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يدرس البحث صور الإنسان العزيز في نقائض جرير والفرزدق بوصفها بنىً لغوية معرفيّة وجمالية، استطاع بها كِلا الشاعرين تسليط الضوء على معاني الحق والخير والجمال، خلاف ما عُرِف عن النقائض من أنّها نصّ يقوم على تقويض البناء الأخلاقي لمنظومة القيم التي شكّلت عماد رسالة الإسلام، والتي اختصرها حديث النبي صلّى الله عليه وسلّم بقوله: إنّما بُعِثْتُ لأتمّمَ مكارم الأخلاق. وقد أثبتَ البحث أنّ صورة الإنسان العزيز في النقائض لم تخرج عن المعاني الدينيّة والأخلاقيّة لمفهوم العزّة التي هي صِنو الإيمان، وصفة من صفات الذات الإلهيّة والذات المثاليّة الإنسانيّة، فأبرزَ من خلال الصورة أهمّ الأسباب الموجِبَة للعزّة في الجماعة الإنسانيّة، وفي الحاكم وفي الشّاعر، فكانَ للقوّة النصيب الأوفر، تليها حماية الذّمار، ونصرة الحقّ، وكثرة الأعوان ونفاذ الكلمة. كما بيّن البحث الهيئات التي تقرّرت بها تلك الصور، والآلية التي اعتمدها الشاعران لتقريبها من المتلقّين، من خلال ما تتضمّنه من قيم فنّية وجماليّة.

Age-related macular degeneration (AMD) is associated with the dysfunction and degeneration of retinal pigment epithelium (RPE) cells. Here, we examined how the formation and expansions of cell clusters are regulated by the differentiation of the RPE　cells. In this study, ARPE-19 cells were cultivated in standard or differentiation media, i.e., without or with nicotinamide, to evaluate the spreading of cell clusters specified with differentiated cell phenotypes. Mitochondria membrane potential (MMP) and the distribution of the RPE cell clusters was also monitored with or without rotenone, a mitochondrial electron transport chain (ETC) complex I inhibitor. Cultured ARPE-19 cells generated scattered cell clusters composed mostly of smaller size cells expressing the differentiation markers mouse anti-cellular retinaldehyde-binding protein (CRALBP) and Bestrophin only in differentiation medium. After the increase of the number of clusters, the clusters appeared to paracellularly merge, resulting in expansion of the area occupied by the clusters. Of note, the cells within the clusters selectively had high MMP and were in accordance with the expression of RPE differentiation markers. Rotenone repressed the formation of the clusters and decreased intracellular MMP. The above results suggest that clustering of RPE cells with functional mitochondria plays a pivotal role in RPE cell differentiation process and the ETC complex I inhibition greatly influences the composition of RPE cells that are degenerated or differentiation disposed., (© 2024. The Author(s).)

Importance: Whether guttae in Fuchs endothelial corneal dystrophy (FECD) can be removed by polishing without Descemet stripping and whether postoperative maintenance of reduced guttae can be achieved through cultured corneal endothelial cell (CEC) transplant therapy are critical issues to be addressed., Objective: To investigate the decrease of guttae through polishing degenerated CECs and abnormal extracellular matrix (ECM) without Descemet stripping and to observe the behavior of guttae following cultured CEC transplant., Design, Setting, and Participants: This case series prospective observational study was conducted in a hospital outpatient clinic setting. Between December 2013 and January 2019, 22 eyes with corneal endothelial failure caused by FECD received cultured CEC transplant therapy at Kyoto Prefectural University Hospital. Of these, 15 eyes were consistently monitored at the same central corneal area during the preoperative phase, as well as in the early (within 1 year) and late (after 3 years) postoperative phases. The images from these phases were categorized into 3 groups: typical guttae, atypical guttae, and no guttae., Exposures: Cultured CEC transplant therapy., Main Outcomes: Proportion of guttae in the observable area was measured, comparing the early and late postoperative phases for each group., Results: The mean age of the patients at the time of surgery was 69 years (range, 49-79 years). All 15 eyes exhibited the presence of confluent guttae preoperatively (100%). Among these, 3 of 15 eyes belonged to male patients. The early postoperative phase of guttae morphologies was classified into 3 groups: 5 eyes with typical guttae, 7 with atypical guttae, and 3 with no guttae. The decrease in the number of these guttae was achieved by surgical procedures. The median percentage of guttae in the typical guttae, atypical guttae, and no guttae groups was 41.8%, 44.4%, and 16.2%, respectively, in the early phase, and 42.2%, 38.2%, and 18.8%, respectively, in the late phase., Conclusions and Relevance: The findings demonstrate that in some cases of FECD, guttae can be removed by scraping and polishing abnormal ECM and degenerated CECs, while preserving the Descemet membrane. Furthermore, cultured CEC transplant resulted in no increase in guttae for up to 3 years, providing insights into surgically eliminating guttae.

Background and Aim: Ustekinumab, a new anti-interleukin-12/23 antibody, is an effective treatment for ulcerative colitis; however, data regarding predictive factors of its efficacy are limited. Predicting treatment efficacy in advance would be useful for selecting a therapeutic agent. This study aimed to identify biomarkers that can predict the long-term outcome of ustekinumab treatment., Materials and Methods: We retrospectively reviewed the records of patients with active ulcerative colitis treated with ustekinumab at Osaka Medical and Pharmaceutical University Hospital from June 2020 to January 2023. We divided patients into non-remission and remission groups, and examined whether baseline biomarkers, including C-reactive protein-to-lymphocyte ratio, and early treatment response could predict clinical remission at week 48 of ustekinumab treatment., Results: Of the 33 patients included in the study, 21 (63.6%) were in clinical remission at week 48 of ustekinumab treatment. Baseline C-reactive protein-to-lymphocyte ratio values were significantly higher in the non-remission than in the remission group. The baseline C-reactive protein-to-lymphocyte ratio value was identified as an independent prognostic factor for clinical remission at week 48 (odds ratio: 10, 95% confidence interval: 1.6-62.4, p = 0.014), with the cutoff value of 3.353 showing excellent prognostic performance (sensitivity: 71.4%, specificity: 83.3%). Furthermore, the clinical response at week 4 (odds ratio: 10, confidence interval: 1.78-56.1, p = 0.009) and that at week 8 (odds ratio: 12, confidence interval: 2.16-66.5, p = 0.005) were significantly associated with clinical remission at week 48., Conclusions: The baseline C-reactive protein-to-lymphocyte ratio value and early treatment response are useful biomarkers to predict the long-term efficacy of ustekinumab treatment., Competing Interests: Shiro Nakamura reports receiving speaking fees from AbbVie GK, EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd, and Janssen Pharmaceutical K.K. Dr., (Copyright: © 2024 Koshiba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Endoscopic mucosal healing serves as a critical predictor for achieving long-term remission in Crohn's disease treatment. Recent data indicate that the effectiveness of healing varies based on the location of gastrointestinal inflammation. Additionally, reports suggest that antitumor necrosis factor-α (anti-TNF-α) agents exhibit reduced efficacy in treating small intestinal inflammation compared to colorectal inflammation. Conversely, limited research exists regarding the impact of the anti-IL12/23 agent ustekinumab (UST) on small intestinal inflammation. This study aimed to compare the effects of anti-TNF-α agents and UST on small intestinal inflammation using propensity score analysis., Methods: This retrospective observational study involved 70 patients with Crohn's disease who had inflammation in the small intestine and had initiated treatment with either anti-TNF agents or UST between March 2015 and August 2021. Endoscopic findings were evaluated before treatment commencement and at 1-2 years post-treatment initiation. The propensity score was employed to compare the efficacy of TNF agents and UST on small bowel inflammation., Results: Ustekinumab exhibited greater improvement in the small intestinal endoscopy score than anti-TNF-α antibodies according to the propensity score analysis (inverse probability weighting; P  = .0448). However, no significant disparity was observed in the overall improvement of endoscopic scores between UST and anti-TNF-α antibodies ( P  = .5938)., Conclusions: This study suggests that UST might be more effective than anti-TNF-α agents in treating small intestinal inflammation in Crohn's disease., Competing Interests: The authors declare no conflicts of interest regarding this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Purpose: The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A., Methods: We assessed cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation and expression of senescence markers ( p16 and p21 ) in hCEnCs exposed to UV-A radiation, and senescent hCEnCs induced by ionizing radiation (IR) were used as positive controls. We performed RNA sequencing and proteomics analyses to compare gene and protein expression profiles between UV-A- and IR-induced senescent hCEnCs, and we also compared the results to non-senescent hCEnCs., Results: Cells exposed to 5 J/cm2 of UV-A or to IR exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation and elevated expression of p16 and p21 . RNA-Seq analysis revealed that 83.9% of the genes significantly upregulated and 82.6% of the genes significantly downregulated in UV-A-induced senescent hCEnCs overlapped with the genes regulated in IR-induced senescent hCEnCs. Proteomics also revealed that 93.8% of the proteins significantly upregulated in UV-A-induced senescent hCEnCs overlapped with those induced by IR. In proteomics analyses, senescent hCEnCs induced by UV-A exhibited elevated expression levels of several factors part of the senescence-associated secretory phenotype., Conclusions: In this study, where senescence was induced by UV-A, a more physiological stress for hCEnCs compared to IR, we determined that UV-A modulated the expression of many genes and proteins typically altered upon IR treatment, a more conventional method of senescence induction, even though UV-A also modulated specific pathways unrelated to IR.

Purpose: The ocular surface microenvironment changes with aging. However, it remains unclear if cellular senescence influences the ocular surface. We investigated the presence of p16 INK4a -expressing senescent cells in healthy human conjunctiva., Study Design: Clinical and experimental., Methods: Healthy conjunctival tissue samples were obtained from middle-aged and elderly subjects. RT-qPCR was performed to assess the expression of senescence markers CDKN2A (p16 INK4a ) and CDKN1A (p21 CIP1/WAF1 ) and immunostaining was performed to examine the expression of the senescence marker p16 INK4a , stem cell markers Ki67 and p63, tight-junction marker ZO-1., Results: Our study involved 19 conjunctival tissue samples (10 elderly and 9 middle-aged), mean age [elderly: 75.8 ± 3.7 years (72-81), middle-aged: 52.7 ± 7 years (38-59)], sex (elderly: 3 men, 7 women; middle-aged: 3 men, 6 women). The expression of p16 INK4a was significantly increased at the RNA level in the elderly compared to middle-aged (p < 0.05). Positivity rate of p16 INK4a was significantly elevated in the elderly (15.0 ± 7.8%) compared to middle-aged (0.2 ± 0.6%) (p < 0.05). Positivity rate of Ki67and p63 was significantly reduced in the elderly (1.7 ± 1.7% and 16.5 ± 9.5%) compared to middle-aged (3.9 ± 1.8% and 24.7 ± 5.7%) (p < 0.05). ZO-1 expression was reduced in tissue samples showing p16 INK4a -positivity but retained in tissue samples in which p16 INK4a was undetectable., Conclusions: Senescent cells accumulate with age in the conjunctival epithelium, accompanied by a decrease in Ki67, p63 and ZO-1 expressing cells., (© 2024. Japanese Ophthalmological Society.)

Background: In recent years, various biomarkers of ulcerative colitis (UC) have emerged; however, few studies have simultaneously examined the utility of multiple biomarkers for monitoring disease activity. Additionally, serum leucine-rich alpha-2 glycoprotein (LRG), a new biomarker, may show a blunt response to anti-TNF antibody therapy. This prospective study explored effective biomarkers that could monitor disease activity changes in patients with UC. In addition, we examined the effect of anti-TNF antibody therapy on changes in LRG., Methods: Blood and stool samples were collected twice from patients with UC: at baseline and at least 8 weeks later. Changes in serum LRG, interleukin (IL)-6, prealbumin (pre-Alb), high-sensitivity C-reactive protein (hs-CRP), CRP, and fecal calprotectin (FC) were measured and correlated with changes in disease activity. The relationship between anti-TNF antibody therapy and LRG levels was also examined in patients with the same disease activity., Results: Forty-eight patients with UC (96 samples) were analyzed. ΔLRG and ΔIL-6 correlated strongly with the change in the partial Mayo (pMayo) score between the two time points (ΔpMayo) (r = 0.686, 0.635, respectively). In contrast, FC and IL-6 were particularly accurate predictors of clinical remission, and their area under the curves (AUCs) were significantly higher than that of CRP (AUC: 0.81, 0.76 vs. 0.50; p = 0.001, 0.005). No association was found between the administration of anti-TNF antibody preparations and the LRG values., Conclusions: Correlations were found between changes in UC disease activity and LRG, IL-6, pre-Alb, hs-CRP, CRP, and FC. LRG reflects disease activity during anti-TNF antibody therapy.

Background: Tacrolimus (TAC) effectively induces remission in refractory ulcerative colitis (UC). However, TAC therapy usually lasts for 3 months. Although azathioprine (AZA) is often used in maintenance therapy, the relapse rate remains high. Herein, we evaluated the efficacy of adalimumab (ADA) for remission maintenance in patients with UC after induction therapy with TAC., Methods: We prospectively enrolled patients with moderate-to-severe UC who achieved clinical remission after 3 months of TAC therapy with endoscopic non-mucosal healing (Cohort A). After TAC discontinuation, the remission maintenance rate up to 1 year after starting ADA therapy was examined. We retrospectively enrolled patients with UC treated with TAC (Cohort B). Among patients in clinical remission after TAC treatment for 3 months, those who received AZA as remission maintenance therapy after TAC discontinuation constituted the AZA group. Patients in Cohort A who received ADA and AZA as remission maintenance therapy after TAC discontinuation constituted the ADA + AZA group. We compared the remission maintenance rates in the AZA and ADA + AZA groups for up to 5 years after TAC discontinuation., Results: In Cohort A, of the 46 patients with UC treated with TAC, 17 were eligible for analysis after receiving ADA as remission maintenance therapy. A notable 88.2% (15/17) were still in remission 1 year after starting ADA. The ADA + AZA group ( n = 16) exhibited a significantly higher relapse-free rate than the AZA group ( n = 26) ( p < 0.05; log-rank test)., Conclusion: switching to ADA for remission maintenance in patients with refractory UC who achieved clinical remission with TAC is clinically useful.

Purpose: This study aimed to investigate the senescent phenotypes of human corneal and conjunctival epithelial cells., Methods: We examined cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation, and expression of senescence markers (p16 and p21). RNA sequencing analysis was conducted to compare gene expression profiles between senescent and non-senescent cells. Finally, the potential involvement of senescent cells in the pathogenesis of ocular surface diseases was investigated., Results: X-irradiated corneal and conjunctival epithelial cells exhibited typical senescence phenotypes, i.e., flattened morphologies, increased SA-β-gal activity, decreased cell proliferation, and increased expression of senescence markers, p16 and p21. RNA-seq analysis revealed substantial differences in gene expression profiles between senescent corneal (SCo) and conjunctival epithelial cells (SCj). Moreover, SCj were detected in pathological conjunctival tissues associated with limbal stem cell deficiency (LSCD) due to Stevens-Johnson syndrome or chemical burns, potentially being involved in abnormal differentiation., Conclusion: This study highlights the cellular and molecular characteristics of senescent ocular surface cells, particularly in SCj that show abnormal keratin expression, and their potential roles in severe ocular surface diseases and pathology.

Dry eye is a multifactorial and common age-related ocular surface disease. Dyslipidemia has been reported to be involved in meibomian gland dysfunction (MGD). However, it has not been clearly identified which lipid abnormality is responsible for MGD. In this systematic review and meta-analysis, we discuss how lipid profile changes with aging is responsible for MGD development., Methods: An article search was performed in PubMed, EMBASE, and Web of Science. Eleven studies involving dyslipidemia in patients with MGD were identified. Five out of eleven studies were further analyzed with meta-analysis. The preferred reporting items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. Study-specific estimates (prevalence of dyslipidemia in MGD patients) were combined using one-group meta-analysis in a random-effects model., Results: Meta-analysis revealed that high total cholesterol (TC) and high triglycerides (TG) were significantly associated with MGD prevalence, with odds ratios of 5.245 (95% confidence interval [CI]: 1.582-17.389; p < 0.001) and 3.264 (95% CI: 1.047-10.181; p < 0.001), respectively, but high low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) were not identified. Systematic review found that the percentage of MGD patients with TC ≥ 200 mg/dL ranged from 20.0-77.6%, TG ≥ 150 mg/dL ranged from 8.3-89.7%, whereas, in the aged-match-adjusted controls, TC range of 200 mg/dL or higher and TG range of 150 mg/dL was 6.1-45.1% and 1.1-47.8%, respectively. The severity of MGD was higher with dyslipidemia., Conclusion: Dyslipidemia and higher TC and TG are significant risk factors for MGD.

Aging is a process often associated with various age-related diseases. Senescence is one of the hallmarks of aging, and senescent cells acquire a complex, often pro-inflammatory, secretory phenotype termed the senescence-associated secretory phenotype (SASP). Here we show that ocular surface cells from human cornea become senescent upon X-irradiation, characterized by increased SA-β-gal activity, decreased cell proliferation, increased expression of p16, and disruption of epithelial barrier. Comprehensive transcriptomic and proteomic analysis revealed that human senescent ocular cells acquire a SASP that disrupts epithelial barrier function. During aging in mice, senescent ocular cells accumulate, resulting in decreased epithelial barrier and chronic inflammation. Lacrimal gland excision, which leads to symptoms of dry eye (DE), resulted in corneal opacity associated with severe angiogenesis only in aged mice but not in young mice, and early senolytic treatment protected old DE mice from corneal opacity. In conclusion, senescent cells alter the ocular microenvironment through their SASP and eliminating these cells could represent a potential approach to alleviate symptoms associated with aged ocular surface., Competing Interests: COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. JC is a founder of Unity Biotechnology, which develops methods to eliminate senescent cells.

Background and Aim: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome., Methods: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis., Results: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group., Conclusion: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group ( p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group ( p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.

Purpose: Dry eye disease (DED) is a common age-related ocular surface disease. However, it is unknown how aging influences the ocular surface microenvironment. This systematic review aims to investigate how the aging process changes the ocular surface microenvironment and impacts the development of DED., Methods: An article search was performed in PubMed, EMBASE, and Web of Science. 44 studies reporting on age-related ocular changes and 14 large epidemiological studies involving the prevalence of DED were identified. 8 out of 14 epidemiological studies were further analyzed with meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. Study-specific estimates (impact of aging on the prevalence of DED) were combined using one-group meta-analysis in a random-effects model., Results: Meta-analysis revealed the prevalence of DED in the elderly aged 60 years old or older was 5519 of 60107 (9.2%) and the odds ratio of aging compared to younger age was 1.313 (95% confidence interval [CI]; 1.107, 1.557). With increasing age, the integrity of the ocular surface and tear film stability decreased. Various inflammatory cells, including senescent-associated T-cells, infiltrated the ocular surface epithelium, lacrimal gland, and meibomian gland, accompanied by senescence-related changes, including accumulation of 8-OHdG and lipofuscin-like inclusions, increased expression of p53 and apoptosis-related genes, and decreased Ki67 positive cells., Conclusions: The aging process greatly impacts the ocular surface microenvironment, consequently leading to DED., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate the safety and efficacy of cultured human corneal endothelial cell (hCEC) injection therapy with mature differentiated (mature) cell subpopulations (SPs) for corneal endothelial failure (CEF)., Design: Comparative, interventional case series., Methods: This study involved 18 eyes with CEF that underwent cultured hCEC injection therapy, categorized into 2 groups: (1) 11 eyes administered a relatively lower proportion (0.1 to 76.3%) of mature cell SPs (group 1 [Gr1]), and (2) 7 eyes administered a relatively higher proportion (>90%) of mature cell SPs (group 2 [Gr2]). From 1 week to 3 years postoperation, corneal endothelial cell (CEC) density (CECD), central corneal thickness (CCT), and best-corrected visual acuity (BCVA) were recorded, and the CEC parameter's "spring constant" was calculated. The proportion of mature SPs was evaluated by fluorescence-activated cell sorting analysis based on cell-surface markers., Results: At 3 years postoperation, corneal restoration with improved BCVA was attained in 10 of the 11 Gr1 eyes and all Gr2 eyes, the median CECD in Gr2 (3083 cells/mm 2 ; range, 2182-4417 cells/mm 2 ) was higher than that in Gr1 (1349 cells/mm 2 ; range, 746-2104 cells/mm 2 ) (P < .001), and the spring constant verified the superiority of the mature cultured hCECs. From 24 weeks through 3 years postoperation, the median percentage of CECD decrease was 3.2% in Gr2 and 23.6% in Gr1 (P < .005). CCT recovery was prompt and constant in Gr2, while diverse in Gr1. No adverse events were observed., Conclusion: Our findings showed that mature cell SPs for hCEC injection therapy provide rapid recovery of CCT, better CECD, and low CECD attrition over 3 years postsurgery., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC., Methods: We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months., Results: Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016)., Conclusion: We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment., (© 2022 S. Karger AG, Basel.)

Background and Aims: A considerable number of patients with ulcerative colitis (UC) who initially respond to golimumab (GLM), an anti-TNF-α antibody, gradually lose clinical response. Therapeutic drug monitoring has been proposed to optimize serum anti-TNF-α antibody concentrations before the loss of response; however, little is known about ideal serum GLM concentrations. We aimed to evaluate whether the serum GLM trough levels (TLs) early after the initiation of induction therapy affect the long-term outcomes in UC and to identify the early GLM TLs that should be targeted for better long-term outcomes., Methods: Thirty-one patients were prospectively evaluated. The primary outcome was clinical remission at 54 weeks, and we measured the serum GLM TLs at weeks 6, 10, and 14. Receiver operating characteristic (ROC) curves were constructed to identify optimal GLM TL thresholds early after induction therapy that were associated with clinical remission at week 54., Results: The GLM TL at week 14, but not at weeks 6 or 10, was significantly associated with clinical remission at week 54 (median [IQR] 1.6 [1.3-1.6] μg/mL vs. 0.9 [0.6-1.3] μg/mL; p = 0.04). The area under the ROC curve for GLM TLs at week 14 was 0.78. We identified a week-14 GLM TL of 1.1 μg/mL as the target threshold for achieving clinical remission at week 54., Conclusion: Our results demonstrate the value of early serum GLM TLs in predicting the long-term outcomes of GLM for patients with UC., (© 2022 S. Karger AG, Basel.)

Purpose: To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group., Design: Prospective observational study., Participants: This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014., Methods: All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded., Main Outcome Measures: The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period., Results: At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean ± standard deviation central corneal ECD was 1257 ± 467 cells/mm 2 (range, 601-2067 cells/mm 2 ), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed., Conclusions: The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Aiming to clarify the role of mitochondria in cell fate decision of cultured human corneal endothelial cell (cHCEC) subpopulations., Methods: The mitochondrial respiratory ability were examined with Mito stress and Mito fuel flex test assays using an extracellular flux analyzer (XFe24; Agilent Technologies; Santa Clara, CA) for human corneal endothelium tissues, mature cHCECs and a variety of cell state transitioned cHCECs. Tricarboxylic acid cycle and acetyl-coenzyme A-related enzymes was analyzed by proteomics for cell lysates using liquid chromatography-tandem mass spectrometry for cHCEC subpopulations., Results: The maximum oxygen consumption rate was found to become stable depending on the maturation of cHCECs. In the Mito stress tests, culture supplements, epidermal growth factor, SB203580, and SB431543 significantly repressed oxygen consumption rate, whereas a Rho-associated protein kinase inhibitor Y-27632 increased. Tricarboxylic acid cycle and mitochondria acetyl-coenzyme A-related enzymes were selectively upregulated in mature cHCECs, but not in cell state transitioned cHCECs. The maximum oxygen consumption rate was found to be higher in healthy human corneal endothelium tissues than those with deeply reduced cell density. An upregulated tricarboxylic acid cycle was linked with metabolic rewiring converting cHCECs to acquire the mitochondria-dependent oxidative phenotype., Conclusions: Mitochondrial metabolic intermediates and energy metabolism are tightly linked to the endothelial cell fate and function. These findings will help us to standardize a protocol for endothelial cell injection.

Purpose: To clarify the expression profiles of ion channels and transporters of metabolic substrates among heterogeneous cultured human corneal endothelial cells (cHCECs) distinct in their effectiveness in reconstituting the corneal endothelium., Methods: Integrated proteomics for cell lysates by liquid chromatography-tandem mass spectrometry was carried out from three aliquots of cHCECs enriched in either cluster of definition (CD)44-/+ (mature) cHCECs or CD44++/+++ cell-state transition (CST) cHCECs. The expression profiles of cations/anions, monocarboxylic acid transporters (MCTs), and solute carrier (SLC) family proteins, as well as carbonic anhydrases (CAs), were investigated., Results: The polarized expression of cations/anions, MCTs, and SLC family proteins, as well as CAs, was clarified for mature and CST cHCECs. Most SLC4 family members, including SLC4A11 and SLC4A4 (NBCe1), were upregulated in the CST cHCECs, whereas SLC9A1 (Na+/H+ exchanger isoform one [NHE1]) and CA5B were detected only in the mature cHCECs. In addition, SLC25A42, catalyzing the entry of coenzyme A into the mitochondria, and SLC25A18, functioning as a mitochondrial glutamate carrier 2 (both relevant for providing the substrates for mitochondrial bioenergetics), were selectively expressed in the mature cHCECs., Conclusions: Our findings may suggest the relevance of qualifying the polarized expression of these ion channels and transporter-like proteins to ensure not only the suitability but also the in vivo biological functionality of cHCECs selected for use in a cell-injection therapy.

Purpose: Aiming to clarify the metabolic interrogation in cell fate decision of cultured human corneal endothelial cells (cHCECs)., Methods: To analyze the metabolites in the culture supernatants (CS), 34 metabolome measurements were carried out for mature differentiated and a variety of cHCECs with cell state transition through a facility service. Integrated proteomics research for cell lysates by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed for 3 aliquots of each high-quality or low-quality cHCEC subpopulations (SP). The investigations for the focused genes involved in cHCEC metabolism were performed by using DAVID and its options "KEGG&#95;PATHWAY.", Results: The clusters of metabolites coincided well with the distinct content of CD44-/+ SPs. Both secreted pyruvic acid and lactic acid in the CS were negatively correlated with the content of high-quality SPs. Lactic acid and pyruvic acid in the CS exhibited the positive correlation with that of Ile, Leu, and Ser, whereas the negative correlation was with glutamine. Platelet-derived growth factor-ββ in the CS negatively correlated with lactic acid in CS, indicating indirectly the positive correlation with the content of CD44-/+ SPs. Upregulated glycolytic enzymes and influx of glutamine to the tricarboxylic acid cycle may be linked with a metabolic rewiring converting oxidative metabolism in mature differentiated CD44-/+SPs into a glycolytic flux-dependent state in immature SPs with cell state transition., Conclusions: The findings suggest that the cell fate decision of cHCECs may be dictated at least partly through metabolic rewiring.

Aims: Pulmonary vein isolation (PVI) by catheter ablation for atrial fibrillation (AF) requires suppression of patient restlessness by sufficient sedation in addition to maintaining stable respiration. We applied adaptive-servo ventilation (ASV) and examined the effects of ASV combined with deep propofol sedation on PVI using a NavX., Methods and Results: We analysed 75 paroxysmal AF (PAF) patients (62 ± 11 years; 53 men and 22 women) who underwent PVI for treatment of PAF using an ASV system combined with deep sedation (ASV group). Control patients included 75 consecutive PAF patients (62 ± 11 years; 51 men and 24 women) who underwent PVI just before introduction of the ASV system. Deep sedation was defined as a Ramsay sedation score of 6. The ASV group had a lower frequency of restless body movements compared with the control group during PVI (1.5 ± 0.7 vs. 7.8 ± 1.4 times, P < 0.01). The frequency of respiratory compensation and EnGuide alignment of catheter position by the NavX was lower in the ASV (4.2 ± 3.3 and 8.8 ± 7.1 times) than control group (7.1 ± 5.1 and 15.2 ± 10.0 times, P < 0.05 and <0.01, respectively). Consequently, significantly lower total electrical energy supply (48.7 ± 6.0 KJ) was required in the ASV than control group (64.5 ± 24.9 KJ, P < 0.01). Further, significantly shorter fluoroscopy and procedural times were observed in the ASV (28 ± 5 and 109 ± 25 min) than the control group (33 ± 6 and 141 ± 38 min, respectively, P < 0.01) and the AF recurrence rate was significantly lower in the ASV than the control group (12 vs. 25%, P < 0.01)., Conclusion: ASV combined with deep sedation is an effective strategy during PVI using the NavX in patients with PAF.

Upon hypoxia, erythrocytes utilize hemoglobin (Hb) to trigger activation of glycolysis through its interaction with band 3. This process contributes to maintenance of ATP, a portion of which is released extracellularly to trigger endothelium-dependent vasorelaxation. However, whether the ATP release results either from metabolic activation of the cells secondarily or from direct regulation of the gating through Hb allostery remains unknown. This study aimed to examine if stabilization of T-state Hb could induce steady-state and hypoxia-induced alterations in glycolysis and the ATP release from erythrocytes. Treatment of deoxygenated erythrocytes with a nitric oxide (NO) donor generated alpha-NO Hb that is stabilized T-state allostery. Under these circumstances, the release of ATP was significantly elevated even under normoxia and not further enhanced upon hypoxia. These events did not coincide with activation of glycolysis of the cells, so far as judged by the fact that intracellular ATP was significantly decreased by the NO treatment. Collectively, the present study suggests that hypoxia-induced ATP release is triggered through mechanisms involving R-T transition of Hb, and the gating process might occur irrespective of hypoxia-responsive regulation of glycolysis.

Therapeutic plasmapheresis has usually been applied to diseases with unknown causes. Clear analysis of the mechanism of the effect that apheresis has on diseases derived from unknown causes has not been completed. The effect of leukocytapheresis on ulcerative colitis (UC) or rheumatoid arthritis (RA) also lacks clear analysis, but removal of 10(10) adhesive cells resulted in the suppression of both acute and chronic inflammatory reactions. The number of cells removed was not unreasonable for efficacy. A quite acceptable explanation is that the cells activated in the inflammatory lesions are more adhesive than nonactivated cells. However, only a few minutes of contact with the surface of the device can activate blood immune cells. All of the apheresis therapies, not only leukocytapheresis, should be evaluated for their efficacies, excluding the effects of contact activation. According to results presently available, the suppressive effect of leukocytapheresis on RA or UC is through to depend upon the removal of activated inflammation related cells that might transfer inflammatory signals. It may be that those cells removed are bound because of cell stimulation caused by microorganisms or foreign bodies.

Properties of PUP-201 for the application to vital organs were estimated. Basic properties of PUP-201 were compared with two kinds of commercial fibrin and synthetic adhesives. Its initial and wet adhesive strength was 40 and 150 times stronger than those of fibrin adhesives respectively. Its curing time was 50 seconds, and elongating rate was 150% nearly as same as that of the intestine. This adhesive had not antimicrobial activities. The strength of adhesive bonded pig skin in shear by tension loading by way of JIS K6850 recorded 2.0-2.7kg/cm2 five minutes after, and 2.0-2.8kg/cm2 after 24 hours. The results of the same test in small intestine defined 0.4-1.0kg/cm2 in sero-sero attachment. There was no toxicity on the pig skin. Practical examinations for application to hemostasis on the section of dog liver and sealing of the lung section were performed successfully. PUP-201 was demonstrated excellently useful material for the adhesive, hemostasis and sealant of vital tissue.

Two new leukocyte removal filters, Nipro CF-1 and CF-2 (Nipo Medical Industries, Osaka, Japan), were evaluated. These non-woven polyester filters, which are gravity flow devices that require no priming and no rinsing after use, were developed for preparing 400 ml of whole blood or red cell concentrates from 400 ml of whole blood. A flow cytometric technique was developed to measure extremely low white blood cell (WBC) counts. To evaluate the efficiency of these filters, leukocyte counts were measured by three techniques: 1) electronic, 2) visual, and 3) flow cytometry. Flow cytometric counting was done using a Coulter EPICS-C cytometer (Coulter Corp., Hialeah, FL). Nipro CF-1 removed 99.97 +/- 0.01% (mean +/- SD, n = 14) of leukocytes measured by flow cytometry, and CF-1 recovered 90.7 +/- 4.47% (n = 21) of red blood cells. After filtration through CF-2, more than a 6 log10 (> 99.9999%) depletion of WBCs was detected in six samples, a 6 log10 (99.9999%) depletion of WBCs was detected in two samples, a 5 log10 (99.999%) depletion was detected in five samples, and a 4 log10 (99.99%) depletion was detected in one sample. CF-1, in which size and priming volume was smaller than other commercial leukocyte removal filters, accomplished a 3 log10 reduction in WBC count, compared with other commercial filters. CF-2 achieved a 4-6 log10 depletion of WBCs assayed by flow cytometry.

We hypothesized that the host immune system is directly stimulated by contact between blood and the materials used in blood purification systems. This concept has never been applied in therapeutic plasmapheresis. Two new materials have been invented since 1983. One of those is lipopolysaccharide (LPS)-immobilized beads, which are chemically bonded bacterial LPS (LPS-B). Another is immobilized pokeweed mitogen (PWM-B). We studied these two materials for their anti-tumor cell activity in vitro and in vivo. Their efficacy on tumor cells was demonstrated to be much stronger than that of lymphocyte activated killer (LAK) cells. Our new concept was proven to be correct.

As an anticoagulant, we compared Nafamostat mesilate (FUT) to heparin in experimental direct hemoperfusion (DHP) and studied the efficacy of FUT in clinical plasma exchange (PE). In in vitro study, FUT (5 micrograms/ml) inhibited the activation of C4 more strongly than heparin (100 U/h), and larger dose of FUT (50 micrograms/ml) inhibited the activation of C3. Experimental DHP with FUT on jaundiced dogs was safely performed, but not with heparin. Clinical PE with FUT was safely performed and the hemostatic condition was not aggravated either during or after PE in patients with bleeding.

For the purpose of activating the immune system in the living body, we made use of pokeweed mitogen (PWM). PWM, a type of lectin, has the potential to induce anticancer cells. In order to utilize this potential and apply it to cancer therapy by hemoperfusion with PWM, the lectin is immobilized on the surface of synthetic polymer beads and these beads are packed into a minicolumn. Human peripheral lymphocytes were activated by circulatory contact stimulation through the PWM column for 1h. After circulatory contact stimulation through the column, lymphocytes were collected and used as effector cells. Cytotoxicity tests were measured by 51Cr-release assay using K-562 cells and Daudi cells for targets. This material could enhance natural killer activity and induce cytotoxicity against natural-killer-resistant Daudi cells. Lymphocytes activated by the PWM column were injected intraregionally into nude mice bearing MKN-1 tumor, and suppression of tumor growth was recognized. Anticancer activities by direct hemoperfusion treatment with a PWM minicolumn were examined in Vx2-tumor-bearing rabbits. A single treatment using the PWM column was performed 6 days after tumor inoculation. Suppression of the tumor growth was observable for 25 days. PWM minicolumns are a likely anticancer material, acting as immunomodulators.

It goes without saying that post-surgical hepatic failure must be treated. But today, the prognosis is very poor. The reasons for this are that HF is usually accompanied by hemostatic disorders and PHF, and the patients have fresh wounds and are under surgical stress. Moreover, there is no treatment, except PE, and this requires an anticoagulant. Nafamostat Mesilate (FUT-175) was invented as a serine protease inhibitor. It is short acting, and its degradation does not require the liver. FUT-175 was applied as an anticoagulant to 15 PHF patients with bleeding. There were no side effects and no aggravation of bleeding. Based on these results, FUT-175 is thought to be an ideal anticoagulant.

Anion exchange resin fiber (Ionex) was used as a heparin adsorbent. Ionex has the adsorption capacity of 70 mg/g (weight by desiccation) for heparin, and was used in an attempt to remove the heparin from blood-perfused artificial organs, before the blood was transfused back into the patients. In the ex vivo study, the 5 systemically heparinized dogs (500 U/kg) were treated with a 35-40 g column of Ionex, by direct hemoperfusion (DHP). The concentration of heparin was significantly reduced, within 15 to 60 minutes, using the Ionex. This suggested the possibility of removing excess heparin from the living body. In in vitro, the relationship between the amount of heparin by Ionex and the blood-flow volume were evaluated. Whole blood taken from dogs was added to 5 U/ml of heparin. This was then introduced into a small column containing 0.9 g Ionex, at blood-flow rates of 0.8, 1.6, and 3.2 ml/min. A good adsorption capacity was shown at the blood-flow rate of 0.8 ml/min. One possible explanation for this is that the heparin dispersed in the blood cells gradually was passed on into the plasma and, so, did not have time to be adsorbed at the faster flow rates.