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BACKGROUND Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE SUMMARY The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn’s disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab. CONCLUSION Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.

Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.

To assess the value of the texture analysis of fluorine-18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in predicting the treatment response of postoperative recurrent or metastatic oral squamous cell carcinoma (POR/M-OSCC) treated with cetuximab. A total of 14 patients undergoing 18F-FDG-PET/CT with POR/M-OSCC were divided into the responder and non-responder groups according to cetuximab response by Response Evaluation Criteria in Solid Tumors (RECIST). The regions of interest (ROI) were set at the POR/M-OSCC lesions with the highest uptake of 18F-FDG, and the volumetric and texture features were analyzed. The features with correlation coefficient of 0.6 or more were further evaluated using the logistic regression analysis to create a model. The SHAPEVolume(vx), SHAPEVolume(mL), metabolic tumor volume (MTV), and gray-level run-length matrix run-length nonuniformity (GLRLMRLNU) were significantly different between the responder (n = 6) and non-responder (n = 8) groups (p = 0.044, 0.042, 0.047, and 0.012, respectively). The model’s area under the curve (AUC) was found to be 0.83, 0.83, 0.79, and 0.92, respectively. The heatmap with PET feature dendrogram showed four distinct clusters including them in patient’s responder and non-responder groups. Higher MTV, GLRLMRLNU, SHAPEVolume(vx), and SHAPEVolume(mL) in 18F-FDG-PET images may have the prediction values for treatment response with POR/M-OSCC treated with cetuximab.

In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. Eighteen patients (aged 29–78 years) with DGCs and nine normal subjects (28–77 years) were examined. The mutation burden in intramucosal DGCs (10–66 mutations per exome) from individuals aged 29–73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2–5 years showed no progression. Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Introduction Increasing evidence suggests the utility of the submandibular approach for ultrasonography to detect tongue fasciculation in amyotrophic lateral sclerosis (ALS). We hypothesized that transoral motion-mode ultrasonography (TOMU) would be useful to detect tongue fasciculation in patients with ALS. Methods Patients with sporadic ALS showing clinically definite tongue fasciculation were retrospectively enrolled, and the ultrasonography findings of patients' tongues on TOMU and ultrasonography by the conventional submandibular approach were analyzed. Results Six patients with clinically definite ALS were enrolled in this study. Though small irregular muscle movements of 5 to 10 mm in amplitude and 0.1 to 0.2 seconds in duration were detected in all patients by TOMU, similar muscle movements were detected in only two of the six patients by the submandibular approach. Discussion TOMU appeared to be useful for detecting tongue fasciculation in ALS patients. Further study is needed to better determine its role as a diagnostic tool for ALS. This article is protected by copyright. All rights reserved.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19–15.97; p 3 cm in diameter (OR 3.28; 95% CI 1.35–7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

We report two cases of fetal intestinal volvulus (jejunum in case A, ileum in case B) with massive bowel dilatation and loss of peristalsis, which suddenly appeared in the third trimester. The bowel was dilated to different sizes and there were various echogenic patterns of the intestines in case A and a sausage-like appearance in case B. Case A developed polyhydramnios, whereas case B did not. Among 47 cases of fetal intestinal volvulus (29 articles) in which 32 were diagnosed prenatally, almost all cases with a prenatal diagnosis showed "whirlpool sign" or "coffee bean sign" by sonography and/or findings indicating intestinal hemorrhage. Even without these findings, the presence of dilatation of the intestines and loss of peristalsis occurring in the third trimester were diagnostic clues. The presence of different sizes and various patterns of bowel dilation and hydramnios may be helpful for predicting the involved site of intestinal volvulus.

Purpose Oral adverse events, such as dental inflammation with exacerbation, are stressful and lead to poor nutrition in patients undergoing cancer therapy. Thus, the prediction of risk factors for dental inflammation with exacerbation is important before cancer therapy is initiated. We hypothesized that, during cancer therapy (DIECT), fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging could be useful to predict dental inflammation with exacerbation. Methods We enrolled 124 patients who underwent FDG-PET/CT for diagnostic staging before cancer treatment. We then assessed DIECT outcomes after basic perioperative oral treatment. Moreover, we evaluated clinical parameters, therapeutic strategies, periodontal examination (probing depth (PD) and bleeding on probing (BOP)), dental imaging, and FDG-PET/CT imaging results of patients with and without DIECT. Furthermore, PET/CT images were assessed as per the FDG accumulation of the dental lesion (PAD) grading system. Results Univariate analysis demonstrated significant differences in age, periodontal examination (PD and BOP), and PAD grade between patients with and without DIECT. Furthermore, multivariate logistic regression analysis identified independent predictive factors for a positive periodontal examination (PD) (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.8–19.7; P = 0.004) and PAD grade (OR 11.6, 95% CI 3.2–41.2; P = 0.0002). In patients with cancer, PAD grade using FDG-PET/CT imaging was an independent and informative risk factor for DIECT. Conclusion Our results suggested that, for patients with DIECT, periodontal examination and PAD grade were independent predictive factors. Hence, regardless of the presence or absence of any lesion on dental imaging, PAD grade might be an additional tool, in addition to periodontal examination that potentially improves oral care management.

Spontaneous regression (SR) has been reported in various malignant tumors. However, SR in colorectal cancer (CRC) is particularly rare and the mechanism remains unclear. We here report three cases of CRCs displaying SR, which were experienced at two institutions. Intriguingly, all of these cases displayed the common endoscopic characteristics; superficial elevated lesion accompanied by a central depression (0-IIa + IIc, in the Paris classification), with a nonpolypoid growth, located in the ascending colon. Furthermore, immunohistology of biopsy specimens revealed the lack of DNA mismatch repair proteins within the CRC lesions, suggesting that these were mismatch repair-deficient (dMMR) CRCs. One of the major features of dMMR cancers is an increase in the number of tumor-infiltrating lymphocytes. Thus, the dMMR phenotype might be associated with SR of CRCs through the activation of anti-tumor host immune responses.

AIM Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. METHODS Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs. RESULTS SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN-1, 0 µg] and 54.9% [SIN-1, 250 µg] during 15 minutes after SIN-1 administration [P

Excessive activation of the sympatho-adrenomedullary system plays a pathogenic role in triggering and sustaining essential hypertension. We previously reported that, in normotensive rats, intracerebroventricularly (i.c.v.) administered neuropeptides, corticotropin-releasing factor and bombesin induced activation of the sympatho-adrenomedullary system, and that brain cannabinoid CB1 receptors negatively regulated this activation. In this study, we investigated the effects of brain CB1 receptor stimulation on blood pressure and the sympatho-adrenomedullary outflow in spontaneously hypertensive rats (SHRs), commonly used animal models of essential hypertension, and in Wistar-Kyoto (WKY) rats, normotensive controls of SHRs. In 18-week-old SHRs and WKY rats under urethane anaesthesia (1.0 g/kg, i.p.), SHRs exhibited significantly higher systolic, mean and diastolic blood pressures and plasma noradrenaline and adrenaline, and a lower heart rate than WKY rats. Single administration of arachidonyl 2'-chloroethylamide (ACEA, CB1 agonist, 1.4 µmol/animal, i.c.v.) significantly but partially reduced mean and diastolic blood pressures and the plasma level of noradrenaline in SHRs compared to vehicle (N,N-dimethylformamide)-treated SHRs. These ACEA-induced reductions were abolished by central pretreatment with rimonabant (CB1 antagonist, 300 nmol/animal, i.c.v.), which alone showed no significant effect on blood pressures or plasma noradrenaline and adrenaline levels of SHRs. On the other hand, ACEA had no significant effect on blood pressure or plasma noradrenaline and adrenaline levels in WKY rats. These results suggest that stimulation of brain CB1 receptors can ameliorate hypertension accompanied by enhanced sympathetic outflow without affecting blood pressure under normotensive conditions.

Objectives To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX). Materials and methods Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle-treated OVX, low-dose SARM-treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high-dose SARM-treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)-treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak-point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues. Results (i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (iii) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (v) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats. Conclusion Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth- and striated muscle-mediated urethral function under stress conditions such as sneezing.

The functions of the lower urinary tract, to storage and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra and external urethral sphincter. This activity is in turn controlled by neural circuits not only in the periphery, but also in the central nervous system (CNS). During urine storage, the outlet is closed and the bladder smooth muscle is quiescent by the neural control mechanism mainly organized in the spinal cord. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces micturition through activation of sacral parasympathetic (pelvic) nerves. The brain rostral to the pons (diencephalon and cerebral cortex) is also involved in excitatory and inhibitory regulation of the micturition reflex. Various transmitters including dopamine, serotonin, norepenephrine, GABA, excitatory and inhibitory amino acids, opioids and acetylcholine are implicated in the modulation of the micturition reflex in the CNS. Therefore, injury or neurodegenerative diseases of the CNS as well as drugs can produce bladder and urethral dysfunctions such as urinary frequency, urgency and incontinence or inefficient bladder emptying.

Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.

PATIENT This clinical report describes treatment with a double-crown-retained removable dental prosthesis fabricated using an intraoral scanner (IOS) and computer-aided design/manufacturing technology (CAD/CAM). A 68-year-old female patient presented with complaints of missing maxillary right first and left second premolars. CAD/CAM technology was applied to plan treatment with a double-crown-retained removable dental prosthesis. The patient consented to this treatment option but did not want orthodontic treatment for the anterior crossbite of the right side. After the definitive preparation of the abutment teeth, the shape of the provisional restoration was adjusted to match the definitive prosthesis. An IOS was used to obtain digital scans of the provisional restoration, occlusion, antagonist arch, and prepared surface of the abutment teeth. First, the primary crowns were milled from cobalt-chromium alloy. Next, using an intraoral scanner, a pickup impression of the primary crowns was performed, and the secondary crowns were designed, milled, and veneered. After delivery, the patient expressed satisfaction with the functionality, esthetics, and fit of the double-crown-retained removable dental prosthesis. DISCUSSION The surface of the primary crowns was coated with scan spray when the pick-up impression was made using the IOS. Practice is needed to achieve a thin and homogeneous coating with scan spray to improve reproducibility. CONCLUSION Double-crown-retained removable dental prostheses can be successfully fabricated using an IOS and CAD/CAM technology, resulting in patient satisfaction.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39–5.40) and CRP (C‐reactive protein) (OR, 1.10; 95% CI, 1.01–1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01–1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60–10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09–4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11–4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000032957.

Highlights • We report the first case of cerebral amyloid angiopathy-related inflammation (CAA-RI) presenting palinopsia initially. • Palinopsia is generally caused by intracranial diseases involving the parietal and occipital areas. • CAA dominantly affects parietal and occipital lobes, therefore palinopsia could be an important phenomenon of the disease.

INTRODUCTION AND OBJECTIVE:Although aging or severe bladder ischemia could be involved in progression of detrusor underactivity (DU), the pathophysiological mechanism of DU is not well clarified. H...

Exposure to psychological/mental stress can affect urinary function, and lead to and exacerbate lower urinary tract dysfunctions. There is increasing evidence showing stress-induced changes not only at phenomenological levels in micturition, but also at multiple levels, lower urinary tract tissues, and peripheral and central nervous systems. The brain plays crucial roles in the regulation of the body's responses to stress; however, it is still unclear how the brain integrates stress-related information to induce changes at these multiple levels, thereby affecting urinary function and lower urinary tract dysfunctions. In this review, we introduce recent urological studies investigating the effects of stress exposure on urinary function and lower urinary tract dysfunctions, and our recent studies exploring "pro-micturition" and "anti-micturition" brain molecules related to stress responses. Based on evidence from these studies, we discuss the future directions of central neurourological research investigating how stress exposure-induced changes at peripheral and central levels affect urinary function and lower urinary tract dysfunctions. Brain molecules that we explored might be entry points into dissecting the stress-mediated process for modulating micturition.

We investigated the involvement of brain-derived neurotrophic factor (BDNF) in bladder and urethral dysfunction using spinal cord-injured mice. We evaluated bladder and urethral function of female mice with 4-wk spinal cord injury (SCI) by filling cystometry and electromyography (EMG) of the external urethral sphincter (EUS) under a conscious condition. Anti-BDNF antibodies (10 μg·kg−1·h−1) were administered in some mice for 1 wk before the evaluation. Bladder and spinal (L6−S1) BDNF protein levels were examined by ELISA. Transcript levels of transient receptor potential channels or acid-sensing ion channels (Asic) in L6−S1 dorsal root ganglia were evaluated by RT-PCR. Voided volume and voiding efficiency were significantly increased without any changes in nonvoiding contractions, and the duration of reduced EMG activity during the voiding phase was significantly prolonged in anti-BDNF antibody-treated SCI mice. Compared with spinal cord-intact mice, SCI mice showed increased concentrations of bladder and spinal BDNF. Anti-BDNF antibody treatment decreased bladder and spinal BDNF protein concentrations of SCI mice. Asic2 and Asic3 transcripts were significantly increased after SCI but decreased after anti-BDNF antibody administration. These results indicate that upregulated expression of bladder and spinal BDNF is involved in the emergence of inefficient voiding in SCI mice. Thus, BDNF-targeting treatment could be an effective modality for the treatment of voiding problems, including inefficient voiding and detrusor sphincter dyssynergia after SCI.

Aim To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). Methods Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 μL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction. Results In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. Conclusions The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI.

The present study evaluated real-time changes in urethral pressure during the storage phase using a rat model with stress urinary incontinence (SUI) induced by simulated multiple birth traumas and investigated the relationship between urethral continence function and dynamic parameters associated with the changes in urethral pressure. Sprague-Dawley rats were divided into the following two groups: the sham group, which underwent three catheterizations of the vagina without distension at 2-wk intervals, and the vaginal distension (VD) group, which underwent three VDs at 2-wk intervals. After transection of the T8–T9 spinal cord, simultaneous bladder and urethral pressure recordings were performed during intravesical pressure elevation. Urodynamic parameters such as leak point pressure (LPP), urethral baseline pressure (UBP), maximum urethral pressure (MUP), the MUP-UBP differential (dUP) during intravesical pressure elevation, the bladder pressure when urethral contraction begins (Puc), and the bladder pressure at bladder neck opening (Pno) were then measured and compared. Compared with the sham group, LPP, UBP, dUP, MUP, Puc, and Pno were significantly decreased in the VD group. Pressure differences between LPP and Pno and between LPP and UBP (LPP-UBP) were also significantly different in the two groups. However, difference values of LPP and MUP or Pno and UBP were not altered after VD. Our new methods of simultaneous recordings of dynamic changes in bladder and urethral pressures are useful to fully evaluate the functional alterations in urethral continence function in the SUI model induced by multiple VDs. Moreover, LPP-UBP values, which correspond to the difference between Valsalva LPP and maximum urethral closure pressure in clinical urodynamics, would be useful to evaluate the impaired urethral continence function after simulated birth traumas in animal models.

Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

Aims The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats. Methods Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry. Results Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure. Conclusions Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.

We report a 65-year-old man who was diagnosed with focal status epilepticus generating a dreamy state, delusions with anxiety, complex audiovisual hallucinations, elementary auditory hallucinations, and metamorphopsia with a growing large lateral temporal lobe lesion. After administrating anti-seizure drugs, all the symptoms disappeared, and brain magnetic resonance imaging revealed ipsilateral hippocampal sclerosis. To the best of our knowledge, this is the first report to present all the symptoms in one epilepsy case. On the basis of semiology, electroencephalography, and brain magnetic resonance imaging, we speculated that epileptic activities that have originated from the lateral lesion might have propagated to the ipsilateral mesial temporal lobe, causing hippocampal sclerosis.

Background and aims Current trends have suggested covert atrial fibrillation as a mechanism of cryptogenic stroke. However, etiological heterogeneity regarding the underlying embolic sources remains a critical issue in cryptogenic stroke. Methods CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) is a multicenter observational registry of cryptogenic stroke patients admitted to participating hospitals, who underwent transesophageal echocardiography between April 2014 and December 2016. We obtained baseline characteristics, radiological and laboratory data, and echocardiographic findings, especially for embolic sources demonstrated on transesophageal echocardiography, and conducted comparisons according to CHADS2 and CHA2DS2-VASc scores (0–1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/ (UMIN000032957). Results The study comprised 677 patients (age, 68.7 ± 12.8 years; 455 males; median National Institutes of Health Stroke Scale score, 2) with cryptogenic stroke. On multiple logistic regression analysis, large aortic arch plaque ≥4 mm (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.51–3.36; p Conclusions The CHALLENGE ESUS/CS registry is a large TEE registry, and clarifies potential embolic etiologies of cryptogenic stroke using TEE. Large aortic arch plaques were associated with high CHADS2 and CHA2DS2-VASc scores, and represented important embolic sources in cryptogenic stroke.

Transoral carotid ultrasonography (TOCU) is a powerful tool for evaluating internal carotid artery (ICA) lesions located from the carotid bifurcation up to the level of the second cervical vertebra. Superb-microvascular imaging (SMI) is a new Doppler imaging technique whose algorithm analyze tissue movements to minimize motion artifacts by eliminating clutter signals. SMI significantly reduces motion artifacts and allows visualization of low-velocity blood flow even in minute vessels. TOCU with SMI produces clear intraluminal image of the distal extracranial ICA, which is not possible with conventional carotid artery ultrasonography (CUS). CUS with SMI and TOCU with SMI were performed in a patient with a history of carotid artery stenting for symptomatic left ICA stenosis, providing images of the full length of the stents with intimal hyperplasia.

Software-defined networks are vulnerable to attacks by compromised switches because commonly used programmable software switches are risky than traditional hardware ones. Although several countermeasures have been proposed to address compromised switches, the accuracy of detecting a malicious behavior depends on the performance of network statistics gathering by a controller. In this paper, we propose that WhiteRabbit is an approach to verify the consistency of the forwarding state by gathering real-time network statistics gathering from switches with accurate time scheduling. WhiteRabbit can detect attacks by compromised switches without being influenced by the performance of statistics gathering of a controller. Given that the proposed utilizes moving average, it mitigates the effect on the verification accuracy from the impact of the switch performance, such as scheduling error. In our previous work, we demonstrated the feasibility of WhiteRabbit using a prototype system. However, we could not evaluate the impact of the difference between the scheduled and actual execution times in our previous work, because we performed the experiment in a minimal setup using Mininet. Thus, we measured the scheduling error and time required to gather statistics in a large-scale environment. We also confirmed that the scheduling error is lower than the time required to gather statistics. Additionally, considering that WhiteRabbit only depends on the scheduling error, we verified that the accuracy of WhiteRabbit is higher than prior arts on the tree topology constructed with 15 switches.

Benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE) is a common proliferative disease, and giving rise to associate with lower urinary tract symptoms (LUTS). However, the pathogenesis is not well clarified, and thought to be multifactorial. There are some lines of evidence that impairment in the blood supply of the lower urinary tract causes development of BPH/BPE. Clinical data showed an association between the development of BPH/BPE and atherosclerotic disease such as hypertension, diabetes and hyperlipidemia. The spontaneously hypertensive rat (SHR) has been used as model of genetic hypertension. SHR also shows decreased blood flow and hyperplastic morphological abnormalities in the ventral prostate. Our previous studies demonstrated that chronic treatment with vasodilative drugs nicorandil (ATP sensitive potassium channel opener) and silodosin (alpha1 adrenoceptor antagonist) increased blood flow and suppressed the growth factor and morphological abnormalities in the SHR ventral prostate. These data suggested that prostatic blood flow could be therapeutic targets for BPH/LUTS.

Carotid artery atherosclerosis is one of the major risk factors for ischemic stroke. Intraplaque neovascularization (IPN) is one of the steps toward the development of vulnerable plaque. Superb microvascular imaging (SMI) is a new ultrasonographic technique for visualizing low-velocity and microvascular flow by clutter suppression to extract flow signals from large to small vessels and enables visualization of intraplaque microvascular flow (IMVF) without echo contrast media. We aimed to investigate the association between IMVF signal in SMI and MRI plaque imaging among patients with atherosclerotic carotid stenosis. We prospectively enrolled patients (>18 years old) with mild to severe carotid stenosis (more than 50% in cross-sectional area) diagnosed by carotid ultrasonography between August 2017 and April 2018, irrespective of sex and history of stroke. A total of 40 patients (31 men, 9 women; mean age, 75.1 ± 10.0 years) were enrolled. SMI revealed IPN findings in 21 patients. SMI clearly visualized the direction of pulsatile flow movement in microvessels and IPN was easily classified into the two types of Type V (n=2) and Type E (n=19). Multivariate logistic regression analysis presented that microvascular flow signal in carotid plaque on SMI was identified as a significant predictor of intraplaque hemorrhage as evaluated by MRI (OR, 8.46; 95%CI, 1.44-49.9; p=0.018). This study demonstrated a significant association between the presence of IMVF signal in SMI and intraplaque hemorrhage characterized by high-intensity lesions on MRI T1-FFE images.

Aims Aging is an obvious risk factor for detrusor underactivity. We investigated the effects of aging on bladder function in spontaneously hypertensive rats. Main methods Male spontaneously hypertensive rats and Wistar Kyoto rats (used as normotensive controls) at the ages of 18, 36, 54, or 72 weeks were used. Bladder weight, blood pressure, bladder blood flow, and urodynamic and renal parameters were measured. Additionally, detrusor thickness and renal histology were evaluated. Key findings In spontaneously hypertensive rats, significant increases were observed in bladder weight/body weight ratio, blood pressure, detrusor thickness, intercontraction interval, urine output, serum creatinine, and renal glomerular and tubular scores, and decreases in bladder blood flow and urine osmolality at 72 weeks as compared to those at 18 weeks. In spontaneously hypertensive rats, significant increases were observed in single voided volume, post voiding residual urine volume, and bladder capacity, with decrease in voiding efficiency were observed at 54 or 72 weeks than at 18 weeks. However, there were no significant differences in blood pressure, urodynamic and renal parameters, detrusor thickness and renal histology among Wistar Kyoto rats of different ages. Significance In spontaneously hypertensive rats, aging induces significant increases in blood pressure, single voided volume, post voiding residual urine volume, intercontraction intervals and urine output, and decreases in voiding efficiency and bladder blood flow indicative of detrusor underactivity. Aging-related severe hypertension could induce voiding dysfunction such as detrusor underactivity via severe bladder ischemia and polyuria. Aged spontaneously hypertensive rats may be useful animal models for detrusor underactivity.

Background: Secretory carcinoma (SC) is a malignancy of the salivary glands, which is similar to SC of the breast in terms of its association with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive gene. SC is a recently described salivary gland tumor, and there are few reports describing oral minor salivary gland-derived SC. We reported two cases of SC in the oral cavity and reviewed the literature.Case presentation: The patients included a 65-year-old Japanese woman presented with a mass of the upper lip and an 84-year-old Japanese man presented with a mass on the buccal mucosa, respectively. Diagnosis was based on histomorphological and immunohistochemical findings and identification of a specific translocation of the ETS variant 6-neurotrophic receptor tyrosine kinase 3 (ETV6-NTRK3) gene fusion. Case 1 was finally diagnosed using reverse transcription-polymerase chain reaction using formalin-fixed paraffin-embedded tissue samples, while case 2 was diagnosed using fluorescence in situ hybridization analysis. Conclusion: It is highly likely for many cases of SC to be initially diagnosed as acinic cell carcinoma (AciCC) owing to their similar histological findings. The treatment strategy for minor salivary gland-originated SC is the same as that for AciCC, but SC is often highly malignant and involves a high risk of cervical lymph node metastasis. Making an accurate diagnosis in cooperation with pathologists and confirming the presence of the ETV6-NTRK3 fusion gene using genetic analysis is important.

Objectives We aimed to predict the possibility of patients with stage I and II anti-resorptive agent-related osteonecrosis of the jaw (ARONJ) developing resistance to our treatment protocol by evaluating their clinical and imaging factors. Materials and methods We enrolled 58 patients with ARONJ who underwent imaging modality. As objective variables, we considered the healing, stage-down, and stable stages as successful outcomes, and the stage-up stage as resistant-to-treatment. As explanatory variables, we investigated the clinical and imaging factors. Furthermore, we examined stage-down as an improvement outcome to compare with the stable and stage-up stages, which were considered as no-improvement outcomes. We conducted unpaired between-group comparisons on all explanatory variables using χ2 tests for independence. Results Among 58 patients, the treatment was successful in 53 (91.4%); however, the disease was resistant in five (8.6%). Among the clinical factors, the resistant patients had a longer duration of administration of bone-modifying agents (BMAs) (cut-off: 1251 days, p = 0.032, odds ratio = 11.2, 95% confidence interval 1.115–122.518). In addition, the target disease that was being treated bone metastasis of malignant tumor was the only significant refractory factor (p = 0.024, OR: 3.667 95% CI 1.159–11.603) Conclusions A combination of metabolic and morphological imaging modalities may be useful for oral surgeons to evaluate the disease activity and predict course of refractory ARONJ.

Autonomous driving of a personal mobility vehicle such as a wheelchair in a walking space is crucial as a means of transportation for the elderly and the physically handicapped. To realize this, accurate pedestrian detection is indispensable. As existing 3D object detection methods are trained with a roadway dataset, they are widely used for object detection in roadways. These methods have two major drawbacks as regards the detection of objects in walking spaces. The first is that they largely depend on the different LIDAR models. To eliminate this issue, we propose a 3D object detection method, CosPointPillars, that does not take the reflection intensities of the LIDAR point cloud, which causes a sensor model dependency, as input. The second drawback is that networks trained with a roadway dataset cannot sufficiently detect pedestrians (who are major traffic participants in walking spaces) located within a short distance; this is because the roadway dataset hardly includes nearby pedestrians. To solve this issue, we generated a new walking space dataset called SimDataset, which includes nearby pedestrians as a training dataset in the simulations. An experiment on a real walking space showed that SimDataset is suitable for use in pedestrian detection.

An elongated styloid process (ESP) causes symptoms such as pharyngeal pain, swallowing pain, and discomfort during mouth opening. The main treatment is surgical resection of the ESP. The authors present a case of ESP with skeletal mandibular protrusion. Because mandibular setback by sagittal splitting ramus osteotomy (SSRO) may lead to deterioration of symptoms of ESP, resection of ESP and bilateral SSRO were performed simultaneously. The patient was a 50-year-old man who visited our department with chief complaints of mandibular protrusion and pain in the left pharynx on mouth opening and swallowing. A lateral cephalogram helped in diagnosis of skeletal mandibular protrusion. In addition, an approximately 42-mm left styloid process elongated inferomedially was observed. Left styloidectomy was first performed via the cervical approach, followed by SSRO. Occlusion, facial appearance, and preoperative symptoms due to the ESP improved after surgery. The cervical appearance was esthetically satisfactory. In a case of ESP with skeletal mandibular protrusion with potential aggravation of symptoms because of mandibular setback of the ESP, resection of the styloid process is necessary together with orthognathic surgery.

Aims We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs). Main methods Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg−1) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Key findings Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. Significance Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.

Background Total colonic aganglionosis (TCA) and long segment aganglionosis (LSA) are rare forms of Hirschsprung disease (HD). Laparoscopic resection of total or the longer segment of the colon has not been unestablished for these forms. Methods We retrospectively reviewed five infants with TCA or LSA who underwent the blunt tip dissector (BD) assisted laparoscopic Soave pull-through procedure, and patients’ characteristics and procedure outcomes were analyzed. Results One infant with TCA had Mowat–Wilson syndrome. Ileostomy for TCA and transanal catheter placement for LSA allowed full enteral feeding with good weight gain before operation. The BD manipulator used in the laparoscopic surgery was simple to use and powerful enough to create tension, expand operating space, and improve access to specific parts of the mesentery or pelvis. No intraoperative complications such as perforation or bleeding were noted; thus, the operation was completed uneventfully, without conversion to open surgery in all cases. All the patients had excellent cosmetic results, without late complications. Conclusions The BD manipulator is safe and effective to facilitate laparoscopy-assisted Soave pull-through procedure in children with TCA and LSA. This approach may be applied to the other pediatric diseases, which require resection of the longer segment of the colon.

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA sequencing datasets, consisting of non-cancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive non-cancerous liver tissues, whereas some cancer-related pathways were up-regulated in the non-cancerous liver tissues of both post-SVR and HCV-positive cases. The persistent up-regulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals (DAAs), including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving DAA therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, up-regulated CYR61 could be a possible biomarker for post-SVR-HCC.

To evaluate the usefulness of soleal vein (SOV) diameter as a predictor of new onset of deep vein thrombosis (DVT) in acute stroke patients. A total of 121 acute stroke patients who were admitted within 48 h of onset underwent a calf vein ultrasonography (CVUS) examination within 7 days after hospitalization. They were evaluated for the presence of DVT and risk factors including maximum SOV diameter. Next, the patients in whom DVT was not detected at the first CVUS examination underwent a second CVUS examination on the 21st hospital day, and were evaluated for the presence of new DVT. DVT was detected in 27 of 121 patients at the first CVUS examination. A significant association was noted between the presence of DVT and higher levels of soluble fibrin monomer, D-dimer, and C-reactive protein, and a higher rate of having cancer concomitantly. Furthermore, 50 of 94 patients without DVT at the first CVUS examination underwent a second CVUS examination. Of the 94 patients, 44 were excluded, because they were discharged by the 21st day. Note that DVT was newly developed in 12 of the 50 patients who underwent the second CVUS. A significant association was found between the presence of new DVT and the rate of history of stroke, hematocrit level, and maximum SOV diameter at the first examination. In our acute stroke patients, SOV dilation, history of stroke, and elevated hematocrit level were found to be associated with risk of developing a new DVT.

While the intravenous recombinant tissue plasminogen activator (rt-PA) therapy for acute ischemic stroke patients with cancer is recommended when survival of ≥ 6 months is expected, the risk factors for death and stroke recurrence within 6 months after stroke are not well known. Thus, we aimed to identify markers for death and recurrence risks within six months from stroke onset in patients with cancer.In a retrospective cohort study, the subjects comprised acute ischemic stroke patients with cancer hospitalized at St. Marianna University hospital from 2008 through 2019. To evaluate the associations between the clinical factors within 24 h of the initial stroke and death or stroke recurrence events within 6 months from stroke onset, Logistic analysis and Cox proportional hazards regression analysis was used respectively. Next, the optimal cutoff point of markers for different mortality groups was determined using the receiver operating characteristic curve analysis and cumulative outcome rate of each group was compared using the Kaplan-Meier method.Among 194 patients with cancer who developed acute stroke, 167 were ultimately selected for analysis. 47 subjects (28.14%) passed away within 6 months following stroke onset, and 20 subjects (11.98%) had stroke recurrence. High D-dimer levels, low fibrinogen levels, high Glasgow prognostic scores (GPS), and multiple vascular territory infarctions was independently associated with death, where higher death rate was significantly confirmed in the group with D-dimer levels of ≥3.95 mg/dl, fibrinogen levels277.5 mg/dl and GPS scores of 2. Low fibrinogen level, lack of antithrombotic therapy, and the presence of metastasis were associated with stroke recurrence.When patients with cancer suffer stroke, D-dimer levels, fibrinogen levels, GPS, and multiple vascular territory infarctions would be associated with the risk of death within 6 months. Low fibrinogen levels, lack of antithrombotic therapy, and the presence of metastasis correlated with high risk of stroke recurrence.

Aims: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke. Methods: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients’ clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed. Results: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p =0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p =0.030), higher frequency of right-to-left shunt (66% vs. 45%, p ＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p =0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959–6.500, p = 0.061). Conclusions: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA’s clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

Objectives To investigate whether a response to hydrogen sulfide donors (GYY4137 and sodium hydrosulfide) and the endogenous hydrogen sulfide system (hydrogen sulfide level and expression of cysteine aminotransferase, cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase) in the spontaneously hypertensive rat bladder differ with age, we compared the responses of hydrogen sulfide donors to micturition and bladder relaxation, and the endogenous hydrogen sulfide system in the bladder of 18-week versus 12-week-old spontaneously hypertensive rats. Methods GYY4137 was intravesically administered and cystometry was performed in anesthetized rats. The responses of sodium hydrosulfide were evaluated in carbachol-mediated precontracted bladder strips. Bladder hydrogen sulfide levels and expression levels of each enzyme were investigated using the methylene blue method and Western blotting, respectively. Results GYY4137 treatment significantly prolonged intercontraction intervals only in 12-week-old rats. Sodium hydrosulfide-induced bladder relaxation was significantly attenuated in the strips of 18-week-old rats compared with that in 12-week-old rats. In the bladder dome, significant increases in hydrogen sulfide levels and in the expression of cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteine aminotransferase were observed in 18-week-old rats compared with 12-week-old rats. However, cystathionine γ-lyase bands were not detected in bladder tissues of either group. Conclusions Bladder relaxation induced by hydrogen sulfide may be attenuated in spontaneously hypertensive rats in an age-dependent manner.