Alteration of reactivity in isolated mesenteric artery from Zucker fatty diabetes mellitus rats.

Obesity and diabetes are major risk factors for cardiovascular diseases. Zucker fatty diabetes mellitus (ZFDM) rats are novel animal model of obesity and type 2 diabetes. We have recently reported that blood pressure in ZFDM-Leprfa/fa (Homo) rats was normal, while blood adrenaline level and heart rate were lower than those in control ZFDM-Leprfa/+ (Hetero) rats. Here, we compared the reactivity in isolated mesenteric artery between Hetero and Homo rats. Contraction induced by phenylephrine was increased, while relaxation induced by isoprenaline was decreased in Homo rats at 21-23 weeks old compared with those in Hetero rats. The mRNA expression for α1A but not ß2 adrenoreceptor in Homo rats was increased. Nitric oxide (NO)-mediated relaxation induced by acetylcholine was decreased, while the mRNA expression for endothelial NO synthase (eNOS) was rather increased in mesenteric artery from Homo rats. These findings for the first time revealed that in Homo rats with reduced plasma adrenaline, blood pressure could be maintained by enhancing vascular contractility induced by adrenaline through the increased α1 adrenoceptor expression and the attenuated ß2 adrenoceptor signaling. Additionally, NO-mediated endothelium-dependent relaxation is impaired perhaps due to eNOS dysfunction, which might also contribute to maintain the blood pressure in Homo rats.

Human Omentin-1 Administration Ameliorates Hypertensive Complications without Affecting Hypertension in Spontaneously Hypertensive Rats.

Hypertension is one of the major risk factors for cardiovascular diseases and is caused by various abnormalities including the contractility of blood vessels. Spontaneously hypertensive rats (SHR), whose systemic blood pressure increases with aging, are a frequently used animal model for investigating essential hypertension and related complications in humans due to the damage of several organs. Human omentin-1 is an adipocytokine consisting of 313 amino acids. Serum omentin-1 levels decreased in hypertensive patients compared with normotensive controls. Furthermore, omentin-1 knockout mice showed elevated blood pressure and impaired endothelial vasodilation. Taken together, we hypothesized that adipocytokine, human omentin-1 may improve the hypertension and its complications including heart and renal failure in the aged SHR (65-68-weeks-old). SHR were subcutaneously administered with human omentin-1 (18 µg/kg/day, 2 weeks). Human omentin-1 had no effect on body weight, heart rate, and systolic blood pressure in SHR. The measurement of isometric contraction revealed that human omentin-1 had no influence on the enhanced vasocontractile or impaired vasodilator responses in the isolated thoracic aorta from SHR. On the other hand, human omentin-1 tended to improve left ventricular diastolic failure and renal failure in SHR. In summary, human omentin-1 tended to improve hypertensive complications (heart and renal failure), while it had no influence on the severe hypertension in the aged SHR. The further study of human omentin-1 may lead to the development of therapeutic agents for hypertensive complications.

[MSI-high ascending colon cancer treated with second-line ipilimumab plus nivolumab for conversion surgery:a case report].

A 68-year-old woman with ascending colon cancer was the patient (cT4bN2M1a [LYM] cStage IVA, BRAF V600E mutation-positive, and MSI-high). She was given modified FOLFOXIRI as first-line therapy but did not respond. The infiltration of the primary lesion in the abdominal wall was alleviated, allowing conversion surgery to be performed.

Regional socio-environmental characteristics associated with inadequate prenatal care during pregnancy: an ecological study of 47 prefectures in Japan.

BACKGROUND: Prenatal care (PNC) is a crucial health service that reduces the potential risks of adverse pregnancy and childbirth outcomes. It is monitored as one of the indicators of Universal Health Coverage (UHC) under the United Nations' Sustainable Development Goals. However, there are still mothers who do not use PNC, even when UHC has been achieved. As there have been few reports on the impact of local socio-environmental characteristics within the country, this study aimed to examine the association between local socio-environmental factors and inadequate use of PNC in Japan. METHODS: We conducted an ecological analysis of 47 prefectures in Japan using public open data. The dependent variables were the inadequate use of PNC, which are the rates of pregnant women who missed visiting PNC until 28 weeks' gestational age (GA) or those who never attended PNC before childbirth, and the independent variables were prefectural data of socio-economic, educational, and healthcare workforce-related factors. Multiple logistic regression analysis was used to examine the associations. RESULTS: The rate of pregnant women with late PNC initiation and never attending PNC before childbirth was 3.00-11.24 and 0.23-8.06 per 1000 pregnant women, respectively. Population numbers and densities, divorce rates, percentages of non-Japanese nationalities, and low percentages of high school enrolment were positively associated with inadequate PNC use. There was no statistically significant association with healthcare workforce, such as the number of obstetricians and gynaecologists. CONCLUSIONS: This ecological study revealed that inadequate PNC use is more common in urban areas with more non-Japanese nationality and lower education enrolment. There may be a need to provide education for those who do not have access to reproductive health education, such as that offered in high schools. Further studies are required to examine factors that affect access to PNC in Japan.

Chemerin-9-induced contraction was enhanced through the upregulation of smooth muscle chemokine-like receptor 1 in isolated pulmonary artery of pulmonary arterial hypertensive rats.

Chemerin is an adipocytokine having cardiovascular effects. Chemokine-like receptor 1 (CMKLR1) and chemokine (CC motif) receptor-like 2 (CCRL2) are chemerin receptors. Chemerin-9, an active fragment, causes contraction via smooth muscle CMKLR1 in isolated blood vessels. Pulmonary arterial hypertension (PAH) is a fatal disease resulting ultimately in right heart failure. To test the hypothesis that chemerin affects pulmonary artery (PA) resistance, we examined the effects of chemerin-9 on contractility of isolated PA from PAH rats. Wistar rats were injected with monocrotaline (MCT) for 2 weeks to make PAH rats (MCT rats). Control (Cont) rats received a saline injection. Chemerin-9-induced contraction of isolated intrapulmonary artery (IPA) from left lung was isometrically measured. Protein expression of CMKLR1 and CCRL2 in isolated left lung was determined by Western blotting. Localization of CMKLR1 in IPA of left lung was examined immunohistochemically. Chemerin-9-induced contraction was significantly enhanced in IPA from MCT compared with Cont rats. Protein expression of CMKLR1 was significantly elevated in isolated left lung from MCT compared with Cont rats, while protein expression of CCRL2, a decoy receptor, was significantly decreased. CMKLR1 was localized mainly in endothelium of IPA in Cont rats. The CMKLR1 expression was significantly decreased in endothelium of IPA in MCT rats, while it was significantly elevated in smooth muscle. The present study for the first time demonstrated that the enhanced chemerin-9-induced contraction of isolated IPA from MCT rats was at least partly caused by the increase of CMKLR1 in smooth muscle.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 lowered blood pressure in spontaneously hypertensive rats via inducing vasorelaxation.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) suppresses protein translation. We previously reported eEF2K expression was upregulated in mesenteric arteries (MA) from spontaneously hypertensive rats (SHR). We have recently revealed A484954, an eEF2K inhibitor, acutely suppressed vasopressor agonists-induced increase of blood pressure (BP) in normal Wistar rats. In this study, we examined the acute effects of A484954 on BP in SHR and explored underlying mechanisms. BP was measured by a carotid cannulation method in SHR. Isometric contraction in MA from SHR was measured. Endothelial nitric oxide synthase (eNOS) dimerization was measured by low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. A484954 lowered BP in 15-week-old SHR. A484954 induced relaxation in MA from both 4- and 7-9-week-old SHR. In MA from 4-week-old SHR, A484954-induced relaxation was inhibited almost completely by a NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME) and significantly by a ß blocker, propranolol. In MA from 7-9-week-old SHR, on the other hand, A484954-induced relaxation was inhibited partly either by l-NAME, indomethacin, a cyclooxygenase inhibitor, or l-NAME + indomethacin. A484954 promoted the dimerization of eNOS in human endothelial cells. In summary, we have revealed A484954 lowers BP in SHR perhaps through the vasorelaxation via the production of endothelium-derived relaxing factors.

Plasma exosomes regulate systemic blood pressure in rats.

Exosomes, the smallest extracellular vesicle, contain various molecules and mediate cell-cell communication. A number of studies demonstrate exosomes are involved in important physiological and pathological processes. Moreover, microRNA (miRNA) regulating hypertension development through the suppression of certain translation was recently reported. However, roles of exosomes containing various molecules including miRNA on development of essential hypertension have not been examined. We tested the hypothesis that plasma exosomes regulate systemic blood pressure in normotensive and spontaneously hypertensive rats (SHR). Normotensive Wistar Kyoto rats (WKY) and SHR (5-10-week-old) were intraperitoneally administrated with exosomes derived from plasma in WKY or SHR weekly for 6 weeks. Exosomes were isolated by an ultracentrifuge method. SHR-derived exosomes significantly increased systolic blood pressure in WKY, while WKY-derived exosomes decreased it in SHR. In WKY, SHR-derived exosomes induced modest structural changes of thoracic aorta, such as wall thickening and decreased abundance of collagen, which were similar to the changes observed in SHR. On the contrary, WKY-derived exosomes tended to reverse the changes in SHR. WKY-derived exosomes significantly suppressed the increased prostaglandin F2α-induced contraction of mesenteric arterial smooth muscle in SHR. In addition, wet weight and perivascular fibrosis of left ventricles in WKY were significantly increased by SHR-derived exosomes, while the fibrosis but not ventricular weight was significantly decreased by WKY-derived exosomes in SHR. We for the first time demonstrated that plasma exosomes can modulate systemic blood pressure as well as structure and function of cardiovascular tissues in both normotensive and hypertensive rats.

Mechanisms underlying the relaxation by A484954, a eukaryotic elongation factor 2 kinase inhibitor, in rat isolated mesenteric artery.

Eukaryotic elongation factor 2 kinase (eEF2K) is a calmodulin-related protein kinase which regulates protein translation. A484954 is an inhibitor of eEF2K. In the present study, we investigated the acute effects of A484954 on contractility of isolated blood vessels. Isometric contraction of rat isolated aorta and main branch of superior mesenteric artery (MA) was measured. Expression of an inward rectifier K+ (Kir) channel subtype mRNA and protein was examined. A484954 caused relaxation in endothelium-intact [E (+)] and -denuded [E (-)] aorta or MA precontracted with noradrenaline (NA). The relaxation was higher in MA than aorta. The relaxation was partially inhibited by a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (300 µM) in E (+) MA. The relaxation was significantly smaller in MA precontracted with high K+ than NA. The A484954-induced relaxation was significantly inhibited by a Kir channel blocker, BaCl2 (1 mM) compared with vehicle control in E (-) MA. Expression of Kir2.2 mRNA and protein was significantly higher in MA than aorta. We for the first time revealed that A484954 induces relaxation through opening smooth muscle Kir (Kir2.2) channel and through endothelium-derived NO in MA.

Visceral adipose tissue-derived serine protease inhibitor prevents the development of monocrotaline-induced pulmonary arterial hypertension in rats.

Visceral adipose tissue-derived serine protease inhibitor (vaspin), a recently identified adipocytokine, inhibits inflammation, migration, and apoptosis of vascular cells. We have recently demonstrated that chronic administration of vaspin to spontaneously hypertensive rats partly prevents systemic hypertension through inhibiting inflammation and remodeling of vascular wall. Pulmonary arterial (PA) hypertension (PAH) is caused by PA remodeling, contractile dysfunction, and inflammatory responses. We tested the hypothesis that vaspin could prevent development of PAH in animal model. PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg), and vaspin (1 µg/kg/day) was treated for 14 days from the day of MCT injection. PA pressure and contractile reactivity of isolated intrapulmonary artery (IPA) were measured. Using isolated lung tissues, IPA wall thickness and fibrosis, matrix metalloproteinase (MMP) activity, and reactive oxygen species (ROS) generation were examined. For in vitro study, after rat PA smooth muscle cells (PASMCs) were stimulated with interleukin (IL)-1ß (10 ng/ml, 48 h) in the presence of vaspin (5 ng/ml, 30 min), MMP activity and ROS generation were examined. Vaspin significantly attenuated MCT-induced rise in PA pressure, while it had no influence on impairment of relaxing function in IPA. Vaspin significantly prevented MCT-induced IPA fibrosis but not hypertrophy. Vaspin significantly inhibited MCT-induced ROS generation and MMP-2 activation in lung tissues. In addition, vaspin significantly inhibited IL-1ß-induced ROS generation and MMP-2 activation in PASMCs. In summary, we for the first time demonstrate that vaspin prevents MCT-induced PAH at least in part via inhibiting ROS/MMP-2/fibrosis pathway.

Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4.

Fatty acid-binding protein (FABP) 4 is an adipocytokine mainly expressed in adipocyte and macrophage. Blood FABP4 is related not only to metabolic disorders including insulin resistance and atherosclerosis but also increased blood pressure. We tested the hypothesis that FABP4 plays roles in pathogenesis of hypertension development including proliferation, migration, and inflammation of vascular smooth muscle cells (SMCs) as well as contractile reactivity. FABP4 alone had no influence on proliferation, migration, and inflammation of rat mesenteric arterial SMCs, while it significantly enhanced smooth muscle contraction and increases of systolic blood pressure (SBP) induced by noradrenaline (NA). BMS-309403, an FABP4 inhibitor, significantly inhibited platelet-derived growth factor-BB-induced DNA synthesis and migration via preventing p38 and HSP27 activation. Further, BMS-309403 significantly inhibited tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 as well as monocyte adhesion via preventing NF-κB activation. Interestingly, SMCs do not express FABP4. Long-term treatment of spontaneously hypertensive rats (SHR) with BMS-309403 significantly inhibited impaired relaxation in isolated mesenteric arteries and left ventricular hypertrophy, while it had no influence on SBP. We for the first time showed that FABP4 acutely enhances NA-induced increases of SBP possibly through the enhancement of peripheral arterial contractility. BMS-309403 prevents proliferation, migration, and inflammatory responses of SMCs, although exogenous application of FABP4 has no influence on the cellular responses. Furthermore, we demonstrated that long-term treatment with BMS-309403 partially improves the pathological conditions of SHR. These results indicate that BMS-309403 would be useful for developing a new pharmacotherapeutic agent against obesity-associated hypertension and complications.

Literature Review of Studies Using the National Database of the Health Insurance Claims of Japan (NDB): Limitations and Strategies in Using the NDB for Research.

The use of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) for research has increased over time. Researchers need to understand the characteristics of the data to generate quality-assured evidence from the NDB. In this review, we mapped and characterized the limitations and related strategies using the NDB for research based on the descriptions of published NDB studies. To find studies that used Japanese healthcare claims data, we searched MEDLINE, EMBASE, and Ichushi-Web up to June 2023. Additionally, we hand-searched the NDB data publication list from the Ministry of Health, Labour and Welfare (2017-2023). We abstracted data based on the NDB data type, research themes, age of the study sample or population, targeted disease, and the limitations and strategies in the NDB studies. Ultimately, 267 studies were included. Overall, the most common research theme was describing and estimating the prescriptions and treatment patterns (125 studies, 46.8%). There was a variation in the frequency of themes according to the type of NDB data. We identified the following categories of limitations: (1) lack of information on confounders/covariates, outcomes, and other clinical content, (2) limitations regarding patients not included in the NDB, (3) misclassification of data, (4) lack of unique identifiers and register of beneficiaries, and (5) others. Although the included studies noted several limitations of using the NDB for research, they also provided some strategies to address them. Organizing the limitations of NDB in research and the related strategies across research fields can help support high-quality NDB studies.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 induced diuresis via nitric oxide production in spontaneously hypertensive rats.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a protein kinase that inactivates eEF2, a protein that mediates a peptidyl-tRNA translocation during an elongation step of protein synthesis. We have previously shown that eEF2K was involved in pathogenesis of essential and pulmonary hypertension. A484954 (7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carboxamide), a selective eEF2K inhibitor, is a membrane permeable small molecule. We have previously shown that A484954 lowered blood pressure and induced diuretic effects in spontaneously hypertensive rats (SHR) due to an increase in renal blood flow. Here we aimed to reveal mechanisms underlying the diuretic effects of A484954 in SHR. A484954-induced diuresis and increase in urinary Na+ excretion were inhibited by N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor. A484954 increased mRNA expression of angiotensin type 2 receptor (AT2R) and nuclear factor-erythroid 2-related factor 2 (Nrf2). In summary, we for the first time revealed that A484954 induces diuresis in SHR at least partly via the activation of NO/Nrf2/AT2R pathway.

Autocrine role of senescent cardiac fibroblasts-derived extracellular vesicles.

Cellular senescence is a highly stable state associated with cell cycle arrest, that is elicited in response to various stresses. The accumulation of senescent cells in tissues drives age-related diseases. Recent studies have shown that the cellular senescence enhances an extracellular vesicles (EV) secretion. EV are lipid-bilayer-capsuled particles released by various cells mediating cell-to-cell communication. It was recently reported that EV secreted by the senescent cells had several functions such as cancer cell proliferation and immune cell activation. In the present study, we investigated whether senescent cardiac fibroblasts-derived EV play an autocrine/paracrine role in the heart cells. Neonatal rat cardiac fibroblasts (NRCFs) were treated with doxorubicin (DOX) to induce cellular senescence. EV were isolated from NRCFs culture media. The vehicle-treated NRCFs-derived EV (D0-EV, 72 hr) increased a living cell number in NRCFs, which was attenuated by DOX (1,000 nM)-treated NRCFs-derived EV (D103-EV, 72 hr). While D0-EV did not affect protein concentration in NRCFs, D103-EV decreased it. Furthermore, D103-EV significantly increased a ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I in NRCFs, indicating an induction of autophagy. In addition, D103-EV increased phosphorylation of adenosine monophosphate-activated kinase (AMPK) α in NRCFs. In neonatal rat cardiomyocytes, however, NRCFs-derived EV (72 hr) had no effect on the living cell number, protein concentration, and ratio of LC3-II to LC3-I. In conclusion, we for the first time revealed that DOX-induced senescent NRCFs-derived EV induce autophagy in NRCFs perhaps partly through the activation of AMPKα.

Human omentin-1 reduces vascular insulin resistance and hypertension in Otsuka Long-Evans Tokushima Fatty rats.

PURPOSE: Hypertension is one of the major risk factors for renal failure and cardiovascular diseases, and is caused by various abnormalities including the contractility of blood vessels. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which mimic human type 2 diabetes, are frequently used to study obesity-induced insulin resistance (IR) and hypertension. Human omentin-1 is one of the recently identified adipocytokines. We previously demonstrated that human omentin-1 not only caused vasodilation in rat isolated blood vessels, but also prevented inflammatory responses, a possible mechanism relating IR, in human vascular endothelial cells. Taken together, we hypothesized that human omentin-1 may reduce obesity-induced IR and hypertension in OLETF rats. METHODS: OLETF rats were intraperitoneally administered with human omentin-1 for 7 days. RESULTS: Human omentin-1 had no influence on overweight, hyperglycemia, urinary glucose extraction, hyperinsulinemia, and systemic IR in OLETF rats. Human omentin-1 decreased systolic blood pressure in OLETF rats. The measurement of isometric contraction revealed that human omentin-1 had no influence on the agonist-induced contractile and relaxant responses in isolated thoracic aorta from OLETF rats. However, the relaxant response mediated by human insulin was converted into the contractile response in thoracic aorta from OLETF rats, which was prevented by human omentin-1. The Western blotting revealed that human omentin-1 improved the decrease in endothelial nitric oxide synthase activation in isolated thoracic aorta from OLETF rats. CONCLUSION: In summary, we for the first time revealed that human omentin-1 partly reduces vascular IR and thereby inhibits hypertension in OLETF rats.

Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs.

Soluble guanylate cyclase (sGC) stimulator riociguat is a relatively novel therapeutic agent for pulmonary hypertension (PH) in human medicine. Riociguat induces endothelium-independent pulmonary artery (PA) relaxation by directly activating the sGC-cyclic guanosine-3',5'-monophosphate (cGMP) pathway in muscle cells. Although riociguat may be effective in the treatment of dogs with refractory PH, basic studies on its clinical application in veterinary medicine are lacking. The present study aimed to explore the effects of riociguat on the contractility of an isolated canine PA and the hemodynamics of dogs with acute PH. In an isolated endothelium-denuded canine PA, the effects of riociguat on endothelin (ET)-1-induced contraction and cGMP levels were investigated using the Magnus method and ELISA, respectively. The effect of riociguat on the hemodynamics of the thromboxane A2 analog U46619-induced PH model dog was examined by invasive catheterization. Riociguat increased cGMP levels and reduced ET-1-induced contraction of the isolated PA. Riociguat inhibited the U46619-induced elevation of PA pressure and pulmonary vascular resistance and increased cardiac output, but it had no effect on basal systemic blood pressure. These results demonstrate for the first time that riociguat can inhibit the elevation of PA pressure through PA relaxation via an endothelium-independent increase in cGMP in dogs with PH.

Studies of Health Insurance Claims Data in Japan: A Scoping Review.

Background: Health insurance claims data are used in various research fields; however, an overview on how they are used in healthcare research is scarce in Japan. Therefore, we conducted a scoping review to systematically map the relevant studies using Japanese claims data. Methods: MEDLINE, EMBASE, and Ichushi-Web were searched up to April 2021 for studies using Japanese healthcare claims data. We abstracted the data on study characteristics and summarized target diseases and research themes by the types of claims database. Moreover, we described the results of studies that aimed to compare health insurance claims data with other data sources narratively. Results: A total of 1,493 studies were included. Overall, the most common disease classifications were "Diseases of the circulatory system" (18.8%, n = 281), "Endocrine, nutritional, and metabolic diseases" (11.5%, n = 171; mostly diabetes), and "Neoplasms" (10.9%, n = 162), and the most common research themes were "medical treatment status" (30.0%, n = 448), "intervention effect" (29.9%, n = 447), and "clinical epidemiology, course of diseases" (27.9%, n = 417). Frequent diseases and themes varied by type of claims databases. A total of 19 studies aimed to assess the validity of the claims-based definition, and 21 aimed to compare the results of claims data with other data sources. Most studies that assessed the validity of claims data compared to medical records were hospital-based, with a small number of institutions. Conclusions: Claims data are used in various research areas and will increasingly provide important evidence for healthcare policy in Japan. It is important to use previous claims database studies and share information on methodology among researchers, including validation studies, while informing policymakers about the applicability of claims data for healthcare planning and management.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction in isolated renal artery.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) repressively regulates protein translation through phosphorylating eEF2. We previously showed that expression and activity of eEF2K are increased in isolated mesenteric arteries from spontaneously hypertensive rats (SHR) contributing to development of essential hypertension. Furthermore, we have recently shown that 7-Amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide (A484954), a selective eEF2K inhibitor, induces endothelium-dependent relaxation in isolated mesenteric arteries from SHR inducing an antihypertensive effect. In order to test the hypothesis that inhibition of eEF2K activity induces vasodilatation by suppressing sympathetic nerve activity, we examined the effects of A484954 on perivascular sympathetic nerve stimulation-induced contraction in isolated renal artery from normotensive and hypertensive rats. Electrodes were placed near the isolated renal arteries that were applied with transmural nerve stimulation (TNS). Then, contraction of the arteries was isometrically measured. A484954 inhibited TNS-induced contraction. The A484954-mediated inhibition of TNS-induced contraction was significantly prevented by NG-nitro-L-arginine methyl ester. In SHR isolated renal artery, TNS-induced contraction was enhanced compared with normotensive Wistar rats. Furthermore, A484954-mediated inhibition of TNS-induced contraction in SHR was enhanced compared with Wistar rats. In conclusion, this study demonstrates for the first time that A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction at least in part perhaps through nitric oxide (NO) release from NO-operating nerve.

Chemerin fragments show different effects on systemic blood pressure dependent on carboxyl-terminal cleavage site.

Chemerin is an adipocytokine whose concentration in blood correlates positively with blood pressure (BP). We have recently revealed that acute intracerebroventricular (i.c.v.) injection of chemerin-9, an active fragment of human chemerin, increased systemic BP in normal Wistar rats, suggesting that chemerin is involved in the central nervous control of peripheral BP. After secreted as an inactive form as prochemerin, a mature form of active chemerin is produced through the cleavage of its carboxyl (C)-terminus by proteases. Although the activity of cleaved products of chemerin has been examined in vitro, in vivo effects remained to be elusive. In order to explore them, we performed acute i.c.v. injection of mouse chemerin-9 (mChemerin-9; 148F-156S), mouse chemerin-8 (mChemerin-8; 148F-155F), and mouse chemerin-7 (mChemerin-7; 148F-154A) into Wistar rats, and examined the effects on systemic BP. After chemerin fragment (1-30 nmol/head, i.c.v.) was cumulatively administered, systemic BP was measured by a cannulation method under an isoflurane anesthesia. mChemerin-9 but not mChemerin-8 and -7 induced a pressor response, which was concentration-dependent. In conclusion, we for the first time demonstrated that mChemerin-9 that corresponds to the C-terminal nine amino acids of active mouse chemerin156S increased systemic BP in rats, and also that chemerin fragments showed different effects on systemic BP dependent on how their C-terminus was cleaved.

Gender Differences in Work Status during Early Career of Dentists: An Analysis of National Survey Cohort Data of 10 Years in Japan.

Few studies have evaluated gender differences in young dentists' career focusing on career breaks and return to work. We created a cohort dataset for dentists registered in 2006 using the national survey between 2006-2016 (men, 1680; women, 984), and examined the work setting of dentists by gender 10 years after registration. The proportion of dentists on career break increased each survey year, and was more pronounced in women than in men (2006 to 2016, men, 11.2% to 14.2%; women, 7.9% to 31.0%). The proportion of those who had career breaks between 2006-2016 was 44.8% in men and 62.9% in women. In the multiple logistic regression for examining the associations between those who returned to work compared to those working continuously, in women, the odds ratios (OR) were significantly higher in those working in dental clinics (owner, OR: 5.39; employee, OR: 3.10), and those working part-time (OR: 2.07); however, in men, there was no significant association with part-time work. These results suggest during early career phase, female dentists are more likely than males to take career breaks and choose part-time on returning. These gender differences should be considered for ensuring adequate workforce in dentistry in the future.