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Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-L-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We generated a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

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.

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.

Ischemic stroke is one of the most prevalent brain disorders and the major cause of long-term disability. In particularly, hippocampal injury after ischemia-reperfusion is a serious problem as it contributes to vascular dementia. Many researches have revealed that ischemia-reperfusion causes increase in reactive oxygen species production and disruption of neuronal Zn2+ homeostasis in the hippocampus, which induces hippocampal neuron death. Glutathione (GSH) is present in all mammalian cells and plays a crucial role in neuronal cell defense against oxidative stress. On the other hand, thiol group of GSH chemically chelates Zn2+ and functions as a regulator of neuronal Zn2+ homeostasis. These evidences suggest that neuronal GSH levels could be an important factor affecting neuronal surviving. The synthesis of GSH is largely influenced by intracellular cysteine availability. In neurons, excitatory amino acid carrier type 1 (EAAC1) acts as a cysteine transporter and provides cysteine substrate for GSH synthesis. Recently, several animal studies have revealed that promotion of neuronal GSH synthesis through EAAC1 reduces ischemia-induced hippocampal neuron death. This review aims to describe neuroprotective role of GSH against hippocampal injury following ischemia-reperfusion, focusing on EAAC1.

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.

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.

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...

Stroke is a major cause of death worldwide, leading to serious disability. Post-ischemic injury, especially in the cerebral ischemia-prone hippocampus, is a serious problem, as it contributes to vascular dementia. Many studies have shown that in the hippocampus, ischemia/reperfusion induces neuronal death through oxidative stress and neuronal zinc (Zn2+) dyshomeostasis. Glutathione (GSH) plays an important role in protecting neurons against oxidative stress as a major intracellular antioxidant. In addition, the thiol group of GSH can function as a principal Zn2+ chelator for the maintenance of Zn2+ homeostasis in neurons. These lines of evidence suggest that neuronal GSH levels could be a key factor in post-stroke neuronal survival. In neurons, excitatory amino acid carrier 1 (EAAC1) is involved in the influx of cysteine, and intracellular cysteine is the rate-limiting substrate for the synthesis of GSH. Recently, several studies have indicated that cysteine uptake through EAAC1 suppresses ischemia-induced neuronal death via the promotion of hippocampal GSH synthesis in ischemic animal models. In this article, we aimed to review and describe the role of GSH in hippocampal neuroprotection after ischemia/reperfusion, focusing on EAAC1.

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.

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.

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.

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.

Epidemiological, clinical, and biological studies convincingly demonstrate that chronic inflammation predisposes to the development of human cancers. In digestive organs, inflammation-associated cancers include colitis-associated colorectal cancers, Helicobacter pylori-associated gastric cancer, as well as Barrett’s esophagus and esophageal adenocarcinoma associated with chronic duodenogastric-esophageal reflux. Cancer is a genomic disease, and stepwise accumulation of genetic and epigenetic alterations of tumor-related genes leads to the development of tumor cells. Recent genome analyses show that genetic alterations, which are evoked by inflammation, are latently accumulated in inflamed epithelial cells of digestive organs. Production of reactive oxygen and aberrant expression of activation-induced cytidine deaminase, a nucleotide-editing enzyme, could be induced in inflamed gastrointestinal epithelial cells and play a role as a genomic modulator of inflammation-associated carcinogenesis. Understanding the molecular linkage between inflammation and genetic alterations will open up a new field of tumor biology and provide a novel strategy for the prevention of inflammation-associated tumorigenesis.

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.

Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.

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.

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.

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. Since patients with MSA often have sleep-related respiratory disorders including upper-airway obstruction and/or central sleep disturbance, appropriate evaluation of the upper airway especially during sleep may be indispensable. Fiberoptic laryngoscopy during diazepam-induced sleep has been reported for upper-airway obstruction verification. However, some patients cannot endure the uncomfortable sensation of the fiberscope. To address these issues, we devised a protocol of four four-dimensional computed tomography (4D-CT) for upper-airway evaluation during sleep. Here, we report the case of patient with MSA who was evaluated for upper-airway obstruction during sleep using 4D-CT. A 46-year-old man (height 1.60 m, weight 79 kg) was admitted to our neurological department for tracheal intubation because of a sudden onset of respiratory failure occurring at night. At the age of 45 years, he was diagnosed as MSA with predominant parkinsonism. As pulmonary disease had been excluded and his swallowing was normal, our differential diagnoses were central sleep apnea or obstructive sleep apnea related to his MSA or obstructive sleep apnea (SA) related to his obesity. A tracheostomy was done to maintain the airway after extubation. Polysomnography showed obstructive SA and not central SA. Awake fiberoptic laryngoscopy showed no upper airway obstruction but bilateral vocal abduction impairment (BVAI) during inspiration. To assess the spatial and temporal conditions of the upper respiratory tract—the patient could not tolerate sleep laryngoscopy—we carried out a 4D-CT. Reconstructed 4D-CT images of respiration during sleep showed clear abnormalities: glottis closure at the terminal stage of inspiration and subsequent velopharyngeal closure. As glottis closure does not occur normally in obesity patients, the cause of the respiratory failure in this patient was considered MSA-related sleep-induced airway obstruction. We decided to keep the tracheostoma, because BVAI in patients with MSA may be getting worse, although central apnea after tracheostomy may cause sudden central origin-related death; 4 months postoperatively, the patient had experienced no further airway-related complications. This report indicates that 4D-CT sequential upper-airway assessment during sleep is useful for determining the abnormalities causing obstructive SA in patients with MSA.

INTRODUCTION AND OBJECTIVE:Glycine is one of major inhibitory neurotransmitters in the central nervous system, and activation of glycine receptors is known to induce a chloride ion influx to cause ...

Recently, hydrogen sulfide (H2S) has been recognized as the third gasotransmitter besides nitric oxide and carbon monoxide, and it has been reported that H2S exhibits various physiological functions such as neuromodulation and vasorelaxation. In the lower urinary tract (bladder and prostate), it is reported that donors of H2S induce contraction of the rat detrusor and relaxation of the pig bladder neck. These reports suggest a possibility that H2S may have site-specific effects on the bladder. However, the detailed functions of H2S in each part of the bladder are still unclear. In addition, there is no report showing physiological roles of H2S in the prostate. In this article, we will review the distribution of enzymes related to H2S biosynthesis and physiological roles of H2S in the lower urinary tract based on reports from our and other groups. We will also introduce a possibility that H2S can be a new therapeutic target against lower urinary tract symptoms (LUTS) based on our data from spontaneously hypertensive rats (SHRs), which develop hypertension-mediated LUTS.

BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA (miRNA) alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS: We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. MiR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilised to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas (TCGA) data were utilised to validate gene expressions. RESULTS: We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a, ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in human intestinal-type GC. CONCLUSION: We found down-regulation of miR-30a in preneoplastic lesions and its tumor suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.

Pathophysiological functions of chloride intracellular channel protein 3 (CLIC3) in human gastric cancer have been unclear. In the tissue microarray analysis using 107 gastric cancer specimens, CLIC3 expression was negatively correlated with pathological tumor depth, and the patients with lower expression of CLIC3 exhibited poorer prognosis. CLIC3 was expressed in the plasma membrane of cancer cells in the tissue. CLIC3 expression was also found in a human gastric cancer cell line (MKN7). In whole-cell patch-clamp recordings of the cells expressing CLIC3, NPPB-sensitive outwardly rectifying Cl− currents were observed. Cell proliferation was significantly accelerated by knockdown of CLIC3 in MKN7 cells. On the other hand, the proliferation was attenuated by exogenous CLIC3 expression in human gastric cancer cells (KATOIII and NUGC-4) in which endogenous CLIC3 expression is negligible. Our results suggest that CLIC3 functions as a Cl− channel in the plasma membrane of gastric cancer cells and that decreased expression of CLIC3 results in unfavorable prognosis of gastric cancer patients.

Psychological stress can induce not only frequent urination but also exacerbation of bladder dysfunctions. However, the brain pathophysiological mechanisms underlying stress-induced effects on the micturition reflex are still unknown. Bombesin (BB)-related peptides and BB receptors in the brain have been reported to mediate and integrate stress responses. We have found that centrally administered BB induced frequent urination in rats through brain BB1 and BB2 receptors, serotoninergic nervous system/5-HT7 receptors and corticotropin-releasing factor (CRF) type1 (CRF1) receptors. Interestingly, the BB-induced frequent urination was independent of the BB-induced activation of the sympatho-adrenomedullary outflow, a representative response to stress. Because the outflow is well known to regulate micturition, the finding was very surprising. These findings indicate that brain BB1, BB2, 5-HT7 and CRF1 receptors could be new therapeutic targets for bladder dysfunction exacerbated by stress exposure.

Chronic gastritis caused by Helicobacter pylori (H. pylori) infection could lead to the development of gastric cancer. The finding that multiple gastric cancers can develop synchronously and/or metachronously suggests the development of field cancerization in chronically inflamed, H. pylori-infected gastric mucosa. The genetic basis of multiple tumorigenesis in the inflamed stomach, however, is not well understood. In this study, we analyzed the microsatellite instability (MSI) status and copy number aberrations (CNAs) of 41 multiple intramucosal early gastric cancers that synchronously or metachronously developed in 19 patients with H. pylori infection. Among the 41 intramucosal gastric carcinomas, 9 (22%) exhibited MSI, and the remaining 32 (78%) exhibited the microsatellite stable (MSS) phenotype. Metachronous multiple intramucosal gastric carcinoma exhibit inter-tumor heterogeneity by individually acquiring genetic aberrations. All synchronous multiple intramucosal gastric carcinoma pairs shared a common MSI/MSS profile, and CNA analysis revealed that synchronous multiple intramucosal gastric carcinoma pairs with the MSS phenotype shared common aberrations of representative tumor-suppressor genes, including focal deletion of APC, TP53, CDKN2A, and CDKN2B. Multiregional CNA analysis revealed that heterogeneous gene amplifications/deletions, including PDL1 amplification, evolved under the presence of shared "trunk" genetic alterations in a subpopulation of individual intramucosal gastric carcinomas. These data suggest that multiple gastric carcinomas develop in a multicentric/multifocal manner exhibiting features of inter- and intra-tumor heterogeneity in H. pylori-infected gastric mucosa, whereas synchronous multiple intramucosal gastric carcinomas could share partially common genetic alterations, possibly via common oncogenic pathways.

New findings What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. Abstract Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 μg kg-1 h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast-Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.

Aims To investigate the role of nerve growth factor (NGF) in lower urinary tract dysfunction in mice with spinal cord injury (SCI). Methods Using 4-week SCI mice, single-filling cystometry and external urethral sphincter (EUS)-electromyography were performed under an awake condition. In some SCI mice, anti-NGF antibodies (10 µg/kg/h) were administered for 1 or 2 weeks before the urodynamic study. NGF levels in the bladder and L6/S1 spinal cord were assayed by ELISA. The transcript levels of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured by RT-PCR. Results In SCI mice, the area under the curve of non-voiding contractions (NVCs) during the storage phase was significantly decreased in both 1- and 2-week anti-NGF antibody-treated SCI groups. However, EUS-electromyogram parameters during voiding were not altered by the treatment. Bladder mucosal and spinal NGF levels were decreased after 2 weeks of anti-NGF antibody treatment. TRPA1 and TRPV1 transcripts in L6/S1 DRG were significantly decreased after 1- or 2-week anti-NGF treatment. Conclusions In SCI mice, NGF is involved in the emergence of NVCs in association with increased expression of TRP receptors that are predominantly found in C-fiber afferent pathways. Thus, NGF targeting treatments could be effective for treating storage problems such as detrusor overactivity after SCI.

Although there is a remarkable increase in diagnostic flexible bronchoscopy (FB) in old patients, safety and efficacy of FB in very old patients remain to be elucidated. In this study, we aimed to evaluate the complications and diagnostic yield of FB in patients aged ≥ 80 years with lung cancer compared with those aged

Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score.Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis.Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores.Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

HOX genes encode transcription factors that function as sequence-specific transcription factors that are involved in cellular proliferation, differentiation, and death. The aim of this study was to investigate the role of a HOX family protein, HOXB7, in the motility and invasiveness of pancreatic cancer cells. We previously identified a HOXB7 transcript that is one of a number of transcripts that are preferentially translated in membrane protrusions in pancreatic cancer cells. Immunocytochemistry showed that HOXB7 was localized to the cell protrusions of migrating pancreatic cancer cells. Knockdown of HOXB7 by transfection with HOXB7-specific siRNA decreased these protrusions and inhibited the motility and invasiveness of the cells. Transfection of a HOXB7-rescue construct into the HOXB7-knockdown cells restored peripheral actin structures in cell protrusions and abrogated the HOXB7 knockdown–induced decrease in cell protrusions. It is generally accepted that the Rho family of GTPases regulate the organization of actin filaments and contribute to the formation of cell protrusions. The levels of the active Rho GTPases were not influenced by HOXB7 in the cells; however, HOXB7 knockdown decreased the level of phosphorylated ERK1/2. This inactivation of ERK1/2 decreased cell protrusions, thereby inhibiting the invasiveness of pancreatic cancer cells. Further investigation showed that HOXB7/ERK1/2 signaling selectively stimulated JNK and HSP27 phosphorylation and thereby increased the motility and invasiveness of pancreatic cancer cells. These results suggested that HOXB7 stimulates ERK1/2 phosphorylation and provided evidence that HOXB7, besides its role in transcriptional regulation, also promotes cell motility and invasiveness.

We examined bladder and urethral sphincter activity in mice with or without spinal cord injury (SCI) after C-fiber afferent desensitization induced by capsaicin pretreatment and changes in electrophysiological properties of mouse bladder afferent neurons 4 wk after SCI. Female C57BL/6N mice were divided into four groups: 1) spinal intact (SI)-control, 2) SI-capsaicin pretreatment (Cap), 3) SCI-control, and 4) SCI-Cap groups. Continuous cystometry and external urethral sphincter (EUS)-electromyogram (EMG) were conducted under an awake condition. In the Cap groups, capsaicin (25, 50, or 100 mg/kg) was injected subcutaneously 4 days before the experiments. In the SI-Cap group, 100 mg/kg capsaicin pretreatment significantly increased bladder capacity and decreased the silent period duration of EUS/EMG compared with the SI-control group. In the SCI-Cap group, 50 and 100 mg/kg capsaicin pretreatment decreased the number of nonvoiding contractions (NVCs) and the duration of reduced EUS activity during voiding, respectively, compared with the SCI-control group. In SCI mice, hexamethonium, a ganglionic blocker, almost completely blocked NVCs, suggesting that they are of neurogenic origin. Patch-clamp recordings in capsaicin-sensitive bladder afferent neurons from SCI mice showed hyperexcitability, which was evidenced by decreased spike thresholds and increased firing rate compared with SI mice. These results indicate that capsaicin-sensitive C-fiber afferent pathways, which become hyperexcitable after SCI, can modulate bladder and urethral sphincter activity in awake SI and SCI mice. Detrusor overactivity as shown by NVCs in SCI mice is significantly but partially dependent on capsaicin-sensitive C-fiber afferents, whereas the EUS relaxation during voiding is enhanced by capsaicin-sensitive C-fiber bladder afferents in SI and SCI mice.

Aims We examined the effect of an E-series prostaglandin 1 (EP1) receptor antagonist on bladder activity using a rat model of spinal cord injury (SCI). Methods Female Sprague-Dawley rats were used. Six weeks after spinal cord transection, conscious-filling cystometry was performed. We evaluated the urodynamic parameters before and after intravenous (0.1 and 1.0 mg/kg) or intrathecal (0.1 and 1.0 µg) administration of SC51089, an EP1 antagonist. Spinal prostaglandin E2 (PGE2) concentration and EP1 receptor transcripts in the spinal cord and dorsal root ganglia (DRG) were measured by enzyme-linked immunosorbent assay and RT-PCR, respectively. Results The time to the first non-voiding contraction (NVC) was significantly prolonged after both 0.1 and 1.0 mg/kg of intravenous administration of SC51089 (75% prolongation at 1.0 mg/kg) whereas other parameters were not significantly changed compared to vehicle treatment. In addition, the time to the first NVC was also significantly prolonged after 1.0 µg of intrathecal administration of SC51089 (18% prolongation at 1.0 µg) whereas other parameters were not significantly changed. The spinal PGE2 concentration in SCI rats was significantly higher than that in spinal intact rats. The mRNA expressions of EP1 receptors in the both spinal cord and DRG from SCI rats were significantly higher than those from spinal intact rats. Conclusions The PGE2-induced activation of EP1 receptors in the spinal cord contributes to the initiation of detrusor overactivity in SCI. Thus, the EP1 receptor could be a therapeutic target for the treatment of neurogenic detrusor overactivity due to SCI.

Purpose To examine (1) whether spinal cord injury (SCI) time-dependently increases the severity of autonomic dysreflexia (AD) and expression levels of bladder nerve growth factor (NGF) protein, and (2) whether local suppression of NGF in the bladder improves SCI-induced AD in rats. Materials and methods SCI was produced by the transection of the T2/3 spinal cord in female Sprague-Dawley rats. At 4 or 8 weeks after SCI, differences in the mean arterial blood pressure (ΔMAP) and heart rate (ΔMHR) during graded increases in intravesical pressure to 20, 40 and 60 cm H2O from those before bladder distention and NGF protein levels in the bladder wall were evaluated in spinal intact and SCI rats under urethane anesthesia. Seven weeks after SCI liposome-NGF antisense conjugates were administered intravesically to the animals. At 1 week after intravesical treatment (8 weeks after SCI), ΔMAP and ΔMHR during bladder distention and bladder NGF protein expression were evaluated. Results The ΔMAP and ΔMHR were increased in a graded manner in response to bladder distention at intravesical pressures of 20, 40 and 60 cm H2O in SCI rats. These AD-like cardiovascular responses and NGF protein expression in the bladder mucosal and muscle layers were increased after SCI in a time-dependent manner. The liposome-NGF antisense treatment significantly reduced the NGF protein overexpression in the mucosal layer of SCI rat bladder and reduced ΔMAP and ΔMHR elicited by bladder distention. Conclusions These results indicate that the duration of the post-SCI recovery period affects the severity of AD induced by bladder distention as well as the level of bladder NGF protein, and that local suppression of NGF expression in the bladder reduces SCI-induced AD. Thus, Intravesical application of liposome-NGF antisense conjugates can be a new effective therapy for bladder distention-induced AD after SCI.