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Abstract Background Arsenic (As) metabolism by soil microorganisms has an impact on As geochemical cycling in paddy soils, which in turn affects As uptake in rice. However, little is known about the key microorganisms involved in this process in Japanese paddy soil. Results Total RNA was extracted from Japanese paddy soils with different levels of dissolved As under flooded conditions, and the transcription of As metabolic genes (arrA, ttrA and arsM) was analyzed via a metatranscriptomic approach. The results showed that ttrA was the predominant respiratory arsenate reductase gene transcribed in these soils rather than arrA, suggesting that ttrA contributes to the reductive dissolution of As. The predominant taxa expressing ttrA differed among soils but were mostly associated with genera known for their iron- and/or sulfate-reduction activity. In addition, a wide variety of microorganisms expressed and upregulated arsM approximately 5.0- to 13.2-fold at 9 d compared with 3 d of incubation under flooded conditions in flasks. Conclusions Our results support the involvement of microbial activity in the geochemical cycling of As in Japanese paddy soils and suggest that ttrA may be one of the key genes involved in the formation of arsenite, an inorganic species taken up by rice.

Abstract Immune cell activation is essential for cancer rejection; however, the tumor microenvironment leads to deterioration of immune function, which enables cancer cells to survive and proliferate. We previously reported that oral ingestion of Lentinula Edodes Mycelia (L.E.M.) extract enhances the tumor antigen-specific T-cell response and exerts an antitumor effect in a tumor-bearing mouse model. In this study, we focused on antigen-presenting cells (APCs) located upstream of the immune system, induced a T-cell response, then examined the impact of L.E.M. extract on the APCs. L.E.M. extract enhanced the expression of MHC-I, MHC-II, CD86, CD80, and CD40 in bone marrow-derived dendritic cells (DCs) and strongly induced the production of IL-12. L.E.M.-stimulated DCs enhanced IFN-γ production from CD8+ T cells and induced their differentiation into effector cells. Furthermore, L.E.M. extract promoted IL-12 production and suppressed the production of IL-10 and TGF-β by transforming bone marrow-derived macrophages into M1-like macrophages. Furthermore, in a B16F10 melanoma inoculation model, DCs in the spleen were decreased and their activation was suppressed by the presence of cancer; however, ingestion of L.E.M. extract prevented this functional deterioration of DCs. In the spleen of cancer-bearing mice, the number of CD11b− F4/80+ macrophages in a hypoactivated state was also increased, whereas L.E.M. extract suppressed the increase of such macrophages. These findings suggest that L.E.M. extract may exhibit an antitumor immune response by regulating the function of APCs to induce cytotoxic T lymphocytes, as well as by suppressing the decline in antigen-presenting cell activity caused by the presence of cancer.

Abstract Introduction This study aimed to evaluate the correlation and agreement between end‐tidal CO2 (EtCO2) measured with the novel portable capnometer (CapnoEye®) and partial pressure of arterial carbon dioxide (PaCO2) levels in patients with respiratory diseases and to compare the efficacy of EtCO2 and PvCO2 in predicting PaCO2 levels. Methods We analyzed the correlation and the agreement between EtCO2 and PaCO2 and between PvCO2 and PaCO2 using Pearson's moment correlation coefficient in patients with type 1 and type 2 respiratory failure and both groups overall. Results A total of 100 samples were included that comprised 67 men (67%). The mean age of the subjects was 77 ± 13 years. Chronic obstructive pulmonary disease (COPD) (43%) was the most common disease. There was a high correlation between EtCO2 and PaCO2 (r = 0.88; p < 0.0001). Sixty‐six PvCO2 samples were obtained, and there was a high correlation between PvCO2 and PaCO2 (r = 0.81; p < 0.0001). Regarding type 2 respiratory failure, there was a high correlation between EtCO2 and PaCO2 (r = 0.81). The Bland–Altman analysis between PaCO2 and EtCO2 revealed a bias of 5.7 mmHg, with limits of agreement ranging from −5.1 mmHg to 16.5 mmHg. In contrast, the analysis between PaCO2 and PvCO2 revealed a bias of −6.8 mmHg, and the limits of agreement ranged from −22.13 mmHg to 8.53 mmHg. Conclusion EtCO2 measured by CapnoEye® was significantly correlated to PaCO2 levels in patients with respiratory diseases. Moreover, CapnoEye® may be more useful for predicting hypercapnia conditions in which respiratory diseases are compared with measure PvCO2.

A HEK293 cell line lacking all Gαi subunits is generated which enables the measurement of coupling between a GPCR and individual Gαi subunits upon transient re-expression of a specific Gαi subunit.

Pulmonary hamartomas are common benign lung tumors; however, endobronchial hamartomas are relatively rare. We report a case of asymptomatic endobronchial hamartoma in a 51-year-old man. Chest computed tomography revealed a 10-mm protrusion in the right main bronchus. Preoperative virtual bronchoscopy (VBS) was performed; subsequently, minimally invasive bronchoscopic resection was safely performed under local anesthesia. The use of VBS is a useful treatment strategy and follow-up modality.

A 70-year-old man began to cough. Chest X-ray showed a tumor in the center, pleural effusion on the left side, and diffuse granular shadows on the right side. Chest computed tomography (CT) showed bronchial wall thickening and numerous granular shadows. We suspected diffuse panbronchiolitis. Thus, transbronchial lung biopsy (TBLB) and transbronchial lung cryobiopsy (TBLC) were performed. The tissue size obtained was 1 mm by TBLB and 6 mm at 5 seconds by TBLC. Histological analysis of the TBLB specimen showed lymphocyte infiltration, no fibrosis in Hematoxylin-eosin (HE) staining, and no elastic fibers in Elastica van Gieson (EVG) staining. On the other hand, TBLC specimens showed inflammatory cell infiltration and fibrosis around the bronchioles in HE staining and hypertrophy of elastic fibers in EVG staining. It was diagnosed as diffuse panbronchiolitis (DPB) from clinical and pathological findings. Cryobiopsy is useful in diagnosing DPB as well as interstitial pneumonia and lung cancer.

Abstract A 78-year-old male presented with a positive fecal occult blood test. Rectal cancer was detected during lower gastrointestinal endoscopy, and further investigations led to a diagnosis of cT1N0M0 cStage I (UICC classification, 8th edition). Preoperative contrast-enhanced computed tomography (CT) showed that the patient also had Leriche syndrome, which is associated with reduced blood flow to the rectum that may result in ischemic anastomosis during rectal cancer surgery with anastomotic reconstruction. The inferior epigastric arteries often function as collateral pathways to the lower limbs in patients with Leriche syndrome; therefore, care is needed to avoid vascular damage during trocar insertion when performing laparoscopic surgeries. We herein described a case of safe laparoscopic low anterior resection in a rectal cancer patient with Leriche syndrome using vascular architecture images obtained by preoperative CT angiography.

BackgroundAdjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known.Methods and ResultsTo characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component.ConclusionsThis study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.

Thoracoscopy under local anaesthesia is effective for the diagnosis of tuberculous pleurisy (TP), mesothelioma and pleural metastases of lung cancer, etc. It has recently been reported that cryobiopsy is useful for obtaining sufficient tissue, achieving a greater depth, and avoiding crush artefact than biopsy forceps. However, the utility of the tissue obtained by cryobiopsy for culture for diagnosing TP is unknown. We compared positivity rates of tissue culture obtained by biopsy forceps and cryobiopsy in seven TP patients. The median tissue size was 2 mm by biopsy forceps and 6 mm by cryobiopsy. The pathological diagnostic rate of pleural tissue was 85.7% with biopsy forceps and 100% with cryobiopsy. However, the positivity rate of tissue culture was 57.1% with biopsy forceps and 28.5% with cryobiopsy. Since rapid freezing with a cryoprobe makes it difficult for bacteria to grow, it is possible that cryobiopsy might not be useful for obtaining a tissue culture in TP cases. However, since the sample size of this study was small, analysis of more cases is required to confirm our results.

Transient receptor potential (TRP) channels are activated by various extracellular and intracellular stimuli and are involved in many physiological events. Because compounds that act on TRP channels are potential candidates for therapeutic agents, a simple method for evaluating TRP channel activation is needed. In this study, we demonstrated that a transforming growth factor alpha (TGFα) shedding assay, previously developed for detecting G-protein-coupled receptor (GPCR) activation, can also detect TRP channel activation. This assay is a low-cost, easily accessible method that requires only an absorbance microplate reader. Mechanistically, TRP-channel-triggered TGFα shedding is achieved by both of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and 17 (ADAM17), whereas the GPCR-induced TGFα shedding response depends solely on ADAM17. This difference may be the result of qualitative or quantitative differences in intracellular Ca2+ kinetics between TRP channels and GPCRs. Use of epidermal growth factor (EGF) and betacellulin (BTC), substrates of ADAM10, improved the specificity of the shedding assay by reducing background responses mediated by endogenously expressed GPCRs. This assay for TRP channel measurement will not only facilitate the high-throughput screening of TRP channel ligands but also contribute to understanding the roles played by TRP channels as regulators of membrane protein ectodomain shedding.

Abstract Docetaxel is a cytotoxic taxane frequently used to treat patients with various cancers, including non‐small cell lung cancer (NSCLC). Docetaxel is known to cause acute myalgias, arthralgias, and neuropathy, but there have been few published case reports of myositis. Here, we describe a rare case of docetaxel‐induced myositis diagnosed based on laboratory data, thigh magnetic resonance imaging (MRI), and electromyography (EEG). A 66‐year‐old male was admitted for thigh pain and fatigue that onset 1 week prior. He had been diagnosed with stage IVA (cT4N0M1a) NSCLC 3 years ago and had been started on docetaxel (60 mg/m2 intravenously every 3 weeks; fourth‐line chemotherapy) 1 month earlier. After the second cycle, he developed both thigh pain and fatigue. On admission, his creatinine phosphokinase (CPK) level was elevated, thigh MRI revealed diffuse muscle edema, and EEG showed myogenic changes. We found no plausible cause for myositis except docetaxel. He was diagnosed with myositis and treated with oral prednisolone. His symptoms were relieved and the CPK level declined. Although rare, this case indicates that clinicians should consider the possibility of myositis as a complication in patients on docetaxel.

Abstract Brain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke. Recently, several microRNAs (miRNAs) in BECs were reported to regulate the endothelial function in ischemic brain. Therefore, modulation of miRNAs in BECs by a therapeutic oligonucleotide to inhibit miRNA (antimiR) could be a useful strategy for treating ischemic stroke. However, few attempts have been made to achieve this strategy via systemic route due to lack of efficient delivery-method toward BECs. Here, we have developed a new technology for delivering an antimiR into BECs and silencing miRNAs in BECs, using a mouse ischemic stroke model. We designed a heteroduplex oligonucleotide, comprising an antimiR against miRNA-126 (miR-126) known as the endothelial-specific miRNA and its complementary RNA, conjugated to α-tocopherol as a delivery ligand (Toc-HDO targeting miR-126). Intravenous administration of Toc-HDO targeting miR-126 remarkably suppressed miR-126 expression in ischemic brain of the model mice. In addition, we showed that Toc-HDO targeting miR-126 was delivered into BECs more efficiently than the parent antimiR in ischemic brain, and that it was delivered more effectively in ischemic brain than non-ischemic brain of this model mice. Our study highlights the potential of this technology as a new clinical therapeutic option for ischemic stroke.

Abstract Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p

Abstract Objective New flex‐rigid pleuroscope enables observations with a maximum angle of curvature of 180°, allowing visualization of the area near the insertion site of the pleuroscope. And, it improved the image quality and channel inner diameter. The aim of this study was to evaluate the clinical effectiveness and safety of a new flex‐rigid pleuroscope. Methods A retrospective analysis of patients who were examined with a new flex‐rigid pleuroscope under local anesthesia at our institution was conducted. Pleuroscopy was performed in 33 patients with undiagnosed exudative pleural effusions from December 2016 to March 2019. Results A total of 33 patients (10 women, 23 men); their median age 74 years (range 24‐90) were investigated. Pleuroscopy showed that 18 had malignant pleural disease (54%), and 15 had benign pleural diseases (46%). The top three most frequent causes of pleural disease were pleural metastases of lung carcinoma (30.3%), pyothorax (15.1%), and malignant pleural mesothelioma (12.1%). In 32 cases (97%), observation at the introducer insertion site was possible. It was not possible in one case due to hard adhesions. The diagnostic rate was 100%, and the complication rate was 6.1%. There were no major complications, and minor complications included mild pain (one case) and minor bleeding (one case) that was stanched spontaneously. Conclusions The new flex‐rigid pleuroscope is effective and safe for diagnosing pleural effusions. The improved bending angle is likely to minimize the blind area. The new pleuroscopy fiberscope may improve the diagnostic rate.

Abstract A 37‐year‐old man was admitted to our hospital with chest pain and fever. Computed tomography showed pleural effusion and irregularly marginated, elevated lesions inside diffuse pleural thickening. Detailed medical examination showed swelling of the left testicle. 18F‐fluorodeoxyglucose positron emission tomography showed uptakes at the thickened pleura and left testis. Pelvic magnetic resonance imaging showed a mass in the left testis with a heterogeneous and partially calcified tumour present interiorly. Thoracoscopy was performed under local anaesthesia, enabling the observation of masses at the pleura and biopsy of the mass, which was diagnosed as malignant pleural mesothelioma. The affected testicle was resected and diagnosed as tunica vaginalis testis mesothelioma. Thus, simultaneous tunica vaginalis testis and pleural mesothelioma were diagnosed. It is necessary to closely examine parts of the body other than the chest.

Abstract The Pfizer‐BioNTech mRNA vaccine (BNT162b2) is an effective and well‐tolerated coronavirus disease 2019 (COVID‐19) vaccine. However, rare adverse events have been reported. We report two cases of COVID‐19 mRNA vaccine‐related interstitial lung disease (ILD). A 67‐year‐old man and a 70‐year‐old man with underlying ILD presented to our hospital with a few days of fever and respiratory symptoms after receiving the BNT162b2 vaccine. Drug‐related pneumonitis due to the COVID‐19 mRNA vaccine was diagnosed. One case was diagnosed with lymphocytic alveolitis by bronchoalveolar lavage fluid and transbronchial lung cryobiopsy. Both patients were successfully treated with corticosteroids, and they attended outpatient clinics thereafter. Although the safety and efficacy of COVID‐19 vaccines have been established, further studies are needed to estimate long‐term data and reports of rare adverse reactions. We present the clinical course of two cases, review previously published case reports on COVID‐19 mRNA vaccine‐related ILD and discuss the relevant findings.

Abstract Immune checkpoint inhibitors (ICIs) are reportedly effective against many kinds of neoplasm, but may be responsible for several kinds of immune‐related adverse events (irAEs). Among these irAEs, the incidence of myelosuppression due to ICIs is relatively low. Corticosteroids are needed to control most cases of myelosuppression. Here, we report an 88‐year‐old woman with squamous cell lung cancer who was administered pembrolizumab. After five cycles of pembrolizumab, she developed severe pancytopenia. The pancytopenia improved under observation without steroid administration after cessation of pembrolizumab. During recovery from this irAE, the patient also maintained long‐term antitumor efficacy. Key points Significant findings of the study There are several kinds of immune‐related adverse events. We encountered a case of pembrolizumab‐induced pancytopenia with squamous cell lung cancer. What this study adds Corticosteroids are needed to control most cases of myelosuppression induced by ICIs, but pancytopenia induced by pembrolizumab in our case improved without steroids.

Bronchial thermoplasty (BT) is a type of bronchoscopic treatment specifically used for patients with severe asthma. Most severe asthmatics receive systemic steroids and are at risk of being immunocompromised. This raises the clinical question of whether or not BT can be effectively and safely performed in such patients. Herein, we report a case highlighting the effectiveness and safety of BT in a patient with severe persistent bronchial asthma and Pseudomonas aeruginosa infection. We performed BT on a 46-year-old woman undergoing treatment for severe persistent asthma with inhaled steroids and 20 mg prednisolone orally. Although she was deemed to be infection-free before the procedure, culture of endobronchial secretions obtained during the first BT procedure grew Pseudomonas aeruginosa. After the first BT, she was given clarithromycin 400 mg orally daily. The amount of sputum decreased with each BT session, and sputum culture for Pseudomonas aeruginosa turned negative by the third BT session. Respiratory function tests showed 23.7% improvement in % post-bronchodilator forced expiratory volume in 1.0 s (%FEV1.0) and the asthma quality of life questionnaire (AQLQ) score increased by 2.41 points after the third BT. Bronchial wall thickness decreased and infiltrative shadows on CT disappeared after the three BT sessions, along with decrease in the amount of purulent sputum. Improvement in her asthma symptoms, after three BT sessions allowed decrease in the prednisolone dose.We report the effectiveness of BT and infection control in a severe asthmatic with Pseudomonas aeruginosa infection.

Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.

Human CYP19 spans a region of chromosome 15 of approximately 130 kb and encodes aromatase, an enzyme required for estrogen synthesis. In the human granulosa cell-line KGN, there are seven open chromatin regions within the CYP19 locus. In this study, we demonstrate that two of these regions ~40 kb upstream and ~15 kb downstream of the CYP19 promoter are cohesin-loading sites, physically interacting with the promoter to negatively and positively regulate transcription, respectively. These observations suggest that CYP19 expression is controlled by a balance between the upstream silencer and downstream enhancer. When cohesin is depleted, CYP19 expression is elevated since the silencer is 2.5-fold further from the promoter than the enhancer and most likely depends on cohesin-mediated tethering to influence expression.

Abstract Introduction Bronchial thermoplasty (BT) is a bronchoscopic procedure that involves the delivery of thermal radiofrequency energy to the bronchial wall for treating severe asthma. It has been suggested that too many radiofrequency activations could induce serious adverse events (SAEs) at an early stage. We aimed to examine the number of radiofrequency activations at each session and early lung function changes from baseline to determine whether these are related to SAEs. Methods We retrospectively investigated 13 consecutive patients who underwent three sessions each of BT for severe asthma from February 2015 to January 2016. Lung function tests were performed on the day before and after each BT procedure. Since we compared the number of activations and lung function changes from baseline after each session, a total of 39 sessions were reviewed. The relationship between the number of radiofrequency activations and each lung function change from baseline was also examined by linear regression analysis. Results A total of 10 SAEs (4 of pneumonia, 3 of atelectasis, 2 of bronchial asthma exacerbation and 1 of hemoptysis) were observed following the 39 BT sessions. When we compared sessions with and without SAEs, there were no differences in the number of activations (mean ± SD, 71.5 ± 28.6 times in sessions with SAEs; 66.5 ± 25.1 times in sessions without SAEs; p = 0.772) and lung function changes (mean changes in FVC/%FVC/FEV1/%FEV1/%PEF from baseline; − 0.49 l/− 14.2%/− 0.36 l/− 11.7%/− 9.6% in sessions with SAEs; − 0.43 l/− 13.3%/− 0.34 l/− 12.1%/− 9.4% in sessions without SAEs; p > 0.05 for all the above). Increase in the number of activations correlated with decreased FEV1 (R 2 = 0.17, p = 0.0088) and %FEV1 (R 2 = 0.11, p = 0.0357). Conclusions Increase in the number of radiofrequency activations during BT is related to a decrease in FEV1 and %FEV1 from baseline. The number of radiofrequency activations, however, is not associated with SAEs after BT.

Phytoextraction by high-Cd-accumulating rice lacking a functional OsHMA3 allele is promising for Cd removal from paddy soils. To increase rice Cd extraction efficiency, we developed a new high-Cd variety, TJN25-11. For this, we pyramided a nonfunctional OsHMA3 allele from a high-Cd variety, Jarjan, and two QTLs for increased shoot Cd concentrations, which were discovered in a mapping population derived from a high-Cd variety, Nepal 555, and a low-Cd variety, Tachisugata. In two Cd-contaminated paddy fields under drained aerobic soil conditions, TJN25-11 presented significantly higher Cd concentrations in the straw and panicles than the OsHMA3-deficient varieties TJTT8 and Cho-ko-koku. Among the varieties, TJN25-11 had a relatively high shoot biomass, resulting in the highest Cd accumulation in the shoots. The soil Cd decreased by approximately 20% after TJN25-11 growth. The amount of Cd that accumulated in the TJN25-11 aerial parts was much greater than the amount of Cd that decreased in the topsoil, suggesting that Cd was absorbed from deeper soil layers. Thus, we revealed the effects of QTL pyramiding on shoot Cd accumulation and Cd phytoextraction efficiency. Since TJN25-11 has favorable agronomic traits for compatibility with Japanese cultivation systems, this variety could be useful for Cd phytoextraction in Cd-contaminated paddy fields.

After a massive disaster, many residents in affected areas are forced to temporarily stay in evacuation shelters. The exact impact of the state of resource supply and infrastructure in evacuation shelters on the health status of evacuees has not been sufficiently studied. Two weeks after the 2011 Great East Japan Earthquake (GEJE), comprehensive surveillance related to the health status and hygiene level was performed for all evacuation shelters (328 shelters with 46,480 evacuees at the peak) in one of the most devastating medical zones after the tsunami hit the area (Ishinomaki City). The joint relief team regularly visited all evacuation shelters across the area to assess the situation of resource supply levels, infrastructural damage, rapid need of resources, and the health status of the evacuees. In this cross-sectional observational study, we evaluated the relationship between the resource supply levels and health status among evacuees in two time periods (days 14–19 and 20–25). Among the evaluated vital resources, clean tap water supply was among the most disrupted by the disaster, and was not fully restored in most shelters during the assessment period. The cross-sectional relationship between resource supplies and morbidity was inconsistent between the two assessment periods, reflecting the multifactorial nature of health status in evacuation shelters. The clean tap water supply level at the first assessment showed a strong negative correlation with the subsequent prevalence of respiratory or gastrointestinal infectious conditions at the second assessment. Restorations in the clean tap water supply and toilet hygiene correlated each other, and both correlated with a decrease in the prevalence of gastrointestinal infectious conditions. In conclusion, disrupted clean tap water supply and inadequate toilet hygiene after a massive disaster would jointly harm the health status of those in shelters. Prompt assessments using quick visual assessment and restorations of these key resources have validity with suppressed environmental health risks among evacuees.

Idiopathic pulmonary fibrosis is a chronic, progressive, and lethal lung disease of unknown etiology. Antifibrotic drugs, including pirfenidone, are currently used for the treatment of the disease. The oral administration of pirfenidone is an effective therapy, as demonstrated by several clinical trials, although it causes severe adverse events in some patients. We hypothesized that low-dose intrapulmonary delivery of pirfenidone is effective in human transforming growth factorβ1-driven pulmonary fibrosis. To demonstrate our hypothesis, we compared the therapeutic efficacy of varying doses of pirfenidone administered by oral and intranasal routes in a human transforming growth factor-β1 transgenic mouse with established pulmonary fibrosis. We found similar amelioration of lung cell infiltration, inflammatory and fibrotic cytokines, lung fibrosis score, and hydroxyproline content in mice with human transforming growth factor-β1-mediated pulmonary fibrosis treated with low-dose intranasal pirfenidone and high-dose oral pirfenidone. This study showed that pirfenidone is a potent inhibitor of human transforming growth factor-β1-driven lung fibrosis and that intrapulmonary delivery of low-dose pirfenidone produces therapeutic responses equivalent to high-dose of oral pirfenidone.

Abstract A 43‐year‐old man presented with cough. His chest X‐ray showed a left‐sided pleural effusion. We suspected tuberculous pleurisy (TP), and thoracoscopy under local anaesthesia was performed. It showed entire pleura with scattered nodules. Nodules were biopsied by conventional biopsy forceps, but the tissue sample was small. Therefore, the nodules were biopsied with a cryoprobe. The tissue size obtained was 2 mm by conventional biopsy forceps, and 6 mm at 5 sec by cryobiopsy. Histological analysis of the conventional biopsy forceps and cryobiopsy specimen showed inflammation with lymphocytes and caseating granulomas. Tissue culture of conventional biopsy forceps was positive for Mycobacterium tuberculosis, and all sensitivity tests were positive. But, the tissue culture of the cryobiopsy sample was negative. There is a possibility that cryobiopsy is not useful for tissue culture for TP.

Abstract An 83‐year‐old woman presented with dyspnoea. Her chest X‐ray showed a right‐sided pleural effusion. Flex‐rigid pleuroscopy was performed and showed a mass in the anterior portion. The mass was biopsied with conventional biopsy forceps, but the mass was solid, and sufficient tissues could not be obtained. Therefore, the mass was biopsied with a cryoprobe. The tip of the probe was attached to the mass, and it was cooled with carbon dioxide once for 5 sec and then for 7 sec in the same place. The tissue size obtained was 2 mm by conventional biopsy forceps, and 5 mm at 5 sec and 12 mm at 7 sec by cryobiopsy. Histological analysis of the conventional biopsy forceps specimen showed cancer cells in the glandular cavity, but it was not sufficient tissue for comprehensive cancer genetic panel (CGP) testing. The cryobiopsy specimens showed cancer cells and sufficient tissue for comprehensive CGP testing.

In general, we have to assume tuberculous pleurisy when a patient presents with pleural effusion and elevated adenosine deaminase (ADA). However, other diseases need to be considered, including immunoglobulin (Ig)G4-related disease (IgG4-RD). This case involved a 65-year-old asymptomatic man with right pleural effusion showing elevated ADA. He had no articular findings or rashes. Results were negative for all autoantibodies. Pleura, mediastinal lymph nodes, and areas around the aorta and vertebra showed high uptake of 18F-fluorodeoxyglucose (FDG) on positron-emission tomography-computed tomography (PET-CT). These findings were specific for IgG4-RD. Based on the results of FDG-PET-CT, we performed thoracoscopy under local anesthesia and bronchoscopy. Pleural biopsy and culture, and other examinations including sputum and blood yielded negative findings for tuberculous pleurisy. A pleural biopsy specimen showed IgG4-positive plasma cells and fibrosis without obliterative phlebitis or storiform fibrosis, and serum IgG4 was also high. The ratio of IgG4-to IgG-positive plasma cells was under 40%, and >10 IgG4-positive cells were seen in high-power fields. This case was classed as ‘possible IgG4-RD’ on the comprehensive diagnostic criteria for IgG4-RD, but did not meet the diagnostic criteria for IgG4-related respiratory disease. Prednisolone proved effective against the pleural effusion. We therefore clinically diagnosed IgG4-RD with pleural effusion based on the 2019 classification criteria for IgG4-RD in the United States. Although few cases of IgG4-RD with pleural effusion have been reported, this disease needs to be considered among the differential diagnoses for high-ADA pleural effusion. FDG-PET-CT and thoracoscopy under local anesthesia may be helpful for diagnosis.

Abstract Background Yellow nail syndrome (YNS) is a rare disease characterized by the triad of thickened, slow-growing yellow nails, lymphedema, and chronic respiratory manifestations. The cause of YNS is not known; however, it is suggested to be due to a congenital lymph abnormality. Since YNS is accompanied by chronic bronchial infection in more than half of patients, we hypothesized that treatment with clarithromycin (CAM) could be effective. We therefore evaluated the effectiveness of CAM against nail discoloration and respiratory manifestation in patients with YNS. Methods We conducted an observational study involving 5 patients with YNS who were treated at our institution between January 2005 and January 2016. CAM was prescribed for every patient. Patient demographic information, comorbidities, medications, chest radiographs, and clinical data such as nail color were extracted to evaluate clinical outcome. Results Mean patient age was 71.6 years, and 2 patients (40%) were male. Four patients had sinusitis, and 2 had rheumatoid arthritis. Regarding respiratory manifestations, 4 patients had sinobronchial syndrome and 2 had pleural effusion. Nail discoloration improved in every patient after CAM treatment. Four patients also experienced improvement in their respiratory manifestations. Conclusions In patients with YNS, the anti-inflammatory activity of macrolides might improve their systemic inflammation. This improvement could help to reduce lymphedema and promote nail growth. Trial registration Ethical approval was provided by the institutional review board of the National Center of Global Health and Medicine (NCGM-G-002143-00), in January 2017. This study is retrospectively registered for UMIN Clinical Trial Registry (UMIN000028514) in August 4th, 2017.

Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.

Abstract In Japan, radiocesium contamination in foods has become of great concern and it is a primary issue to reduce grain radiocesium concentration in rice (Oryza sativa L.). Here, we report a low-cesium rice mutant 1 (lcs1) with the radiocesium concentration in grain about half that in the wild-type cultivar. Genetic analyses revealed that a mutation in OsSOS2, which encodes a serine/threonine-protein kinase required for the salt overly sensitive (SOS) pathway in plants, is responsible for the decreased cesium (Cs) concentrations in lcs1. Physiological analyses showed that Cs+ uptake by lcs1 roots was significantly decreased under low-potassium (K+) conditions in the presence of sodium (Na+) (low K+/Na+). The transcript levels of several K+ and Na+ transporter genes, such as OsHAK1, OsHAK5, OsAKT1, and OsHKT2;1 were significantly down-regulated in lcs1 grown at low K+/Na+. The decreased Cs+ uptake in lcs1 might be closely related to the lower expression of these genes due to the K+/Na+ imbalance in the lcs1 roots caused by the OsSOS2 mutation. Since the lcs1 plant had no significant negative effects on agronomic traits when grown in radiocesium-contaminated paddy fields, this mutant could be used directly in agriculture for reducing radiocesium in rice grains.

This case report describes the re-administration of abatacept to successfully reduce the articularsymptoms of a patient with rheumatoid arthritisduring the intensive phase of anti-tuberculous therapy. A 75-year-old man developed active pulmonary tuberculosis during the administration of abatacept for rheumatoid arthritis. The patient experienced a paradoxical reaction and exacerbation of rheumatoid arthritis that caused us to discontinue the abatacept. Later re-administration of abatacept along with anti-tuberculosis treatment led to well-controlled rheumatoid arthritis without exacerbation of the tuberculosis. This case shows that re-administration of abatacept may be much safer than TNF inhibitor to treat patients who are infected with mycobacteria during thetreatment of immunological diseases such asrheumatoid arthritiswith biological agents.

Abstract Objective Here, we report a case of fetal sick sinus syndrome (SSS) caused by pulmonary stenosis regurgitation (PSR) that spontaneously resolved during pregnancy. Case Report A 29-year-old woman was referred to our hospital at 21 weeks of gestation for persistent fetal bradycardia. Fetal echocardiography revealed PSR and ventricular septal defect (VSD). The ventricular rate was 60 to 70 beats/minute with 1:1 atrioventricular conduction. Thus, congenital SSS owing to PSR was suspected. During pregnancy, fetal SSS spontaneously resolved at 28 weeks of gestation despite persistent PSR. The ventricular rate was increased to approximately 120 beats/minute with regular rhythm. A 2,390-g male neonate was delivered via Caesarean section at 38 weeks of gestation. Consequently, detailed echocardiography revealed PSR and VSD without SSS. Conclusion Although fetal PSR can cause fetal SSS owing to immaturity at an earlier gestational age, SSS might be spontaneously resolved by fetal heart development as pregnancy progresses.

BackgroundThere have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer.MethodsQuantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010.Results(1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability.ConclusionsPromoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.

Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC.

In acute ischemic stroke, collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia, and in increasing the successful recanalization rate without hemorrhagic transformation. We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome, and it disappears promptly once the effective recanalization is achieved. Contrary to the belief that collateral vessels develop over time in chronic stenotic condition, there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress, which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries. We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1, which is a known shear-stress mechanosensing protein.

Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC.The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1.The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively.CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

Continuous maintenance of an appropriate position of the mandible and head purely by manual manipulation is difficult, although the maneuver can restore airway patency during sleep and anesthesia. The aim of this paper was to examine the effect of head elevation with jaw closure using a remote-controlled airbag device, such as the airbag system, on passive upper airway collapsibility during propofol anesthesia. Seven male subjects were studied. Propofol infusion was used for anesthesia induction and maintenance, with a target blood propofol concentration of 1.5-2 μg/ml. Nasal mask pressure (PN) was intermittently reduced to evaluate upper airway collapsibility (passive PCRIT) and upstream resistance (RUS) at three different head and jaw positions, jaw opening position in the supine position, jaw opening position in the sniffing position with 6-cm head elevation, and jaw closure at a 6-cm height sniffing position. The 6-cm height sniffing position with jaw closure was achieved by an airbag device that was attached to the subject's head-like headgear. Patient demographics, PCRIT and RUS in each condition were compared using one-way ANOVA with a post hoc Tukey test. P CRIT ~ -3.4-cm H2O) compared with the baseline position (PCRIT ~ -0.8-cm H2O, P = 0.0001). In the clinical study, there was improvement of upper airway obstruction in sleep apnea patients, including decreased apnea and hypopnea duration and increased the lowest level of oxygen saturation. We demonstrated that establishment of head elevation with jaw closure achieved by a remote-controlled airbag device using an inflatable airbag system can produce substantial decreases in upper airway collapsibility and maintain upper airway patency during propofol anesthesia and sleep.

The authors of article “Genetic diversity of arsenic accumulation in rice and QTL analysis of methylated arsenic in rice grains” (Kuramata et al. 2013) would like to note that the original version of the article online unfortunately contains the following errors:

The flow field in highly turbulent premixed combustion has been examined, using a cyclone-jet combustor. The shear-strain rate is obtained by PIV system. Results show that, in combustion field, mean axial velocity does not decay along center axis and RMS fluctuation velocity is much lower, compared with those in cold flow. The reaction zone detected by an ion probe well corresponds to region of large shear-strain rate. In combustion, turbulence is small around reaction zone to have the undiminished jet velocity, which leads to an increase in length of potential core, although the flame generated turbulence is observed through flow expansion.

Deformation behaviors of polycrystalline metals are quite complex, and we are not easy to directly investigate them; thus, analyses employing simple models such as bicrystals are required. In this study, we conducted crystal plasticity analysis of unidirectional tensile tests, using compatible-symmetric-type bicrystal models with the not-inclined grain boundary and incompatible-type bicrystal model with the inclined grain boundary; we investigated changes in patterns of geometrically necessary dislocation (GND) bans and the density of GNDs in the initial deformation. In the condition where the grain boundary contacted with the constrained faces, GND bans were formed and the distribution was changed with changing the inclination angle α of the grain boundary. In contrast, GNDs were not localized in high density in the condition where the grain boundary contacted with the free surfaces; the changes were caused by two-reasons: one was changes of compatibility of the bicrystal model with changing the inclination angle α, and the other was that deformation shapes of the bicrystal model under tensile loading were changed with changing the inclination angle α and the deformation was constrained by the constrained faces. The compatibility of and average density of GNDs in the bicrystal model could be estimated using differences of components of Schmid tensors between the crystal grains.

The human CYP19 gene encodes aromatase, which converts androgens to estrogens. CYP19 mRNA variants are transcribed mainly from three promoters. Quantitative RT-PCR was used to measure the relative amounts of each of the three transcripts and determine the on/off state of the promoters. While some of the promoters were silent, CYP19 mRNA production differed among the other promoters, whose estimated transcription levels were 0.001% to 0.1% of that of the TUBB control gene. To investigate the structural aspects of chromatin that were responsible for this wide range of activity of the CYP19 promoters, we used a fractionation protocol, designated SEVENS, which sequentially separates densely packed nucleosomes from dispersed nucleosomes. The fractional distribution of each inactive promoter showed a similar pattern to that of the repressed reference loci; the inactive regions were distributed toward lower fractions, in which closed chromatin comprising packed nucleosomes was enriched. In contrast, active CYP19 promoters were raised toward upper fractions, including dispersed nucleosomes in open chromatin. Importantly, these active promoters were moderately enriched in the upper fractions as compared to active reference loci, such as the TUBB promoter; the proportion of open chromatin appeared to be positively correlated to the promoter strength. These results, together with ectopic transcription accompanied by an increase in the proportion of open chromatin in cells treated with an H3K27me inhibitor, indicate that CYP19 mRNA could be transcribed from a promoter in which chromatin is shifted toward an open state in the equilibrium between closed and open chromatin.

Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.

Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia.In C57Bl/6 mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p.) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO) 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated.In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after CCAO. Administration of the S1PR1 selective agonist significantly increased cerebral blood flow (CBF) and the diameter of leptomeningeal collateral vessels (42.9 ± 2.6 μm) compared with the controls (27.6 ± 5.7 μm; P < 0.01). S1PR1 inverse agonist administration diminished the effect of the S1PR1 agonist (P < 0.001). After pMCAO, S1PR1 agonist pretreated animals showed significantly smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01) and better functional recovery than vehicle-treated controls.These results suggest that S1PR1 is one of the principal regulators of leptomeningeal collateral recruitment at the site of increased shear stress and provide evidence that an S1PR1 selective agonist has a role in promoting collateral growth and preventing of ischemic damage and neurological dysfunction after subsequent stroke in patients with intracranial major artery stenosis or occlusion.

Viral infection is one of the risk factors for asthma exacerbation. However, which pathogens are related to asthma exacerbation in adults remains unclear.The relation between various infections and adult asthma exacerbations was investigated in clinical practice.The study subjects included 50 adult inpatients due to asthma exacerbations and 20 stable outpatients for comparison. The pathogens from a nasopharyngeal swab were measured by multiplex PCR analysis.Asthma exacerbations occurred after a common cold in 48 inpatients. The numbers of patients with viral, bacterial, or both infections were 16, 9, and 9, respectively. The dominant viruses were rhinoviruses, respiratory syncytial virus, influenza virus, and metapneumovirus. The major bacteria were S. pneumoniae and H. influenzae. Compared to pathogen-free patients, the patients with pathogens were older and non-atopic and had later onset of disease, lower FeNO levels, lower IgE titers, and a higher incidence of comorbid sinusitis, COPD, or pneumonia. Compared to stable outpatients, asthma exacerbation inpatients had a higher incidence of smoking and comorbid sinusitis, COPD, or pneumonia. Viruses were detected in 50% of stable outpatients, but a higher incidence of rhinovirus, respiratory syncytial virus, and metapneumovirus infections was observed in asthma exacerbation inpatients. H. influenzae was observed in stable asthmatic patients. Other bacteria, especially S. pneumoniae, were important in asthma exacerbation inpatients.Viral or bacterial infections were observed in 70% of inpatients with an asthma exacerbation in clinical practice. Infection with S. pneumoniae was related to adult asthma exacerbation.

A cellular manufacturing system is a kind of lean and flexible manufacturing systems in which a worker or a group of workers carry out all assembly processes of a product. Assembly times of workers are generally improved in an exponential manner by repeating same assembly processes. However, the workers in the cellular manufacturing system are not provided with enough time to learn the assembly processes, since product mixes and production volumes are changeable in a short period of time. The objective of this study is to propose a work instruction system for untrained workers in assembly cells to understand the assembly processes quickly and reduce their assembly times of products without repeating same assembly processes. This study firstly records workers' assembly processes by using video equipment and analyzes the learning processes of the workers in order to propose an effective strategy for the workers to reduce the assembly processes in the cellular manufacturing system. According to the proposed strategy, a prototype of a work instruction system is developed for untrained workers in assembly cells. The prototype system provides graphical user interfaces explaining the information of assembly processes for the workers to facilitate understanding the assembly processes. Some experiments are carried out for assembling same toy cars built with Lego blocks in order to evaluate the effectiveness of the developed work instruction system. Experimental results of the proposed work instruction system are compared with the ones of a simple work instruction system. Through the comparison, it is recognized that the proposed work instruction system is superior to the simple work instruction system from the viewpoint of the reduction of assembly times. At the last part of this study, we propose a prediction method of assembly times of workers by measuring biological information as a heart rate, in order to carry out dynamic production management through the work instruction system.

Cellular manufacturing systems are well known as flexible manufacturing systems for assembly processes. Single workers carry out all assembly processes of products in the typical cellular manufacturing systems. The cellular manufacturing systems are required to cope with dynamic changes of product mix and production volumes. The workers are not able to be trained by repeating same assembly processes. The objective of this study is to propose a work instruction system for workers to understand the assembly processes quickly and reduce their assembly times of products without repeating same assembly processes. According to the learning curve of workers, it is important that the assembly time should be reduced from the first time the workers assemble the products in order to increase the productivity of cellular manufacturing systems. This study firstly records workers' assembly processes by using video equipment and analyzes the learning processes of the workers in order to propose an effective strategy for the workers to reduce the assembly processes in the cellular manufacturing systems. According to the proposed strategy, a prototype of a work instruction system is developed for an assembly cell. The prototype system provides a graphical user interface explaining the information of assembly processes for the workers to facilitate understanding the assembly processes. Some experiments are carried out for assembling a toy car built with Lego blocks in order to evaluate the effectiveness of the developed work instruction system. Experimental results of the proposed work instruction system are compared with the ones of a simple work instruction system. Through the comparison, it is recognized that the proposed work instruction system is superior to the simple work instruction system from the viewpoint of the reduction of assembly times.