TNF-α and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes

BACKGROUND: Serine proteases have important roles in skin barrier function and desquamation, and the aberrant expression or the dysfunction of serine proteases is associated with the pathogenesis of skin diseases. Serine protease activities are tightly regulated by serine proteases such as kallikrein-related peptidases (KLKs) and serine protease inhibitors such as lympho-epithelial Kazal-type related inhibitor (LEKTI). For a better understating of diseases' pathogenesis, the regulation mechanism of serine proteases and the inhibitors' expression in epidermal keratinocytes must be clarified. OBJECTIVES: To investigate the effects of the cytokines on the expression of LEKTI in epidermal keratinocytes. METHODS: Normal human epidermal keratinocytes (NHEKs) were stimulated with panels of inflammatory cytokines. The expression of serine protease inhibitors was analyzed using quantitative real-time PCR and ELISA. LEKTI expression in normal human skin and lesions from psoriasis or atopic dermatitis (AD) were analyzed by immunohistochemically and tape-stripping. Trypsin- and chymotrypsin-like serine protease activities in culture supernatants were measured by using specific substrates. RESULTS: TNF-α and IL-17A significantly induced the expression of LEKTI in NHEKs. The immunohistochemical and tape-stripping analysis revealed that psoriatic skin lesions had higher LEKTI expression compared to normal skin and AD lesions. Trypsin- and chymotrypsin-like protease activities in the culture media were upregulated 3-5 days later but attenuated 6-7 days later period by these cytokines. CONCLUSIONS: In epidermal keratinocytes, the Th1&Th17 cytokines TNF-α and IL-17A induce the expression of serine protease inhibitor LEKTI, and it might occur to suppress the increase in the serine protease activities under inflammation

Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis

The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD

P-NETG2に対しPRRTを施行した4例に関する検討

In June 2021, 177Lu-oxodotreotide, a PRRT, was approved by insurance for unresectable or recurrent NETs. We investigated the efficacy and safety of PRRT in four patients with P-NETs at our hospital. All patients were confirmed to be positive for somatostatin receptors by using octreoscan. PRRT treatment was then performed and retrospectively evaluated for efficacy and safety. PRRT was administered as lutetium oxodotreotide（177Lu） at 7.4 GBq per dose over 30 - minutes for up to 1 - 4 doses at 8 - week intervals. Efficacy was evaluated using RECIST v1. 1. Adverse effects were evaluated by CTCAE（v5.0 JCOG）. The mean patient age was 60±12.0 years, and all patients were male. Three patients had a PS of 0, and one patient had a PS of 1 or higher. Metastatic organs were the liver in four patients and intra-abdominal lymph nodes in one patient, all of whom were Stage IV. Three patients underwent transarterial embolization. 177Lu-DOTATOC PRRT was administered every 8 weeks, and a total of four courses were administered in two patients, three courses in one patient, and one course in one patient. One patient had grade 2 thrombocytopenia after one course, and the second course was administered at a half dose（3.7 GBq）. The overall response rate（ORR） was 25%, with one PR and two SD. The median PFS was 9 months（95% Cl, 8-NA）, and the median overall survival from diagnosis was 119 months（95%Cl, 31 - NA）. Adverse events during PRRT included leukopenia in two patients（one G3, one G2）, lymphopenia in one patient（one G3）, thrombocytopenia in two patients（two G2, one G3）, creatinine increase in one patient（one G2）, and skin rash in one patient. In conclusion, PRRT is expected to be highly effective and safe compared with conventional therapy for neuroendocrine tumors with unresectable or distant metastases

子宮内膜症性腸閉塞に対する経肛門的イレウスチューブの有用性

One of the causative diseases of intestinal obstruction in young women is bowel endometriosis. During the course of ectopic endometriosis, it is estimated that about １０％ of patients develop bowel endometriosis. The first step in treatment is drug therapy. In cases of bowel endometriosis of the colon or rectum leading to intestinal obstruction, laparotomy is often required. A ４７-year-old woman with a history of endometriosis was undergoing drug therapy. She developed abdominal pain and nausea, and was diagnosed with septic shock and fecal ileus. A transanal drainage tube was inserted for decompression. The patient’s general condition improved, and a laparoscopic low anterior resection was performed on the ２３rd day. The patient was discharged on the １０th postoperative day without any postoperative problems. This case suggests that even in the case of septic shock caused by rectal stricture due to intestinal endometriosis, initial treatment with transanal decompression may stabilize the general condition, and may be superior in cosmetic change

幼稚園教諭養成課程における「領域に関する専門的事項」に求められる授業内容に関する一考察 : 保育内容領域「人間関係」及び「環境」のモデルカリキュラムを手がかりとして

本論の目的は，幼稚園教諭養成課程において新設された「領域に関する専門的事項」において取り扱うべき内容の射程について検討することである．具体的には，保育教諭養成課程研究会が作成したモデルカリキュラムと授業モデルについて，活動内容，教育内容，及び取り扱っている内容の種別等の観点から分析した．その結果，授業モデルには，①幼児の発達に関する内容，②幼稚園外における経験や現代的特徴，諸課題，③「幼児期の終わりまでに育ってほしい姿」等が示されており，「領域に関する専門的事項」は乳児期・児童期や幼稚園外の生活も射程に含むことを明らかにした．また，「領域に関する専門的事項」と「保育内容の指導法」の教育内容の射程が，教材研究における観点から区別できることを示した．今後，より具体的に取り上げるべき内容について論考するとともに，各養成校において質の高いカリキュラム及びシラバスを作成することが肝要である

Supernova Relic Neutrino Search at Super-Kamiokande

A new Super-Kamiokande (SK) search for Supernova Relic Neutrinos (SRNs) was conducted using 2853 live days of data. Sensitivity is now greatly improved compared to the 2003 SK result, which placed a flux limit near many theoretical predictions. This more detailed analysis includes a variety of improvements such as increased efficiency, a lower energy threshold, and an expanded data set. New combined upper limits on SRN flux are between 2.8 and 3.0 nu_e cm^-2 s^-1 > 16 MeV total positron energy (17.3 MeV E_nu)

Search for Proton Decay into Muon plus Neutral Kaon in Super-Kamiokande I, II, and III

We have searched for proton into muon plus neutral kaon using data from a 91.7 kiloton-year exposure of Super-Kamiokande-I, a 49.2 kiloton-year exposure of Super-Kamiokande-II, and a 31.9 kiloton-year exposure of Super-Kamiokande-III. The number of candidate events in the data was consistent with the atmospheric neutrino background expectation and no evidence for proton decay in this mode was found. We set a partial lifetime lower limit of 1.6x10^33 years at the 90% confidence level.Comment: 15 pages, 13 figure

A history of mild shocks experienced by the regolith particles on hydrated asteroid Ryugu

Micrometeorites, a possible major source of Earth’s water, are thought to form from explosive dispersal of hydrated chondritic materials during impact events on their parental asteroids. However, this provenance and formation mechanism have yet to be directly confirmed using asteroid returned samples. Here, we report evidence of mild shock metamorphism in the surface particles of asteroid Ryugu based on electron microscopy. All particles are dominated by phyllosilicates but lack dehydration textures, which are indicative of shock-heating temperatures below ~500 °C. Microfault-like textures associated with extensively shock-deformed framboidal magnetites and a high-pressure polymorph of Fe–Cr–sulfide have been identified. These findings indicate that the average peak pressure was -2 GPa. The vast majority of ejecta formed during impact on Ryugu-like asteroids would be hydrated materials, larger than a millimetre, originating far from the impact point. These characteristics are inconsistent with current micrometeorite production models, and consequently, a new formation mechanism is required

Machine Learning Prediction for Supplemental Oxygen Requirement in Patients with COVID-19

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