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Hiroki Ishikawa,1 Ryuichi Nagashima,1 Yoshihiro Kuno,1,2 Hiraku Sasaki,3 Chikara Kohda,1 Masayuki Iyoda1,2 1Department of Microbiology and Immunology, Showa University School of Medicine, Tokyo, 142-8555, Japan; 2Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8666, Japan; 3Department of Health Science, Faculty of Health and Sports Science, Juntendo University, Inzai, Chiba, 270-1695, JapanCorrespondence: Hiroki Ishikawa, Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan, Tel +81-3-3784-8131, Fax +81-3-3784-3069, Email h_ishikawa@med.showa-u.ac.jpPurpose: The purpose of this study was to investigate whether NKT cells play an important role in preventing or exacerbating diseases caused by high-fat diet (HFD) using CD1d-knockout (KO) mice which lack NKT cells.Methods: Five-week-old male Balb/c (wild-type; WT) or CD1dKO mice were fed with control-diet (CTD) or HFD for 16 weeks.Results: The present study revealed four main findings. First, CD1dKO mice were susceptible to obesity caused by HFD in comparison to WT mice. Second, clinical conditions of fatty liver caused by HFD were comparable between CD1dKO mice and WT mice. Third, HFD-fed WT mice showed high levels of serum biochemical markers, involved in lipid metabolisms, in comparison to WT mice fed a CTD. Notably, the serum concentrations of ALT, T-CHO, TG and HDL-C in CD1dKO mice fed a HFD were almost comparable to those of CD1dKO mice fed a CTD. Fourth, the expression of peroxisome proliferator-activated receptor (PPAR) γ, low-density lipoprotein receptor (LDLR), CD36 of epididymal adipose tissue enhanced and proprotein convertase subtilisin/kexin type (PCSK) 9 in serum decreased.Conclusion: NKT cells were responsible for protection against HFD-induced obesity. However, CD1dKO mice were resistant to serum biochemical marker abnormalities after HFD feeding. One possible explanation is that the epididymal adipose tissue of CD1dKO mice could take up greater amounts of excess lipids in serum in comparison to WT mice.Keywords: NKT cells, high-fat diet, obesity, serum biochemical markers, adipose tissue

Objective: Subchondral bone (SB) is one of the important tissues in development and progression of osteoarthritis (OA). To identify genes involved in the disease process, comprehensive gene expression analysis of SB was performed. Patients and Methods: Medial dominant knee OA patients were selected, and SB of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) was collected at the time of total knee arthroplasty. After RNA extraction, gene expression levels were compared between the MFC and LFC using microarrays. Genes that changed more than two-fold in the MFC were compared with the previously reported gene list from the same type of study that used the affected tibial plateau. Pathway analysis and immuno-histochemical analysis of selected molecules were performed. Results: Eighty genes were identified as commonly affected genes in both the present study and a previous study. Among them periostin was conspicuously up-regulated. Pathway analysis revealed up-regulated osteoclast activities. Periostin was detected in the cytoplasm of mononuclear cells in the SB, except for osteocytes. Conclusions: Among the 80 genes detected and thought to be important, periostin was the most highly up-regulated. Its importance in OA pathogenesis is indicated. [ABSTRACT FROM AUTHOR]

The present study assessed the inhibitory action of exopolysaccharides (EPS) produced by Lactobacillus delbrueckii ssp. bulgaricus OLL1073R‐1 against influenza virus infection followed by secondary bacterial infection. We found that the presence of 200 or 400 μg ml−1 of EPS significantly protected against influenza virus infection in a dose‐dependent manner when A549 cells were treated with EPS before infection but not after it. The expression of carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1), an adhesion molecule for bacteria adherence, on A549 cells was significantly enhanced during influenza virus infection compared with viral‐non‐infected A549 cells. However, this upregulated CEACAM‐1 expression was significantly decreased by EPS treatment before viral infection in association with the reduction in the virus titre in A549 cells. In a bacterial adhesion assay using Staphylococcus aureus, the bacterial adherence to viral‐infected A549 cells was significantly greater than that to viral‐non‐infected A549 cells, and the increased bacterial adherence induced by influenza virus infection tended to be decreased by EPS treatment before the infection. Our findings show that EPS treatment before viral infection can inhibit influenza virus infection and alleviate secondary bacterial infection through decreased CEACAM‐1 expression. [ABSTRACT FROM AUTHOR]

Nuclear quadrupole resonance measurements were performed on the heavy-fermion superconductor Ce2PdIn8· Above the Kondo coherence temperature Tcoh≃30 K, the spin-lattice relaxation rate 1/T1 is temperature independent, whereas at lower temperatures, down to the onset of superconductivity at Tc = 0.64 K, it is nearly proportional to T1/2. Below Tc, 1/T1 shows no coherence peak and decreases as T³ down to 75 mK. All these findings indicate that Ce2PdIn8 is close to the antiferromagnetic quantum critical point, and the superconducting state has an unconventional character with line nodes in the superconducting gap. [ABSTRACT FROM AUTHOR]

BACKGROUND: In Japan, urea breath-testing includes mouth rinsing with water immediately after the ingestion of (13)C-urea solution, to prevent false-positive results that are caused by oral bacteria with urease activity. Our objective was to evaluate the diagnostic performance of a urea breath test using a film-coated (13)C-urea tablet and omitting mouth rinsing. METHODS: The study was a multicenter trial comparing the solution- and tablet-based urea breath tests (UBTs). Helicobacter pylori status was determined by histology, culture, and rapid urease testing. RESULTS: Of the 255 subjects who completed the study, evaluation of the tablet-based UBT was possible in 254, and comparison of the tablet-based UBT and the solution-based UBT was possible in 250 patients. When the assessment achieved by a combination of biopsy-based methods was used as a reference standard, the sensitivity, specificity, and accuracy of the tablet-based method were determined to be 97.7%, 98.4%, and 98.0%, respectively. When the results of the solution-based UBT were used as a reference standard, the sensitivity, specificity, and accuracy of the tablet-based UBT were determined to be 96.9%, 97.6%, and 97.2%, respectively. CONCLUSIONS: The (13)C-urea tablet-based method proved to be a simple and accurate test for the diagnosis of H. Pylori infection. Mouth rinsing was not required. [ABSTRACT FROM AUTHOR]

Detecting plasma protein loss from the stomach is quite difficult by measuring fecal alpha1-AT clearance because alpha1-AT is rapidly destroyed in the gastric juice at values below pH 3. We examined protein loss from the stomach using fecal alpha1-AT clearance with lansoprazole, a proton pump inhibitor. A 38-year-old Japanese male presented with hypoproteinemia (total serum protein: 4.4 g/dl). Abdominal scintigraphy using technetium-99m-labeled albumin revealed distinct radioactivity accumulation in the small intestine. It strongly suggested excessive protein loss to the gastrointestinal tract. Although, regular fecal alpha1-AT clearance was within the normal range (<13 ml/day), the fecal alpha1-AT clearance with the administration of lansoprazole was 80.5 ml/day. The results indicated that this method using lansoprazole is simple and useful for detecting protein-losing gastropathy. [ABSTRACT FROM AUTHOR]

A patient with primary small cell carcinoma of the esophagus is reported, in whom we have studied the secretion of a variety of hormones and cytokines. The tumor was an intermediate cell type of small cell carcinoma and had either epithelial and neuroendocrinological characteristics. Furthermore, hypercalcemia and neutrophilia were present, and the tumor was shown to produce PTHrp, secretin, and G-CSF. The present case is the first report of primary small cell carcinoma of the esophagus with ectopic production of PTHrp, secretin, and G-CSF. [ABSTRACT FROM AUTHOR]

Objective: This study assessed whether patients with potentially preventable emergency admissions had limited access to outpatient care immediately before admission and whether they received appropriate outpatient care during their outpatient visits., Design: Retrospective observational study., Setting: Linked outpatient and inpatient care records obtained from a nationwide claims database in Japan., Participants: Patients who experienced emergency admissions for ambulatory care-sensitive conditions between April 2005 and March 2020. Patient and regional characteristics were examined to assess the types of patients who faced difficulties with outpatient visits and receiving outpatient care related to the disease that resulted in admissions (hereafter referred to as admission-related outpatient care)., Main Outcome Measures: (1) Whether patients had an outpatient visit during the 2 weeks preceding admission and (2) whether patients received admission-related outpatient care during the 2 weeks before admission., Results: This study included 18 449 emergency admissions for ambulatory care-sensitive conditions, representing 16.3% (18 449/113 669) of all emergency admissions in our data. Among patients with emergency admissions for ambulatory care-sensitive conditions, 37.4% did not have an outpatient visit within the 2 weeks preceding admission and 29.9% did not receive admission-related outpatient care despite having an outpatient visit. In total, 67.4% did not receive admission-related outpatient care during the 2 weeks preceding admission. Patients in their 40s and 50s were less likely to have outpatient visits and receive admission-related outpatient care before admission. No evidence associates regional characteristics with outpatient visits and receiving admission-related outpatient care before admission., Conclusion: Most patients who underwent emergency admissions for ambulatory care-sensitive conditions did not have an outpatient visit or receive admission-related outpatient care, despite having an outpatient visit immediately before admission. Our findings suggest that emergency admissions may be prevented by improving access to timely and effective outpatient care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathy that develops in patients treated with certain anticancer drugs. Oxaliplatin (OXA) causes CIPN in approximately 80-90 % of patients; thus, it is necessary to elucidate its underlying mechanism and develop effective treatments and prevention methods. The purpose of this study was to determine whether the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system in the spinal dorsal horn is involved in OXA-induced acute cold allodynia and examine the effect of a PAC1 receptor antagonist. Administration of OXA induced acute cold allodynia in wild-type mice, but not in PACAP-/- mice. In the dorsal root ganglia, OXA upregulated PACAP expression, particularly in small-sized neurons. OXA-induced cold allodynia was ameliorated by intrathecal (i.t.) injection of PACAP6-38 (peptide antagonist for PACAP receptor) and PA-8 (small-molecule antagonist specific for PAC1 receptor). I.t. PACAP, but not vasoactive intestinal polypeptide, resulted in cold allodynia, which was blocked by PA-8. OXA induced the activation of spinal astrocytes in a PAC1 receptor-dependent manner. The results suggest that spinal PACAP/PAC1 receptor systems are involved in OXA-induced acute cold allodynia through astrocyte activation. Furthermore, we demonstrated that the systemic administration of PA-8 resulted in therapeutic and preventative effects on OXA-induced acute cold allodynia. Because PA-8 did not affect the anticancer effects of OXA, we propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of CIPN. PERSPECTIVE: Cold allodynia is a hallmark of OXA-induced peripheral neuropathy. This study demonstrated the involvement of spinal PACAP/PAC1 receptors in OXA-induced acute cold allodynia. We propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of OXA-induced acute cold allodynia., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest to report., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

To determine the characteristics of the changes in the amplitude of the flicker electroretinograms (ERGs) after combined cataract surgery and vitrectomy for an idiopathic epiretinal membrane (ERM). To accomplish this, we conducted a prospective study on 20 patients. Flicker ERGs and central macular thickness (CMT) were measured before the surgery (baseline), and at 1 week, 1 month, 3 months, and 6 months postoperatively. The mean amplitude of the flicker ERGs increased significantly by 63.5% at 1 week after surgery (P < 0.001) and then gradually decreased. The amplitude at 6 months was not significantly different from the baseline amplitude. This transient increase in the flicker ERG amplitudes after ERM surgery suggests that electrophysiologic evaluations of the therapeutic effects of vitrectomy should be performed 6 months postoperatively. The mean CMT decreased significantly at 1 week postoperatively (P < 0.001) and continued to decrease progressively over six months. The relative increase of amplitude at 1 week was significantly associated with the relative decrease of CMT at 6 months, and evaluation of retinal functional changes at 1 week may be able to predict the postoperative course of the ERM., (© 2024. The Author(s).)

Renal fibrosis is a common pathway of chronic kidney disease (CKD) progression involving primary kidney injury and kidney diseases. Group 2 innate lymphoid cells (ILC2s) mediate type 2 immune responses irrespective of antigen presentation and play a reno-protective role in kidney injury and disease. In the present study, we observed a decrease in kidney-resident ILC2s in CKD and found that enrichment of ILC2s in the kidney ameliorates renal fibrosis. In CKD kidney, ILC2s preferentially produced IL-13 over IL-5 in response to IL-33 stimulation, regardless of ST2L expression. Moreover, GATA3 expression was decreased in ILC2s, and T-bet+ ILC1s and RORγt+ ILC3s were increased in CKD kidney. Adoptive transfer of kidney ILC2s into adenine-induced CKD model mouse improved renal function and fibrosis. Renal fibroblasts cultured with IL33-activated kidney ILC2s suppressed myofibroblast trans-differentiation through Acta2 and Fn-1 regulation. These results suggest that kidney ILC2s prevent CKD progression via improvement of renal fibrosis. Our findings also suggest that ILC2s may contribute to the development of new therapeutic agents and strategies for tissue fibroses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Intrinsic foot muscles (IFMs) play an important role in lower-limb motor control, including biomechanics and neuromuscular control function. Short foot exercise (SFE) and toe curl exercise (TC) are methods used to train the IFMs, but their effect on lower-limb motor control has not been reported in previous studies. This study evaluated the effects of SFE and TC on lower-limb motor control function during single-leg standing (SLS)., Trial Design: Randomized control trial., Method: Thirty-six participants with flatfoot were randomly assigned to the SFE or TC group and performed exercise for 8 weeks. The assessment items were navicular drop test, toe grip strength (TGS), plantar sensation, and SLS. In the SLS assessment, we measured the mean center of pressure (COP) amplitude in the anteroposterior (AP) and mediolateral (ML) directions, onset time of gluteus maximus (G. max) and gluteus medius (G. med), angle of forefoot/hindfoot protonation and hip adduction, and lateral pelvic shift. Mixed-model repeated-measures analysis of variance and Bonferroni corrections were performed in statistical analysis., Results: The SFE group showed significant differences between pre- and post-intervention for TGS (p < 0.001), COP ML (p = 0.039), and onset times of G. max (p = 0.015), and G. med (p < 0.001). The TC group showed no significant differences in all assessment items., Conclusion: Our finding suggests that SFE contributes to lower neuromuscular control function in people with flatfoot., Trial Registration: UMIN000049963., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

It is a problem that influenza virus infection increases susceptibility to secondary bacterial infection in lungs leading to lethal pneumonia. We previously reported that exopolysaccharides (EPS) derived from Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (OLL1073R-1) could prevent against influenza virus infection followed by secondary bacterial infection in vitro. Therefore, the present study assessed whether EPS derived OLL1073R-1 protects the alveolar epithelial barrier disfunction caused by influenza virus infection. After A549 cells treated with EPS or without EPS were infected influenza virus A/Puerto Rico/8/34 (IFV) for 12 h, the levels of tight junction genes expression and inflammatory genes expression were measured by reverse transcription polymerase chain reaction. As results, EPS treatment could protect against low-titer IFV infection, but not high-titer IFV infection, followed by suppression of the increased expression of inflammatory cytokine gene levels and recovery of the decrease in the expression level of ZO-1 gene that was caused by low-titer IFV infection, leading to an improvement trend in the barrier function. Our findings showed that EPS derived from OLL1073R-1 could inhibit low-titer IFV infection leading to maintenance of the epithelial barrier function through the suppression of inflammatory cytokine genes expression., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Purpose: To report our findings of reduced full-field electroretinograms (ff-ERGs) and abnormal optical coherence tomographic (OCT) images in a patient with poor visual acuity after cataract surgery who was eventually diagnosed with vitamin A deficiency (VAD)., Methods: This was a clinical study of a patient who complained of blurred vision after cataract surgery. To determine the cause of the reduced vision, we recorded full-field electroretinograms (ff-ERGs) to determine the scotopic and photopic status of the retina. We also performed optical coherence tomography to assess the changes in the retinal structure. Serological tests were performed., Results: A 74-year-old man presented with persistent corneal epithelial damages and reduced vision that developed after conventional cataract surgery. OCT showed an interrupted ellipsoid zone, and fundus autofluorescence (FAF) showed a severe hypofluorescence in the retina of the left eye. The scotopic ff-ERGs were severely reduced, and the photopic ff-ERGs were mildly reduced. Serological examinations revealed a vitamin A concentration < 7 IU/dL (normal, 97-316 IU/dL). Based on these findings, we diagnosed the patient with VAD and started treatment with oral vitamin A supplements. After three months, his visual acuity, ff-ERGs, and OCT findings recovered to normal levels. The amplitudes and implicit times of the RETeval flicker ERGs increased to be within the normal range, and the hypofluorescence of the left eye disappeared. The length of the photoreceptor outer segments increased after the vitamin A supplementation., Conclusion: Our findings indicate that the ERGs are helpful for diagnosing patients with VAD associated with persistent corneal epithelial damages., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 68-year-old man with a history of valve-sparing aortic root replacement and endoscopic aortic valve replacement was admitted to our hospital with dyspnea. Transthoracic echocardiography revealed severe pulmonary valve regurgitation. The patient had undergone cardiac surgery twice, through median sternotomy and right thoracotomy; therefore, we planned endoscopic pulmonary valve replacement via the left thoracic approach. The patient was placed in a modified right lateral decubitus position and underwent mild hypothermic cardiopulmonary bypass. An on-pump beating-heart technique was used during surgery. The 3D endoscopic system and trocars for surgical instruments were inserted through the left 3rd and 4th intercostal spaces. After incision of the pulmonary artery, the pulmonary cusps were resected. A 27-mm St Jude Medical Epic heart valve was implanted in the intra-annular position. Subsequently, the left atrial appendage was resected. The patient was discharged without complications. To our knowledge, this is the first case of totally endoscopic pulmonary valve replacement.

Intraocular inflammations (IOIs) have been reported to occur after intravitreal injections of brolucizumab, and one of their causes has been suggested to be drug-specific features. We evaluated the anterior chamber by the aqueous flare value (AFV) and the retina by flicker electroretinography (ERG) after the initial intravitreal injection of aflibercept (IVA), brolucizumab (IVBr), or faricimab (IVF) for neovascular age-related macular degeneration (nAMD). The AFV and flicker ERGs were determined before, 2 weeks after, and 4 weeks after the injections in 14 eyes of 14 patients for each drug. After the injections, none of the patients had an IOI, but the AFV increased significantly in the IVA and IVF groups. The increase in the IVF group was +4.6 photon count/ms, which was significantly greater than in the other groups, but was not clinically significant. The implicit time was significantly prolonged in the IVBr group but unchanged in the IVA and IVF groups. These results suggest that brolucizumab, administered at high molar doses, may cause transient retinal disturbances that are not detectable by general ophthalmologic examinations but affect the implicit ERG times.

Minimal change disease (MCD), a common cause of idiopathic nephrotic syndrome, has been postulated to exhibit an association with allergic conditions. Recent studies revealed the crucial role of interleukin (IL)-33 in type 2 innate immunity. We hypothesized that development of MCD involves an IL-33-related immune response. We examined 49 patients with biopsy-proven MCD, 6 healthy volunteers, and 29 patients in remission. In addition to clinical features, serum and urinary levels of IL-33 and soluble suppression of tumorigenicity 2 protein (sST2), a secreted form of the receptor of IL-33, were analyzed. Although IL-33 was barely detectable in either MCD or control samples, sST2 levels at diagnosis were elevated in MCD patients. Serum sST2 levels of MCD patients were correlated with serum total protein level (r =  - 0.36, p = 0.010) and serum creatinine level (r = 0.34, p = 0.016). Furthermore, the elevated sST2 levels were observed to decrease following remission. Immunofluorescence revealed IL-33 expression in the podocytes among MCD patients, with a significant increase compared with controls. In vitro, mouse podocyte cells incubated with serum from a MCD patient at disease onset showed increased IL-33 secretion. These results suggest an IL-33-related immune response plays a role in MCD., (© 2023. The Author(s).)

Human cytomegalovirus (HCMV) is a member of Herpesviridae. It has been reported that HCMV is reactivated in the breast milk of HCMV-seropositive lactating women. As we have reported various aspects of the roles of indigenous microbiota, its role in the murine CMV (MCMV) reactivation was examined in this study. MCMV was latently infected in the salivary gland, mammary tissues, and colon in the pregnant mice. When the salivary gland, mammary tissues, and colon were removed 5 days after delivery, MCMV reactivation of latent infection in each organ was confirmed by the detection of MCMV IE1 mRNA using reverse transcription-quantitative PCR. MCMV reactivation was observed in 100% of the mice during pregnancy. Next, for the elimination of intestinal microbiota, the pregnant mice were treated with low-dose or high-dose non-absorbable antibiotics. Although the numbers of aerobe/anaerobe in cecal content in low-dose antibiotic-treated mice were comparable to those in untreated controls, high-dose antibiotic treatment decreased the number of aerobe/anaerobe microbes from ca.9.0 Log10 to ca.3.0 Log10 (cfu/g). However, it could not be confirmed in 16S rRNA analysis that specific bacterial phylum or genus was eliminated by this high-dose treatment. Interestingly, MCMV reactivation was also observed in 100% of low-dose antibiotic-treated mice, whereas, in high-dose antibiotic-treated mice, MCMV reactivation was not observed in the salivary gland or colon. MCMV IE1 mRNA was detected only in 33% of the mammary tissues of those high-dose-treated mice. These results suggest that the indigenous microbiota played a crucial role in the reactivation of latent infection. IMPORTANCE Human cytomegalovirus (HCMV) infection via breast milk is a serious problem for very preterm infants such as developing a sepsis-like syndrome, cholestasis, or bronchopulmonary dysplasia, among others. It has been reported that HCMV is reactivated in the breast milk of HCMV-seropositive lactating women. In this study, the roles of indigenous microbiota in the murine CMV (MCMV) reactivation were examined using a mouse model. In MCMV latently infected mice, MCMV reactivation was observed in 100% of the mice during pregnancy. For the elimination of intestinal microbiota, MCMV-latent mice were treated with non-absorbable antibiotics. After delivery, MCMV reactivation was not observed in antibiotic-treated mice. This result suggested that the indigenous microbiota played a crucial role in the reactivation of latent infection.

Objectives: The purpose of this study was to clarify the prevalence of pain outside the foot, and to determine the associations of pain outside the foot with foot-specific quality of life (QOL) in patients with hallux valgus., Methods: Patients scheduled to undergo hallux valgus surgery were recruited. Patients answered whether they experienced disabling pain in 13 body regions other than the foot. Foot-specific QOLwas assessed using the Self-Administered Foot Evaluation questionnaire (SAFE-Q). Foot pain was quantified using the visual analogue scale (VAS). Patient characteristics, including age, sex, comorbidity, anxiety, and depression, were also surveyed. The association between pain elsewhere and the SAFE-Q and pain VAS scores were assessed using univariate and multivariate analyses., Results: Of 102 patients, 55 (54%) experienced pain other than the foot. All SAFE-Q subscale scores were lower, and pain VAS was higher in patients with pain elsewhere than in patients without. In the multivariate analysis, an increase in the number of pain regions was independently associated with a decrease in SAFE-Q scores and an increase in pain VAS., Conclusion: More than half of the patients with hallux valgus experienced pain elsewhere. The presence of pain elsewhere was associated with poorer foot-specific QOL and severer foot pain., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitors are therapeutic agents for renal anemia that work through HIF2-mediated upregulation of erythropoietin (EPO) and have also been reported to suppress renal fibrosis. Group 2 innate lymphoid cells (ILC2s) have been proven to be involved in the pathogenesis of fibrosis in various organs, including the kidney. However, the relationship between the HIF pathway, renal fibrosis, and kidney ILC2s remains unclear. In the present study, we found that HIF activation by HIF-PHD inhibitors suppressed type 2 cytokine production from kidney ILC2s. The enhanced HIF pathway downregulated the IL-33 receptor ST2L on ILC2s, and phosphorylation of downstream p38 MAPK was attenuated. M2 macrophages that promote renal fibrosis were polarized by ILC2 supernatants, but reduced cytokine production from ILC2s treated with HIF-PHD inhibitors suppressed this polarization. Our findings suggest that HIF-PHD inhibitors are potential therapeutic agents for renal fibrosis that are mediated by the alteration of ILC2 function., (© 2023. The Author(s).)

Purpose: To determine the characteristics and cause of the increase in the amplitude of flicker electroretinography (ERG) after cataract surgery., Design: Prospective, observational clinical study., Participants: Thirty patients who underwent cataract surgery., Methods: Flicker ERGs were recorded with the RETeval system without mydriasis. The central macular thickness (CMT) was measured by OCT and the aqueous flare value (AFV) by laser flare-cell photometry. These examinations were performed before surgery and 1 day, 1 week, 1 month, 2 months, and 3 months after surgery. Linear regression analysis through the origin was used to compare the correlations between the relative changes in flicker ERG amplitudes and the changes in the CMT and AFV at different times after the surgery., Main Outcome Measures: The amplitude of flicker ERGs, CMT, and AFV., Results: The mean amplitude of flicker ERGs increased significantly by 31% at 1 week after surgery ( P  < 0.001); a significant increase in the amplitudes was not present at 3 months after the surgery. The mean AFV was significantly increased at 1 day after surgery ( P < 0.001), and the CMT was significantly increased at 1 to 3 months after surgery ( P < 0.001). The changes in flicker ERG amplitudes at 1 week after surgery were significantly associated with the changes in the CMT at 1 to 3 months after surgery ( P < 0.05), and they were weakly associated with the changes in AFV at 1 day after surgery ( P  = 0.05)., Conclusions: These results suggest that the increase in the amplitude of flicker ERGs after cataract surgery is a transient phenomenon that has a peak at 1 week after surgery. The increase of flicker ERG amplitude was associated with measures that are frequently used to evaluate postoperative inflammation., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2022 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Renal fibrosis is a common pathway in the progression of various kidney diseases and injuries. Unilateral ureteral obstruction (UUO) induces renal fibrosis, and immune responses profoundly affect its pathogenesis. Group2 innate lymphoid cells (ILC2s) are strongly activated by interleukin (IL) -33, which is a member of IL-1 family and recognize as alarmin. ILC2s quickly produce large amounts of type 2 cytokines including IL-5 and IL-13, which are involved in inflammation, tissue homeostasis, and wound healing. However, the relationship between renal fibrosis and ILC2s has been unclear. In the present study, we investigated the roles of the ILC2/L-33 axis in renal fibrosis using a UUO model. We found that kidney ILC2s decreased in UUO-affected kidneys compared with their counterpart kidneys despite IL-33 upregulation. There was no effect of reactive oxygen species or TGF-β from reduced ILC2 caused by UUO. Pretreatment with IL-33 before UUO induced ILC2s and Tregs in kidneys and alleviated renal fibrosis. Furthermore, this protective effect was maintained even when CD4 + T cells was depleted. These findings demonstrated that ILC2s play a predominant role in the suppressive function of renal fibrosis mediated by pretreatment with IL-33. In contrast, post-treatment with IL-33 after UUO increased ILC2s in kidneys but had no therapeutic effect on renal fibrosis. Our findings suggest that ILC2s have potential roles in the prevention of renal fibrosis and can serve as a therapeutic and diagnostic target., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Aims: Microsurface patterns of the gastric mucosa can be observed using magnifying narrow-band imaging (M-NBI). However, the efficacy of M-NBI at low-magnification (LM-NBI) screening for detecting small gastric neoplasms is unclear., Methods: This prospective study was conducted at a single institution. LM-NBI, defined as minimal magnification that could reveal the microsurface pattern of the gastric mucosa, was performed after routine white-light imaging (WLI) observation of the stomach. Depending on the phase in which the neoplastic lesions were initially found, they were divided into the WLI group and the LM-NBI group, and the characteristics of these neoplastic lesions were investigated accordingly., Results: Sixty-five epithelial lesions (adenomas or noninvasive carcinomas) of 20 mm or less in diameter were identified in this study. Sixteen lesions were detected only with LM-NBI. Smaller lesions were detected using LM-NBI ( P  = .01). WLI took about 160 to 260 seconds, while LM-NBI required about 70 to 80 seconds. All lesions in the LM-NBI group had a background of map-like redness (n = 5) or atrophic/metaplastic mucosa (n = 11)., Conclusions: LM-NBI was able to detect lesions overlooked by WLI, especially those in areas of map-like redness or atrophic/metaplastic mucosa of the stomach. Approximately one-quarter of newly diagnosed neoplasms were retrieved on routine examination during an extra 1.5 minutes., (© 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.

Purpose: To report abnormal full-field electroretinograms (ERGs) in a patient with cystoid macular edema (CME) induced by systemic paclitaxel., Methods: This is an observational case report. Full-field ERGs were recorded to evaluate the retinal function using the RETeval system and conventional ERGs using contact lens electrodes with built-in white light-emitting diodes. Optical coherence tomography (OCT) was also used to assess the retinal morphology., Results: A 70-year-old man, who was diagnosed with gastric cancer, had undergone gastrectomy. Subsequently, systemic paclitaxel was administered once a week as an adjuvant therapy. After the tenth course of paclitaxel, he experienced blurred vision in both eyes and visited our department of ophthalmology. OCT revealed the presence of CME in both eyes, and the RETeval flicker ERGs showed a marked reduction in the amplitudes and a prolongation of the implicit times in both eyes. Conventional ERGs showed that the amplitudes of the oscillatory potentials (OPs) were also severely attenuated. The abnormal OCT findings and reduced visual acuity recovered to normal at 1 and 2 months, respectively, after the discontinuation of paclitaxel. However, the flicker ERGs did not recover to normal values until 4 months after the discontinuation of paclitaxel., Conclusion: These results suggest that the ERGs can be used to monitor the changes in the overall retinal function in patients receiving paclitaxel., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abiotic stresses, such as high light and salinity, are major factors that limit crop productivity and sustainability worldwide. Chemical priming is a promising strategy for improving the abiotic stress tolerance of plants. Recently, we discovered that ethanol enhances high-salinity stress tolerance in Arabidopsis thaliana and rice by detoxifying reactive oxygen species (ROS). However, the effect of ethanol on other abiotic stress responses is unclear. Therefore, we investigated the effect of ethanol on the high-light stress response. Measurement of chlorophyll fluorescence showed that ethanol mitigates photoinhibition under high-light stress. Staining with 3,3'-diaminobenzidine (DAB) showed that the accumulation of hydrogen peroxide (H 2 O 2 ) was inhibited by ethanol under high-light stress conditions in A. thaliana . We found that ethanol increased the gene expressions and enzymatic activities of antioxidative enzymes, including ASCORBATE PEROXIDASE1 ( AtAPX1 ), Catalase (AtCAT1 and AtCAT2) . Moreover, the expression of flavonoid biosynthetic genes and anthocyanin contents were upregulated by ethanol treatment during exposure to high-light stress. These results imply that ethanol alleviates oxidative damage from high-light stress in A. thaliana by suppressing ROS accumulation. Our findings support the hypothesis that ethanol improves tolerance to multiple stresses in field-grown crops., (© 2021 Japanese Society for Plant Biotechnology.)

Innate lymphoid cells (ILCs) are a recently discovered lymphocyte population with high cytokine productive capacity. Type-2 ILCs (ILC2s) are the most studied, and they exert a rapid type-2 immune response to eliminate helminth infections. Massive and sustainable ILC2 activation induces allergic tissue inflammation, so it is important to maintain correct ILC2 activity for immune homeostasis. The ILC2-activating cytokine IL-33 is released from epithelial cells upon tissue damage, and it is upregulated in various kidney disease mouse models and in kidney disease patients. Various kidney diseases eventually lead to renal fibrosis, which is a common pathway leading to end-stage renal disease and is a chronic kidney disease symptom. The progression of renal fibrosis is affected by the innate immune system, including renal-resident ILC2s; however, the roles of ILC2s in renal fibrosis are not well understood. In this review, we summarize renal ILC2 function and characterization in various kidney diseases and highlight the known and potential contributions of ILC2s to kidney fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nagashima and Iyoda.)

Background: We describe herein an extremely rare case of intracardiac ectopic thymoma-only two pure cases have been reported to date-associated with myasthenia gravis, an infrequent complication of ectopic thymoma., Case Presentation: A 71-year-old woman with superior vena cava syndrome was found to have a large mass mainly located in the right atrium. Tumor resection under cardiopulmonary bypass was performed. The pathological diagnosis was type AB ectopic thymoma. The postoperative course was complicated by progressive respiratory failure, and she was diagnosed with myasthenic crisis based on clinical signs and the edrophonium test. The patient recovered and was weaned from prolonged mechanical ventilation after receiving intravenous immunoglobulin, and was subsequently discharged uneventfully., Conclusions: This is the first report of myasthenic crisis due to intracardiac ectopic thymoma. Residual thymoma is a risk factor for the development of post-thymectomy myasthenia gravis, and long-term follow-up is required.

Background: A new handheld electroretinographic (ERG) recording system can record ERGs without mydriasis. However, this RETeval system cannot record ERGs from both eyes simultaneously. Thus, the purpose of this study was to determine whether the sequence of the ERG recordings will alter the results., Methods: We studied 30 eyes of 30 healthy subjects. The flicker ERGs were recorded with the RETeval system without mydriasis and were elicited by 8, 16 and 32 photopic Td-s. The flicker ERGs were recorded at two sessions. Session 1, the ERGs were recorded from the right eye and then the left eye, and Session 2, ERGs were recorded from the left eye then the right eye. We compared the implicit times, amplitudes and pupil diameters of the right eye between these two sessions., Results: The implicit time of the flicker ERGs was significantly shorter (p < 0.001), and the pupil diameters were significantly smaller (p = 0.013) at Session 2 than Session 1 but only for the lower stimulus intensity of eight Td-s. There was a significant correlation of the differences in the implicit times and the differences in the pupil diameter between the two sessions (r = 0.406, p = 0.026)., Conclusions: The results indicate that the implicit times of the fundamental components of RETeval flicker ERGs can be affected by the sequence of recordings for lower stimulus intensities. This was most likely due to the differences of the pupil diameter during the recordings. We recommend that stronger stimuli be used to record the RETeval flicker ERGs to minimize the effects of the sequence of recordings., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

In the activation of cell-mediated adaptive immune responses that play major roles in the elimination of virus-infected or tumor cells, it is important that dendritic cells present antigen peptides on major histocompatibility complex (MHC) class I molecules and activate pathogen-specific cytotoxic T lymphocytes (CTL). As exogenous peptide antigens are generally presented on MHC class II but not class I, the development of a method for exogenous antigen delivery that facilitates MHC class I presentation is necessary for a potentially effective vaccine that is expected to provoke cell-mediated adaptive immune responses. Here, we developed extracellular vesicles that incorporate antigenic proteins by utilizing endosomal sorting complexes required for transport (ESCRT)-mediated vesicle formation pathway. Furthermore, we proved that these vesicles could deliver their contents to the cytoplasm of dendritic cells and activate antigen-specific CTLs. These technologies could be applied to the development of novel CTL-inducing peptide vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)