Dasatinib promotes muscle differentiation and disrupts normal muscle regeneration.

Dasatinib is one of the second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia and has a broad target spectrum, including KIT, PDGFR, and SRC family kinases. Due to its broad drug spectrum, dasatinib has been reported at the basic research level to improve athletic performance by eliminating senescent cell removal and to have an effect on muscle diseases such as Duchenne muscular dystrophy, but its effect on myoblasts has not been investigated. In this study, we evaluated the effects of dasatinib on skeletal muscle both under normal conditions and in the regenerating state. Dasatinib suppressed the proliferation and promoted the fusion of C2C12 myoblasts. During muscle regeneration, dasatinib increased the gene expressions of myogenic-related genes (Myod, Myog, and Mymx), and caused abnormally thin muscle fibers on the CTX-induced muscle injury mouse model. From these results, dasatinib changes the closely regulated gene expression pattern of myogenic regulatory factors during muscle differentiation and disrupts normal muscle regeneration. Our data suggest that when using dasatinib, its effects on skeletal muscle should be considered, particularly at regenerating stages.

Deep learning image reconstruction to improve accuracy of iodine quantification and image quality in dual-energy CT of the abdomen: a phantom and clinical study.

OBJECTIVES: To investigate the effect of deep learning image reconstruction (DLIR) on the accuracy of iodine quantification and image quality of dual-energy CT (DECT) compared to that of other reconstruction algorithms in a phantom experiment and an abdominal clinical study. METHODS: An elliptical phantom with five different iodine concentrations (1-12 mgI/mL) was imaged five times with fast-kilovoltage-switching DECT for three target volume CT dose indexes. All images were reconstructed using filtered back-projection, iterative reconstruction (two levels), and DLIR algorithms. Measured and nominal iodine concentrations were compared among the algorithms. Contrast-enhanced CT of the abdomen with the same scanner was acquired in clinical patients. In arterial and portal venous phase images, iodine concentration, image noise, and coefficients of variation for four locations were retrospectively compared among the algorithms. One-way repeated-measures analyses of variance were used to evaluate differences in the iodine concentrations, standard deviations, coefficients of variation, and percentages of error among the algorithms. RESULTS: In the phantom study, the measured iodine concentrations were equivalent among the algorithms: within ± 8% of the nominal values, with root-mean-square deviations of 0.08-0.36 mgI/mL, regardless of radiation dose. In the clinical study (50 patients; 35 men; mean age, 68 ± 11 years), iodine concentrations were equivalent among the algorithms for each location (all p > .99). Image noise and coefficients of variation were lower with DLIR than with the other algorithms (all p < .01). CONCLUSIONS: The DLIR algorithm reduced image noise and variability of iodine concentration values compared with other reconstruction algorithms in the fast-kilovoltage-switching dual-energy CT. KEY POINTS: • In the phantom study, standard deviations and coefficients of variation in iodine quantification were lower on images with the deep learning image reconstruction algorithm than on those with other algorithms. • In the clinical study, iodine concentrations of measurement location in the upper abdomen were consistent across four reconstruction algorithms, while image noise and variability of iodine concentrations were lower on images with the deep learning image reconstruction algorithm.

Global analyses and potential effects of extracellular vesicles on the establishment of conceptus implantation during the peri-implantation period.

Intrauterine extracellular vesicles (EVs) are involved in establishing proper conceptus-endometrial communication, which is essential for conceptus implantation and subsequent successful placentation. Despite several studies on intrauterine EVs, the composition and quantitative changes in conceptus and endometrial EVs, as well as the effects of intrauterine EVs on endometrial epithelial cells (EECs) during the peri-implantation period, have not been well characterized. To elucidate global changes in proteins in EVs extracted from uterine flushings (UFs) during the pre-implantation (P17), just-implantation (P20), and post-implantation (P22) periods, the datasets of the proteome iTRAQ analysis were compared among P17, P20, and P22 EVs. These analyses revealed that the composition and function of proteins in the EVs changed dramatically during peri-implantation in cattle. Notably, intrauterine P17 EVs affected the high expression of "Developmental Biology" and "morphogenesis of an endothelium" compared with those in P20 and P22 EVs. Furthermore, P20 EVs had the functions of the high expression of "mitochondrial calcium ion homeostasis" and "Viral mRNA Translation" compared with those in P17 EVs. Transcripts extracted from EECs treated with P17, P20, or P22 EVs were subjected to RNA-seq analysis. These analyses identified 60 transcripts in EECs commonly induced by intrauterine EVs recovered from P17, P20, and P22, a large number of which were associated with "type I interferon signaling pathway". Collectively, these findings reveal the presence and multiple functions of EVs that are potentially implicated in facilitating conceptus implantation into the uterine epithelium during the peri-implantation period.

Abbreviated Gadoxetic Acid-Enhanced MRI for the Detection of Liver Metastases in Patients With Potentially Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Gadoxetic acid-enhanced magnetic resonance imaging (MRI) is useful in detecting liver metastases from pancreatic ductal adenocarcinoma (PDAC). However, the long examination time limits its utility in the initial workup of patients with PDAC. PURPOSE: To evaluate the incremental value of an abbreviated gadoxetic acid-enhanced MRI for the detection of liver metastases in patients with PDAC. STUDY TYPE: Retrospective. POPULATION: Patients (N = 130) with potentially resectable PDAC (women, 58 [44.6%]). FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T; gradient dual-echo T1-weighted (in-phase and opposed-phase), fat-suppressed fast spin-echo T2-weighted, single-shot echo-planar diffusion-weighted, and three-dimensional fat-suppressed T1-weighted gradient-echo dynamic contrast-enhanced and hepatobiliary phase sequences, as well as contrast-enhanced computed tomography (CECT). ASSESSMENT: Three radiologists independently reviewed three different image sets to detect liver metastases: set 1, CECT alone; set 2, CECT and abbreviated MRI comprising fat-suppressed T2-weighted, diffusion-weighted, and hepatobiliary phase images; and set 3, CECT and standard gadoxetic acid-enhanced MRI. STATISTICAL TESTS: Figure of merit (FOM) was compared using the jackknife alternative free-response receiver operating characteristics, and other per-lesion and per-patient diagnostic parameters for each image set were compared using McNemar's and Fisher's test. P < 0.05 was considered statistically significant. RESULTS: A total of 43 liver metastases were identified in 13 patients. Reader-averaged FOM to detect liver metastases were significantly higher for sets 2 (0.884) and 3 (0.886) than for set 1 (0.609), while they were comparable between sets 2 and 3 (P = 0.96). The mean per-patient sensitivities, negative predictive values, and accuracies were significantly higher for sets 2 and 3 than for set 1, while those between sets 2 and 3 were not significantly different (not applicable, P > 0.99, and P > 0.99, respectively). DATA CONCLUSION: Gadoxetic acid-enhanced MRI combined with CECT had higher diagnostic performance than CECT alone for the detection of liver metastases in patients with PDAC. The incremental values were comparable for the abbreviated MRI and standard MRI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The effect of bta-miR-26b in intrauterine extracellular vesicles on maternal immune system during the implantation period.

Extracellular vesicles (EVs) in utero play a role in cellular interactions between endometrium-conceptuses (embryo plus extraembryonic membranes) during peri-implantation periods. However, how intrauterine EVs function on endometrium have not been well characterized. In our previous study, bta-miR-98 found in intrauterine EVs from uterine flushing fluids (UFs) on pregnant day 20 (a half day after initial conceptus attachment, P20) could regulate the maternal immune system and collaborate with other miRNAs and/or components of EVs for conceptus implantation. We, therefore, hypothesized that in addition to bta-miR-98, other miRNAs present in bovine intrauterine EVs may regulate the maternal immune system in the endometrial epithelium. A global analysis of differentially expressed proteins between EVs from P17 and P20 UFs revealed that components of intrauterine P20 EVs had the effect on the down-regulation of "neutrophil activation involved in immune response" and "neutrophil mediated immunity". In silico analyses predicted bta-miR-26b as one of potential miRNA to regulate maternal immune system. In our cell culture experiments, bta-miR-26b negatively regulated several immune system-related genes PSMC6, CD40, and IER3 in bovine endometrial epithelial cells. Our findings revealed that intrauterine EV-derived bta-miR-26b contributes to the down-regulation of the maternal immune system, allowing conceptus implantation to the uterine endometrium. Furthermore, our results suggest that intrauterine EVs extracted from P20 UFs could regulate neutrophils, the first line of immunological defense, to modulate endometrial immune and inflammatory responses for implanting conceptuses.

Deep learning model for predicting gestational age after the first trimester using fetal MRI.

OBJECTIVES: To evaluate a deep learning model for predicting gestational age from fetal brain MRI acquired after the first trimester in comparison to biparietal diameter (BPD). MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study, and a total of 184 T2-weighted MRI acquisitions from 184 fetuses (mean gestational age: 29.4 weeks) who underwent MRI between January 2014 and June 2019 were included. The reference standard gestational age was based on the last menstruation and ultrasonography measurements in the first trimester. The deep learning model was trained with T2-weighted images from 126 training cases and 29 validation cases. The remaining 29 cases were used as test data, with fetal age estimated by both the model and BPD measurement. The relationship between the estimated gestational age and the reference standard was evaluated with Lin's concordance correlation coefficient (ρc) and a Bland-Altman plot. The ρc was assessed with McBride's definition. RESULTS: The ρc of the model prediction was substantial (ρc = 0.964), but the ρc of the BPD prediction was moderate (ρc = 0.920). Both the model and BPD predictions had greater differences from the reference standard at increasing gestational age. However, the upper limit of the model's prediction (2.45 weeks) was significantly shorter than that of BPD (5.62 weeks). CONCLUSIONS: Deep learning can accurately predict gestational age from fetal brain MR acquired after the first trimester. KEY POINTS: • The prediction of gestational age using ultrasound is accurate in the first trimester but becomes inaccurate as gestational age increases. • Deep learning can accurately predict gestational age from fetal brain MRI acquired in the second and third trimester. • Prediction of gestational age by deep learning may have benefits for prenatal care in pregnancies that are underserved during the first trimester.

A Novel Noninvasive Method for Quantitative Detection of Colonic Dysmotility Using Real-Time Ultrasonography.

INTRODUCTION: Colonic motility disorders are a frequent clinical problem caused by various drugs and diseases. However, the etiology of colonic dysmotility is often unclear due to the lack of in vivo methods, including rapid dynamic assessment. OBJECTIVES: The aim of this study was to establish a novel quantitative method to objectively assess colonic motility using ultrasonography. METHODS: We applied echocardiographic speckle tracking-based strain imaging to analyze murine colonic motility. A trace line was placed on the boundary between the proximal wall of the colon and the inner cavity to analyze colonic wall displacement and strain rate. Locomotion activities of the colonic wall were used to quantify colonic motility via ultrasonography. RESULTS: We found that ultrasonography can quantitatively detect a decrease in colonic motility induced by loperamide, an antidiarrheal drug. These quantitative data were consistent with the imaging findings of colonic peristalsis and colon transit time. Additionally, ultrasonography also revealed changes in colonic motility over short intervals. Furthermore, we have shown that ultrasonography can quantitatively and noninvasively detect colonic dysmotility and hypervascularity of the colonic wall in colitis mice. CONCLUSIONS: These findings suggest that ultrasonography is a useful in vivo method for objectively monitoring changes in colonic motility caused by drugs and diseases.

Contribution of Serotonin 3A Receptor to Motor Function and Its Expression in the Gastrointestinal Tract.

INTRODUCTION: The serotonin 3A receptor (5-HT3AR) is involved in vomiting and gastrointestinal motility. However, it is not well understood the expression pattern of 5-HT3AR in the gut immunohistochemically and how much contribution of 5-HT3AR to upper or lower intestinal motility. OBJECTIVES: We investigated the contribution of 5-HT3AR to gastrointestinal motor function by using 5-HT3AR KO mice and sought to identify 5-HT3AR-expressing cells via immunohistochemical staining using 5-HT3AR-GFP reporter mice. METHODS: The expression of 5-HT3AR was measured in each section of the gut through real-time PCR. The motor function of the stomach and colon was assessed via the 13C-octanoic acid breath test and colonic bead expulsion test, respectively, using 5-HT3AR KO mice. 5-HT3AR-expressing cells in the muscle layer of the gut were identified by immunohistochemical staining using 5-HT3AR-GFP reporter mice. RESULTS: 5-HT3AR was expressed throughout the digestive tract, and 5-HT3AR expression in the stomach and lower digestive tract was higher than that in the other sections. Motor function in the stomach and colon was lower in 5-HT3AR KO mice than in WT mice. As a result of immunohistochemical staining using GFP reporter mice, cholinergic neurons and PDGFRα+ cells were shown to express 5-HT3AR. In contrast, 5-HT3AR indicated by GFP fluorescence was rarely detected in ICC and smooth muscle cells. CONCLUSIONS: These results show that 5-HT3AR is highly expressed in the stomach and large intestine and that the activation of 5-HT3AR accelerates gastric emptying and large intestine transit. Additionally, 5-HT3AR is highly expressed in cholinergic neurons and some interstitial cells, such as PDGFRα+ cells.

Protease-Activated Receptor-2 Is Associated With Adverse Outcomes in Canine Mammary Carcinoma.

Protease-activated receptor-2 (PAR2) is a G protein-coupled receptor that is activated by serine proteases. In humans, PAR2 is highly expressed in various cancers, including breast cancer, and is associated with cancer progression and metastasis. However, the expression and roles of PAR2 in canine mammary carcinoma remain unclear. The purpose of this study was to examine the expression of PAR2 in canine mammary carcinoma, the association between PAR2 expression and clinical characteristics, and the role of PAR2 in the metastatic phenotypes of tumor cells. Mammary carcinoma from 31 dogs and 10 normal mammary glands were included in this study, and used for immunohistochemical analysis of PAR2 expression. Normal mammary glands did not express PAR2. In contrast, mammary carcinomas showed PAR2 immunoreactivity in the cytoplasm, and its expression level varied between specimens from negative to strongly positive. The overall survival of dogs with high PAR2 expression was shorter than that of dogs with low PAR2 expression. Moreover, PAR2 expression level was associated with the presence of lymph node involvement, advanced clinical stage, and high histopathological grade. In vitro analyses revealed that a PAR2 agonist accelerated cell migration and invasion in a canine mammary carcinoma cell line. In addition, the PAR2 agonist induced epithelial-mesenchymal transition and actin polymerization. These results suggest that PAR2 expression plays a role in tumor progression and clinical outcomes in canine mammary carcinoma.

IFNT-independent effects of intrauterine extracellular vesicles (EVs) in cattle.

Extracellular vesicles (EVs) present in uterine lumen are involved in conceptus-endometrial interactions during the pre-implantation period. Despite numerous studies conducted on interferon tau (IFNT), a major protein of maternal recognition of pregnancy, the effect of intrauterine EVs on the endometrium during pre-implantation periods has not been well-characterized. To characterize conceptus-derived intrauterine EVs independent of IFNT, transcripts found from RNA-seq analysis in RNAs extracted from primary bovine endometrial epithelial cells (EECs) treated with cyclic day 17 (C17) EVs, pregnant day 17 (P17) EVs or IFNT were analyzed. These analyses identified 82 transcripts uniquely induced by IFNT-independent P17 EVs, of which a large number of transcripts were associated with 'the TNF signaling pathway' and 'Inflammatory response'. Moreover, high expression of CD40L, a member of the TNF superfamily, and its receptor CD40 were found in P17 EVs and in EECs, respectively. Furthermore, the expression of TNF signaling pathway-related genes was up-regulated by the treatment with P17 EVs, but these increases were down-regulated by NF-kB signaling inhibitor. These findings suggest that P17 EVs could induce a pro-inflammatory response in the endometrium, independent of IFNT, to regulate uterine receptivity, facilitating conceptus implantation.

Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF-α production by enhancing serotonin release from enterochromaffin cells.

Antagonists of the 5-hydroxytryptamine (serotonin) 3 receptor (5-HT3R) have anti-inflammatory and anti-apoptotic activities, but the detailed, underlying mechanisms are not well understood. We focused on anti-apoptotic activities via 5-HT3R signaling to clarify the underlying mechanisms. Mice were administered 5-fluorouracil (5-FU), which induced apoptosis in intestinal epithelial cells. Coadministration with 5-HT3R antagonists or agonists tended to decrease or increase the number of apoptotic cells, respectively. In serotonin 3A receptor (5-HT3AR) null (HTR3A-/-) mice, the number of apoptotic cells induced by 5-FU was decreased compared with that in wild-type (WT) mice. Bone marrow (BM) transplantation was performed to determine if BM-derived immune cells regulated 5-FU-induced apoptosis, but they were found to be unrelated to this process. Data from 5-HT3AR/enhanced green fluorescent protein reporter mice revealed that 50% of enterochromaffin (EC) cells expressed 5-HT3AR, but the number of apoptotic cells induced by 5-FU in the intestinal crypt organoids of HTR3A-/- mice was not altered compared with WT mice. In contrast, plasma 5-HT concentrations in WT mice but not in HTR3A-/- mice administered 5-FU were increased significantly. In conclusion, 5-HT3R signaling may enhance 5-HT release, possibly from EC cells intravascularly, or paracrine, resulting in increases in plasma 5-HT concentration, which in turn, enhances apoptotic activities induced by 5-FU.-Mikawa, S., Kondo, M., Kaji, N., Mihara, T., Yoshitake, R., Nakagawa, T., Takamoto, M., Nishimura, R., Shimada, S., Ozaki, H., Hori, M. Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF-α production by enhancing serotonin release from enterochromaffin cells.

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.

The Bezold-Jarisch Reflex in a Patient With Stanford Type A Acute Aortic Dissection.

BACKGROUND: The Bezold-Jarisch reflex is a depressor reflex of the heart due to the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a case of Stanford type A acute aortic dissection, in which coronary spastic angina caused the Bezold-Jarisch reflex in the acute phase. CASE REPORT: A 53-year-old man presented with left chest pain and cold sweating. An electrocardiogram was normal and the high-sensitivity cardiac troponin T level was negative. A diagnosis of Stanford type A acute aortic dissection was made based on computed tomography (CT); there was no evidence of ischemic heart disease on coronary CT angiogram obtained simultaneously. While waiting for emergency surgical repair, chest pain worsened, followed by bradycardia and hypotension, along with ST-segment elevations in the inferior leads, all of which were resolved by conservative treatment. During surgery, no evidence to suggest an extension of the dissection to the ostium of the right coronary artery was observed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The present case highlights the importance of recognizing the Bezold-Jarisch reflex because this depressor reflex may require different management than other conditions.

Insight into the Time Course of Type III Kounis Syndrome: A Case Report.

BACKGROUND: Kounis syndrome is a rare condition that is characterized by the coexistence of acute coronary syndrome and allergic reactions; however, its time course remains unclear. We report a case of anaphylactic shock with subsequent development of ST-segment elevation myocardial infarction. CASE REPORT: A 47-year-old man with food allergies presented to the emergency department of our hospital with breathing difficulties after eating bread. He had a history of angina and underwent stent implantation 3 years earlier. On examination, he was lethargic, disoriented, and in shock. He had a rash on his face and anterior chest wall, as well as severe itching and sweating. Anaphylaxis was diagnosed and, 3 min after presentation, 0.5 mg epinephrine was injected intramuscularly into the right thigh. Electrocardiography, which was recorded 2 min after the administration of epinephrine, was normal; however, chest pain developed suddenly 18 min later. Repeat electrocardiography showed ST-segment elevations, and emergency coronary angiography revealed total occlusion of the left anterior descending coronary artery (i.e., the previous stenting site). Recanalization of the left anterior descending coronary artery was achieved after repeated thrombus aspiration with difficulty, followed by stent implantation inside of the stent under the support of intra-aortic balloon pumping. The clinical course was uneventful. He was discharged and advised to avoid eating wheat and carry an epinephrine self-injection kit for anaphylaxis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The present case highlights the importance of recognizing Kounis syndrome in the management of anaphylactic shock because treatment may be difficult, particularly in patients with type III Kounis syndrome.

Emerging Role of Extracellular Vesicles in Embryo-Maternal Communication throughout Implantation Processes.

In ruminants, the establishment of proper conceptus-endometrial communication is essential for conceptus implantation and subsequent successful placentation. Accumulated evidence supports the idea that extracellular vesicles (EVs) present in uterine lumen are involved in conceptus-endometrial interactions during the preimplantation period. EVs make up a new field of intercellular communicators, which transport a variety of bioactive molecules, including soluble and membrane-bound proteins, lipids, DNA, and RNAs. EVs thus regulate gene expression and elicit biological effects including increased cell proliferation, migration, and adhesion in recipient cells. Uterine EVs are interactive and coordinate with ovarian progesterone (P4), trophectoderm-derived interferon tau (IFNT) and/or prostaglandins (PGs) in the physiological or pathological microenvironment. In this review, we will focus on intrauterine EVs in embryo-maternal interactions during the early stage of pregnancy, especially the implantation period in ruminant ungulates.

The essential role of phospho-T38 CPI-17 in the maintenance of physiological blood pressure using genetically modified mice.

PKC-potentiated phosphorylation-dependent inhibitory protein of protein phosphatase 1 (CPI-17), an endogenous myosin phosphatase inhibitory protein, is considered a key molecule for Ca2+ sensitization of the contractile apparatus. Here, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 to generate CPI-17-deficient [knockout (KO)] and threonine 38 (T38)-phospho-resistant mice [threonine mutant into alanine (TA)], and then effects of CPI-17 on vascular contractility in vitro and mean blood pressure (MBP) in vivo were investigated. In isolated thoracic aorta, phorbol 12, 13-dibutyrate induced a sustained contraction of wild-type (WT) mice, whereas no contraction showed from TA or KO mice. A high concentration of KCl solution-induced contraction was not different between transgenic and WT mice. In contrast, phenylephrine (PE)-induced contractions in both mutant strains were significantly smaller than those of WT mice in association with a low level of myosin phosphorylation, suggesting that at least part of PE-induced contraction is regulated by phosphorylation of CPI-17 at T38. Finally, the physiologic role of CPI-17 in the regulation of blood pressure was investigated using radio telemetry. MBP was decreased significantly in both transgenic mice, even with a compensatory increase in heart rate. In summary, we generated KO and constitutively phospho-resistant mouse models of CPI-17 for the first time. p-CPI-17 at T38, possibly by PKC, could be important to maintain vascular contractility and blood pressure in vivo. -Yang, Q., Fujii, W., Kaji, N., Kakuta, S., Kada, K., Kuwahara, M., Tsubone, H., Ozaki, H., Hori, M. The essential role of phospho-T38 CPI-17 in the maintenance of physiological blood pressure using genetically modified mice.

Role of transient receptor potential melastatin 2 in surgical inflammation and dysmotility in a mouse model of postoperative ileus.

In this study, we investigated the role of transient receptor potential melastatin 2 (TRPM2), a nonselective cation channel abundantly expressed in inflammatory cells such as macrophages, in the development of postoperative ileus, a complication of abdominal surgery characterized by gastrointestinal dysmotility. In wild-type mice, we found that intestinal manipulation, a maneuver that elicits symptoms typical of postoperative ileus, delays the transit of fluorescein-labeled dextran, promotes the infiltration of CD68+ macrophages, Ly6B.2+ neutrophils, and MPO+ cells into intestinal muscles, boosts expression of IL-1ß, IL-6, TNF-α, iNOS, and CXCL2 in intestinal muscles and peritoneal macrophages, enhances phosphorylation of ERK and p38 MAPK in intestinal muscles, and amplifies IL-1ß, IL-6, TNF-α, iNOS, and CXCL2 expression in resident and thioglycolate-elicited peritoneal macrophages following exposure to lipopolysaccharide. Remarkably, TRPM2 deficiency completely blocks or diminishes these effects. Indeed, intestinal manipulation appears to activate TRPM2 in resident muscularis macrophages and elicits release of inflammatory cytokines and chemokines, which, in turn, promote infiltration of macrophages and neutrophils into the muscle, ultimately resulting in dysmotility. NEW & NOTEWORTHY Activation of transient receptor potential melastatin 2 (TRPM2) releases inflammatory cytokines and chemokines, which, in turn, promote the infiltration of inflammatory cells and macrophages into intestinal muscles, ultimately resulting in dysmotility. Thus TRPM2 is a promising target in treating dysmotility due to postoperative ileus, a complication of abdominal surgery.

Phantom Study of In-Stent Restenosis at High-Spatial-Resolution CT.

Purpose To examine the diagnostic performance of high-spatial-resolution (HSR) CT with 0.25-mm section thickness for evaluating renal artery in-stent restenosis. Materials and Methods A 0.05-mm wire phantom and vessel phantoms with renal stents with in-stent stenotic sections of varying diameters were scanned with both an HSR CT scanner equipped with 160-section multi-detector rows (0.25-mm section thickness) and a conventional CT scanner. The wire phantom was used to analyze modulation transfer function (MTF). With the vessel phantoms, the error rates were calculated as the absolute difference between the measured diameters and true diameters divided by the true diameters at the narrowing sections. For qualitative evaluation, overall image quality and diagnostic accuracy for evaluating stenosis in three stages were assessed by two radiologists. Statistical analyses included the paired t test, Wilcoxon signed-rank test, and McNemar test. Results HSR CT achieved 24.3 line pairs per centimeter ± 0.5 (standard deviation) and 29.1 line pairs per centimeter ± 0.4 at 10% and 2% MTF, respectively; and conventional CT was 12.5 line pairs per centimeter ± 0.1 and 14.3 line pairs per centimeter ± 0.1 at 10% and 2% MTF, respectively. The mean error rate of the measured diameter at HSR CT (8.0% ± 5.8) was significantly lower than that at at conventional CT (16.9% ± 9.3; P < .001). Image quality at HSR CT was significantly better than that at conventional CT (P < .001), but HSR CT was not significantly superior to conventional CT in terms of diagnostic accuracy. Conclusion Compared with conventional CT, high-spatial-resolution CT achieved spatial resolutions of up to 29 line pairs per centimeter at 2% modulation transfer function and yielded improved measurement accuracy for the evaluation of in-stent restenosis in a phantom study of renal artery stents. Published under a CC BY 4.0 license.

Possible anti-inflammatory role of Zingiberis processum rhizoma, one component of the Kampo formula daikenchuto, against neutrophil infiltration through muscarinic acetylcholine receptor activation.

Zingiberis processum rhizoma (ZPR) is a major active component of daikenchuto (DKT), which induces anti-inflammatory action by inhibiting macrophage infiltration. However, it is unclear whether ZPR is related to DKT-induced anti-inflammatory action via a reduction of neutrophil infiltration against postoperative ileus (POI). In this study, we orally administered individual herbal components of DKT to mice four times before and after intestinal manipulation (IM). The anti-inflammatory action of each crude drug was evaluated by histochemical analysis of relevant molecules. The results showed that treatment with all herbal components of DKT significantly inhibits neutrophil infiltration. This inhibition of neutrophil infiltration by ZPR was significantly reduced in 5-hydroxytryptamine receptor 4 (5-HT4R) knockout (KO) mice but not in alpha-7 nicotinic acetylcholine receptor (α7nAChR) KO mice. Also, transient receptor potential ankyrin 1 (TRPA1) and muscarinic acetylcholine receptor (mAChR) antagonists partly and significantly inhibited the amelioration of neutrophil infiltration by ZPR. Therefore, DKT-induced anti-inflammatory action, mediated by inhibition of neutrophil infiltration in POI, depends, in part, on the effects of ZPR. ZPR activates TRPA1 channels, possibly in enterochromaffin (EC) cells, to release 5-HT. This 5-HT stimulates 5-HT4R in the myenteric plexus neurons to release acetylcholine, which, in turn, activates mAChR to inhibit inflammation in POI.

Assessment of Myometrial Invasion in Premenopausal Grade 1 Endometrial Carcinoma: Is Magnetic Resonance Imaging a Reliable Tool in Selecting Patients for Fertility-Preserving Therapy?

OBJECTIVES: The aim of this study was to evaluate the diagnostic ability of magnetic resonance imaging (MRI) in premenopausal women with G1 endometrial carcinoma. METHODS: Twenty-six patients underwent T2W, diffusion weighted, and dynamic contrast-enhanced 3-T MRI. The degree of myometrial invasion was pathologically classified into no invasion, shallow (3 mm or less), and more. Two radiologists assessed myometrial invasion on MRI. Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values, AUC, and interobserver agreement were analyzed. RESULTS: For assessing myometrial invasion, mean accuracy, sensitivity, specificity, positive predictive values, negative predictive values, and AUC, respectively, were as follows: 63%, 42%, 85%, 79%, 47%, and 0.75. Mean interobserver agreement was fair (k = 0.36). Shallow invasions were underestimated as no invasion on MRI in all 6 cases. CONCLUSIONS: Magnetic resonance imaging produced false-negative result on half of patients. The misjudgments tended to happen in patients with shallow invasion.