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Objective The left atrial appendage (LAA) is one of the major sources of cardiac thrombus formation. Three-dimensional transesophageal echocardiography (TEE) made it possible to perform a detailed evaluation of the LAA morphologies. This study aimed to evaluate the clinical implications of the LAA orifice area. Methods A total of 149 patients who underwent TEE without significant valvular disease were studied. The LAA orifice area was measured using three-dimensional TEE. The patients were divided into two groups according to the LAA orifice area (large LAA orifice group, ≥median value, and small LAA orifice group). The clinical characteristics and echocardiographic findings were evaluated. Results The median LAA orifice area among all patients was 4.09 cm2 (interquartile range 2.92-5.40). The large LAA orifice group were older (67.2±10.4 vs. 62.4±15.3 years, p=0.02), more often had hypertension (66.7% vs. 44.6%, p=0.007), and atrial fibrillation (70.7% vs. 39.2%, p

In cryoballoon ablation (CBA), a contrast medium is commonly used to confirm balloon occlusion of the pulmonary veins (PVs). However, a contrast medium cannot always be used in patients with renal dysfunction and allergy. The present study aimed to assess the efficacy and safety of CBA without the use of a contrast medium. We retrospectively examined consecutive patients with paroxysmal atrial fibrillation (PAF) who underwent first-time CBA. We compared the procedural results and outcomes in patients for whom a contrast medium was used (contrast group) and those from whom a contrast medium was not used (non-contrast group). In the non-contrast group, we used saline injection on the intracardiac echocardiography and pressure wave monitoring for PV occlusion. Fifty patients (200 PVs) and 22 patients (88 PVs) underwent CBA with and without a contrast medium, respectively. The success rate of PV isolation with CBA alone was 93% and 90% in the non-contrast and contrast groups, respectively (p = 0.40). The fluoroscopy time and nadir temperature were significantly lower in the non-contrast group as compared to that in the contrast group. The recurrence rate 1 year after ablation did not differ between the two groups (18% vs. 18%, p > 0.99). Furthermore, the number of reconnected PVs in patients with recurrence was significantly lower in the non-contrast group than in the contrast group (6% vs. 36%, p = 0.017). In conclusion, CBA using the intracardiac echocardiography and pressure monitoring approach without the use of a contrast medium was safe and efficient.

INTRODUCTION With regard to short-term outcome in atrial fibrillation (AF), the benefit of cryoballoon ablation (CBA) by pressing a balloon against the earliest pulmonary vein (PV) potential site during PV isolation (earliest potential [EP]-guided CBA) has been previously demonstrated. The present study aimed to evaluate the long-term outcome of the EP-guided CBA. METHODS AND RESULTS This study included 136 patients from two randomized studies, who underwent CBA for paroxysmal AF for the first time. Patients were randomly assigned to the EP-guided and conventional CBA groups in each study. In the EP-guided CBA group, we pressed a balloon against the EP site when the time-to-isolation (TTI) after cryoapplication exceeded 60 and 45 s in the first and second studies, respectively. We compared the clinical outcomes for 1 year after the procedure between the EP-guided CBA group (68 patients) and the conventional CBA group (68 patients). The primary endpoint was the recurrence of atrial arrhythmia after ablation. No significant differences in baseline characteristics were observed between the two groups. Compared with the conventional CBA group, the EP-guided CBA group had a significantly higher success rate at TTI ≤ 90 s (98.5% vs. 90.0%, p

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

The Clinical Frailty Scale (CFS) is a simple tool to assess patients' frailty and may help to predict adverse outcomes in elderly patients. The aim of the present study was to examine the impact of CFS on clinical outcomes and bleeding events after successful percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI). We enrolled 266 consecutive patients with STEMI who underwent primary PCI in between January 2015 and June 2018. Patients were categorized into two groups based on the CFS stages: CFS 1-3 and CFS ≥ 4. We collected the data and evaluated the relationship between the CFS grade and the incidence of major adverse cardiovascular events (MACE) and Bleeding Academic Research Consortium 3 or 5 bleeding events. Of these patients, CFS ≥ 4 was present in 59 (22.2%). During the follow-up, 37.3% in the CFS ≥ 4 group and 8.2% in the CFS 1-3 group experienced MACE. In Kaplan–Meier analysis, the proportion of MACE-free survival for 4 years was significantly lower in the CFS ≥ 4 group (log-rank P

Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.

Predicting outcomes of children after cardiac arrest (CA) remains challenging. To identify useful prognostic markers for pediatric CA, we retrospectively analyzed the early findings of head computed tomography (CT) of patients. Subjects were non-traumatic, out-of-hospital CA patients p = 0.035). All 3 patients with mASPECTS scores ≥ 20 survived, while an sGWR ≥ 1.14 indicated a higher chance of survival than an sGWR

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn’s disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis; however, these findings, including the histopathology, did not confirm Crohn’s disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1β monoclonal antibody (canakinumab). The patient’s symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn’s disease.

We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma‑associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle‑mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial‑mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2‑high expression patients had fewer numbers of CD3+ and CD8+ tumor‑infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD‑L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD‑L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.

Background Trigger point blocks are now widely practiced, especially in pain treatment. Among the complications of lumbar trigger point injection, reports of medically induced kidney injury are very rare, and diagnosis during emergency treatment is rare. Case presentation A 78-year-old woman on antiplatelet medication following a stroke was diagnosed with treatable type A aortic dissection at another hospital after undergoing lumbar trigger point injection. On arrival at our hospital, there were no signs of hemodynamic deterioration. Additional careful medical re-interview and ultrasonography by anesthesiologists enabled a definitive diagnosis of acute kidney damage and hematoma caused by lumbar trigger point injection, and aortic dissection surgery was abandoned. Conclusion This clinical case demonstrates the importance of awareness of potential kidney injury and hematoma during lumbar trigger point injection.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the “ATN” (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer’s disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aβ1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

Maxillofacial trauma that occurs in a traffic accident often results in not only missing teeth but also sever bone defects, with bone augmentation including possible reconstruction of occlusion needed for treatment. This case report describes bone augmentation treatment for a patient with severe bone injuries because of a traffic accident, in which titanium mesh and an iliac bone (autogenous particulate cancellous bone and marrow: PCBM) graft were utilized. A 33-year-old male was involved in a traffic accident and referred to visited Kyushu Dental University Hospital 2 months later. Computerized tomographic scanning showed a maxillary and mandibular anterior alveolar bone defects. Mandibular surgery was performed under general anesthesia, and a reconstructive plate was used for fixation with titanium mesh as well as PCBM graft. For the alveolar bone defect in the maxillary anterior region, bone augmentation using titanium mesh was also performed. At 6 months after the operation, the plate and titanium mesh were removed, then 5 implants were successfully placed and remained intact for more than 5 years. Additionally, the esthetic and functional results successfully matched the expectations of the patients.

Mechanical small bowel obstruction (SBO) is a common postoperative complication, and most cases are caused by postoperative adhesions. We herein report a case of SBO with superior mesenteric vein occlusion caused by a metal staple after laparoscopic appendectomy. A 35-year-old Japanese woman presented to our department with severe upper abdominal pain and vomiting. She had undergone laparoscopic appendectomy using a linear stapler 7 years before. Abdominal CT showed mild small intestinal dilation with mesenteric edema and volvulus of the small bowel mesentery. Moreover, occlusion of the superior mesenteric vein was observed. Emergency exploratory laparoscopy revealed a strangulated SBO caused by a free unformed staple. The obstruction was released by a laparoscopic technique without bowel resection. The number of laparoscopic surgeries has recently been increasing, and complications specific to laparoscopic surgery have been recognized. All spilled and unformed staples should be removed to the greatest extent possible during laparoscopic operations.

Background: CXCR5+ T follicular helper (TFH) cells primarily promote B cells to produce an antigen-specific antibody through germinal centers (GCs). TFH cells exist in circulation, and circulating(c) TFH2 cells, a subset of cTFH cells, are able to help naïve B cells produce IgE in healthy individuals. Conversely, IL-10-producing regulatory B (Breg) cells inhibit an accelerated immune response. Methods: We investigated the roles of cTFH cells and cBreg cells based on a TH2 response in patients with atopic asthma (AA). Thirty-two patients with AA and 35 healthy volunteers (HV) were enrolled. We examined cTFH cells including their subsets, their expression of ICOS and PD-1, and cBreg cells by flow cytometry and their associations with clinical biomarkers. Plasma levels of CXCL13, which is a counterpart of CXCR5, were also measured using ELISA. Results: In patients with AA, cTFH2 cells were increased and cTFH1 cells were decreased compared with those in HV. The expression levels of ICOS on cTFH and their subset cells were elevated and Breg cells were greatly decreased. The plasma levels of CXCL13 in patients with AA were significantly elevated and correlated well with the cTFH2/cBreg ratio. These cells were examined in 10 patients AA before and after inhaled corticosteroid (ICS) treatment. Interestingly, the percentages and numbers of TFH2 and ICOS+ cTFH cells declined after ICS treatment together with improvements in symptoms and clinical biomarkers. Conclusions: The percentages and numbers of cTFH2 and ICOS+ cTFH cells might be useful as biomarkers of TH2 typed airway inflammation in patients with AA. Keywords: CXCL13, ICS, IgE, Regulatory B cell, T follicular helper cell

Hypoxia is a characteristic feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). We have recently explored new targeting molecules and pathways in PDAC cells under hypoxic conditions. In this study, we performed a microarray experiment to analyze the genes up-regulated in PDAC cell lines under hypoxia compared to normoxia, and identified human family with sequence similarity 115, member C (FAM115C) as a candidate gene for further study. Our data showed that FAM115C was overexpressed in PDAC cell lines under hypoxia, and FAM115C inhibition promoted PDAC cell migration and invasion in vitro. FAM115C inhibition did not affect tumor cell proliferation in PDAC. Immunohistochemically, FAM115C expression was observed ubiquitously in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) and PDAC tissue, and it was located mainly in the nucleus but also in the cytoplasm of cells. In qPCR analysis, high expression of FAM115C was correlated with better prognosis in patients with PDAC. Our findings suggest that FAM115C could be a novel tumor suppressor associated with prolonged survival in patients with PDAC.

Electrophysiological studies have rarely evaluated the sites prone to pulmonary vein (PV) conduction gap during cryoballoon ablation (CBA) for atrial fibrillation (AF). In addition, no studies have analyzed the sequence of PV potentials just before PV isolation during CBA for AF. Of the 238 patients who underwent first-time CBA for paroxysmal AF, 115 PVs of 29 patients who underwent repeat session due to recurrence after the procedure were retrospectively evaluated in the study. We evaluated the disappearance pattern of PV potential and PV reconnection on intracardiac electrograms and investigated whether the conduction gap site of the PV was related to the last remaining earliest PV potential (EP) and sequence pattern during the first-time CBA. Time to isolation was observed in 81 PVs during the first-time CBA. At the repeat session, PV reconnection was only observed in 22 of 81 PVs. PV potentials disappeared with sequence changes in 36 PVs and without sequence changes in 38 PVs. Multivariate analysis demonstrated that disappearance of PV potentials without change in the EP site but with delay or disappearance of other PV potentials was independently associated with PV reconnection (12/22 PVs [55%] vs. 4/59 PVs [6.8%]; odds ratio 14.4; 95% confidence interval 3.75–55.5; p

Background With regards to short-term outcome in atrial fibrillation (AF), the benefit of cryoballoon ablation (CBA) by pressing a balloon against the earliest pulmonary vein (PV) potential site during pulmonary vein isolation, (earliest potential [EP]-guided CBA) has been previously demonstrated. Objective The present study aimed to evaluate the long-term outcome of the EP-guided CBA. Methods This study included 136 patients from two randomized studies, who underwent CBA for paroxysmal AF for the first time. Patients were randomly assigned to the EP-guided and conventional CBA groups in each study. In the EP-guided CBA group, we pressed a balloon against the EP site when the time to isolation (TTI) after cryoapplication exceeded 60 s and 45 s in the first and second studies, respectively. The patients were followed up for 1 year after procedure. We compared the clinical outcomes between the EP-guided CBA group (68 patients) and the conventional CBA group (68 patients). Results No significant differences in baseline characteristics were observed between the two groups. Compared with the conventional CBA group, the EP-guided CBA group had a significantly higher success rate at TTI ≤90 s (98.5% vs. 90.0%, P Conclusions The EP-guided CBA approach can facilitate the ablation procedure and achieve low recurrence at 1-year after ablation. Funding Acknowledgement Type of funding sources: None. Earliest potential [EP]-guided CBAThe recurrence at 1-year after ablation

ObjectivesTo determine the neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight MethodsThis study prospectively recruited 224 VLBWIs born from 2003 to 2009 in Kyushu University Hospital, Japan. Comorbidities of neurocognitive impairment, epilepsy, and autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) were assessed at age 3, 6, and 9 years.ResultsNeurodevelopmental profiles were obtained from 185 (83%), 150 (67%), and 119 (53%) participants at age 3, 6, and 9 years, respectively. At age 9 years, 25 (21%) VLBWIs showed intelligence quotient (IQ) ConclusionThese data suggest that VLBWIs showed a higher prevalence of developmental delay, epilepsy, and ASD/ADHD at age 9 years than the general population. Distinct mechanisms might be involved in the pathogenic process of ASD/ADHD from those of developmental delay and epilepsy.

Highlights • PTPN3 suppression associates with lymphocyte activation and cancer suppression. • PTPN3 is involved in the induction of malignant traits. • PTPN3 is associated with cellular immunosuppression. • Signals from PTPN3 go through MAPK and PI3K signaling. • PTPN3-inhibited lung NET cells enhance PTPN3-suppressed activated lymphocytes., In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.

Low skeletal muscle mass is one of the components of sarcopenia. However, the prognostic impact of skeletal muscle mass on clinical outcomes in patients after transcatheter aortic valve replacement (TAVR) remains unclear. Therefore, we assessed the impact of skeletal muscle mass on future cardiovascular events in patients undergoing TAVR. We enrolled 71 consecutive patients who underwent TAVR for symptomatic severe aortic stenosis. We applied bilateral psoas muscles as an indicator of skeletal muscle mass. Psoas muscle volumes were measured from the origin of psoas at the level of the lumbar vertebrae to its insertion in the lesser trochanter on three-dimensional computed tomography datasets. Psoas muscle mass index (PMI) was calculated as psoas muscle volume/height2 (cm3/m2). According to the median value of PMIs (79.8 and 60.0 cm3/m2 for men and women), the enrolled patients were divided into two groups. During the follow-up, 11 (31.4%) patients in low PMI group and 4 (11.1%) in high PMI group experienced major adverse cardiovascular events (MACE) defined as a composite of death from any cause, myocardial infarction, heart failure hospitalization, and stroke. The proportion of MACE-free survival was significantly lower in low PMI group (log-rank P = 0.033), mainly due to the difference of hospital readmission for congestive heart failure. On multivariate Cox proportional hazard analysis, PMI remained an independent negative predictor of MACE [hazard ratio 0.95 (95% confidence interval 0.92–0.98, P = 0.002)]. In conclusion, low skeletal muscle mass independently predicted MACE in patients undergoing TAVR.

Objectives To characterize the real size and morphology of tracheas in childhood for the optimal selection of endotracheal tube. Design A retrospective cohort study of pediatric patients who received CT scan of the cervical spine from July 2011 to March 2018. Cross-sectional CT images vertical to trachea were reconstructed and the accurate tracheal diameters were measured. The validity of the traditional age-based formula for predicting the endotracheal tube size was assessed for the best fit to trachea. Setting Tertiary Emergency and Critical Care Center of Kyushu University Hospital. Patients Children, who are 1 month to 15 years old, received CT scan of the cervical spine. Interventions None. Measurements and main results We enrolled 86 children with median age of 53 months. The cross-sectional shape of pediatric trachea was circular at the cricoid level and elliptical at the infraglottic level. The narrowest part of pediatric trachea was the transverse diameter at the infraglottic level at any age. Significant positive correlation between age and the narrowest diameter was observed. When compared the transverse diameter at the infraglottic level with the outer diameter of endotracheal tubes, uncuffed endotracheal tubes selection based on the traditional age-based formula ran a significant risk of oversized endotracheal intubation until 10 years old compared with cuffed endotracheal tubes selection (60.0% vs 23.8%; p Conclusions These findings indicate the safety and efficacy of cuffed endotracheal tubes in infants and children and the reconsideration for the airway management in pediatric anesthesia and intensive care.

POU domain class 2-associating factor 1 (also called Bob1), which is mainly expressed in B cells, regulates B cell homeostasis and controls humoral immune responses. Although Bob1 is known to function reliably in T cell subsets including follicular helper T cells, Th1 cells and Th2 cells, it is unknown whether Bob1 functions in other T cell subsets. In this study, we found that Bob1 knock out (KO) mice are resistant to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide and that Bob1 KO T cells are defective in Th17 differentiation. Importantly, Bob1 interacts with retinoid acid receptor-related orphan receptor (ROR) gamma t (RORγt), a signature transcription factor for Th17 cells, through the ligand-binding domain of RORγt, thereby enhancing IL-17A transcription activity. IL-17A induction by Bob1 requires the ability for its formation of a DNA-Oct1-Bobl ternary complex. Thus, our findings demonstrate that Bob1 enhances IL-17A expression in vivo and in vitro by interacting with RORγt in Th17 cells, suggesting that Bob1 plays a pivotal role in Th17-mediated autoimmune disease.

Background Bicycle-spoke injuries rarely cause late complications of infection, including sepsis and sepsis-associated encephalopathy, with appropriate treatments. Case presentation We experienced a 2-year-old girl who developed the signs of encephalopathy with fever 6 months after a spoke-injury. On admission, the injured skin was inflamed with cellulitis. The blood culture was positive for methicillin-sensitive Staphylococcus aureus. Electroencephalogram showed diffuse slow-wave activity. Diffusion-weighted magnetic resonance imaging detected a high-intensity lesion with decreased diffusivity at the right frontal cortex. She received immunoglobulin and combined antibiotics treatments in the intensive care unit, and successfully overcame the sepsis-associated encephalopathy without neurological impairments. Conclusion This is the first report demonstrating that sepsis and its associated encephalopathy occurs in a remote period after the bicycle-spoke injury.

IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory disease characterized by elevation of serum IgG4 level as well as infiltration of IgG4+ plasma cells in various affected organs. The etiology of IgG4-RD is still not fully understood. Since IgG4-RD is more prevalent in the elderly, aging in itself is considered to be an important risk factor of IgG4-RD. However, the relationship between the pathogenesis of IgG4-RD and immunosenescence remains unknown. To clarify age-related features underlying IgG4-RD, we focused on T follicular regulatory (Tfr) cells, which share forkhead box P3 with regulatory T cells, since the percentage of Tfr cells is known to depend on age. Studies of blood specimens from patients with IgG4-RD and from healthy volunteers demonstrated a marked elevation of circulating Tfr (cTfr) cells in patients with IgG4-RD. Moreover, the percentage of cTfr cells was significantly correlated with various clinical parameters including the level of serum IgG4 and the number of involved organs in IgG4-RD patients. The percentages of tonsillar and blood Tfr cells were increased with aging in healthy volunteers, whereas the suppressive effect of cTfr cells on B cell function in elderly subjects was impaired in comparison with that in young subjects due to a defect in the production of a regulatory cytokine, IL-10. Given that the number of IL-10-producing cTfr cells in IgG4-RD patients was markedly increased compared with that in healthy elderly subjects, these findings suggest that an abnormal aging process of Tfr cells may be related to the pathogenesis of IgG4-RD.

Purpose of review New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. Recent findings Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1hiCXCR5- peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5+ Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. Summary Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4+ T-cell subsets in IgG4-RD.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood-onset encephalopathy, but the precise pathophysiology remains unclear. We encountered a child with Moyamoya syndrome and AESD. He exhibited left-predominant stenosis of the middle cerebral artery (MCA), and later developed broad lesions in the left hemisphere, raising the possibility that insufficient blood supply relates to formation of the lesions. To test the hypothesis, we investigated the relationship between MCA volume and lesion extent in seven AESD children without preexisting diseases. The MCA volume and lesion extent were quantified with time of flight images for construction of magnetic resonance angiography and apparent diffusion coefficient maps, respectively. Lateralization indices ([right − left]/[right + left]) of the MCA volume and lesion extent were calculated. We found that the lateralization indices were negatively correlated (r = −0.786, p = .036), that is, when the MCA volume was smaller in one side than the other side, the lesions were likely to develop more extensively in the ipsilateral side than the contralateral side. This indicates the association of insufficient blood supply with the lesions. The present study provides the first observation to suggest the involvement of vascular mechanism in AESD and has potential implications for novel therapeutic approach.

Although primarily a respiratory illness, several studies have shown that COVID-19 causes elevation of liver enzymes and various gastrointestinal (GI) symptoms. The aim of this study was to undertake a systematic review and meta-analysis to determine whether the presence of gastrointestinal (GI) symptoms contributed toward COVID-19 severity, and identify the GI symptoms characteristic of severe COVID-19. We conducted a literature search of PubMed from December 1, 2019, to June 30, 2020, and identified all reports with GI symptoms reported. A meta-analysis comparing the severity of COVID-19 with the presence of liver enzyme elevation and GI symptoms was performed using RevMan version 5.4. Pooled data from 15,305 unique reverse transcriptase–polymerase chain reaction positive COVID-19 patients from 44 studies were analyzed. We found that the severe COVID-19 patients significantly had abdominal pain compared to the non-severe COVID-19 patients (OR = 2.70, 95% CI 1.17–6.27, Z = 2.32, p = 0.02, I2 = 0%) by analyzed 609 patients of 4 studies who reported both abdominal pain and COVID-19 severity. However, there was no significant difference in the incidence of diarrhea, nausea, or vomiting between the two groups. Thus, this systematic review and meta-analysis demonstrated that abdominal pain could be characteristic of severe COVID-19 infections. Compared with other viral infections that primarily infect the respiratory system, patients with COVID-19 have a slightly lower frequency of diarrheal symptoms with abdominal pain. However, to confirm this, further studies with COVID-19 patients across various countries and ethnicities are required. Supplementary Information The online version contains supplementary material available at 10.1007/s00535-021-01778-z.

Objective To clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE). Methods We retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups. Results The response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH3, procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3− Conclusion Incidence data and prediction scores for AESD will be useful for future intervention trials for AESD.

Although drug-eluting stents (DESs) reduce the rates of in-stent restenosis (ISR) and subsequent target lesion revascularization, stent fracture (SF) after DES implantation has become an important concern because of its potential association with restenosis and stent thrombosis. We aimed to assess the pathogenic impact of SF on in-stent restenotic neointimal tissue components after DES implantation. We analyzed 43 consecutive patients (14 with SF and 29 without SF) with ISR requiring revascularization after DES implantation between January 2008 and March 2014. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. SF was defined as complete or partial separation of stent segments observed using plain fluoroscopy or intravascular ultrasound. On volumetric IB-IVUS analyses, patients with SF had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than those without (37.3 ± 18.9% versus 24.9 ± 12.4%, P = 0.02, and 61.2 ± 18.3 versus 72.6 ± 12.1%, P = 0.04, respectively). Moreover, SF was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (β = 0.36, P = 0.03). The interval from stent implantation was similar in both groups (47.0 ± 28.7 versus 37.7 ± 33.3 months; P = 0.39). In conclusion, SF is associated with larger lipid tissue volume within the neointima after DES placement, suggesting a contribution to the development of neoatherosclerosis and vulnerable neointima. Thus SF might lead to future adverse coronary events.