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Competing Interests: Declarations. Ethical Approval: This case report was approved by the Ethics Committee of the University of Tokyo (No. 2487, 2022179NI). Consent for Publication: Written informed consent was obtained from the patient Conflicts of Interest: On behalf of all the authors, the corresponding author states that there are no conflicts of interest.

MID1-COMPLEMENTING ACTIVITY (MCA) is a land plant-specific, plasma membrane protein and Ca2+ signaling component that responds to exogenous mechanical stimuli, such as touch, gravity, and hypotonic-osmotic stress, in various plant species. MCA is essential for cell proliferation and differentiation during growth and development in rice (Oryza sativa) and maize (Zea mays). However, the mechanism by which MCA mediates cell proliferation and differentiation via Ca2+ signaling remains unknown. Here, we address this question using the liverwort Marchantia polymorpha. We show that the M. polymorpha MCA ortholog, MpMCA, is highly expressed in actively dividing regions, such as apical notches in the thalli and developing gametangiophores, and that MpMCA is a plasma membrane protein. In vivo Ca2+ imaging using a Ca2+ sensor (yellow cameleon) revealed that MpMCA is required for maintaining proper [Ca2+]cyt levels in the apical notch region, egg cells, and antheridium cells. Mpmca mutant plants showed severe cell proliferation and differentiation defects in the thalli, gametangiophores, and gametangia, resulting in abnormal development and unsuccessful fertilization. Furthermore, expression of the Arabidopsis MCA1 gene complemented most of the defects in the growth and development of the Mpmca mutant plants. Our findings indicate that MpMCA is an evolutionarily conserved Ca2+-signaling component that regulates cell proliferation and development across the life cycle of land plants., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

The pathophysiology of laryngopharyngeal reflux (LPR) and its impact on the vocal fold is not well understood, but may involve acid damage to vocal fold barrier functions. Two different components encompass vocal fold barrier function: the mucus barrier and tight junctions. Mucus retained on epithelial microprojections protects the inside of the vocal fold by neutralizing acidic damage. Tight junctions control permeability between cells. Here we developed an in vitro experimental system to evaluate acidic injury and repair of vocal fold barrier functions. We first established an in vitro model of rat vocal fold epithelium that could survive at least one week after barrier function maturation. The model enabled repeated evaluation of the course of vocal fold repair processes. Then, an injury experiment was conducted in which vocal fold cells were exposed to a 5-min treatment with acidic pepsin that injured tight junctions and cell surface microprojections. Both of them healed within one day of injury. Comparing vocal fold cells treated with acid alone with cells treated with acidic pepsin showed that acidic pepsin had a stronger effect on intercellular permeability than acid alone, whereas pepsin had little effect on microprojections. This result suggests that the proteolytic action of pepsin has a larger effect on protein-based tight junctions than on phospholipids in microprojections. This experimental system could contribute to a better understanding of vocal fold repair processes after chemical or physical injuries, as well as voice problems due to LPR pathogenesis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masanobu Mizuta, Ichiro Tateya reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they 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.)

Many insects are obligatorily associated with and dependent on specific microbial species as essential mutualistic partners. In the host insects, such microbial mutualists are usually maintained in specialized cells or organs, called bacteriocytes or symbiotic organs. Hence, potentially exponential microbial growth cannot be realized but must be strongly constrained by spatial and resource limitations within the host cells or tissues. How such endosymbiotic bacteria grow, divide, and proliferate is important for understanding the interactions and dynamics underpinning intimate host-microbe symbiotic associations. Here we report that Blattabacterium , the ancient and essential endosymbiont of cockroaches, exhibits unexpectedly high rates of cell division (20%-58%) and, in addition, the cell division is asymmetric (average asymmetry index >1.5) when isolated from the German cockroach Blattella germanica . The asymmetric division of endosymbiont cells at high frequencies was observed irrespective of host tissues (fat bodies vs ovaries) or developmental stages (adults vs nymphs vs embryos) of B. germanica , and also observed in several different cockroach species. By contrast, such asymmetric and frequent cell division was observed neither in Buchnera , the obligatory bacterial endosymbiont of aphids, nor in Pantoea , the obligatory bacterial gut symbiont of stinkbugs. Comparative genomics of cell division-related genes uncovered that the Blattabacterium genome lacks the Min system genes that determine the cell division plane, which may be relevant to asymmetric cell division. These observations combined with comparative symbiont genomics provide insight into what processes and regulations may underpin the growth, division, and proliferation of such bacterial mutualists continuously constrained under within-host conditions.IMPORTANCEDiverse insects are dependent on specific bacterial mutualists for their survival and reproduction. Due to the long-lasting coevolutionary history, such symbiotic bacteria tend to exhibit degenerative genomes and suffer uncultivability. Because of their microbiological fastidiousness, the cell division patterns of such uncultivable symbiotic bacteria have been poorly described. Here, using fine microscopic and quantitative morphometric approaches, we report that, although bacterial cell division usually proceeds through symmetric binary fission, Blattabacterium , the ancient and essential endosymbiont of cockroaches, exhibits frequent and asymmetric cell division. Such peculiar cell division patterns were not observed with other uncultivable essential symbiotic bacteria of aphids and stinkbugs. Gene repertoire analysis revealed that the molecular machinery for regulating the bacterial cell division plane are lost in the Blattabacterium genome, suggesting the possibility that the general trend toward the reductive genome evolution of symbiotic bacteria may underpin their bizarre cytological/morphological traits., Competing Interests: The authors declare no conflict of interest.

Background: Increased fall risk caused by vestibular system impairment is a significant problem associated with aging. A vestibule is composed of linear acceleration-sensing otoliths and rotation-sensing semicircular canals. Otoliths, composed of utricle and saccule, detect linear accelerations. Otolithic organs partially play a role in falls due to aging. Aging possibly changes the morphology and functions of otoliths. However, the specific associations between aging and otolith changes remain unknown. Therefore, this study aimed to clarify these associations in mice., Methods: Young C56BL/6 N (8 week old) and old (108-117 weeks old) mice were used in a micro-computed tomography (μCT) experiment for morphological analysis and a linear acceleration experiment for functional analysis. Young C56BL/6 N (8 week old) and middle-aged (50 week old) mice were used in electron microscopy experiments for morphological analysis., Results: μCT revealed no significant differences in the otolith volume ( p  = 0.11) but significant differences in the otolith density ( p  = 0.001) between young and old mice. μCT and electron microscopy revealed significant differences in the structure of striola at the center of the otolith (μCT; p  = 0.029, electron microscopy; p  = 0.017). Significant differences were also observed in the amplitude of the eye movement during the vestibulo-ocular reflex induced by linear acceleration (maximum amplitude of stimulation = 1.3G [ p  = 0.014]; maximum amplitude of stimulation = 0.7G [ p  = 0.015]), indicating that the otolith function was worse in old mice than in young mice., Discussion: This study demonstrated the decline in otolith function with age caused by age-related morphological changes. Specifically, when otolith density decreased, inertial force acting on the hair cells decreased, and when the structure of striola collapsed, the function of cross-striolar inhibition decreased, thereby causing a decline in the overall otolith function., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ueda, Imai, Ito, Okayasu, Harada, Kamakura, Ono, Katsuno, Tanaka, Tatsumi, Hibino, Wanaka and Kitahara.)

Lymphomatoid granulomatosis (LYG) is a rare, T-cell-rich Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative systemic disease. Only a few cases of LYG have been described in patients with autoimmune disorders, with only one case described in a patient with systemic lupus erythematosus (SLE). However, no cases of isolated central nervous system (CNS)-LYG have been reported in patients with autoimmune diseases. Since isolated CNS involvement is rare, its clinicopathological features remain incompletely understood. Herein, we report about an 85-year-old Japanese woman who was diagnosed with SLE 26 years ago and was stable and maintained on prednisone (5 mg/day) for 20 years. Twenty-six days before admission, she developed cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed multiple nodular lesions with ring-like enhancements seen on gadolinium-enhanced T1-weighted imaging. A brain biopsy was performed on the right frontal lobe lesion. Pathological findings revealed T-cell infiltration surrounding the blood vessels with fibrin deposition, a few multinucleated cells, and large atypical cells with prominent nucleoli. Large atypical cells positive for CD20 and EBV-encoded RNA (EBER) were seen at a density of >100 cells per high-power field. Based on laboratory testing, imaging, and pathology findings, the patient was diagnosed with grade III LYG. Treatment with tirabrutinib (480 mg once daily) was started. The patient achieved clinical response to treatment, as evidenced by improved mental status. In patients with SLE who present with multiple nodular or ring-like lesions on brain MRI, brain biopsy with histological diagnosis is crucial for the exclusion of CNS-LYG., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objective: The clinical impact of malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria in patients with kidney dysfunction remains poorly understood. This study investigated the usefulness of GLIM criteria for malnutrition in predicting mortality in patients with kidney dysfunction and different clinical renal states, including no kidney disease (NKD), acute kidney injury (AKI), and chronic kidney disease (CKD)., Methods: This single-center retrospective cohort study included 6,712 patients aged ≥18 admitted between 2018 and 2019. The relationship between the estimated glomerular filtration rate (eGFR) groups, nutritional status based on the GLIM criteria, and the incidence of all-cause mortality was evaluated using a multivariate Cox proportional hazards model. Malnutrition was defined as at least one phenotype (weight loss, low body mass index, or reduced muscle mass) and one etiological criterion (reduced intake/assimilation or disease burden/inflammation)., Results: Multivariate Cox proportional hazards model showed that eGFR ≤29 (vs. eGFR: 60-89, adjusted hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.52-2.22), 30-59 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.20-1.64), and ≥90 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.14-1.71), moderate and severe malnutrition (vs. without malnutrition, adjusted HR = 1.38 [1.18-1.62] and 2.18 [1.86-2.54], respectively) were independently associated with the incidence of death. The all-cause mortality rate was higher in patients with malnutrition or eGFR ≤29 (adjusted HR, 3.31; 95% CI: 2.51-4.35) than in patients without malnutrition or eGFR 60-89. Furthermore, moderate and severe malnutrition (vs. no malnutrition) was independently associated with death in patients with NKD, AKI, and CKD., Conclusion: Malnutrition based on the GLIM criteria was associated with increased all-cause mortality in inpatients, and malnutrition combined with kidney dysfunction was associated with a higher risk of mortality. Furthermore, patients with NKD, AKI, and CKD showed an association between malnutrition based on GLIM criteria and mortality., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We developed a rat dorsal root ganglion (DRG)-derived sensory nerve organotypic model by culturing DRG explants on an organoid culture device. With this method, a large number of organotypic cultures can be produced simultaneously with high reproducibility simply by seeding DRG explants derived from rat embryos. Unlike previous DRG explant models, this organotypic model consists of a ganglion and an axon bundle with myelinated A fibers, unmyelinated C fibers, and stereo-myelin-forming nodes of Ranvier. The model also exhibits Ca 2+ signaling in cell bodies in response to application of chemical stimuli to nerve terminals. Further, axonal transection increases the activating transcription factor 3 mRNA level in ganglia. Axons and myelin are shown to regenerate 14 days following transection. Our sensory organotypic model enables analysis of neuronal excitability in response to pain stimuli and tracking of morphological changes in the axon bundle over weeks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Echinococcosis, caused by Echinococcus spp., often affects the lungs and liver, and spinal involvement is rare. Echinococcus multilocularis is prevalent in Japan, particularly in Hokkaido. We herein report a rare case of spinal echinococcosis in a 31-year-old woman who was diagnosed in Tokyo. Spinal echinococcosis is uncommon and often leads to misdiagnoses. The patient likely contracted the disease via contaminated fresh produce transported from an endemic region. This study emphasizes the diagnostic challenges of spinal echinococcosis in non-endemic regions and highlights the public health concerns related to the spread of infections in non-endemic areas.

The characteristic feature of chronic peritoneal damage in peritoneal dialysis (PD) is a decline in ultrafiltration capacity associated with pathological fibrosis and angiogenesis. The pathogenesis of peritoneal fibrosis is attributed to bioincompatible factors of PD fluid and peritonitis. Uremia is associated with peritoneal membrane inflammation that affects fibrosis, neoangiogenesis, and baseline peritoneal membrane function. Net ultrafiltration volume is affected by capillary surface area, vasculopathy, peritoneal fibrosis, and lymphangiogenesis. Many inflammatory cytokines induce fibrogenic growth factors, with crosstalk between macrophages and fibroblasts. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-A are the key mediators of fibrosis and angiogenesis, respectively. Bioincompatible factors of PD fluid upregulate TGF-β expression by mesothelial cells that contributes to the development of fibrosis. Angiogenesis and lymphangiogenesis can progress during fibrosis via TGF-β-VEGF-A/C pathways. Complement activation occurs in fungal peritonitis and progresses insidiously during PD. Analyses of the human peritoneal membrane have clarified the mechanisms by which encapsulating peritoneal sclerosis develops. Different effects of dialysates on the peritoneal membrane were also recognized, particularly in terms of vascular damage. Understanding the pathophysiologies of the peritoneal membrane will lead to preservation of peritoneal membrane function and improvements in technical survival, mortality, and quality of life for PD patients.

Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests 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 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

This study aimed to evaluate diagnostic accuracy of SARS-CoV-2 RNA detection in saliva samples treated with a guanidine-based or guanidine-free inactivator, using nasopharyngeal swab samples (NPS) as referents. Based on the NPS reverse transcription-polymerase chain reaction (RT-PCR) results, participants were classified as with or without COVID-19. Fifty sets of samples comprising NPS, self-collected raw saliva, and saliva with a guanidine-based, and guanidine-free inactivator were collected from each group. In patients with COVID-19, the sensitivity of direct RT-PCR using raw saliva and saliva treated with a guanidine-based and guanidine-free inactivator was 100.0%, 65.9%, and 82.9%, respectively, with corresponding concordance rates of 94.3% (κ=88.5), 82.8% (κ=64.8), and 92.0% (κ=83.7). Among patients with a PCR Ct value of <30 in the NPS sample, the positive predictive value for the three samples was 100.0%, 80.0%, and 96.0%, respectively. The sensitivity of SARS-CoV-2 RNA detection was lower in inactivated saliva than in raw saliva and lower in samples treated with a guanidine-based than with a guanidine-free inactivator. However, in individuals contributing to infection spread, inactivated saliva showed adequate accuracy regardless of the inactivator used. Inactivators can be added to saliva samples collected for RT-PCR to reduce viral transmission risk while maintaining adequate diagnostic accuracy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takashi Katsuno, Moto Kimura, and Wataru Sugiura received research grants from the SB Coronavirus Inspection Center Corp. Disclosure statement Takashi Katsuno, Moto Kimura, and Wataru Sugiura received research grants from the SB Coronavirus Inspection Center Corp. Yukumasa Kazuyama is the director and Masato Ikeda is the president of SB Coronavirus Inspection Center Corp. All other authors report no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cassidine leaf beetles are associated with genome-reduced symbiotic bacteria Stammera involved in pectin digestion. Stammera cells appear to be harbored in paired symbiotic organs located at the foregut-midgut junction either intracellularly or extracellularly, whereas the symbiont is extracellular in the ovary-accessory glands of adult females and during caplet transmission in eggs. However, using fluorescence and electron microscopy, an intracellular symbiotic configuration of Stammera was observed in Notosacantha species. Detailed inspection of other cassidine species revealed fragmented cell membrane and cytoplasm of the symbiotic organs, wherein Stammera cells are in an intermediate status between intracellularity and extracellularity. We also identified a mitochondria-rich region adjacent to the symbiont-filled region and well-developed muscle fibers surrounding the whole symbiotic organ. Based on these observations, we discuss why the Stammera genome has been reduced so drastically and how symbiont-derived pectinases are produced and supplied to the host's alimentary tract for plant cell wall digestion., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Aims: Glomerular damage and proximal tubular damage play an important role in the pathogenesis of diabetic kidney disease. This study aimed to investigate the relationship between the urinary markers of proximal tubular injury, including urinary liver-type fatty acid-binding protein-to-creatinine ratio (uL-FABP/Cr) and urinary N-acetyl-β-D-glucosaminidase-to-creatinine ratio (uNAG/Cr), and glycemic control status., Methods: This cross-sectional study included 245 and 39 patients with type 2 diabetes mellitus (T2DM) and non-T2DM (NDM), respectively. The participants of this study were fitted with retrospective CGM, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated., Results: The results were presented as medians (interquartile ranges). The uL-FABP/Cr was significantly higher in the microalbuminuria than in the normo-albuminuria group [4.2 (2.7-7.1) and 2.2 (1.4-3.4) μg/gCr, respectively, P < 0.001], while the uNAG/Cr in the normo-albuminuria group [6.3 (4.5-10.1) U/gCr] was significantly higher than that in the NDM group [5.3 (3.8-6.3) U/gCr, P = 0.048] but significantly lower than that in the microalbuminuria group [9.2 (6.4-11.1) U/gCr, P = 0.004]. The multivariate logistic regression analysis indicated that CGM-derived TIR was significantly associated with the urinary albumin-to-creatinine ratio [uAlb/Cr, odds ratio (OR) 0.985, 95% confidence interval (CI) 0.971-0.998, P = 0.029] and uNAG/Cr (OR 0.973, 95% CI 0.957-0.989, P = 0.001) independent of renal function. GRI was similarly associated with uAlb/Cr and uNAG/Cr., Conclusion: The findings of this study indicated that uNAG/Cr was elevated before albuminuria development and was associated with CGM-derived TIR and GRI., (© 2023. The Author(s).)

For mucociliary clearance of pathogens, tracheal multiciliated epithelial cells (MCCs) organize coordinated beating of cilia, which originate from basal bodies (BBs) with basal feet (BFs) on one side. To clarify the self-organizing mechanism of coordinated intracellular BB-arrays composed of a well-ordered BB-alignment and unidirectional BB-orientation, determined by the direction of BB to BF, we generated double transgenic mice with GFP-centrin2-labeled BBs and mRuby3-Cep128-labeled BFs for long-term, high-resolution, dual-color live-cell imaging in primary-cultured tracheal MCCs. At early timepoints of MCC differentiation, BB-orientation and BB-local alignment antecedently coordinated in an apical microtubule-dependent manner. Later during MCC differentiation, fluctuations in BB-orientation were restricted, and locally aligned BB-arrays were further coordinated to align across the entire cell (BB-global alignment), mainly in an apical intermediate-sized filament-lattice-dependent manner. Thus, the high coordination of the BB-array was established for efficient mucociliary clearance as the primary defense against pathogen infection, identifying apical cytoskeletons as potential therapeutic targets., (© 2024. The Author(s).)

Systemic effects associated with hormones and cytokines secreted by tumor cells can cause paraneoplastic syndrome. Leukemoid reactions and hypercalcemia are relatively common manifestations of paraneoplastic syndrome. Here, we describe the case of a 90-year-old woman who presented with leukocytosis and hypercalcemia and was diagnosed with granulocyte-colony stimulating factor (G-CSF)-producing cervical cancer with elevated levels of parathyroid hormone-related protein (PTHrP). The patient visited our hospital complaining of general fatigue and anorexia. On admission, she presented with marked leukocytosis, hypercalcemia, and an increase in C-reactive protein level. On the basis of abdominal magnetic resonance imaging and histopathological examination, the patient was diagnosed with cervical cancer. Additional tests confirmed elevated plasma levels of G-CSF, PTHrP, and serum interleukin-6. Immunostaining of pathological specimens of the uterine cervix showed expression of G-CSF in tumor cells. The patient was diagnosed with G-CSF-producing cervical cancer accompanied by elevation of PTHrP levels. As a treatment for hypercalcemia, discontinuation of oral vitamin D derivative and administration of saline and elcatonin were ineffective, and therapeutic intervention with zoledronic acid hydrate was required. Considering the patient's advanced age, surgical resection of cervical cancer was not performed. She died from congestive heart failure approximately 3 months after hospitalization. This case was indicated to be a paraneoplastic syndrome in which G-CSF and PTHrP-induced leukocytosis and hypercalcemia. To the best of our knowledge, there have been no reports of G-CSF-producing cervical cancer with elevated PTHrP levels, and our case is the first report., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Introduction: Although type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic control indices and brain imaging biomarkers assessed by MRI., Research Design and Methods: This cross-sectional study included 150 patients with T2DM. The severity of cerebral white matter lesions (WMLs) was assessed using MRI for deep and subcortical white matter and periventricular hyperintensities. The degree of medial temporal lobe atrophy (MTA) was assessed using voxel-based morphometry. Each participant wore a retrospective CGM for 14 consecutive days, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated., Results: The proportion of patients with severe WMLs showed a decreasing trend with increasing TIR ( P for trend=0.006). The proportion of patients with severe WMLs showed an increasing trend with worsening GRI ( P for trend=0.011). In contrast, no significant association was observed between the degree of MTA and CGM-derived glycemic control indices, including TIR ( P for trend=0.325) and GRI ( P for trend=0.447)., Conclusions: The findings of this study indicate that the severity of WMLs is associated with TIR and GRI, which are indices of the quality of glycemic control., Trial Registration Number: UMIN000032143., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Proper management of aspirated material above the tracheostomy tube cuff is crucial to prevent complications, such as aspiration pneumonia. This study aimed to thoroughly examine the effects of aspirated liquid viscosity, suction port positioning, and tube tilt angle on residual volume above the cuff (RVAC)., Methods: Five types of tracheostomy tubes (approximately 9 mm outer diameter) were placed through a transparent cylinder with an inner diameter of 18 mm. The cuff was inflated to completely seal the interior of the cylinder. Four liquids with different viscosities were poured onto the cuff, and the liquid above the cuff was suctioned from the side port. The cylinder was angled at 90° and 20°, and each test was performed thrice to determine the average RVAC., Results: After side-port suctioning, some liquid residue was observed on the cuff of all tracheostomy tubes. The RVAC increased with higher liquid viscosity. The tubes with a longer distance from the suction port opening to the cuff top exhibited more RVAC. Moreover, the RVAC was almost the same regardless of the cylinder angle for tubes with a suction port on the lateral side. However, tubes with backside ports showed a decreased RVAC with cylinder tilt., Conclusions: This study underscores the persistence of residual material on cuffed tracheostomy tubes even with regular subglottic secretion drainage. This emphasizes the need for specialized tracheostomy tube development aimed at reducing post-suction RVAC. Improved designs can potentially minimize complications associated with residue accumulation., (© 2023. The Author(s).)

Objectives: Despite the identification of risk factors for relapses in antineutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein (CRP) levels after the initial treatment and the incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of CRP levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis., Methods: This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after 6 months of immunosuppressive treatment at the Aichi Medical University Hospital between 2009 and 2017. The relationship between the time to normalisation of CRP after the initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models., Results: During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P = .025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. The hazard ratios [95% confidence intervals (CIs)] for the time to normalisation of CRP of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95% CI: 0.92-6.39), and 3.48 (95% CI: 1.56-7.76), respectively., Conclusions: A significant association between the time to normalisation of CRP and the relapse incidence in Japanese patients with microscopic polyangiitis was observed., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We present a single-center retrospective analysis of 228 Japanese patients with peritoneal dialysis, in which we examined whether reduced left ventricular ejection fraction (LVEF) is a risk factor for peritonitis development. Time-dependent multivariable-adjusted Cox proportional hazards models revealed that reduced LVEF (LVEF < 50% vs. preserved LVEF ≥ 50%, hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.16-3.82) was associated with peritonitis. Qualitatively, similar associations with reduced LVEF (< 50%) were observed for enteric peritonitis (adjusted HR 7.68; 95% CI 2.51-23.5) but not for non-enteric peritonitis (adjusted HR 1.15; 95% CI 0.54-2.44). Reduced LVEF is associated with a significantly higher risk of subsequent peritonitis, particularly enteric peritonitis. These results indicate that patients with reduced LVEF may be at risk of enteric peritonitis from bowel sources caused by intestinal involvement due to cardiac dysfunction., (© 2023. The Author(s).)

Objectives: Successful renal transplantation reduces mortality rates. However, the decline in the estimated glomerular filtration rate (eGFR) after transplantation is strongly associated with premature mortality in renal transplant recipients (RTRs). Physical activity (PA) is a modifiable lifestyle factor with the potential to maintain or improve eGFR. However, the effects of the type or intensity of PA and sedentary behavior (SB) on eGFR in RTRs remain unclear. The purpose of this study was to clarify the association between accelerometry-measured PA and SB and eGFR in RTRs using isotemporal substitution (IS) analysis., Methods: A total of 82 renal transplant outpatients participated in this cross-sectional study, of which 65 (average age, 56.9 years; average time post-transplant, 83.0 months) were finally analyzed. All RTRs wore a triaxial accelerometer to measure PA for 7 consecutive days. The measured PA was classified based on intensity into light PA, moderate-to-vigorous PA (MVPA), and SB. The association of each type of PA with eGFR was examined using multi-regression analyses of single-factor, partition, and IS models. The IS model was applied to examine the estimated effects of substituting 30 minutes of SB with an equal amount of time of light PA or MVPA on eGFR., Results: The partition model showed that MVPA was an independent explanatory variable for eGFR (β = 5.503; P < .05), and the IS model identified that the substitution of time spent in SB with MVPA led to improvements in eGFR (β = 5.902; P < .05)., Conclusions: The present study suggests that MVPA has an independent and positive association with eGFR, and replacing 30 minutes of SB with MVPA after renal transplantation might lead to the maintenance or improvement of eGFR in RTRs., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The maintenance of planar polarity in airway multiciliated cells (MCCs) has been poorly characterized. We recently reported that the direction of ciliary beating in a surgically inverted tracheal segment remained inverted beyond the time required for the turnover of cells, without adjustment to global distal-to-proximal polarity. We hypothesized that the local maintenance of tissue-level polarity occurs via locally reproduced cells. To provide further insight regarding this hypothetical property, we performed allotransplantation of an inverted tracheal segment between wild-type (donor) and tdTomato-expressing (host) rats, with and without scratching the mucosa of the transplants. The origin of cells in the transplants was assessed using tdTomato-specific immunostaining. Ciliary movement and structures were observed by high-speed video and electron microscopy to analyze MCC orientations. Variabilities in the orientations of closely and distantly located MCCs were analyzed to evaluate the local- and broad-scale coordination of polarity, respectively. The epithelium was maintained by donor-derived cells in the non-scratched inverted transplant over 6 months, beyond one cycle of turnover. The inverted orientation of MCCs was also maintained throughout the non-scratched transplant. MCCs regenerated in the scratched transplant were derived from the host and exhibited diverse orientations across the transplant. However, the orientations of adjacent regenerated MCCs were often coordinated, indicating that airway MCCs can locally coordinate their orientations. A steady-state airway may maintain MCC orientation by locally reproducing MCCs via the local coordination of polarity. This local coordination enables the formation and maintenance of tissue-level polarity in small regions after mucosal injury., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer cells generally exhibit increased iron uptake, which contributes to their abnormal growth and metastatic ability. Iron chelators have thus recently attracted attention as potential anticancer agents. Here, we show that deferriferrichrysin (Dfcy), a natural product from Aspergillus oryzae acts as an iron chelator to induce paraptosis (a programmed cell death pathway characterized by ER dilation) in MCF-7 human breast cancer cells and H1299 human lung cancer cells. We first examined the anticancer efficacy of Dfcy in cancer cells and found that Dfcy induced ER dilation and reduced the number of viable cells. Extracellular signal-related kinase (ERK) was activated by Dfcy treatment, and the MEK inhibitor U0126, a small molecule commonly used to inhibit ERK activity, prevented the increase in ER dilation in Dfcy-treated cells. Concomitantly, the decrease in the number of viable cells upon treatment with Dfcy was attenuated by U0126. Taken together, these results demonstrate that the iron chelator Dfcy exhibits anticancer effects via induction of ERK-dependent paraptosis., (© 2023 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Objective: Previous studies have identified the predictors of severe infections in ANCA-associated vasculitis. However, lymphopenia has not been fully evaluated as a predictor of subsequent severe infections in patients with microscopic polyangiitis (MPA). The aim of this study was to assess the association between lymphopenia and severe infections requiring hospitalization after receiving immunosuppressive therapy for MPA., Methods: This single-centre retrospective cohort study included 130 consecutive patients with newly diagnosed MPA from Aichi Medical University Hospital, Japan, who received immunosuppressive therapy between March 2004 and December 2020. The relationship between lymphopenia and subsequent severe infections was assessed using time-dependent multivariate Cox proportional hazard models adjusted for clinically relevant factors., Results: During the follow-up period (median: 38 months; interquartile range: 15-63 months), 56 severe infectious episodes occurred in 51 patients (39.2%). Time-dependent multivariate Cox proportional hazard analyses identified older age [adjusted hazard ratio (HR) = 1.74 per 10 years, 95% CI: 1.13, 2.67], methylprednisolone pulse therapy (adjusted HR = 2.04, 95% CI: 1.03, 4.02), moderate lymphopenia ( vs normal, adjusted HR = 7.17, 95% CI: 3.10, 16.6) and severe lymphopenia ( vs normal, adjusted HR = 36.1, 95% CI: 11.8, 110.9) as significant predictors of severe infection., Conclusion: Lymphopenia is a predictor of subsequent severe infections in patients with MPA who receive immunosuppressive therapy. These results suggest the importance of sustained infection surveillance, particularly in older patients who develop lymphopenia during strong immunosuppressive therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that leads to the accumulation of poorly soluble 2,8-dihydroxyadenine (DHA) in the kidneys, resulting in a variety of renal presentations including nephrolithiasis, acute kidney injury, and chronic kidney disease (CKD) caused by crystal nephropathy. Here, we report a case of a 43-year-old man with 2,8-DHA crystalline nephropathy caused by APRT deficiency strongly suspected by renal biopsy results and definitively diagnosed by a urine gas chromatography-mass spectrometry (GC/MS)-based plasma metabolomic assessment. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition and its progression to CKD, which can be prevented by the early administration of xanthine oxidoreductase inhibitors., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Previous studies have revealed that age-related hearing loss (AHL) in Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1)-knockout mice is associated with pathology in the cochlea. Here, we aimed to identify mitochondrial alterations in the cochlea of Cdk5rap1-knockout mice with AHL. Mitochondria in the spiral ganglion neurons (SGNs) and hair cells (HCs) were normal despite senescence; however, the mitochondria of types I, II, and IV spiral ligament fibrocytes were ballooned, damaged, and ballooned, respectively, in the stria vascularis. Our results suggest that the accumulation of dysfunctional mitochondria in the lateral wall, rather than the loss of HCs and SGNs, leads to the onset of AHL. Our results provide valuable information regarding the underlying mechanisms of AHL and the relationship between aberrant tRNA modification-induced hearing loss and mitochondrial dysfunction., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background & Aims: Cardiovascular disease (CVD) is a significant cause of mortality and rising healthcare costs, involving numerous chronic and nutritional risk. Although several studies have reported that malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria is associated with mortality in patients with CVD, they have not evaluated this association in terms of malnutrition severity (moderate or severe). Furthermore, the relationship between malnutrition combined with renal dysfunction, a risk factor for death in CVD patients, and mortality has not been previously evaluated. Thus, we aimed to assess the association between malnutrition severity and mortality, as well as malnutrition status stratified by kidney function and mortality, in patients hospitalized due to CVD events., Methods: This single-centre, retrospective cohort study included 621 patients with CVD aged ≥18 years admitted to Aichi Medical University between 2019 and 2020. The relationship between nutritional status based on the GLIM criteria (without malnutrition, moderate malnutrition, or severe malnutrition) and the incidence of all-cause mortality was evaluated by multivariable Cox proportional hazards models., Results: Patients with moderate and severe malnutrition were significantly more prone to mortality than those without malnutrition (adjusted hazard ratio [HR] of patients without, with moderate, and with severe malnutrition: 1.00 [reference], 1.94 [1.12-3.35], and 2.63 [1.53-4.50], respectively). Furthermore, we found the highest all-cause mortality rate in patients with malnutrition and a lower estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m 2 ) (adjusted HR, 10.1; confidence interval, 3.90-26.4) than in patients without malnutrition and normal eGFR (eGFR ≥60 mL/min/1.73 m 2 )., Conclusions: The present study indicated that malnutrition according to the GLIM criteria was associated with increased all-cause mortality in patients with CVD, and malnutrition associated with kidney dysfunction was associated with a higher risk of mortality. These findings provide clinically relevant information to identify high mortality risk in patients with CVD and highlight the need for giving careful attention to malnutrition with kidney dysfunction among patients with CVD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Hair follicles (HFs) undergo cyclic phases of growth, regression, and rest in association with hair shafts to maintain the hair coat. Nonsense mutations in the tight junction protein claudin (CLDN)-1 cause hair loss in humans. Therefore, we evaluated the roles of CLDNs in hair retention. Among the 27 CLDN family members, CLDN1, CLDN3, CLDN4, CLDN6, and CLDN7 were expressed in the inner bulge layer, isthmus, and sebaceous gland of murine HFs. Hair phenotypes were observed in Cldn1 weaker knockdown and Cldn3-knockout (Cldn1 Δ/Δ Cldn3 -/- ) mice. Although hair growth was normal, Cldn1 Δ/Δ Cldn3 -/- mice showed striking hair loss in the first telogen. Simultaneous deficiencies in CLDN1 and CLDN3 caused abnormalities in telogen HFs, such as an aberrantly layered architecture of epithelial cell sheets in bulges with multiple cell layers, mislocalization of bulges adjacent to sebaceous glands, and dilated hair canals. Along with the telogen HF abnormalities, which shortened the hair retention period, there was an enhanced proliferation of the epithelium surrounding HFs in Cldn1 Δ/Δ Cldn3 -/- mice, causing accelerated hair regrowth in adults. Our findings suggested that CLDN1 and CLDN3 may regulate hair retention in infant mice by maintaining the appropriate layered architecture of HFs, a deficiency of which can lead to alopecia., (© 2023 New York Academy of Sciences.)

Aims: Low-carbohydrate diets have become popular in the general community. The mutual relationship between the percentage of total energy intake from carbohydrates (CHO/E), glycemic control indices, and diabetes complications remains unclear., Materials and Methods: This cross-sectional study included 177 patients with type 2 diabetes mellitus who regularly visited outpatient clinics. In this study, dietary questionnaires were used to assess the intake ratio of the three macronutrients, and the low-carbohydrate-diet score was calculated. We investigated the association between the low-carbohydrate-diet score, continuous glucose monitoring (CGM)-derived short-term glycemic control indices, and diabetes complications in patients with type 2 diabetes mellitus., Results: The results are presented as medians (interquartile ranges) unless otherwise stated. Hemoglobin A1c was 7.1% (6.6-7.7%), CGM-derived time in range (TIR) was 75.3% (62.8-87.0%), body mass index (BMI) was 24.0 (22.1-26.3) kg/m 2 , and CHO/E was 49.8% (44.8-55.6%). BMI, triglycerides, and CGM-derived time above range decreased significantly with increasing low-carbohydrate-diet scores. However, no significant association was found between the low-carbohydrate-diet score and glycemic control indices, including TIR, mean amplitude of glycemic excursions, and vascular complications of type 2 diabetes mellitus., Conclusion: Moderate-carbohydrate diets positively impact weight control and lipid metabolism but may have a limited effect on short-term glycemic variability in Japanese patients with type 2 diabetes mellitus., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Although the core constituents of the Wnt/planar cell polarity (PCP) signaling have been extensively studied, their downstream molecules and protein-protein interactions have not yet been fully elucidated. Here, we show genetic and molecular evidence that the PCP factor, Vangl2, functionally interacts with the cell-cell adhesion molecule, N-cadherin (also known as Cdh2), for typical PCP-dependent neural development. Vangl2 and N-cadherin physically interact in the neural plates undergoing convergent extension. Unlike monogenic heterozygotes, digenic heterozygous mice with Vangl2 and Cdh2 mutants exhibited defects in neural tube closure and cochlear hair cell orientation. Despite this genetic interaction, neuroepithelial cells derived from the digenic heterozygotes did not show additive changes from the monogenic heterozygotes of Vangl2 in the RhoA-ROCK-Mypt1 and c-Jun N-terminal kinase (JNK)-Jun pathways of Wnt/PCP signaling. Thus, cooperation between Vangl2 and N-cadherin is at least partly via direct molecular interaction; it is essential for the planar polarized development of neural tissues but not significantly associated with RhoA or JNK pathways., (© 2023. The Author(s).)

High-flow nasal cannula (HFNC) can be effective in treating type 1 respiratory failure by reducing the severity of coronavirus disease 2019 (COVID-19). The purpose of this study was to assess the reduction of disease severity and safety of HFNC treatment in patients with severe COVID-19. We retrospectively observed 513 consecutive patients with COVID-19 admitted to our hospital from January 2020 to January 2021. We included patients with severe COVID-19 who received HFNC for their deteriorating respiratory status. HFNC success was defined as improvement in respiratory status after HFNC and transfer to conventional oxygen therapy, while HFNC failure was defined as transfer to non-invasive positive pressure ventilation or ventilator, or death after HFNC. Predictive factors associated with failure to prevent severe disease were identified. Thirty-eight patients received HFNC. Twenty-five (65.8%) patients were classified in the HFNC success group. In the univariate analysis, age, history of chronic kidney disease (CKD), non-respiratory sequential organ failure assessment (SOFA) ≥ 1, oxygen saturation to fraction of inspired oxygen ratio (SpO 2 /FiO 2 ) before HFNC ≤ 169.2, were significant predictors of HFNC failure. Multivariate analysis revealed that SpO 2 /FiO 2 value before HFNC ≤ 169.2 was an independent predictor of HFNC failure. No apparent nosocomial infection occurred during the study period. Appropriate use of HFNC for acute respiratory failure caused by COVID-19 can reduce the severity of severe disease without causing nosocomial infection. Age, history of CKD, non-respiratory SOFA before HFNC ≤ 1, and SpO 2 /FiO 2 before HFNC ≤ 169.2 were associated with HFNC failure., Competing Interests: The authors have no conflicts of interest to disclose., (2023, National Center for Global Health and Medicine.)

Liquid-liquid phase separation (LLPS) is involved in various dynamic biological phenomena. In epithelial cells, dynamic regulation of junctional actin filaments tethered to the apical junctional complex (AJC) is critical for maintaining internal homeostasis against external perturbations; however, the role of LLPS in this process remains unknown. Here, after identifying a multifunctional actin nucleator, cordon bleu (Cobl), as an AJC-enriched microtubule-associated protein, we conducted comprehensive in vitro and in vivo analyses. We found that apical microtubules promoted LLPS of Cobl at the AJC, and Cobl actin assembly activity increased upon LLPS. Thus, microtubules spatiotemporally regulated junctional actin assembly for epithelial morphogenesis and paracellular barriers. Collectively, these findings established that LLPS of the actin nucleator Cobl mediated dynamic microtubule-actin cross-talk in junctions, which fine-tuned the epithelial barrier.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of anti-neutrophil cytoplasmic antibody-associated vasculitis characterised by small- to medium-sized vessel vasculitis and is typically associated with eosinophilic granulomatous inflammation. EGPA can affect any organ system, most commonly the lungs, skin, and the nervous system. However, limb ulcers are rare complications and have only been described in few case reports. Furthermore, no documented cases of EGPA have been treated with mepolizumab. Herein, we report a case of an 86-year-old Japanese woman with anti-neutrophil cytoplasmic antibody-negative EGPA, who had an abrupt onset of upper limb ulcers and bilateral foot drop due to multiple mononeuropathy. Clinicopathological sural nerve biopsy showed eosinophil-associated vascular damage. The patient was administered steroids, intravenous immunoglobulin, vasodilators, and mepolizumab; this resulted in clinical improvement of her finger ulcers and peripheral neuropathy without any adverse effects. In cases of an abrupt onset of limb ischaemia and peripheral neuropathy, physicians should consider the possibility of EGPA as a differential diagnosis. Furthermore, the early administration of mepolizumab might yield better outcomes in terms of improving limb ischaemia and peripheral neuropathy., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ciliated cells in the airway epithelium generate mucus streams to remove extraneous particles and microorganisms by beating the motile cilia. This defense mechanism is crucial for maintaining homeostasis and preventing infection in the airway. Conventional methods to assess ciliary beating have revealed that rapid (>10 times per second) and metachronal beating of cilia enables efficient mucus transport. Cilia are oriented to excrete mucus toward the outside of the body. However, conventional methods to directly observe ciliary movements uses transmitted light, which requires translucent samples. Sliced or fragmented tissues are used to observe ciliary movements in thick human airway tissues. Therefore, conventional methods are unsuitable for assessing in situ orientation of ciliary movements. The orientation of ciliary beating can be indirectly analyzed by tracking particles spread onto the epithelium; however, the particles are not efficiently transported by immature cilia. To address this issue, we developed a method for labeling airway motile cilia with fluorescently labeled wheat germ agglutinin (FL-WGA). The new method enables microscopic observation of ciliary movements without slicing or fragmenting the airway tissues. Since the airway epithelium is observed from the apical side, in situ orientation of ciliary beating can be analyzed using this method. Additionally, epithelial damage, and the number and maturity of cilia can be assessed during the observation of ciliary beating. The new method, in combination with other methods, can provide more comprehensive data regarding ciliary movements., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To gain a better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). This retrospective, multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identified during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: < 2, mild: 2-4, moderate: 5-7, and severe: > 7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We confirmed that biologics significantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decreased risk according to COX regression analysis, P < 0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decreased risk according to COX regression analysis, P = 0.606). Biologics may improve remission duration, but these agents had no significant impact in reducing the risk of surgical resection in moderate to severe active UC., (© 2022. The Author(s).)

Background: Several previous studies have evaluated the predictors of relapse in antineutrophil cytoplasmic antibody-associated vasculitis. Nonetheless, the association between renal-limited vasculitis and relapse has not been evaluated., Objective: To assess the association between renal-limited vasculitis and the incidence of relapse in Japan among patients with microscopic polyangiitis/renal-limited vasculitis., Methods: This retrospective cohort study included consecutive patients in remission at 6 months, with renal-limited vasculitis (n = 24, renal-limited vasculitis group) and microscopic polyangiitis with renal and extra-renal involvement (n = 56, non-renal-limited vasculitis group) between 2004 and 2020., Results: During the median follow-up period of 35 (range, 15‒57) months, 28 (35.0%) patients had a relapse. Multivariable Cox proportional hazards models revealed that the lower estimated glomerular filtration rate (per -10 mL/min/1.73 m2; adjusted hazard ratio = 0.87, 95% confidence interval: 0.76-0.99; P =  0.043), renal-limited vasculitis (adjusted hazard ratio =  0.23, 95% confidence interval: 0.08-0.68; P =  0.008), and glucocorticoid combined with intravenous cyclophosphamide or rituximab (adjusted HR = 0.32, 95% CI: 0.11-0.96; P = 0.042) were associated with a decreased risk of relapse. Glucocorticoid dose during the observation period was lower in the renal-limited vasculitis group than in the non-renal-limited vasculitis group., Conclusions: Renal-limited vasculitis was associated with a lower risk of relapse than non-renal-limited vasculitis. Our data may contribute to the development of optimal management for renal-limited vasculitis, which may assist in minimizing the adverse effects of immunosuppressive therapy., Competing Interests: The authors have declared that no competing interests exist.

Highlight: This study found that the increase in serum secreted protein acidic and rich in cysteine (SPARC) levels might be mediated by lactate accumulation and might, hence, be influenced by exercise intensity rather than exercise duration.An association was found between SPARC response to exercise and skeletal muscle mass.Our results provide a better understanding of the preventive effects of exercise on colon cancer.

Thrombotic microangiopathy is characterised by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage, leading to acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia. Among the autoimmune diseases related to thrombotic microangiopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy cases have been rarely reported; therefore, the optimal treatment for associated vasculitis-related thrombotic microangiopathy remains unknown. An 84-year-old woman without significant medical history presented with a 1-month history of general fatigue, fever, and deteriorating bilateral leg numbness and was admitted to our hospital. She had elevated myeloperoxidase anti-neutrophil cytoplasmic antibody levels, polyneuropathy, and rapid progressive glomerulonephritis because of pauci-immune crescentic glomerulonephritis, as revealed by a kidney biopsy. Accordingly, we diagnosed her with microscopic polyangiitis. After administering methylprednisolone pulse therapy, rituximab, and intravenous immunoglobulin, the patient's mental state deteriorated, presenting signs of thrombotic microangiopathy with posterior reversible encephalopathy syndrome. Intermittent haemodialysis and plasma exchange were initiated; however, her condition did not improve, and eculizumab administration was initiated thereafter. The patient's symptoms showed a remarkable response to eculizumab; thrombotic microangiopathy findings, kidney function, and neurological symptoms improved after only two doses of eculizumab, and she achieved sustained remission. The extremely effective course of eculizumab treatment indicated that overt complement activation affected the development of thrombotic microangiopathy. Anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy may be mediated by complement activation, and prompt induction of eculizumab therapy may be a superior strategy to prevent organ damage. Further studies should elucidate the role of complement activation in associated vasculitis-related thrombotic microangiopathy and the efficacy of eculizumab treatment., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex., Methods: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m 2 ) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m 2 ; decreased from the baseline eGFR by 25%)., Results: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men., Conclusions: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction., (© 2022. The Author(s).)

A 33-year-old woman with a fever, cough, and pharyngitis was admitted after left-sided pleural effusion was detected. The fever and upper respiratory symptoms were confirmed, and she was diagnosed with coronavirus disease (COVID-19) after showing a positive polymerase chain reaction (PCR) test. After thoracentesis, pleural fluid revealed elevated adenosine deaminase values and a positive QuantiFeron test; tuberculous pleurisy was thus suspected. Subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR and anti-SARS-CoV-2 Spike IgG tests were negative, suggesting that the initial PCR result had been erroneous. However, we were unable to confirm this. Data concerning COVID-19 diagnostics are insufficient at present. It is important to make comprehensive judgments regarding the diagnosis and treatment of patients as well as public health.

A 53-year-old woman diagnosed with rheumatoid arthritis (RA) demonstrated thick-walled large cavities with consolidation in the left upper lobe on chest computed tomography (CT). Mycobacterium avium was isolated from sputum cultures, and she was diagnosed as having the fibrocavitary (FC) form of pulmonary Mycobacterium avium complex (MAC) disease. Clarithromycin-containing, multidrug, anti-MAC chemotherapy was started immediately. After 7 months, the cavitary lesions improved, and sputum cultures showed negative conversion. Thereafter, abatacept monotherapy was started due to high RA disease activity. Clinical remission of RA has been sustained and cavitary lesions disappeared by concomitant abatacept and anti-MAC therapy for more than 5 years. Immediate initiation of anti-MAC therapy and prior confirmed efficacy are needed for the treatment of the FC form. Abatacept and anti-MAC therapy could be continued, leading to the withdrawal of prednisolone, along with careful observation by strict chest CT evaluation and repeated sputum cultures. Biologics are generally contraindicated for pulmonary MAC disease, particularly the FC form. When there is a pre-existing lung lesion apparently of FC type, abatacept cannot be started without prior anti-MAC chemotherapy. This case suggests that abatacept may be carefully used to avoid progressive joint destruction after FC lesions of pulmonary MAC disease are resolved., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Left ventricular hypertrophy commonly occurs in dialysis patients and is associated with a risk of developing cardiovascular disease events and all-cause mortality. Although hypertension treatment reduces left ventricular mass index (LVMI) in hemodialysis patients, the relationships of prescription pattern, dose, and changes in the dose of antihypertensive drugs with LVMI have not been completely elucidated. Here, we hypothesized that volume reduction would lead to a decrease in the antihypertensive drug dose and subsequently to a reduction in LVMI; conversely, fluid retention would lead to an increase in the antihypertensive drug use and, subsequently, to LVMI progression. To assess this hypothesis, we investigated the relationship between changes in the dose of antihypertensive drugs and subsequent changes in LVMI in 240 patients who had just started hemodialysis using a retrospective hemodialysis cohort in Japan. Using multiple linear regression analysis, we assessed the association between changes in the antihypertensive drug dose over 1 year after hemodialysis initiation and changes in LVMI during this period. A decrease and an increase in the antihypertensive drug dose were significantly associated with a reduction in LVMI (vs. no change; β  = - 17.386, p < .001) and LVMI progression (vs. no change; β  = 16.192, p < .001), respectively. In conclusion, our findings suggested that volume reduction, leading to a decrease in the use of antihypertensive drugs, is a therapeutic strategy in patients undergoing hemodialysis to prevent LVMI progression.

Competing Interests: Conflicts of interest and sources of funding: none declared.

Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL., Competing Interests: The authors have declared that no competing interests exist.

Background: During peritoneal dialysis (PD), solute transport and ultrafiltration are mainly achieved by the peritoneal blood vasculature. Glycocalyx lies on the surface of endothelial cells and plays a role in vascular permeability. Low-glucose degradation product (GDP), pH-neutral PD solutions reportedly offer higher biocompatibility and lead to less peritoneal injury. However, the effects on the vasculature have not been clarified., Methods: Peritoneal tissues from 11 patients treated with conventional acidic solutions (acidic group) and 11 patients treated with low-GDP, pH-neutral solutions (neutral group) were examined. Control tissues were acquired from 5 healthy donors of kidney transplants (control group). CD31 and ratio of luminal diameter to vessel diameter (L/V ratio) were evaluated to identify endothelial cells and vasculopathy, respectively. Immunostaining for heparan sulfate (HS) domains and Ulex europaeus agglutinin-1 (UEA-1) binding was performed to assess sulfated glycosaminoglycans and the fucose-containing sugar chain of glycocalyx., Results: Compared with the acidic group, the neutral group showed higher CD31 positivity. L/V ratio was significantly higher in the neutral group, suggesting less progression of vasculopathy. Both HS expression and UEA-1 binding were higher in the neutral group, whereas HS expression was markedly more preserved than UEA-1 binding in the acidic group. In vessels with low L/V ratio, which were found only in the acidic group, HS expression and UEA-1 binding were diminished, suggesting a loss of glycocalyx., Conclusion: Peritoneal endothelial glycocalyx was more preserved in patients treated with low-GDP, pH-neutral solution. The use of low-GDP, pH-neutral solutions could help to protect peritoneal vascular structures and functions., (© 2021. Japanese Society of Nephrology.)

Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Competing Interests: Competing interests: None declared.

Background: The current gold standard in coronavirus disease (COVID-19) diagnostics is the real-time reverse transcription-polymerase chain reaction (RT-PCR) assay for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in nasopharyngeal swab (NPS) samples. Alternatively, nasal swab (NS) or saliva swab (SS) specimens are used, although available data on test accuracy are limited. We examined the diagnostic accuracy of NPS/NS/SS samples for this purpose., Methods: Ten patients were included after being tested positive for SARS-CoV-2 RT-PCR in NPS samples according to the National Institute of Infectious Disease guidelines. In comparison with this conventional diagnostic method, NPS/NS/SS samples were tested using the cobas 6800 systems RT-PCR device. To investigate the usefulness of the cobas method and the difference among sample types, the agreement and sensitivity were calculated. Five to six samples were collected over a total period of 5-6 d from each patient., Results: Fifty-seven sets of NPS/NS/SS samples were collected, of which 40 tested positive for COVID-19 by the conventional method. Overall, the concordance rates using the conventional method were 86.0%/70.2%/54.4% for NPS/NS/SS samples (cobas); however, for samples collected up to and including on Day 9 after disease onset (22 negative and one positive specimens), the corresponding rates were 95.7%/87.0%/65.2%. The overall sensitivity estimates were 100.0%/67.5%/37.5% for NPS/NS/SS samples (cobas). For samples up to 9 d after onset, the corresponding values were 100.0%/86.4%/63.6%., Conclusions: NS samples are more reliable than SS samples and can be an alternative to NPS samples. They can be a useful diagnostic method in the future.