Prazosin Potentiates Mast Cell-Stabilizing Property of Adrenaline.

BACKGROUND/AIMS: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSION: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß2-adrenergic receptors.

Japanese clinical practice guidelines for prostate cancer 2023.

This fourth edition of the Japanese Clinical Practice Guidelines for Prostate Cancer 2023 is compiled. It was revised under the leadership of the Japanese Urological Association, with members selected from multiple academic societies and related organizations (Japan Radiological Society, Japanese Society for Radiation Oncology, the Department of EBM and guidelines, Japan Council for Quality Health Care (Minds), Japanese Society of Pathology, and the patient group (NPO Prostate Cancer Patients Association)), in accordance with the Minds Manual for Guideline Development (2020 ver. 3.0). The most important feature of this revision is the adoption of systematic reviews (SRs) in determining recommendations for 14 clinical questions (CQs). Qualitative SRs for these questions were conducted, and the final recommendations were made based on the results through the votes of 24 members of the guideline development group. Five algorithms based on these results were also created. Contents not covered by the SRs, which are considered textbook material, have been described in the general statement. In the general statement, a literature search for 14 areas was conducted; then, based on the general statement and CQs of the Japanese Clinical Practice Guidelines for Prostate Cancer 2016, the findings revealed after the 2016 guidelines were mainly described. This article provides an overview of these guidelines.

CYP27A1-27-hydroxycholesterol axis in the respiratory system contributes to house dust mite-induced allergic airway inflammation.

BACKGROUND: 27-Hydroxycholesterol (27-HC) derived from sterol 27-hydroxylase (CYP27A1) has pro-inflammatory biological activity and is associated with oxidative stress and chronic inflammation in COPD. However, the role of regulation of CYP27A1- 27-HC axis in asthma is unclear. This study aimed to elucidate the contribution of the axis to the pathophysiology of asthma. METHODS: House dust mite (HDM) extract was intranasally administered to C57BL/6 mice and the expression of CYP27A1 in the airways was analyzed by immunostaining. The effect of pre-treatment with PBS or CYP27A1 inhibitors on the cell fraction in the bronchoalveolar lavage fluid (BALF) was analyzed in the murine model. In vitro, BEAS-2B cells were treated with HDM and the levels of CYP27A1 expression were examined. Furthermore, the effect of 27-HC on the expressions of E-cadherin and ZO-1 in the cells was analyzed. The amounts of RANTES and eotaxin from the 27-HC-treated cells were analyzed by ELISA. RESULTS: The administration of HDM increased the expression of CYP27A1 in the airways of mice as well as the number of eosinophils in the BALF. CYP27A1 inhibitors ameliorated the HDM-induced increase in the number of eosinophils in the BALF. Treatment with HDM increased the expression of CYP27A1 in BEAS-2B cells. The administration of 27-HC to BEAS-2B cells suppressed the expression of E-cadherin and ZO-1, and augmented the production of RANTES and eotaxin. CONCLUSIONS: The results of this study suggest that aeroallergen could enhance the induction of CYP27A1, leading to allergic airway inflammation and disruption of the airway epithelial tight junction through 27-HC production.

Comparison Between Amide Proton Transfer Magnetic Resonance Imaging Using 3-Dimensional Acquisition and Diffusion-Weighted Imaging for Characterization of Prostate Cancer: A Preliminary Study.

OBJECTIVE: This study aimed to compare diagnostic performance for tumor detection and for assessment of tumor aggressiveness in prostate cancer (PC) between amide proton transfer magnetic resonance imaging (MRI) with 3-dimensional acquisition (3DAPT) and diffusion-weighted imaging. METHODS: The subjects were 23 patients with 27 pathologically proven PCs who underwent 3T multiparametric MRI. With reference to the pathology findings, 2 readers in consensus identified the location of PC on multiparametric MRI and measured APT signal intensity (APT SI [%]) and mean apparent diffusion coefficient (ADC) of the benign region and each PC lesion. RESULTS: The mean ADC showed a significant difference between benign regions and PC lesions (0.74 ± 0.15 vs 1.37 ± 0.21, P < 0.001), whereas APT SI did not ( P = 0.091). Lesion APT SI was significantly higher and lesion ADC was significantly lower in PCs with Gleason group (GG) ≥3 than in PCs with GG ≤2 (3.37 ± 1.30 vs 1.78 ± 0.67, P < 0.001, and 0.71 ± 0.18 vs 0.79 ± 0.10, P = 0.038, respectively). The APT SI was significantly higher in GG3 than in GG1, in GG3 than in GG2, and in GG4 than in GG2 ( P = 0.009, P = 0.001, and P = 0.006, respectively). The area under the curve for separating tumor lesions and benign regions was 0.601 for 3DAPT and 0.983 for ADC ( P < 0.001). The area under the curve for separating tumors with GG ≤2 from tumors with GG ≥3 was 0.912 for 3DAPT and 0.734 for ADC ( P = 0.172). CONCLUSIONS: In patients with PC, it might be preferable to use ADC to discriminate benign from malignant tissue and use APT SI for assessment of tumor aggressiveness.

Pyridoxine Synergistically Potentiates Mast Cell-Stabilizing Property of Ascorbic Acid.

BACKGROUND/AIMS: Besides their physiological properties, vitamins, such as vitamin C (ascorbic acid) and B6 (pyridoxine), ameliorate the symptoms of allergic disorders. Because exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of these vitamins would determine their mast cell-stabilizing, anti-allergic properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of ascorbic acid and pyridoxine on the degranulation of mast cells and the increase in the Cm during exocytosis. RESULTS: Both ascorbic acid and pyridoxine dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells. Surprisingly enough, relatively low concentrations of pyridoxine (1, 2 mM) synergistically enhanced the suppressive effect of 2 mM ascorbic acid on mast cell degranulation. CONCLUSION: These results provided electrophysiological evidence for the first time that ascorbic acid and pyridoxine inhibited the process of exocytosis in a dose-dependent manner. At relatively lower concentrations, these vitamins were not enough to stabilize mast cells. However, such concentrations of pyridoxine synergistically potentiated the mast cell-stabilizing property of ascorbic acid.

Value of 3-T MR imaging in intraductal papillary mucinous neoplasm with a concomitant invasive carcinoma.

OBJECTIVES: To examine the value of 3-T MRI for evaluating the difference between the pancreatic parenchyma of intraductal papillary mucinous neoplasm with a concomitant invasive carcinoma (IPMN-IC) and the pancreatic parenchyma of patients without an IPMN-IC. METHODS: A total of 132 patients underwent abdominal 3-T MRI. Of the normal pancreatic parenchymal measurements, the pancreas-to-muscle signal intensity ratio in in-phase imaging (SIR-I), SIR in opposed-phase imaging (SIR-O), SIR in T2-weighted imaging (SIR-T2), ADC (×10-3 mm2/s) in DWI, and proton density fat fraction (PDFF [%]) in multi-echo 3D DIXON were calculated. The patients were divided into three groups (normal pancreas group: n = 60, intraductal papillary mucinous neoplasm (IPMN) group: n = 60, IPMN-IC group: n = 12). RESULTS: No significant differences were observed among the three groups in age, sex, body mass index, prevalence of diabetes mellitus, and hemoglobin A1c (p = 0.141 to p = 0.657). In comparisons among the three groups, the PDFF showed a significant difference (p < 0.001), and there were no significant differences among the three groups in SIR-I, SIR-O, SIR-T2, and ADC (p = 0.153 to p = 0.684). The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group (p < 0.001 and p < 0.001, respectively), with no significant difference between the normal pancreas group and the IPMN group (p = 0.916). CONCLUSIONS: These observations suggest that the PDFF of the pancreas is associated with the presence of IPMN-IC. KEY POINTS: • The cause and risk factors of IPMN with a concomitant invasive carcinoma have not yet been clarified. • The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group. • Pancreatic PDFF may be a potential biomarker for the development of IPMN with a concomitant invasive carcinoma.

Diffusion-weighted imaging in prostate cancer.

Diffusion-weighted imaging (DWI), a key component in multiparametric MRI (mpMRI), is useful for tumor detection and localization in clinically significant prostate cancer (csPCa). The Prostate Imaging Reporting and Data System versions 2 and 2.1 (PI-RADS v2 and PI-RADS v2.1) emphasize the role of DWI in determining PIRADS Assessment Category in each of the transition and peripheral zones. In addition, several recent studies have demonstrated comparable performance of abbreviated biparametric MRI (bpMRI), which incorporates only T2-weighted imaging and DWI, compared with mpMRI with dynamic contrast-enhanced MRI. Therefore, further optimization of DWI is essential to achieve clinical application of bpMRI for efficient detection of csPC in patients with elevated PSA levels. Although DWI acquisition is routinely performed using single-shot echo-planar imaging, this method suffers from such as susceptibility artifact and anatomic distortion, which remain to be solved. In this review article, we will outline existing problems in standard DWI using the single-shot echo-planar imaging sequence; discuss solutions that employ newly developed imaging techniques, state-of-the-art technologies, and sequences in DWI; and evaluate the current status of quantitative DWI for assessment of tumor aggressiveness in PC.

Clinical application of single-shot echo-planar diffusion-weighted imaging with compressed SENSE in prostate MRI at 3T: preliminary experience.

OBJECTIVES: Image quality (IQ) of diffusion-weighted imaging (DWI) with single-shot echo-planar imaging (ssEPI) suffers from low signal-to-noise ratio (SNR) in high b-value acquisitions. Compressed SENSE (C-SENSE), which combines SENSE with compressed sensing, enables SNR to be improved by reducing noise. The aim of this study was to compare IQ and prostate cancer (PC) detectability between DWI with ssEPI using SENSE (EPIS) and using C-SENSE (EPICS). MATERIALS AND METHODS: Twenty-five patients with pathologically proven PC underwent multi-parametric magnetic resonance imaging at 3T. DW images acquired with EPIS and EPICS were assessed for the following: lesion conspicuity (LC), SNR, contrast-to-noise ratio (CNR), mean and standard deviation (SD) of apparent diffusion coefficient (ADC) of lesion (lADCm and lADCsd), coefficient of variation of lesion ADC (lADCcv), and mean ADC of benign prostate (bADCm). RESULTS: LC were comparable between EPIS and EPICS (p > 0.050), and SNR and CNR were significantly higher in EPICS than EPIS (p = 0.001 and p < 0.001). In both EPIS and EPICS, lADCm was significantly lower than bADCm (p < 0.001). In addition, lADCcv was significantly lower in EPICS than in EPIS (p < 0.001). CONCLUSION: Compared with EPIS, EPICS has improved IQ and comparable diagnostic performance in PC.

Feasibility of magnetic resonance imaging-ultrasound guided high-dose-rate brachytherapy for localized prostate cancer: Preliminary results from a prospective study.

OBJECTIVE: This study aimed to investigate preliminary outcomes of a prospective trial of magnetic resonance imaging-ultrasound fusion-guided ultrafocal high-dose-rate brachytherapy in localized prostate cancer. METHODS: In our prospective study, data from patients who underwent this treatment between April 1, 2020 and March 31, 2021 were analyzed. In the procedure, the applicator needle was inserted through the perineum to target the lesion on the multiparametric magnetic resonance imaging, which was fused onto the transrectal ultrasound image. The prescription dose was set at a single fraction of 19 Gy. Data from patients who received whole-gland high-dose-rate brachytherapy were extracted and compared with data from patients who received ultrafocal high-dose-rate brachytherapy, to evaluate the frequency of acute adverse events. RESULTS: Eight patients underwent ultrafocal high-dose-rate brachytherapy with a median observation period of 7.75 months (range 5.96-15.36 months). No acute genitourinary or gastrointestinal adverse events were observed in this cohort. The planned procedure was completed in all patients, and no unexpected adverse events were observed; however, prostate-specific antigen failure was detected in one patient. In the 25 patients who underwent whole-gland high-dose-rate brachytherapy, acute genitourinary and gastrointestinal adverse events were observed in 88% and 20% of the patients, respectively. Ultrafocal high-dose-rate brachytherapy was a significant factor in avoiding acute adverse genitourinary events in univariate and multivariate analyses (P < 0.001 and P = 0.032, respectively). CONCLUSIONS: Magnetic resonance imaging-ultrasound fusion-guided ultrafocal high-dose-rate brachytherapy in localized prostate cancer is a safe and feasible treatment without acute genitourinary and gastrointestinal adverse events. Long-term observation and further investigation are warranted.

Summary of the Clinical Practice Guidelines for Penile Cancer 2021 by the Japanese Urological Association.

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

Effects of indacaterol on the LPS-evoked changes in fluid secretion rate and pH in swine tracheal membrane.

An acquired dysregulation of airway secretion is likely involved in the pathophysiology of chronic bronchitis and chronic obstructive pulmonary disease (COPD). Nowadays, it is widely known that several kinds of long-acting bronchodilators reduce the frequency of COPD exacerbations. However, limited data are available concerning the complementary additive effects on airflow obstruction. Using an optical method and a selective pH indicator, we succeeded in evaluating the gland secretion rate and the pH in swine tracheal membrane. A physiologically relevant concentration of acetylcholine (ACh) 100 nM induced a gradual increase in the amount of gland secretion. Lipopolysaccharides (LPS) accelerated the ACh-induced secretory responses up to around threefold and lowered the pH level significantly. Long-acting ß2-agonists (LABAs) including indacaterol (IND), formoterol, and salmeterol restored the LPS-induced changes in both the hypersecretion and acidification. The subsequent addition of the long-acting muscarine antagonist, glycopyrronium, further increased the pH values. Two different inhibitors for cystic fibrosis transmembrane conductance regulator (CFTR), NPPB and CFTRinh172, abolished the IND-mediated pH normalization in the presence of both ACh and ACh + LPS. Both immunofluorescence staining and western blotting analysis revealed that LPS downregulated the abundant expression of CFTR protein. However, IND did not restore the LPS-induced decrease in CFTR expression on Calu-3 cells. These findings suggest that the activation of cAMP-dependent HCO3- secretion through CFTR would be partly involved in the IND-mediated pH normalization in gland secretion and may be suitable for the maintenance of airway defense against exacerbating factors including LPS.

Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation.

BACKGROUND: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD. METHODS: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice. RESULTS: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model. CONCLUSIONS: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

PGC-1α regulates airway epithelial barrier dysfunction induced by house dust mite.

BACKGROUND: The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens. METHODS: BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated. RESULTS: The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin. CONCLUSIONS: The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

Comparison of Biparametric and Multiparametric MRI for Clinically Significant Prostate Cancer Detection With PI-RADS Version 2.1.

BACKGROUND: Biparametric MRI (bpMRI) without dynamic contrast-enhanced MRI (DCE-MRI) results in an elimination of adverse events, shortened examination time, and reduced costs, compared to multiparametric MRI (mpMRI). The ability of bpMRI to detect clinically significant prostate cancer (csPC) with the Prostate Imaging and Reporting Data System version 2.1 (PI-RADS v2.1) compared to standard mpMRI has not been studied extensively. PURPOSE: To compare the interobserver reliability and diagnostic performance for detecting csPC of bpMRI and mpMRI using PI-RADS v2.1. STUDY TYPE: Retrospective. POPULATION: In all, 103 patients with elevated prostate-specific antigen (PSA) levels who underwent mpMRI and subsequent MRI-ultrasonography fusion-guided prostate-targeted biopsy (MRGB) with or without prostatectomy. FIELD STRENGTH/SEQUENCES: T2 -weighted imaging (T2 WI), diffusion-weighted imaging (DWI), and DCE-MRI at 3T. ASSESSMENT: Three readers independently assessed each suspected PC lesion, assigning a score of 1-5 for T2 WI, a score of 1-5 for DWI, and positive and negative for DCE-MRI according to PI-RADS v2.1 and determined the overall PI-RADS assessment category of bpMRI (T2 WI and DWI) and mpMRI (T2 WI, DWI, and DCE-MRI). The reference standard was MRGB or prostatectomy-derived histopathology. STATISTICAL TESTING: Statistical analysis was performed using the kappa statistic and McNemar and Delong tests. RESULTS: Of the 165 suspected PC lesions in 103 patients, 81 were diagnosed with csPC and 84 with benign conditions. Interobserver variability of PI-RADS assessment category showed good agreement for bpMRI (kappa value = 0.642) and mpMRI (kappa value = 0.644). For three readers, the diagnostic sensitivity was significantly higher for mpMRI than for bpMRI (P < 0.001 to P = 0.016, respectively), whereas diagnostic specificity was significantly higher for bpMRI than for mpMRI (P < 0.001 each). For three readers, the area under the receiver operating characteristic curve (AUC) was higher for bpMRI than for mpMRI; however, the difference was significant only for Reader 1 and Reader 3 (Reader 1: 0.823 vs. 0.785, P = 0.035; Reader 2: 0.852 vs. 0.829, P = 0.099; and Reader 3: 0.828 vs. 0.773, P = 0.002). DATA CONCLUSION: For detecting csPC using PI-RADS v2.1, the interobserver reliability and diagnostic performance of bpMRI was comparable with those of mpMRI. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

VI-RADS: Multiinstitutional Multireader Diagnostic Accuracy and Interobserver Agreement Study.

BACKGROUND. The Vesical Imaging Reporting and Data System (VI-RADS), based on multiparametric MRI (mpMRI), was developed to provide accurate information for the diagnosis of muscle-invasive bladder cancer (MIBC). OBJECTIVE. The purpose of our study was to evaluate the interobserver agreement and diagnostic performance of VI-RADS among readers with different levels of experience. METHODS. This retrospective study included 91 consecutive patients who underwent mpMRI before transurethral resection of bladder tumor (TURBT) from July 2010 through August 2018. After attending a training session, seven radiologists (five radiologists experienced in bladder MRI and two inexperienced radiologists) reviewed and scored all MRI examinations according to VI-RADS. The interobserver agreement was assessed by kappa statistics. ROC analysis was used to evaluate the diagnostic performance for MIBC. AUCs were estimated. RESULTS. Among 91 patients (72 men and 19 women; mean age ± SD, 73.2 ± 10.2 years), 48 (52.7%) had MIBC and 43 (47.3%) had non-muscle-invasive bladder cancer. Sixty-eight patients were treated with TURBT, and 23 were treated with radical cystectomy. Interobserver agreement was moderate to substantial (κ = 0.60-0.80) among the experienced readers, substantial (κ = 0.67) between the two inexperienced readers, and moderate to substantial (κ = 0.55-0.75) between the experienced and inexperienced readers. The pooled AUC was 0.88 (range, 0.82-0.91) for experienced readers and 0.84 (range, 0.83-0.85) for inexperienced readers, and 0.87 for all readers. Using a VI-RADS score of 4 or greater as the cutoff value for MIBC, the pooled sensitivity and specificity were 74.1% (range, 66.0-80.9%) and 94.1% (range, 88.6-97.7%) for experienced readers and 63.9% (range, 59.6-68.1%) and 86.4% (range, 84.1-88.6%) for inexperienced readers. Using a VI-RADS score of 3 or greater as the cutoff value, the pooled sensitivity and specificity were 83.4% (range, 80.9-85.1%) and 77.3% (range, 61.4-88.6%) for experienced readers and 82.0% (range, 80.9-83.0%) and 73.9% (range, 72.7-75.0%) for inexperienced readers. CONCLUSION. We observed moderate to substantial interobserver agreement and a pooled AUC of 0.87 among radiologists of different levels of expertise using VI-RADS. CLINICAL IMPACT. VI-RADS could help determine the depth and range of excision in TURBT, decreasing the risk of complications and enhancing the accuracy of pathologic diagnosis.

Gadoxetate disodium-related event during image acquisition: a prospective multi-institutional study for better MR practice.

PURPOSE: To acknowledge the facts of gadoxetate disodium-related events in Japan and to achieve better MR practice by analyzing large cohort data with various MR parameters. MATERIALS AND METHODS: This prospective multi-institutional study included 1993 patients (1201 men, mean age 66.4 ± 12.8 years), who received dynamic MRI with gadoxetate disodium (gadoxetate group, n = 1646) or extracellular gadolinium-based contrast agents (other-GBCAs group, n = 347) between January and November 2016. Recorded data covered adverse reactions including dyspnea, breath-hold failure during acquisition, respiratory artifacts rated with a four-point scale, and MR parameters. We compared data between the two groups in whole cohort and age-, gender-, and institution-matched subcohort using χ2 test (n = 640). Logistic regression model was used to reveal independent associates of substantial artifacts in arterial phase imaging. RESULTS: Transient dyspnea rarely occurred in gadoxetate or other-GBCAs group (both < 1%). Gadoxetate group (vs other-GBCAs group) showed higher rates of breath-hold failure (whole cohort, 18.2% vs 7.7%, p < 0.001; subcohort, 17.6% vs 6.3%, p < 0.001) and substantial artifacts in arterial phase (7.2% vs 2.2%, p = 0.001; 7.4% vs 1.7%, p = 0.001). With single arterial phase protocol, substantial artifacts under gadoxetate were independently associated with age (odds ratio [OR] = 1.04, p < 0.001), hearing difficulty (OR = 2.92, p = 0.008), breath-hold practice required (OR = 1.61, p = 0.039), and short acquisition time (OR = 0.43, p = 0.005). Multiple arterial phase acquisition did not reduce the incident rate of substantial artifacts. CONCLUSION: Gadoxetate disodium was associated with breath-hold failure and substantial artifacts in arterial phase imaging, but not with dyspnea in Japan. Shorter acquisition time should be used to sustain image quality in gadoxetate disodium-enhanced arterial phase imaging. KEY POINTS: • Gadoxetate disodium administration leads to breath-hold failure and substantial imaging artifacts in arterial phase MRI in Japan. • Contrast agent-induced dyspnea in arterial phase and adverse reactions are rare in Japan, without showing differences between gadoxetate disodium or other extracellular gadolinium-based contrast agents. • Shorter acquisition time significantly reduces gadoxetate-induced imaging artifacts in the arterial phase.

Nitrosative stress in patients with asthma-chronic obstructive pulmonary disease overlap.

BACKGROUND: Asthma-chronic obstructive pulmonary disease overlap (ACO) has frequent exacerbations and a poor quality of life and prognosis compared with those of chronic obstructive pulmonary disease alone. However, the pathogenesis of ACO has not been fully elucidated yet. OBJECTIVES: The aim of this study was to investigate nitrosative stress, which causes a redox imbalance and tissue inflammation in the airways of patients with ACO, and to evaluate the relationship between nitrosative stress and the clinical course in study subjects. METHODS: Thirty healthy subjects and 56 asthmatic patients participated in this study. The asthmatic patients were divided into 33 asthmatic patients and 23 patients with ACO. The study subjects had been followed prospectively for 2 years to evaluate the clinical course. Nitrosative stress was evaluated based on the production of 3-nitrotyrosine (3-NT) in sputum cells. RESULTS: Production of 3-NT was significantly enhanced in patients with ACO compared with that in asthmatic patients. Amounts of reactive persulfides and polysulfides, newly identified powerful antioxidants, were significantly decreased in the ACO group. Baseline levels of 3-NT were significantly correlated with the frequency of exacerbations and decrease in FEV1 adjusted by age, smoking history, and blood eosinophil count. The 3-NT-positive cells were also significantly correlated with amounts of proinflammatory chemokines and cytokines. CONCLUSIONS: These findings suggested that greater nitrosative stress occurred in the airways of patients with ACO, and the degree of nitrosative stress was correlated with an impairment in the clinical course. Nitrosative stress might be related to the pathogenesis of ACO.

[A CASE OF BRONCHIAL ASTHMA IN A YOUNGER PATIENT WITH VOCAL CORD DYSFUNCTION].

We present a case of a 17-year-old woman with a history of bronchial asthma since two years of age. She had daily asthma attacks from the age of fourteen, and the addition of oral corticosteroids and omalizumab to regular inhaled corticosteroid inhalation failed to relieve symptoms. She was referred to our hospital for detailed examination. On admission, physical examination was normal, but she had complained of dyspnea at the round. Monophonic wheezes and stridor were heard over the anterior neck, while no rales were audible over any part of the chest. Laryngoscopy revealed paradoxical movement of the vocal cords, and a diagnosis of vocal cord dysfunction (VCD) was made. The apparent severe asthma symptoms were considered to reflect VCD, and the treatment for bronchial asthma was stepped down without any recurrence of asthma attacks. Although the etiology of the VCD was unknown, VCD is more common in young women, so stress and personality factors are thought to be involved. It has been noted that childhood asthma often improves between childhood and adolescence, but refractory cases have been noted. In intractable bronchial asthma cases, it is necessary to consider the complications of other diseases, such as VCD, and to perform appropriate management.

Symptoms that are associated with decreased pancreatic enzyme flow: MRCP assessment.

BACKGROUND: Pancreatic exocrine insufficiency is one of the causes of malabsorption syndrome. In many cases of malabsorption syndrome, pancreatic exocrine insufficiency can be treated with pancreatic enzyme replacement therapy. Therefore, it is important to detect pancreatic endocrine insufficiency as early and accurately as possible. Recent studies have shown that cine-dynamic MR cholangiopancreatography (MRCP) may be useful to evaluate pancreatic exocrine function PURPOSE: To identify abdominal symptoms that suggest decreased flow of pancreatic enzyme secretion for which cine-dynamic MRCP should be performed to diagnose pancreatic exocrine insufficiency. STUDY TYPE: Prospective. POPULATION: In all, 111 patients with various types of abdominal symptoms. FIELD STRENGTH/SEQUENCE: 5 T or 3 T, MRCP with spatially selective inversion recovery pulse (cine-dynamic MRCP). ASSESSMENT: Cine-dynamic MRCP was performed and an 18-question clinical questionnaire on abdominal symptoms was administered. The secretion grade derived from cine-dynamic MRCP was compared between those answering "yes" and "no" for all 18 items STATISTICAL TESTS: Univariate analysis and further analyzed using multiple regression analysis. The associations between the secretion grade and the items in the clinical questionnaire were analyzed by univariate analysis and further analyzed using multiple regression analysis. RESULTS: The following three items showed significantly negative correlations with secretion grade: Q9, Does your rectal gas smell foul? (ß = -0.44, P = 0.001); Q13, Is stool quantity large? (ß = -0.41, P = 0.001); and Q18, Are your stools soft? (ß = -0.53, P < 0.001). No significant correlations with exocrine pancreatic function measured by cine-dynamic MRCP were seen for the remaining 15 abdominal symptom items. DATA CONCLUSION: Abdominal symptoms that suggest decreased flow of pancreatic enzyme secretion were foul rectal gas, large stool, and soft stool. Pancreatic exocrine insufficiency due to decreased pancreatic enzyme flow may be suspected in patients with these abdominal symptoms. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:417-423.

TLR7 agonist attenuates acetylcholine-induced, Ca2+ -dependent ionic currents in swine tracheal submucosal gland cells.

NEW FINDINGS: What is the central question of this study? Does Toll-like receptor 7 (TLR7) have any direct effects on Ca2+ -dependent physiological function of tracheal submucosal gland cells? What is the main finding and its importance? TLR7 is co-localized with SERCA2 in tracheal submucosal gland cells and causes a rapid attenuation of acetylcholine (ACh)-induced, Ca2+ -dependent ionic currents through the activation of SERCA2-dependent Ca2+ clearance. TLR7 is abundantly expressed in the airways of both swine and healthy human subjects, but is significantly downregulated in chronic obstructive pulmonary disease (COPD) airways. These findings suggest that a dysfunction of TLR7 in COPD removes the brake on ACh-induced serous secretion during viral infections, resulting in prolonged airway hypersecretion, and that it is one of the triggers of COPD exacerbations. ABSTRACT: Airway surface fluids are mainly secreted from submucosal glands (SMGs) and play important roles in the defence of airways via the activation of mucociliary transport. Toll-like receptor 7 (TLR7) recognizes and eliminates single stranded RNA (ssRNA) viruses through the induction of innate immunity. However, there is no obvious connection between TLR7 and mucus secretion, aside from TLR7 recognizing ssRNA viruses, which are often associated with airway hypersecretion in chronic obstructive pulmonary disease (COPD). Here, we investigated whether TLR7 has any direct effects on the Ca2+ -dependent physiological function of tracheal SMG cells. Patch-clamp analyses revealed that TLR7 ligand inhibited the acetylcholine (ACh)-induced ionic currents in isolated tracheal SMG cells. Intracellular calcium assays and pharmacological analyses revealed that TLR7 attenuated the transient rises in the intracellular calcium concentration evoked by ACh by activating sarco/endoplasmic reticulum Ca2+ -ATPase 2 (SERCA2). Immunofluorescence staining and immunohistochemical staining revealed that TLR7 was co-localized with SERCA2. These findings suggest that the activation of TLR7 during viral infections contributes to the rapid attenuation of ACh-induced ionic currents through an increase in SERCA2-dependent Ca2+ clearance in healthy airway SMG cells. Our study also revealed that TLR7 expression was significantly downregulated in COPD airways. Based on these findings, we speculate that a dysfunction of TLR7 may not only have an adverse effect on the elimination of these viruses but also remove the brake on ACh-induced serous secretion, resulting in prolonged hypersecretion and acting as one of the triggers of COPD exacerbations.