[A case of myasthenia gravis with coexistence of anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies].

A 79-year-old woman who presented ptosis and dysphagia were admitted to our hospital. Anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies were both positive. Electrophysiological examination showed postsynaptic pattern which supported myasthenia gravis. She did not meet the diagnostic criteria for Lambert-Eaton myasthenic syndrome (LEMS). In cases which these antibodies coexist, careful electrophysiological evaluation is required for the diagnosis. In addition, although anti-P/Q-type VGCC antibodies have been specific to LEMS, patients with these antibodies represent various symptoms other than LEMS. Low and middle titer of the antibodies may be not specific to LEMS.

Association between stopping renin-angiotensin system inhibitors immediately before hemodialysis initiation and subsequent cardiovascular events.

It is controversial whether renin-angiotensin system inhibitors (RASIs) should be stopped in patients with advanced chronic kidney disease (CKD). Recently, it was reported that stopping RASIs in advanced CKD was associated with increased mortality and cardiovascular (CV) events; however, it remains unclear whether stopping RASIs before dialysis initiation affects clinical outcomes after dialysis, which this study aimed to evaluate. In this multicenter prospective cohort study in Japan, we included 717 patients (mean age, 67 years; 68% male) who had a nephrology care duration ≥90 days, initiated hemodialysis, and used RASIs 3 months before hemodialysis initiation. The multivariable adjusted Cox models were used to compare mortality and CV event risk between 650 (91%) patients who continued RASIs until hemodialysis initiation and 67 (9.3%) patients who stopped RASIs. During a median follow-up period of 3.5 years, 170 (24%) patients died and 228 (32%) experienced CV events. Compared with continuing RASIs, stopping RASIs was unassociated with mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.50-1.34) but was associated with higher CV events (aHR: 1.59; 95% CI: 1.06-2.38). Subgroup analyses showed that the risk of stopping RASIs for CV events was particularly high in patients aged <75 years, with a significant interaction between stopping RASIs and age. This study revealed that patients who stopped RASIs immediately before dialysis initiation were associated with subsequent higher CV events. Active screening for CV disease may be especially beneficial for these patients.

Relationship between peak aortic jet velocity and progression of aortic stenosis in patients undergoing hemodialysis.

BACKGROUND: The natural history of aortic stenosis (AS) progression, especially before severe AS development, is not well documented. We aimed to investigate the time course of peak aortic jet velocity (Vmax) and AS progression risk according to baseline Vmax, particularly whether there is a Vmax threshold. METHODS: In a retrospective multicenter cohort study of patients on hemodialysis with aortic valve calcification, we investigated the time series of Vmax and the relationship between the baseline Vmax and progression to severe AS by analyzing longitudinal echocardiographic data. RESULTS: Among 758 included patients (mean age, 71 years; 65% male), patients with Vmax <1.5, 1.5-1.9, 2.0-2.4, 2.5-2.9, and 3.0-3.9 m/s were 395 (52%), 216 (29%), 85 (11%), 39 (5.1%), and 23 (3.0%), respectively. The Vmax slope was gradual (mean 0.05-0.07 m/s/year) at Vmax <2 m/s, but steeper (mean 0.13-0.21 m/s/year) at Vmax ≥2 m/s. During a median 3.2-year follow-up, 52 (6.9%) patients developed severe AS. While patients with Vmax <2 m/s rarely developed severe AS, the risk of those with Vmax ≥2 m/s increased remarkably with an increasing baseline Vmax; the adjusted incidence rates in patients with Vmax <1.5, 1.5-1.9, 2.0-2.4, 2.5-2.9, and 3.0-3.9 m/s were 0.59, 0.57, 4.25, 13.8, and 56.1 per 100 person-years, respectively; the adjusted hazard ratio per 0.2 m/s increase in the baseline Vmax was 1.49 (95% confidence interval: 1.32-1.68) when Vmax ≥2 m/s. CONCLUSIONS: The risk of progression to severe AS increased with the baseline Vmax primarily at ≥2 m/s; a Vmax threshold of 2 m/s was observed.

Platelet-derived growth factor signaling in pericytes promotes hypothalamic inflammation and obesity.

BACKGROUND: Pericytes are a vital component of the blood-brain barrier, and their involvement in acute inflammation was recently suggested. However, it remains unclear whether pericytes contribute to hypothalamic chronic inflammation and energy metabolism in obesity. The present study investigated the impact of pericytes on the pathophysiology of obesity by focusing on platelet-derived growth factor (PDGF) signaling, which regulates pericyte functions. METHODS: Tamoxifen-inducible systemic conditional PDGF receptor ß knockout mice (Pdgfrb∆SYS-KO) and Calcium/calmodulin-dependent protein kinase type IIa (CaMKIIa)-positive neuron-specific PDGF receptor ß knockout mice (Pdgfrb∆CaMKII-KO) were fed a high-fat diet, and metabolic phenotypes before and 3 to 4 weeks after dietary loading were examined. Intracellular energy metabolism and relevant signal transduction in lipopolysaccharide- and/or platelet-derived growth factor-BB (PDGF-BB)-stimulated human brain pericytes (HBPCs) were assessed by the Seahorse XFe24 Analyzer and Western blotting. The pericyte secretome in conditioned medium from HBPCs was studied using cytokine array kit, and its impact on polarization was examined in bone marrow-derived macrophages (BMDMs), which are microglia-like cells. RESULTS: Energy consumption increased and body weight gain decreased after high-fat diet loading in Pdgfrb∆SYS-KO mice. Cellular oncogene fos (cFos) expression increased in proopiomelanocortin (POMC) neurons, whereas microglial numbers and inflammatory gene expression decreased in the hypothalamus of Pdgfrb∆SYS-KO mice. No significant changes were observed in Pdgfrb∆CaMKII-KO mice. In HBPCs, a co-stimulation with lipopolysaccharide and PDGF-BB shifted intracellular metabolism towards glycolysis, activated mitogen-activated protein kinase (MAPK), and modulated the secretome to the inflammatory phenotype. Consequently, the secretome showed an increase in various proinflammatory chemokines and growth factors including Epithelial-derived neutrophil-activating peptide 78 (C-X-C motif chemokine ligand (CXCL)5), Thymus and activation-regulated chemokine (C-C motif chemokine (CCL)17), Monocyte chemoattractant protein 1 (CCL2), and Growth-regulated oncogene α (CXCL1). Furthermore, conditioned medium from HBPCs stimulated the inflammatory priming of BMDMs, and this change was abolished by the C-X-C motif chemokine receptor (CXCR) inhibitor. Consistently, mRNA expression of CXCL5 was elevated by lipopolysaccharide and PDGF-BB treatment in HBPCs, and the expression was significantly lower in the hypothalamus of Pdgfrb∆SYS-KO mice than in control Pdgfrbflox/flox mice (FL) following 4 weeks of HFD feeding. CONCLUSIONS: PDGF receptor ß signaling in hypothalamic pericytes promotes polarization of macrophages by changing their secretome and contributes to the progression of obesity.

Histopathological vertical margin positivity in cold snare polypectomy and mucosal resection for sessile serrated lesions.

BACKGROUND AND AIMS: Evidence regarding the status of the vertical margin of sessile serrated lesions (SSLs) resected using cold snare polypectomy (CSP) is lacking, and whether a histopathologically positive vertical margin is related to recurrence remains unclear. Therefore, this preliminary study aimed to clarify the rates of positive or unevaluable vertical and horizontal margins and the rate of muscularis mucosae resection in SSLs treated using CSP compared with those treated with endoscopic mucosal resection (EMR). METHODS: Histological outcomes of patients treated with CSP or EMR for SSL were evaluated in this single-center observational study. The primary outcome was the incidence of histopathologically positive vertical margins in CSP and EMR. Furthermore, the comparisons were adjusted for confounding factors using propensity score matching. RESULTS: Overall, 82 patients with SSLs were included in the CSP and EMR groups after matching. The incidence of positive histological vertical margins in the CSP and EMR groups were 67.1% and 2.4%, respectively (p<0.001). Regarding the evaluation of the presence of muscularis mucosae, 29.3% and 98.8% of the patients in the CSP and EMR groups, respectively, had a complete muscularis mucosae resection (p<0.001). CONCLUSIONS: A rigorous histopathologic evaluation revealed that for SSLs, CSP more frequently leads to positive vertical margins than EMR.

Impella-Supported Optical Coherence Tomography-Guided Aggressive Rotational Atherectomy for Heavily Calcified Lesions in Left Main Trunk Bifurcation in a Patient with Severe Left Ventricular Systolic Dysfunction.

The Impella, a percutaneous left ventricular assist device, has been reported to minimize the risk of hemodynamic compromise and improve clinical outcomes during percutaneous coronary intervention (PCI) in complex high-risk indicated patients (CHIPs). Optical coherence tomography (OCT) provides information on calcified plaque thickness, which is helpful in determining the indication and endpoint of atherectomy during PCI for calcified lesions. However, there are few reports on OCT-guided aggressive rotational atherectomy with Impella assistance in CHIPs. A 71-year-old man on dialysis for end-stage renal failure was admitted for congestive heart failure. Transthoracic echocardiography revealed severe left ventricular systolic dysfunction, and coronary angiography performed after improvement of heart failure showed severe stenosis with heavily calcified lesions in the left main trunk (LMT) bifurcation and right coronary artery. The patient refused coronary artery bypass surgery and was revascularized using PCI. PCI was started with prophylactic Impella CP insertion because of the high risk of hemodynamic collapse. After OCT-guided rotational atherectomy with 1.5- and 2.0-mm burr toward the left anterior descending artery and left circumflex artery, respectively, double-kissing culotte stenting was performed in the LMT, and good dilation was obtained. Impella CP was removed immediately after PCI without hemodynamic compromise, and the procedure was completed.

Spiral Chiral Metamaterial Structure Shape for Optical Activity Improvements.

We report on a spiral structure suitable for obtaining a large optical response. We constructed a structural mechanics model of the shape of the planar spiral structure when deformed and verified the effectiveness of the model. As a verification structure, we fabricated a large-scale spiral structure that operates in the GHz band by laser processing. Based on the GHz radio wave experiments, a more uniform deformation structure exhibited a higher cross-polarization component. This result suggests that uniform deformation structures can improve circular dichroism. Since large-scale devices enable speedy prototype verification, the obtained knowledge can be exported to miniaturized-scale devices, such as MEMS terahertz metamaterials.

Delayed Perforation of Colorectal Endoscopic Submucosal Dissection Treated by Endoscopic Ultrasound-Guided Drainage.

We report a case of a 70-year-old male with delayed perforation in the cecum treated by endoscopic ultrasonography-guided drainage for a pelvic abscess. The lesion was a 50-mm laterally spreading tumor, and endoscopic submucosal dissection (ESD) was performed. No perforation was detected during the operation, and en bloc resection was achieved. He had fever and abdominal pain on postoperative day (POD) 2. Computed tomography (CT) revealed the intra-abdominal free air, leading to a diagnosis of delayed perforation after ESD. Vital signs were stable, the perforation was considered minor, and endoscopic closure was attempted. The colonoscopy under fluoroscopy showed no perforation in the ulcer and no leakage of the contrast medium. He was managed conservatively with antibiotics and nothing per os. Symptoms improved; however, a follow-up CT on POD 13 revealed a 65-mm pelvic abscess, and endoscopic ultrasound (EUS)-guided drainage was successfully performed. The follow-up CT on POD 23 showed the reduction of abscess, and the drainage tubes were removed. Emergent surgical treatment is crucial in delayed perforation because it has a poor prognosis, and reports of conservative therapy for colonic ESD with delayed perforation are few. The present case was managed with antibiotics and EUS-guided drainage. Thus, EUS-guided drainage can be a treatment option for delayed perforation after colorectal ESD, if the abscess is localized.

Number of calcified aortic valve leaflets: natural history and prognostic value in patients undergoing haemodialysis.

AIMS: Aortic valve calcification in aortic sclerosis, a precursor of aortic stenosis (AS), is not always present in all three leaflets; how calcification develops in each leaflet is unknown. We aimed to investigate the natural history of calcification development in each aortic valve leaflet and the prognostic value of the number of calcified leaflets. METHODS AND RESULTS: In a retrospective multicentre cohort study of patients undergoing haemodialysis without AS, we observed calcification development in each aortic valve leaflet using echocardiography. We investigated the association between the number of calcified leaflets and AS development and mortality using time-to-event analysis. Among the 1507 patients (mean age, 66 years; 66% male) included in the longitudinal echocardiography analysis, 709 (47%) had aortic sclerosis at baseline: one-leaflet calcified, 370 (52%); two-leaflet calcified, 215 (30%); and three-leaflet calcified, 124 (17%). The median time for one calcified leaflet increase was 3-4 years, and 251 (17%) patients developed AS during a median 3.2-year follow-up. The increased number of calcified aortic valve leaflets was associated with developing AS; compared with that of one-leaflet calcified, the adjusted hazard ratios (aHRs) [95% confidence intervals (CIs)] of two- and three-leaflet calcified were 2.12 (1.49-3.00) and 4.43 (3.01-6.52), respectively; the aHR (95% CI) per one calcified leaflet increase was 2.24 (1.96-2.55). It was also associated with all-cause mortality; the aHR (95% CI) per one calcified leaflet increase was 1.18 (1.08-1.27). CONCLUSION: The number of calcified aortic valve leaflets strongly predicted AS development and even mortality in patients undergoing haemodialysis, suggesting the usefulness of assessing calcification for each valve leaflet separately using echocardiography.

Enhanced angiogenic properties of umbilical cord blood primed by OP9 stromal cells ameliorates neurological deficits in cerebral infarction mouse model.

Umbilical cord blood (UCB) transplantation shows proangiogenic effects and contributes to symptom amelioration in animal models of cerebral infarction. However, the effect of specific cell types within a heterogeneous UCB population are still controversial. OP9 is a stromal cell line used as feeder cells to promote the hematoendothelial differentiation of embryonic stem cells. Hence, we investigated the changes in angiogenic properties, underlying mechanisms, and impact on behavioral deficiencies caused by cerebral infarction in UCB co-cultured with OP9 for up to 24 h. In the network formation assay, only OP9 pre-conditioned UCB formed network structures. Single-cell RNA sequencing and flow cytometry analysis showed a prominent phenotypic shift toward M2 in the monocytic fraction of OP9 pre-conditioned UCB. Further, OP9 pre-conditioned UCB transplantation in mice models of cerebral infarction facilitated angiogenesis in the peri-infarct lesions and ameliorated the associated symptoms. In this study, we developed a strong, fast, and feasible method to augment the M2, tissue-protecting, pro-angiogenic features of UCB using OP9. The ameliorative effect of OP9-pre-conditioned UCB in vivo could be partly due to promotion of innate angiogenesis in peri-infarct lesions.

Immense Reduction in Interfacial Resistance between Sulfide Electrolyte and Positive Electrode.

Low interfacial resistance between the solid sulfide electrolyte and the electrode is critical for developing all-solid-state Li batteries; however, the origin of interfacial resistance has not been quantitatively reported in the literature. This study reports the resistance values across the interface between an amorphous Li3PS4 solid electrolyte and a LiCoO2(001) epitaxial thin film electrode in a thin-film Li battery model. High interfacial resistance is observed, which is attributed to the spontaneous formation of an interfacial layer between the solid electrolyte and the positive electrode upon contact. That is, the interfacial resistance originates from an interphase mixed layer instead of a space charge layer. The introduction of a 10 nm thick Li3PO4 buffer layer between the solid electrolyte and positive electrode layers suppresses the formation of the interphase mixed layer, thereby leading to a 2800-fold decrease in the interfacial resistance. These results provide insight into reducing the interfacial resistance of all-solid-state Li batteries with sulfide electrolytes by utilizing buffer layers.

Identification of Novel Multipotent Stem Cells in Mouse Spinal Cord Following Traumatic Injury.

We showed that injury-induced multipotent stem cells (iSCs) emerge in the brain after stroke. These brain-derived iSCs (B-iSCs) can differentiate into various lineages, including neurons. This study aimed to determine whether similar stem cells can be induced even after nonischemic injuries, such as trauma to the spinal cord. We characterized these cells, mainly focusing on their stemness, multipotency, and neuronal differentiation activities. Spinal cord injury (SCI) was produced using forceps in adult mice. On day 3 after SCI, samples were obtained from the injured areas. Spinal cord sections were subjected to histological analyses. Cells were isolated and assessed for proliferative activities, immunohistochemistry, reverse transcriptase-polymerase chain reaction, fluorescence-activated cell sorter, and microarray analysis. Although nerve cell morphology was disrupted within the injured spinal cord, our histological observations revealed the presence of cells expressing stem cells, such as nestin and Sox2 in these areas. In addition, cells extracted from injured areas exhibited high proliferative abilities. These cells also expressed markers of both neural stem cells (eg, nestin, Sox2) and multipotent stem cells (eg, Sox2, c-myc, Klf4). They differentiated into adipocytes, osteocytes, and chondrocytes, as well as neuronal cells. Microarray analysis further identified similar properties between spinal cord (SC)-derived iSCs and B-iSCs. However, SC-iSCs revealed specific genes related to the regulation of stemness and neurogenesis. We identified similar features related to multipotency in SC-iSCs compared with B-iSCs, including neuronal differentiation potential. Although the differences between SC-iSCs and B-iSCs remain largely undetermined, this study shows that iSCs can develop even after nonischemic injuries such as trauma. This phenomenon can occur outside the brain within the central nervous system.

Early-phase administration of human amnion-derived stem cells ameliorates neurobehavioral deficits of intracerebral hemorrhage by suppressing local inflammation and apoptosis.

BACKGROUND: Intracerebral hemorrhage (ICH) is a significant cause of death and disabilities. Recently, cell therapies using mesenchymal stem cells have been shown to improve ICH-induced neurobehavioral deficits. Based on these findings, we designed this study to evaluate the therapeutic efficacy and underlying mechanisms by which human amnion-derived stem cells (hAMSCs) would ameliorate neurobehavioral deficits of ICH-bearing hosts. METHODS: hAMSCs were induced from amnia obtained by cesarean section and administered intravenously to ICH-bearing mice during the acute phase. The mice were then subject to multitask neurobehavioral tests at the subacute phase. We attempted to optimize the dosage and timing of the hAMSC administrations. In parallel with the hAMSCs, a tenfold higher dose of human adipose-derived stem cells (ADSCs) were used as an experimental control. Specimens were obtained from the ICH lesions to conduct immunostaining, flow cytometry, and Western blotting to elucidate the underlying mechanisms of the hAMSC treatment. RESULTS: The intravenous administration of hAMSCs to the ICH-bearing mice effectively improved their neurobehavioral deficits, particularly when the treatment was initiated at Day 1 after the ICH induction. Of note, the hAMSCs promoted clinical efficacy equivalent to or better than that of hADSCs at 1/10 the cell number. The systemically administered hAMSCs were found in the ICH lesions along with the local accumulation of macrophages/microglia. In detail, the hAMSC treatment decreased the number of CD11b+CD45+ and Ly6G+ cells in the ICH lesions, while splenocytes were not affected. Moreover, the hAMSC treatment decreased the number of apoptotic cells in the ICH lesions. These results were associated with suppression of the protein expression levels of macrophage-related factors iNOS and TNFα. CONCLUSIONS: Intravenous hAMSC administration during the acute phase would improve ICH-induced neurobehavioral disorders. The underlying mechanism was suggested to be the suppression of subacute inflammation and apoptosis by suppressing macrophage/microglia cell numbers and macrophage functions (such as TNFα and iNOS). From a clinical point of view, hAMSC-based treatment may be a novel strategy for the treatment of ICH.

Maternal exposure to fine particulate matter over the first trimester and umbilical cord insertion abnormalities.

BACKGROUND: Our hypothesis was that exposure to fine particulate matter (PM2.5) is related to abnormal cord insertion, which is categorized as a form of placental implantation abnormality. We investigated the association between exposure to total PM2.5 and its chemical components over the first trimester and abnormal cord insertion, which contributes to the occurrence of adverse birth outcomes. METHODS: From the Japan Perinatal Registry Network database, we used data on 83 708 women who delivered singleton births at 39 cooperating hospitals in 23 Tokyo wards (2013-2015). We collected PM2.5 on a filter and measured daily concentrations of carbon and ion components. Then, we calculated the average concentrations over the first trimester (0-13 weeks of gestation) for each woman. A multilevel logistic-regression model with the hospital as a random effect was used to estimate the odds ratios (ORs) of abnormal cord insertion. RESULTS: Among the 83 708 women (mean age at delivery = 33.7 years), the frequency of abnormal cord insertion was 4.5%, the median concentration [interquartile range (IQR)] of total PM2.5 was 16.1 (3.61) µg/m3 and the OR per IQR for total PM2.5 was 1.14 (95% confidence interval = 1.06-1.23). In the total PM2.5-adjusted models, total carbon, organic carbon, nitrate, ammonium and chloride were positively associated with abnormal insertion. Organic carbon was consistently, and nitrate tended to be, associated with specific types of abnormal insertion (marginal or velamentous cord insertion). CONCLUSIONS: Exposure to total PM2.5 and some of its components over the first trimester increased the likelihood of abnormal cord insertion.

Exposure to chemical components of fine particulate matter and ozone, and placenta-mediated pregnancy complications in Tokyo: a register-based study.

BACKGROUND: Maternal exposure to fine particulate matter (PM2.5) was associated with pregnancy complications. However, we still lack comprehensive evidence regarding which specific chemical components of PM2.5 are more harmful for maternal and foetal health. OBJECTIVE: We focused on exposure over the first trimester (0-13 weeks of gestation), which includes the early placentation period, and investigated whether PM2.5 and its components were associated with placenta-mediated pregnancy complications (combined outcome of small for gestational age, preeclampsia, placental abruption, and stillbirth). METHODS: From 2013 to 2015, we obtained information, from the Japan Perinatal Registry Network database, on 83,454 women who delivered singleton infants within 23 Tokyo wards (≈627 km2). Using daily filter sampling of PM2.5 at one monitoring location, we analysed carbon and ion components, and assigned the first trimester average of the respective pollutant concentrations to each woman. RESULTS: The ORs of placenta-mediated pregnancy complications were 1.14 (95% CI = 1.08-1.22) per 0.51 µg/m3 (interquartile range) increase of organic carbon and 1.11 (1.03-1.18) per 0.06 µg/m3 increase of sodium. Organic carbon was also associated with four individual complications. There was no association between ozone and outcome. SIGNIFICANCE: There were specific components of PM2.5 that have adverse effects on maternal and foetal health.

Trimester-Specific Association of Maternal Exposure to Fine Particulate Matter and its Components With Birth and Placental Weight in Japan.

OBJECTIVE: We investigated which trimester of exposure to PM2.5 and its components was associated with birth and placental weight, and the fetoplacental weight ratio. METHODS: The study included 63,990 women who delivered singleton term births within 23 Tokyo wards between 2013 and 2015. Each day, we collected fine particles on a filter, and analyzed their chemical constituents, including carbons and ions. Trimester-specific exposure to each pollutant was estimated based on the average daily concentrations. RESULTS: Over the third trimester, sulfate exposure tended to be inversely associated with birth weight, and decreased placental weight (difference for highest vs lowest quintile groups = -6.7 g, 95% confidence interval = -12.5 to -0.9). For fetoplacental weight ratio, there was no relationship. CONCLUSIONS: Sulfate exposure over the third trimester may reduce birth weight, particularly placental weight.

Compressive mechanical stress enhances susceptibility to interleukin-1 by increasing interleukin-1 receptor expression in 3D-cultured ATDC5 cells.

BACKGROUND: Mechanical overload applied on the articular cartilage may play an important role in the pathogenesis of osteoarthritis. However, the mechanism of chondrocyte mechanotransduction is not fully understood. The purpose of this study was to assess the effects of compressive mechanical stress on interleukin-1 receptor (IL-1R) and matrix-degrading enzyme expression by three-dimensional (3D) cultured ATDC5 cells. In addition, the implications of transient receptor potential vanilloid 4 (TRPV4) channel regulation in promoting effects of compressive mechanical loading were elucidated. METHODS: ATDC5 cells were cultured in alginate beads with the growth medium containing insulin-transferrin-selenium and BMP-2 for 6 days. The cultured cell pellet was seeded in collagen scaffolds to produce 3D-cultured constructs. Cyclic compressive loading was applied on the 3D-cultured constructs at 0.5 Hz for 3 h. The mRNA expressions of a disintegrin and metalloproteinases with thrombospondin motifs 4 (ADAMTS4) and IL-1R were determined with or without compressive loading, and effects of TRPV4 agonist/antagonist on mRNA expressions were examined. Immunoreactivities of reactive oxygen species (ROS), TRPV4 and IL-1R were assessed in 3D-cultured ATDC5 cells. RESULTS: In 3D-cultured ATDC5 cells, ROS was induced by cyclic compressive loading stress. The mRNA expression levels of ADAMTS4 and IL-1R were increased by cyclic compressive loading, which was mostly prevented by pyrollidine dithiocarbamate. Small amounts of IL-1ß upregulated ADAMTS4 and IL-1R mRNA expressions only when combined with compressive loading. TRPV4 agonist suppressed ADAMTS4 and IL-1R mRNA levels induced by the compressive loading, whereas TRPV4 antagonist enhanced these levels. Immunoreactivities to TRPV4 and IL-1R significantly increased in constructs with cyclic compressive loading. CONCLUSION: Cyclic compressive loading induced mRNA expressions of ADAMTS4 and IL-1R through reactive oxygen species. TRPV4 regulated these mRNA expressions, but excessive compressive loading may impair TRPV4 regulation. These findings suggested that TRPV4 regulates the expression level of IL-1R and subsequent IL-1 signaling induced by cyclic compressive loading and participates in cartilage homeostasis.

Overexpression of Interleukin-1α Suppresses Liver Metastasis of Lymphoma: Implications for Antitumor Effects of CD8+ T-cells.

Interleukin (IL)-1 plays a key role in carcinogenesis, tumor progression, and metastasis. Although IL-1 may enhance the expansion of CD8+ T-cells, the pathological contribution of IL-1-activated CD8+ T-cells to tumor metastasis remains unclear. This study used a liver metastasis model of the EL4 T-cell lymphoma cells transplanted into human IL (hIL)-1α conditional transgenic (hIL-1α cTg) mice. Overproduction of hIL-1α suppressed both macroscopic and histological liver metastasis of EL4 T-cell lymphoma. The hIL-1α-induced inflammatory state increased the number of CD8+ T-cells both within and around metastatic tumors. Moreover, larger numbers of CD8+ T-cells showed greater infiltration of liver blood vessels in hIL-1α cTg mice than in control wild-type mice. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining of liver tissue from hIL-1α cTg mice indicated increased apoptosis of cells in the tumor. Localization of apoptosis cells resembled that of CD8+ T-cells. In addition, cytotoxicity assay showed that CD8+ T-cell counts from tumor-bearing hIL-1α cTg mice correlated with cytotoxicity against EL4. In summary, IL-1α suppresses lymphoma metastasis, and IL-1α-activated CD8+ T-cells may play important roles in inhibiting both tumor metastasis and metastatic tumor growth.

Etiology and mortality in severe acute pancreatitis: A multicenter study in Japan.

BACKGROUND/OBJECTIVES: Severe acute pancreatitis (SAP) has a high mortality rate despite ongoing attempts to improve prognosis through a various therapeutic modalities. This study aimed to delineate etiology-based routes that may guide clinical decisions for the treatment of SAP. METHODS: Using data from a recent retrospective multicenter study in Japan, we analyzed the association between clinical outcomes, mainly in-hospital mortality and pancreatic infection, and various etiologies while considering confounding factors. We performed additional multivariate analyses and built decision tree models. RESULTS: The 1097 participating patients were classified into the following groups by etiology: alcohol (n = 436, 39.7%); cholelithiasis (n = 230, 21.0%); idiopathic (n = 227, 20.7%); and others (n = 204, 18.6%). Mortality at hospital discharge was 8.4%, 12.2%, 16.7%, and 16.2% in the alcohol, cholelithiasis, idiopathic, and others groups, respectively. According to multivariable analysis, early enteral nutrition (EN) was significantly associated with reduced in-hospital mortality only in the cholelithiasis group. However, there was a consistent association between age and the need for mechanical ventilation and increased mortality, regardless of etiology. Our decision tree models presented different contributing factors depending on the etiology and patient background. Interaction analysis showed that EN and the use of prophylactic antibiotics may influence these results differently according to etiology. CONCLUSIONS: No study has yet used comprehensive models to investigate etiology-related prognostic factors for SAP; our results can, therefore, be used as a reference for improving clinical decisions.

Vitamin D Status in Japanese Adults: Relationship of Serum 25-Hydroxyvitamin D with Simultaneously Measured Dietary Vitamin D Intake and Ultraviolet Ray Exposure.

Vitamin D insufficiency/deficiency is prevalent worldwide. We investigated the effect of vitamin D intake and ultraviolet ray (UV) exposure on serum vitamin D concentration in Japan. A total of 107 healthy adult participants were recruited from Hokkaido (43°N) and Kumamoto (33°N) prefectures. All participants undertook surveys in both summer and winter. Serum 25-hydroxyvitamin D (25(OH)D3) was examined, and vitamin D intake was assessed with a diet history questionnaire. UV exposure was measured with a wearable UV dosimeter. Regression analysis was performed to investigate the relationship between these factors, with covariates such as sun avoidance behavior. The prevalence of vitamin D insufficiency (serum 25(OH)D3; 12 ng/ml (30 nmol/L) ≤ and <20 ng/ml (50 nmol/L))/deficiency (<12 ng/ml) was 47.7% in summer and 82.2% in winter. UV exposure time was short in Kumamoto (the urban area), at 11.6 minutes in summer and 14.9 minutes in winter. In Hokkaido (the rural area), UV exposure time was 58.3 minutes in summer and 22.5 minutes in winter. Vitamin D intake was significantly associated with serum 25(OH)D3, and a 1 µg/1000kcal increase in intake was necessary to increase 25(OH)D3 by 0.88 ng/ml in summer and by 1.7 ng/ml in winter. UV exposure time was significantly associated with serum 25(OH)D3 in summer, and a 10 min increase in UV exposure time was necessary to increase 25(OH)D3 by 0.47 ng/ml. Although consideration of personal occupation and lifestyle is necessary, most Japanese may need to increase both vitamin D intake and UV exposure.