the tumor in the lateral segment was on the hepatoduodenal ligament, and all other tumors were on the diaphragm. A left lobectomy and partial diaphragmatic resection were performed. The final pathological diagnosis was multiple malignant epithelioid mesotheliomas. Our patient has had no recurrence for 20 months postoperatively. Conclusions In general, malignant peritoneal mesotheliomas are classified as diffuse tumors, which are often unresectable and have a poor prognosis. However, early diagnosis and treatment, particularly with the localized type, as in our patient, could lead to long-term survival of the patient. We recommend that multiple malignant epithelioid mesotheliomas be included in the differential diagnosis for patients with subcapsular hepatic tumors.

Summary: Although pluripotent stem cells can generate various types of differentiated cells, it is unclear why lineage-committed stem/progenitor cells derived from pluripotent stem cells are decelerated and why the differentiation-resistant propensity of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived cells is predominant compared with the in vivo equivalents derived from embryonic/adult tissues. In this study, we demonstrated that iPSCs reprogrammed and maintained with three chemical inhibitors of the fibroblast growth factor 4-mitogen-activated protein kinase cascade and GSK3β (3i) could be differentiated into all three germ layers more efficiently than the iPSCs reprogrammed without the 3i chemicals, even though they were maintained with 3i chemicals once they were reprogrammed. Although the iPSCs reprogrammed with 3i had increased numbers of Zscan4-positive cells, the Zscan4-positive cells among iPSCs that were reprogrammed without 3i did not have an accelerated differentiation ability. These observations suggest that 3i exposure during the reprogramming period determines the accelerated differentiation/maturation potentials of iPSCs that are stably maintained at the distinct state. : Mouse iPSCs reprogrammed and maintained with three chemical inhibitors of the FGF4-MAPK cascade and GSK3β (3i; PD184352, CHIR99021, and SU5402) could be differentiated into all three germ layers efficiently and contain increased numbers of Zscan4, a 2-cell stage marker, positive cells. Keywords: induced pluripotent stem cells (iPSCs), culture conditions, 3i, differentiation potentials, Zscan4, 2-cell genes

Background: Although hen's egg (HE) allergy was thought to be usually resolved by late childhood, majority of HE allergy patients with a high level of egg white (HEW)-specific IgE could not acquire tolerance for HE by age 8 years.Objective: The aim is to investigate whether the avoidance of HE until 6 years of age increased the risk of heated HE allergy at age 6 years.Methods: This was a retrospective case-control study. The HE tolerance children (n = 17) and children with low-dose HE reactor [a positive reaction to ≤ 4 g of heated HEW in oral food challenges (OFCs)] children (n = 26) were included based on the results of OFC at 6 years old. Multivariate logistic regression analysis was applied to examine the associations between HE avoidance until age 6 years and HE allergy status confirmed by OFC, adjusting the level of ovomucoid-specific IgE (OM-sIgE) during early infancy.Results: A lower proportion of strict avoidance of HE was observed in the HE tolerance group than in the low-dose HE reactor group (6 vs. 46%, p = 0.006). OM-sIgE levels in children younger than 2 years old were significantly higher in the low-dose HE reactor group than those in the HE tolerance group (median [interquartile], 26.7 UA/mL [11.9–53.4] vs. 7.9 UA/mL [0.35–23.4]; p =0.024). The avoidance of HE until 6 years of age increased the risk of heated HE allergy even after adjusting OM-sIgE levels.Conclusions: The long-term avoidance of HE from infancy increased the risk of heated HE allergy confirmed by OFC at age 6 years.

Allergic rhino-conjunctivitis with pollen allergy has been prevalent worldwide and Pollen-food allergy syndrome (PFAS) refers to individuals with pollen allergy who develop oral allergy syndrome (OAS) on consuming fruits and vegetables. The prevalence of PFAS varies by region and that in Japanese adolescents remains to be elucidated. In this cross-sectional study, we examined the epidemiological characteristics of PFAS in a general population of Japanese adolescents according to pollen allergy, OAS, and IgE component sensitization. Participants comprised adolescents, at age 13 years, from a prospective birth cohort study in Japan. We administered questionnaires to collect information from parents regarding pollen allergy, PFAS and OAS at each child's age 13 years. ImmunoCAP ISAC was used to assess IgE component sensitization. Among 506 participants with a complete questionnaire and ISAC measurement results, 56.5% had a history of hay fever, 16.0% had a history of OAS, 51.0% had pollen allergy, and 11.7% had a history of PFAS; additionally, 72.7% were sensitized to one or more tree, grass, and/or weed allergens. The most common sensitization (95.7%) among adolescents with pollen allergy was to Japanese cedar (Cry j 1). The most common causal foods were kiwi and pineapple (both 39.0%). Knowledge levels about PFAS were poor among affected adolescents. We found a high prevalence of PFAS among adolescents in Japan. Although it affects approximately 1/10 adolescents in the general population, public awareness regarding PFAS is poor. Interventional strategies are needed to increase knowledge and to prevent PFAS in the general population.

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

Background: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases. Methods: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center. Results: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively. Conclusions: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our ‘classic’ KD at the present stage.

Purpose. To investigate the factors that contribute to the exceptionally high affinity binding of UCN-01 to human α1-acid glycoprotein (hAGP).Methods. Interactions between UCN-01, UCN-02, and staurosporine with native and chemically modified hAGPs were examined using ultracentrifugation and spectroscopic analysis.Results. The binding affinity of staurosporine, as well as UCN-02, to hAGP was lower than that of UCN-01 by 20- and 100-fold respectively. The percentage of UCN-01 that binds to hAGP was low at acidic pH but increased with increasing pH, reaching a maximum at pH 7.4. The binding of UCN-01 to desialylated hAGP was comparable to that of hAGP. No significant difference was found for the binding of UCN-01 to F1*S and A variants of hAGP. Chemical modification of the His, Lys, Trp, and Tyr residues caused a decrease in percentage of bound UCN-01. Trp-modified hAGP showed the largest decrease in binding. Tryptophanyl fluorescence quenching results indicate that Trp residues play a prominent role in the binding of UCN-01 to hAGP.Conclusions. A substituent at position C-7 of UCN-01 appeared to influence the binding specificity of the drug, and Trp residues in hAGP play a prominent role in the high affinity binding of UCN-01 to hAGP. [ABSTRACT FROM AUTHOR]

Background: There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. Methods: In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160 mg/m2/day for six cycles of 1 week on and 1 week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). Findings: Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160 mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10 mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40 mg/m2/day cohort, and improved in one patient by 3 points in the 160 mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10 mg/m2/day cohort, and improved in one patient in the 40 mg/m2/day cohort. Interpretation: This study showed that administration of 10 or 40 mg/m2/day intravenous PRI-724 over 12 weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160 mg/m2/day cohort. Funding Source: AMED.

Repair of cyclobutane pyrimidine dimers requires access to DNA by the nucleotide excision repair machinery. Here the authors show that HBO1 facilitates accumulation of SNF2H and ACF1 to make chromatin more accessible after ultraviolet damage.

BACKGROUND:Spontaneous pneumothorax is a complication that occurs in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD); however, few studies on the clinical implications of pneumothorax for patients with CTD-ILD have been performed. OBJECTIVES:This study aimed to investigate the incidence and prognostic significance of pneumothorax and the risk factors for its onset in patients with CTD-ILD. METHODS:This study included 140 consecutive patients with CTD-ILD. Clinical characteristics, laboratory findings, pulmonary function test results, and chest high-resolution computed tomography (HRCT) images were retrospectively evaluated. RESULTS:A total of 18 patients (12.9%) developed pneumothorax during their clinical course. The cumulative incidence of pneumothorax from the time of CTD-ILD diagnosis was 6.5%, 8.7%, and 11.3% at 1, 3, and 5 years, respectively. The 10-year survival rate was significantly lower in patients with pneumothorax (29.6%) than that in those without pneumothorax (81.3%). The development of pneumothorax was significantly associated with poor prognosis (HR 22.0; p < 0.010). Furthermore, a lower body mass index, greater extent of reticular abnormalities on HRCT, and administration of methylprednisolone pulse therapy were significantly associated with the development of pneumothorax. CONCLUSION:Pneumothorax is a serious complication in the clinical course of patients with CTD-ILD and the onset of pneumothorax predicts a poor outcome.

BackgroundIn Japan, swimming school attendance is promoted as a form of therapy or as a prophylactic measure against asthma in young children. However, the putative beneficial effects have not been sufficiently verified.ObjectiveThe aim of the present study was to clarify whether or not swimming school attendance at age 3 years affects the onset and/or improvement of wheeze and rhinitis at age 5 years.MethodsThis study was a single-center, prospective, general, longitudinal cohort study (T-CHILD Study). Between November 2003 and December 2005, 1776 pregnant women were enrolled, and their offspring were followed up until age 5 years. Swimming school attendance at age 3 years and the presence of wheeze and/or rhinitis in the previous one year were examined using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. The relationship between swimming school attendance and wheeze and/or rhinitis was analyzed using multivariable logistic regression analysis.ResultsData on the 1097 children were analyzed. At age 3 years, 126 (11.5%) children attended a swimming school, and at age 5 years, the prevalence of wheeze was 180 (16.4%) while that of rhinitis was 387 (35.3%). Swimming school attendance at age 3 showed no significant relationship with the development of either wheeze (aOR 0.83, 95% CI (0.43-1.60) or rhinitis (aOR 0.80, 95% CI (0.43-1.60) at age 5.ConclusionsSwimming school attendance at age 3 years showed neither a preventive nor therapeutic effect on wheeze or rhinitis at age 5 years. There is thus no scientific evidence yet that swimming school attendance has a positive impact on the development of childhood wheeze or rhinitis.

Nature Communications 8: Article number: 16102 (2017); Published online 18 July 2017; Updated 20 April 2018 The original version of this Article contained an error in Fig. 1b, in which the cells were incorrectly labelled as ‘HeLa’, rather than the correct ‘HEK293’ Also, the following was omitted from the end of the legend of Fig.

Resident macrophages reside in all tissues throughout the body and play a central role in both tissue homeostasis and inflammation. Although the inner ear was once believed to be “immune-privileged,” recent studies have shown that macrophages are distributed in the cochlea and may play important roles in the immune system thereof. Resident macrophages have heterogeneous origins among tissues and throughout developmental stages. However, the origins of embryonic cochlear macrophages remain unknown. Here, we show that the early development of resident macrophages in the mouse cochlea depends on yolk sac hematopoiesis. Accordingly, our results found that macrophages emerging around the developing otocyst at E10.5 exhibited dynamic changes in distribution and in situ proliferative capacity during embryonic and neonatal stages. Cochlear examination in Csf1r-null mice revealed a substantial decrease in the number of Iba1-positive macrophages in the spiral ganglion and spiral ligament, whereas they were still observed in the cochlear mesenchyme or on the intraluminal surface of the perilymphatic space. Our results demonstrated that two subtypes of resident macrophages are present in the embryonic cochlea, one being Csf1r-dependent macrophages that originate from the yolk sac and the other being Csf1r-independent macrophages that appear to be derived from the fetal liver via systemic circulation. We consider the present study to be a starting point for elucidating the roles of embryonic cochlear resident macrophages. Furthermore, resident macrophages in the embryonic cochlea could be a novel target for the treatment of various inner ear disorders.

Background/objective The ADL-focused Occupation-based Neurobehavioral Evaluation (A-ONE) can be used to evaluate both performances of activities of daily living (ADL) tasks and neurobehavioural problems that interfere with ADL task performance among clients with neurological disorders. Research studies have demonstrated acceptable psychometric properties of the original version of the A-ONE as well as the Rasch analysed version. The aim of this study was to examine the reliability and validity of the Japanese version of the A-ONE (A-ONE J). Methods Rasch analysis was performed on data obtained from eight different hospitals in Japan on performances of 150 individuals diagnosed with a stroke based on the functional independence (FI) scale items. The rating scale structure was investigated and internal validity and reliability were examined. Unidimensionality of the items was examined by mean square infit values and principal component analysis of residuals. The targeting between person ability and item difficulty was explored, as well as the separation reliability. Finally, psychometric values and item difficulty hierarchies obtained in this study were compared to the original Rasch analysis of the A-ONE. Results The rating scale structure might be improved by collapsing two categories twice (from five categories to three categories). Unidimensionality of the items was obtained for 20 items. Targeting was acceptable, and separation reliability for item calibrations was high and acceptable for people. Conclusion/limitations: This study provides important information regarding the possibilities for revising the ordinal A-ONE J FI Scale, converting it into a unidimensional scale. Further study with increased and more diverse sample is needed.

Abstract DIAPH1 encodes human DIA1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH1 mutation causes autosomal dominant nonsyndromic sensorineural hearing loss, DFNA1, characterized by progressive deafness starting in childhood. The mutation occurs near the C‐terminus of the diaphanous autoregulatory domain (DAD) of DIA1, which interacts with its N‐terminal diaphanous inhibitory domain (DID), and may engender constitutive activation of DIA1. However, the underlying pathogenesis that causes DFNA1 is unclear. We describe a novel patient‐derived DIAPH1 mutation (c.3610C>T) in two unrelated families, which results in early termination prior to a basic amino acid motif (RRKR1204–1207) at the DAD C‐terminus. The mutant DIA1(R1204X) disrupted the autoinhibitory DID‐DAD interaction and was constitutively active. This unscheduled activity caused increased rates of directional actin polymerization movement and induced formation of elongated microvilli. Mice expressing FLAG‐tagged DIA1(R1204X) experienced progressive deafness and hair cell loss at the basal turn and had various morphological abnormalities in stereocilia (short, fused, elongated, sparse). Thus, the basic region of the DAD mediates DIA1 autoinhibition; disruption of the DID‐DAD interaction and consequent activation of DIA1(R1204X) causes DFNA1.

In 1985, a hepatitis B (HB) vaccination strategy against vertical HB virus transmission was introduced in Japan that recommended vaccination of infants at two, three, and five months of age (delayed strategy). This schedule was revised in 2013, recommending to vaccinate at birth and at 1 and 6 months of age (non-delayed strategy). We aimed to compare the vertical HB virus transmission rates and immunogenic responses between these two vaccination strategies. This Japanese multicenter prospective cohort study included 222 infants born between 2008 and 2017 to serum hepatitis B surface (HBs) antigen (HBsAg)-positive mothers. During the study period, 136 and 86 infants received delayed and non-delayed strategies, respectively. A positive vertical HB virus transmission was defined as a positive serum HBsAg status. Seropositive immunogenic response was defined as a serum anti-HBs titer of ≥10 mIU/mL. Post-vaccination serum HBsAg positivity rates did not differ significantly between the delayed (0/136 [0.0%, 95% confidence interval, 0.0–2.7%]) and non-delayed (2/86 [2.3%, 95% confidence interval, 0.3–8.1%]) strategy groups. Seropositive immunogenic response rates were 100.0% (136/136) and 97.7% (84/86), respectively. Although this study was under-powered to detect a statistically significant result, no vertical HB virus transmission was observed in the delayed strategy.

Objective: Severe motor vehicle accidents involving pregnant women can result in fetal and neonatal death. We describe a case in which fetal death occurred due to relatively mild seatbelt injuries and present the characteristic magnetic resonance imaging (MRI) findings of the placenta. Case Report: A 26-year-old primigravid woman at 20 weeks gestation was involved in an automobile accident. Although she suffered only a seatbelt injury, fetal death subsequently occurred. Contrast-enhanced MRI showed the region compressed by the seatbelt as a low-intensity band without enhancement, and serum alpha-fetoprotein and hemoglobin F levels were elevated. Conclusion: Careful monitoring, including blood and abdominal examinations, should be performed when pregnant women suffer seatbelt injuries.

Hearing loss can develop as a consequence of primary auditory neuron degeneration. These neurons are present within the spiral ganglion of the inner ear and co-exist with glial cells that assist in neuronal maintenance and function. There are limited interventions for individuals with hearing impairment, hence novel biological solutions must be explored. Regenerative strategies can benefit from in vitro methods to examine the long-term culture of purified cell populations. The culturing of neuronal, glial, and non-neuronal, non-glial cell types in both neonatal and adult mice is presented along with the whole-organ explant culture of the spiral ganglion. High yields of spiral ganglion glial and non-glial cells were cultured from both neonatal and adult mice. Dissociated spiral ganglion cells from Sox2-EGFP mice were sorted based on EGFP expression using fluorescence activated cell sorting. The EGFP+ fraction included purified glial populations, whereas the EGFP- fraction contained non-glial cells. Purified glial cells could be reprogrammed into induced neurons displaying neuronal markers and morphology at a higher efficiency than non-glial cells. Previous studies have only allowed for the short-term culturing of spiral ganglion cell populations and have placed emphasis on neonatal cells. There has also been a lack of methods able to cultivate pure cell populations. Here, the coupling of transgenic mouse lines, fluorescence activated cell sorting and advanced culture conditions allow cultivation and characterization of neuronal, glial and non-neuronal, non-glial cells from the spiral ganglion. These techniques are used to demonstrate that different spiral ganglion cell subtypes (glial vs. non-glial) display different competencies for direct neuronal reprogramming.

Case summary A 32-month-old spayed female Singapura cat presented with a non-pruritic erythematous nodule on the upper lip. The cat also had multiple nodules in the liver but exhibited no other clinical signs consistent with classical feline infectious peritonitis (FIP), such as pleural effusion or ascites, uveitis or neurological symptoms. Histopathological and immunohistochemical analyses of the cutaneous nodule revealed pyogranulomatous dermatitis with intralesional macrophages laden with feline coronavirus (FCoV) antigen. Real-time reverse transcription (RT)-PCR of a cutaneous sample revealed a single nucleotide substitution in the spike protein gene of FCoV (mutation M1058L), which is consistent with an FCoV genotype commonly associated with FIP. The cat received a blood transfusion and supportive therapy, but the owner declined to continue the treatments owing to poor response. The cat was lost to follow-up 5 months after discharge. Relevance and novel information This report describes a case of a coronavirus-associated cutaneous nodule in which the evidence of amino acid changes in the spike protein gene identified by RT-PCR were consistent with an FCoV genotype commonly seen in cases of FIP. To the best of our knowledge, this is the first report of a case of cutaneous disease associated with the mutated FCoV that was confirmed by molecular diagnostic testing.

Primary auditory neurons (PANs) play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs), comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs). The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.

The falling liquid flow rate under flooding conditions is limited at a square top end of a vertical pipe in the pressurizer surge line with the diameter of about 300 mm that consists of a vertical pipe, a vertical elbow, and a slightly inclined pipe with elbows. In this study, therefore, we evaluated effects of diameters on countercurrent flow limitation (CCFL) at the square top end in vertical pipes by using existing air-water data in the diameter range of D = 19-250 mm. As a result, we found that there was a strong relationship between the constant CK and the slope m in the Wallis-type correlation where the Kutateladze parameters were used for the dimensionless gas and liquid velocities. The constant CK and the slope m increased when the water level is increased in the upper tank h. CCFL at the square top end of the vertical pipes could be expressed by the Kutateladze parameters with CK = 1.53±0.11 and m = 0.97 for D ≥ 30 mm. The CK values were smaller for D = 19-25 mm than those for D ≥ 30 mm.

Spinal fusion and bone defect after injuries, removal of bone tumors, and infections need to be repaired by implantation. In an aging society, recovery from these procedures is often difficult. In this study, we found that injection of SPG-178 leads to expression of several bone marker genes and mineralization in vitro, and revealed a significantly higher degree of newly formed bone matrix with use of SPG-178 in vivo. MC3T3-E1 cells were used to evaluate osteoblast differentiation promoted by SPG-178. To analyze gene expression, total RNA was isolated from MC3T3-E1 cells cultured for 7 and 14 days with control medium or SPG-178 medium. Among the several bone marker genes examined, SPG-178 significantly increased the mRNA levels for ALP, BMP-2 and Osteocalcin, OPN, BSP and for the Osterix. Ten-week-old female Wistar rats were used for all transplantation procedures. A PEEK cage was implanted into a bony defect (5 mm) within the left femoral mid-shaft, and stability was maintained by an external fixator. The PEEK cages were filled with either a SPG-178 hydrogel plus allogeneic bone chips (n = 4) or only allogeneic bone chips (n = 4). The rats were then kept for 56 days. Newly formed bone matrix was revealed inside the PEEK cage and there was an increased bone volume per total volume with the cage filled with SPG-178, compared to the control group. SPG-178 has potential in clinical applications because it has several benefits. These include its favorable bone conduction properties its ability to act as a support for various different cells and growth factors, its lack of infection risk compared with materials of animal origin such as ECM, and the ease with which it can be used to fill defects with complex shapes and combined with a wide range of other materials.

BACKGROUND:Recent studies have shown that the microbiome, namely Aspergillus species, play a previously unrecognized role in both stable and exacerbated chronic obstructive pulmonary disease (COPD). Galactomannan is a major component of the Aspergillus cell wall that has been widely used as a diagnostic marker. OBJECTIVES:To explore whether serum levels of Aspergillus-galactomannan antigen could be used to evaluate the risk of severe acute exacerbation of COPD (AE-COPD). METHODS:We measured the Aspergillus-galactomannan antigen levels of 191 patients with stable COPD, and examined its clinical relevance including AE-COPD. RESULTS:There were 77 (40.3%) patients who were positive for serum Aspergillus-galactomannan antigen (≥0.5). High Aspergillus-galactomannan antigen level (≥0.7) was associated with older age and presence of bronchiectasis and cysts on computed tomography images. Compared to patients with low Aspergillus-galactomannan antigen level (

Impetigo is a contagious skin infection predominantly caused by Staphylococcus aureus. Decontamination of S. aureus from the skin is becoming more difficult because of the emergence of antibiotic-resistant strains. Bacteriophage endolysins are less likely to invoke resistance and can eliminate the target bacteria without disturbance of the normal microflora. In this study, we investigated the therapeutic potential of a recombinant endolysin derived from kayvirus S25-3 against staphylococcal impetigo in an experimental setting. First, the recombinant S25-3 endolysin required an incubation period of over 15 minutes to exhibit efficient bactericidal effects against S. aureus. Second, topical application of the recombinant S25-3 endolysin decreased the number of intraepidermal staphylococci and the size of pustules in an experimental mouse model of impetigo. Third, treatment with the recombinant S25-3 endolysin increased the diversity of the skin microbiota in the same mice. Finally, we revealed the genus-specific bacteriolytic effect of recombinant S25-3 endolysin against staphylococci, particularly S. aureus, among human skin commensal bacteria. Therefore, topical treatment with recombinant S25-3 endolysin can be a promising disease management procedure for staphylococcal impetigo by efficient bacteriolysis of S. aureus while improving the cutaneous bacterial microflora.

It is well known that humans run with a fore-foot strike (FFS), a mid-foot strike (MFS) or a rear-foot strike (RFS). A modular neural control mechanism of human walking and running has been discussed in terms of muscle synergies. However, the neural control mechanisms for different foot strike patterns during running have been overlooked even though kinetic and kinematic differences between different foot strike patterns have been reported. Thus, we examined the differences in the neural control mechanisms of human running between FFS and RFS by comparing the muscle synergies extracted from each foot strike pattern during running. Muscle synergies were extracted using non-negative matrix factorization with electromyogram activity recorded bilaterally from 12 limb and trunk muscles in ten male subjects during FFS and RFS running at different speeds (5-15 km/h). Six muscle synergies were extracted from all conditions, and each synergy had a specific function and a single main peak of activity in a cycle. The six muscle synergies were similar between FFS and RFS as well as across subjects and speeds. However, some muscle weightings showed significant differences between FFS and RFS, especially the weightings of the tibialis anterior of the landing leg in synergies activated just before touchdown. The activation patterns of the synergies were also different for each foot strike pattern in terms of the timing, duration, and magnitude of the main peak of activity. These results suggest that the central nervous system controls running by sending a sequence of signals to six muscle synergies. Furthermore, a change in the foot strike pattern is accomplished by modulating the timing, duration and magnitude of the muscle synergy activity and by selectively activating other muscle synergies or subsets of the muscle synergies.

Radiologic pleuroparenchymal fibroelastosis (PPFE)-like lesion including pulmonary apical cap can be occasionally observed in clinical settings. However, the significance of radiologic PPFE-like lesion is unclear in connective tissue disease (CTD)-related interstitial lung disease (ILD).A total of 113 patients with CTD-related ILD were enrolled and assessed for radiologic PPFE-like lesion, which was defined as bilateral, upper lobe, and subpleural dense consolidations with or without pleural thickening on chest high-resolution computed tomography. The clinical, radiologic, and pathologic characteristics were evaluated.Radiologic PPFE-like lesion was found in 21 patients (19%) and were relatively frequent in those with systemic sclerosis (6/14: 43%) and primary Sjögren's syndrome (4/14: 29%). Patients with PPFE-like lesion were significantly older, had lower body mass index, higher ratio of residual volume to total lung capacity, and higher complication rate of pneumothorax and/or pneumomediastinum than those without. Twelve of the 21 patients were diagnosed radiologically as usual interstitial pneumonia (UIP) or possible UIP pattern. Two of three patients who underwent surgical lung biopsy of the upper lobes showed UIP on histopathology. Another patient was confirmed to have upper lobe PPFE on autopsy. During the clinical course, progression of the radiologic PPFE-like lesions was observed in 13 of 21 patients. Six patients died (mortality rate: 29%) and their PPFE-like lesions were commonly progressive. In the total cohort, our multivariate analysis identified the presence of PPFE-like lesion as a significant risk factor for respiratory death (hazard ratio: 4.10, 95% confidence interval: 1.33-12.65, p = 0.01).In patients with CTD-related ILD, radiologic PPFE-like lesion, which may present as not only PPFE but also apical cap and upper lobe subpleural fibrosis commonly due to UIP, was not uncommon and was associated with poor prognosis. Clinicians should be cautious with this radiologic finding, particularly when it is progressive.

Primary auditory neurons (PANs) connect cochlear sensory hair cells in the mammalian inner ear to cochlear nucleus neurons in the brainstem. PANs develop from neuroblasts delaminated from the proneurosensory domain of the otocyst and keep maturing until the onset of hearing after birth. There are two types of PANs: type I, which innervate the inner hair cells (IHCs), and type II, which innervate the outer hair cells (OHCs). Glial cells surrounding these neurons originate from neural crest cells and migrate to the spiral ganglion. Several transcription factors are known to regulate the development and differentiation of PANs. Here we systematically examined the spatiotemporal expression of five transcription factors: Sox2, Sox10, Gata3, Mafb, and Prox1 from early delamination at embryonic day (E) 10.5 to adult. We found that Sox2 and Sox10 were initially expressed in the proneurosensory cells in the otocyst (E10.5). By E12.75 both Sox2 and Sox10 were downregulated in the developing PANs; however, Sox2 expression transiently increased in the neurons around birth. Furthermore, both Sox2 and Sox10 continued to be expressed in spiral ganglion glial cells. We also show that Gata3 and Prox1 were first expressed in all developing neurons, followed by a decrease in expression of Gata3 and Mafb in type I PANs and Prox1 in type II PANs as they matured. Moreover, we describe two subtypes of type II neurons based on Peripherin expression. These results suggest that Sox2, Gata3 and Prox1 play a role during neurogenesis as well as maturation of the PANs.