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Coronavirus disease 2019 (COVID-19) is associated with fatal acute respiratory distress syndrome, which can be ameliorated by methylprednisolone pulse therapy, thereby reducing the risk of progression to respiratory failure and death. We aimed to determine the efficacy and safety of methylprednisolone pulse therapy for patients with COVID-19 pneumonia. In this retrospective, observational cohort study, seventy patients (age, 35–91 years) who were admitted to Saitama Medical University Hospital in Japan between March 2020 and January 2021 due to COVID-19 pneumonia were included. The difference in mortality between the methylprednisolone pulse therapy (n = 22) and dexamethasone therapy (n = 48) groups was the primary outcome. Between-group differences in the average length of intensive care unit stay, duration of invasive mechanical ventilation, and incidence of treatment-related adverse events were the secondary outcomes. The methylprednisolone pulse therapy group showed a significantly lower mortality rate (3.8% vs. 20.2%, p = 0.006) and increased survival rate compared with the dexamethasone therapy group (p = 0.044). Additionally, without statistical significance, the average length of intensive care unit stay tended to be shorter in the methylprednisolone pulse therapy group (11.5 ± 6.1 days) than in the dexamethasone therapy group (22.3 ± 23.1 days) (p = 0.793). The average duration of invasive mechanical ventilation also tended to be shorter in the methylprednisolone pulse therapy group (15.3 ± 10.1 vs. 28.8 ± 9.2 days, p = 0.120). There were no significant differences in the incidence of treatment-related serious adverse events between the two groups. In conclusion, methylprednisolone pulse therapy for patients with COVID-19 pneumonia significantly reduced mortality and increased the survival rate compared to conventional dexamethasone therapy.

Introduction: Most pulmonary vasodilators are administered orally; however, in patients with pulmonary hypertension undergoing gastrointestinal surgery, a switch to parenteral drugs is needed. Parenteral pulmonary vasodilators carry a risk of infection and reduced quality of life owing to long-term central venous catheterization; therefore, it is preferable to switch them to oral vasodilators after surgery. Here, we present the case of a patient with systemic sclerosis complicated by pulmonary hypertension and colon cancer, for which treatment was successfully switched from epoprostenol to selexipag postoperatively. Case Description: A 59-year-old woman, who was diagnosed with mixed group I and III pulmonary hypertension and systemic sclerosis, was on oral triple pulmonary vasodilators for pulmonary hypertension and Raynaud’s phenomenon. She was diagnosed as having colon cancer 3 months before admission. Despite the severe pulmonary condition and treatment with oral triple pulmonary vasodilators, colon cancer resection surgery was performed with the management for pulmonary hypertension through multidisciplinary treatments in collaboration with cardiology specialists. Medications for patients with pulmonary hypertension undergoing gastrointestinal surgery need to be switched from oral vasodilators to epoprostenol perioperatively. On postoperative day 19, 0.4 mg/day of selexipag was administered with epoprostenol. Subsequently, the epoprostenol dosage was gradually decreased, and selexipag was increased. On postoperative day 30, the dose of selexipag was increased to 1.2 mg/day and epoprostenol was discontinued. The patient was discharged on postoperative day 40. Conclusion: In our case, transition from epoprostenol to selexipag contributed to a more useful management strategy for systemic sclerosis and pulmonary hypertension in the postoperative period.

Hypoxia inducible factor -1α (HIF-1α) and Wnt/β-catenin signal pathway has been reported to be involved in tumor progression in various types of cancers. However, the molecular mechanism by which HIF-1α regulate malignant features in esophageal squamous cell carcninoma (ESCC) are still poorly understood. This study aimed to clarify the significance of the crosstalk between HIF-1α and the Wnt/β-catenin pathway in ESCC. The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. Then we performed qRT-PCR, western blotting, Cell Counting-8 assay, trans-well assay, flow cytometry, immunofluorescence, Co-IP and ChIP assays, chemo resistance test in vitro, tumor xenograft model in vivo. The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in ESCC cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, igration/invasion and EMT progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumor tissues. High levels of HIF-1α and TCF4/TCF7L2 were correlated with poor prognosis in ESCC. HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway. Our study clarifies the critical role of HIF-1α in ESCC progression.

We report the case of a 52-year-old hyperglycemic woman with type 2 diabetes and severe coronavirus disease 2019 (COVID-19)-associated pneumonia, possibly involving the subcutaneous insulin resistance (SIR) syndrome. After admission for pneumonia, her average daily blood glucose (BG) levels remained at 300–400 mg/dL, although the required dosage of subcutaneous insulin markedly increased (~ 150 units/day; ~ 2.63 units/kg/day). Furthermore, the patient had generalized edema along with hypoalbuminemia, developed extensive abdominal purpuras, and had increased plasma D-dimer levels during treatment, suggestive of coagulation abnormalities. Therefore, intravenous infusion of regular insulin was initiated. The BG level subsequently decreased to

Whether diagnostic computed tomography (CT) scans to cardiac implantable electronic devices (CIED) is safe in recent models remains unknown.A two-centers observational study. Over 14 years, consecutive 2362 chest CT scans (1666 pacemakers [PMs], 145 cardiac resynchronization therapy PM, 316 implantable cardioverter-defibrillator, and 233 cardiac resynchronization therapy defibrillator) were interrogated and monitored upon imaging.Electromagnetic interference occurred only in a few old models: InSync 8040 (n = 14), InSync III Marquis (n = 1), and Kappa (n = 4), which resulted no adverse events.CIEDs, especially recent ones, are confirmed safe on chest CT.

Many clinical studies have identified significant predictors or risk factors for the severity or mortality of coronavirus disease 2019 (COVID-19) cases. However, there are very limited reports on the risk factors for requiring oxygen therapy during hospitalization. In particular, we sought to investigate whether plasma glucose and HbA1c levels could be risk factors for oxygen therapy requirement.A single-center, retrospective study was conducted of 131 COVID-19 patients hospitalized at Saitama Medical University Hospital between March 2020 and November 2020. To identify the risk factors for oxygen therapy requirement during hospitalization, a stepwise multivariate binary logistic regression analysis was performed using several clinical parameters commonly obtained on admission, including plasma glucose and HbA1c levels.Of the 131 patients with COVID-19, 33.6% (44/131) received oxygen therapy during hospitalization. According to the logistic regression analysis, male sex (odds ratio [OR]: 8.76, 95% confidence interval [CI]: 1.65-46.5, P 0.05), age (OR: 1.07, 95% CI: 1.02-1.12, P 0.01), HbA1c levels (OR: 1.94, 95% CI: 1.09-3.44, P 0.05), and serum C-reactive protein (CRP) levels (OR: 2.22, 95% CI: 1.54-3.20, P 0.01) emerged as independent variables associated with oxygen therapy requirement during hospitalization.In addition to male sex, age, and serum CRP levels, HbA1c levels on admission may serve as a risk factor for oxygen therapy requirement during the clinical course of COVID-19, irrespective of diabetes history and status. This may contribute to the efficient delegation of limited numbers of hospital beds to patients at risk for oxygen therapy requirement.

Aims/Introduction The aim of the present study was to examine the associations of pregestational body mass index (BMI) and gestational weight change with birthweight for gestational age in Japanese mothers with gestational diabetes mellitus (GDM). Materials and Methods We retrospectively examined the clinical and laboratory characteristics of 101 mothers with GDM (pregestational BMI 24.7 ± 5.8 kg/m2; maternal age at delivery 34.7 ± 5.1 years; gestational age 38.5 ± 1.4 weeks) at a single center from January 2011 to December 2016. Results Gestational weight changes were 6.22 ± 5.39 kg, and infant birthweights were 2,987.3 ± 393.6 g. Multivariable analysis showed that, in all mothers, pregestational BMI and gestational weight change were positively associated with infant birthweight (P

To examine the effects of strict glycemic control on the birthweight of infants born to Japanese patients with early- or mid-to-late-detected gestational diabetes mellitus (ed- or md-GDM).We retrospectively examined the characteristics of 101 patients with GDM who underwent guideline-based glycemic control. A 75-g oral glucose tolerance test was conducted to diagnose GDM at gestational weeks 11-15 (ed-GDM subgroup) and 24-28 (md-GDM subgroup).Infant birthweight was significantly lower in the ed-GDM subgroup (n = 25) than in the md-GDM subgroup (n = 76) (2688.3 ± 470.4 g vs. 3052.4 ± 383.1 g, p 0.05), and the proportion of low-birthweight infants (2500 g) was significantly higher in the ed-GDM subgroup than in the md-GDM subgroup (32.0% vs. 5.3%, p 0.005). Fasting plasma glucose (FPG) levels during early treatment and before delivery were significantly lower in the ed-GDM subgroup than in the md-GDM subgroup (76.1 ± 10.4 mg/dL vs. 85.5 ± 9.6 mg/dL, p 0.001; 80.5 ± 10.4 mg/dL vs. 90.4 ± 10.3 mg/dL, p 0.0001).Patients with ed-GDM showed significantly lower FPG levels during treatment compared to those with md-GDM, presumably indicating an association with the delivery of low-birthweight infants.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

The AcrAB-TolC efflux pump is involved in the organic solvent tolerance of

Background Primary aldosteronism (PA) plus subclinical Cushing’s syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled. Methods A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans. Results The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p p p Conclusions Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.

The AcrAB-TolC efflux pump is involved in the organic solvent tolerance of Escherichia coli. Most E. coli strains are highly sensitive to organic solvents such as n-hexane and cyclohexane. Here, a recombinant E. coli transformed with an expression plasmid containing acrAB and tolC became tolerant to n-hexane and cyclohexane. The levels of AcrA, AcrB, and TolC in the recombinant increased by 3- to 5-fold compared to those in the control strain without the plasmid for acrAB or tolC. To investigate the usability of the recombinant as a biocatalyst in an aqueous-organic solvent two-phase system, we further introduced xylMA xylene monooxygenase genes from Pseudomonas putida mt-2 into the recombinant and examined the production of styrene oxide from styrene. The resulting recombinant produced 1.8 mg and 1.0 mg styrene oxide mL−1 of medium in a medium overlaid with a 25% volume of n-hexane and cyclohexane containing 10% (wt vol−1) styrene, respectively. A recombinant Escherichia coli with enhanced AcrAB-TolC efflux pump level increased production of styrene oxide from styrene in an aqueous-organic solvent two-phase system.

Statins and/or PCSK9 inhibitors cause the regression of coronary atheroma and reduce clinical events. However, it currently remains unclear whether these drugs modulate coronary atheroma calcification in vivo. Coronary artery calcium (CAC) scores (Agatston Units, AUs) were estimated in 120 patients receiving coronary computed tomographic angiography (CCTA) (63% males; median age 56 years). The CAC scores were compared among the three groups: (1) neither statin nor PCSK9 inhibitor therapy, (2) statin monotherapy, and (3) statin and PCSK9 inhibitor combination therapy in an unpaired cross-sectional study. Additionally, CCTA was performed twice at an interval in 15 patients undergoing statin monotherapy to compare the previous (baseline) and subsequent (follow-up) CAC scores in a paired longitudinal study. In addition, a PCSK9 inhibitor was administered to 16 patients undergoing statin therapy. Before and after that, CCTA was performed twice to compare the previous and subsequent CAC scores in a paired longitudinal study. The unpaired cross-sectional study and paired longitudinal study consist of completely different patients. Among 120 patients, 40 (33%) had a CAC score >100 AUs. The median CAC score increased in the following order: statin group, statin and PCSK9 group, and no-statin-no-PCSK9 group. Annual CAC score progression was 29.7% by statin monotherapy and 14.3% following the addition of the PCSK9 inhibitor to statin therapy. The annual rate of CAC with the combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. CAC may be prevented with PCSK9 Inhibitor., Coronary artery calcification: entry to new frontier of PCSK9 inhibitors Today, rapid aging in society is making progress in developed countries. One of the most serious health problems in an aging society is atherosclerosis, of which final phase is coronary artery calcification (CAC). CAC could increase the risk of complications during coronary catheterization and coronary artery bypass surgery as well as ischemic heart disease (IHD). We, members in the aging society, would see much more patients with CAC in the near future. We, however, have no medications for CAC today. Moreover, statins that are used in the world have been known for CAC formation after long-term use. The team led by Yuichi Ikegami and Ikuo Inoue in Japan’s Saitama Medical University found that CAC in patients with atherosclerosis is improved by PCSK9 inhibitors compared to statins by using coronary computed tomographic angiography. This study shows us a hint that could lead us to new preventive therapies of IHD.

Carbon monoxide (CO) levels in expired gas are higher in patients with bronchial asthma than in healthy individuals. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes the degradation of heme to yield biliverdin, CO and free iron. Thus, HO-1 is implicated in the pathogenesis of bronchial asthma. However, whether HO-1 expression and activity in lung tissue are related to allergic airway inflammation remains unclear. We investigated whether expression of HO-1 is related to allergic airway inflammation in lungs and whether HO-1 could influence airway hyperresponsiveness and eosinophilia in mice sensitized to ovalbumin (OVA).C57BL/6 mice immunized with OVA were challenged thrice with an aerosol of OVA every second day for 8 days. HO-1-positive cells were identified by immunostaining in lung tissue, and zinc protoporphyrin (Zn-PP), a competitive inhibitor of HO-1, was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 23 (day before inhalation of OVA) and immediately before inhalation on the subsequent 4 days (total five doses). Mice were analyzed for effects of HO-1 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue. Ethical approval was obtained from the concerned institutional review board.Number of HO-1-positive cells increased in the subepithelium of the bronchi after OVA challenge, and HO-1 localized to alveolar macrophages. Zn-PP clearly inhibited AHR, pulmonary eosinophilia and IL-5 and IL-13 expression in the lung tissue.Expression of HO-1 is induced in lung tissue during attacks of allergic bronchial asthma, and its activity likely amplifies and prolongs allergic airway inflammation.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

Sigmoid-shaped ventricular septum (SSVS) is frequently observed in elderly patients, but association of mid-ventricular obstruction is rare. In this report, we describe 2 patients with SSVS who had mid-ventricular obstruction and intracavity pressure gradient detected by echocardiography and cine magnetic resonance imaging. Attention should be paid to SSVS because it may cause clinically significant hemodynamic derangements related to mid-ventricular obstruction.

A common gene variant of human extracellular superoxide dismutase (ecSOD), in ∼5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSODR213G) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSODR213G, or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 ± 4% relaxation, means ± SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 ± 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 ± 0.2 to 0.9 ± 0.2 relative light units per second per millimeter squared (RLU·s−1·mm−2)] and peroxynitrite (from 2.4 ± 0.2 to 0.9 ± 0.1 RLU·s−1·mm−2) in the aorta from rats with heart failure. Gene transfer of ecSODR213G produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSODR213G in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSODR213G in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSODR213G.

Our goal was to develop a model of accelerated hypertension with renal microangiopathy. Transgenic mice that are hypertensive because of overexpression of human renin (R+ mice) and human angiotensin (A+ mice) genes were studied. To Increase arterial pressure to levels comparable to those that may be seen in malignant hypertension, high salt was added to the diet and/or the nitric oxide synthase inhibitor, Nω-nitro-L-arginine methylester (L-NAME), was added to the drinking water. Renal lesions, decline in renal function, and proteinuria developed within 10 weeks in R+/A+ mice given both L-NAME and a high-salt diet, and within 24 weeks in mice given either L-NAME or a high-salt diet. Renal morphology showed features of severe thrombotic microangiopathy, with extensive vascular and glomerular lesions in all R+/A+ mice on high salt, L-NAME, or high salt plus L-NAME. Vascular lesions included fibrin thrombi and onion skinning of the vessel walls, whereas glomerular lesions Included segmental sclerosis, mesangiolysis, fibrin thrombi within glomerular capillaries, and double-contour formation of glomerular capillary walls. Renal morphology was normal in control mice fed high salt and/or L-NAME. No R+/A+ mice fed a normal diet developed vascular lesions, whereas a few mice developed mild focal glomerular lesions. In summary, these studies characterize vascular and glomerular lesions in R+/A+ mice fed high salt, L-NAME, or both high salt and L-NAME, and provide a murine model of malignant hypertension with renal thrombotic microangiopathy.

Background— Extracellular superoxide dismutase (ECSOD) is a major extracellular antioxidant enzyme. We have demonstrated that vascular effects of ECSOD require an intact heparin-binding domain. A common genetic variant with a substitution in the heparin-binding domain (ECSOD R213G ) was reported recently to be associated with ischemic heart disease. The goal of this study was to examine vascular effects of ECSOD R213G . Methods and Results— A recombinant adenovirus (Ad) that expresses ECSOD R213G was constructed. ECSOD R213G and ECSOD proteins bound to collagen type I in vitro, but binding to aorta ex vivo was 10-fold greater with ECSOD than ECSOD R213G . Three days after intravenous injection of AdECSOD R213G or AdECSOD in spontaneously hypertensive rats (SHR), immunostaining demonstrated binding of ECSOD to carotid arteries and kidneys but minimal binding of ECSOD R213G . Binding to aorta and carotid artery was 2.5- to 3-fold greater with ECSOD than ECSOD R213G by immunoblotting. Arterial pressure was significantly reduced by AdECSOD but not by AdECSOD R213G . Responses to acetylcholine and basal levels of nitric oxide in carotid arteries were impaired in SHR compared with normotensive Wistar-Kyoto rats and were improved after AdECSOD but not AdECSOD R213G . Levels of superoxide and nitrotyrosine in aorta were higher in SHR than Wistar-Kyoto rats and were greatly reduced after AdECSOD but not AdECSOD R213G . Conclusions— In contrast to ECSOD, ECSOD R213G has no significant protective effect on arterial pressure, vascular function, or vascular levels of oxidative stress in SHR. These findings may provide a mechanistic basis for association studies that suggest that human beings carrying ECSOD R213G are predisposed to vascular diseases.

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODΔHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODΔHBD. Gene transfer of ecSOD, but not ecSODΔHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.

Oxidative stress may contribute to hypertension. The goals of this study were to determine whether extracellular superoxide dismutase (ECSOD) reduces arterial pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding domain (HBD), which is responsible for cellular binding, is necessary for the function of ECSOD. Three days after intravenous injection of an adenoviral vector expressing human ECSOD (AdECSOD), mean arterial pressure (MAP) decreased from 165±4 mm Hg (mean±SE, n=7) to 124±3 mm Hg (n=7) in adult anesthetized SHR ( P

A 48-year-old man was admitted to our hospital with 1-month history of petechiae and edema of the bilateral lower extremities, polyarthralgia, gait disturbance, and hematochezia. He also had 2-year history of anorexia and an unbalanced diet that did not include any fresh vegetables or fruits. On examination, his conjunctivae were pale and his hemoglobin was 5.7g/dL. He had leukopenia (2970/μL), thrombocytopenia (620000/μL), and hypoalbuminemia (2.9g/dL). The serum vitamin B1 level was 11.0ng/mL (24– 66ng/mL), the serum vitamin C level was

Apelin and its G-protein-coupled receptor APJ are potent regulators of the cardiovascular system. Recent studies have suggested that apelin-APJ reverses the function of angiotensin II (Ang II)-the Ang II type 1 receptor (AT(1)). However, the mechanism remains unclear because of the accumulating evidences that apelin-APJ may contribute to both cardioprotection and pathological progression. In human embryonic kidney 293 cells, we found that coexpression with APJ significantly suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by Ang II-AT(1), whereas apelin abolished this attenuation through activated APJ independently of its heterodimerization. Pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the ERK1/2 phosphorylation level similar to that found with AT(1) and APJ coexpression without apelin stimulation. In contrast, coexpression of the beta-2-adrenergic receptor or the pharmacologically non-activated Ang II type 2 receptor (AT(2)) pretreated with the AT(2)-specific antagonist, PD123319, did not affect ERK1/2 phosphorylation through AT(1). Pretreatment with 30 nM of the AT(1) blocker (ARB) TA-606A suppressed 50% of the AT(1)-mediated ERK1/2 phosphorylation, whereas 30 nM of TA-606A achieved 75% suppression when the non-activated APJ was coexpressed without ligand or PTX. However, 120 nM of TA-606A failed to reach the target phosphorylation when it was coexpressed with activated APJ with apelin. Based on these results, we demonstrated that non-activated APJ may suppress Ang II-AT(1) signaling, whereas this ligand-independent function was diminished with apelin activation. These results may be relevant to the potential contribution of apelin-APJ to ARB treatment in the clinical realm.

The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin-angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the amino-terminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space.

(Pro)renin receptor is a new molecule of the renin-angiotensin system. The (pro)renin receptor binds both renin and prorenin leading to protease activity. Furthermore, the binding of renin/prorenin to (pro)renin receptor activates intracellular signaling. Although these studies show the classical function of the (pro)renin receptor on the plasma membrane as a receptor, subcellular distribution and extracellular secretion of (pro)renin receptor remained controversial until recently when Cousin et al. reported possible existence of the soluble form of (pro)renin receptor. Chinese hamster ovary (CHO) cells transfected with human (pro)renin tagged with Venus showed bands at 74 kDa and 35 kDa without any stimulation in Western blot analysis. Moreover, these cells secreted a 29 kDa form, which was the amino-terminal fragment of the (pro)renin receptor. In immunofluorescent staining, (pro)renin receptor tagged with Venus was mainly stained on the endoplasmic reticulum and in vesicle-like structures, but not on the plasma membrane. These data suggest that the (pro)renin receptor may be cleaved in the intracellular compartments of cells and secreted into the extracellular space.

Histological discrimination of mesothelioma from adenocarcinoma is often difficult, therefore, many investigators have tried immunohistochemical, ultrastructual, and molecular methods. Economically, immunohistological studies are more excellent, compared with ultrastractual and molecular biological methods. Immunohistologically, many well known markers are divided into two category; adenocarcinoma-related markers, which expressed by adenocarcinoma, and mesothelioma-related makers, which are positive for mesothelioma. CEA, TTF-1, and Ber-Ep4 are well known adenocarcinoma-related markers, mesothelin, TM, HBME-1 and calretinin, have been used as mesothelioma-related markers. Most previous reports associated with discrimination of adenocarcinoma and mesothelioma mentioned that a diagnosis of epithelioid mesothelioma would be excluded by the presence of adenocarcinoma-related antibody. The positive ratio of mesothelioma-related antibodies is lower than that of adenocarcinoma-related antibodies. Only a single mesothelioma-related marker cannot lead to a diagnosis of epithelioid mesothelioma and a correct diagnosis can be made by combination of several makers, which contain both mesothelioma-related markers and adenocarcinoma-related markers. We immunohistologically examined 41 cases of mesothelioma and 16 cases of adenocarcinoma of the lung, and re-evaluated the use of immunohistochemical markers, compared with previous reports. Reactivity for mesothelin was obtained in 19 (73%) of the epithelioid mesotheliomas, but none (0%) of the lung adenocarcinomas. None of the sarcomatoid mesotheliomas exhibited positivity for this marker, nor was any reactivity seen in the spindle cell component of the biphasic mesotheliomas. These findings indicate that, in some instances, mesothelin immunostaining can assist in the diagnosis of mesothelioma.

A 66-year-old woman was admitted due to right cervical lymphadenopathy and an abnormal chest radiograph. Acid-fast bacilli smear of fine needle aspiration from a right cervical lymph node was positive. Histopathological examination of the specimen obtained by percutaneous right cervical lymph node biopsy showed necrotizing epithelioid granulomas and no malignant cells. Therefore, right cervical tuberculous lymphadenitis was diagnosed. Partial lung resection of the right S4 was carried out by video-assisted thoracoscopic surgery and primary lung cancer was diagnosed. To our knowledge, there has been no previous report of both primary lung cancer and cervical tuberculous lymphadenitis being present at the time of the first examination. We report this very rare case.

Hypertension is the most common risk factor for hemorrhagic stroke. An experimental model of stroke, the stroke-prone spontaneously hypertensive rat (SHRSP), which has been enormously useful in studies of cerebral circulation, has been used in1000 papers. However, SHRSP usually have an ischemic or less commonly hemorrhagic stroke in the cortex, not in the brain stem, cerebellum, or basal ganglia, as in patients with hypertension. The goal of this study was to develop a model of hemorrhagic stroke in hypertensive mice.A genetic model of hypertensive mice, double transgenic mice (R+/A+) that overexpress both human renin (R+) and human angiotensinogen (A+), and nonhypertensive control mice were divided into 3 groups: (1) high-salt diet; (2) Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthases, in drinking water; and (3) high-salt diet and L-NAME.All R+/A+ mice on high-salt diet and L-NAME died within 10 weeks, with hemorrhage in the brain stem, and several of the mice had hemorrhages in brain stem, cerebellum, and basal ganglia. No control mice on high-salt diet and L-NAME had hemorrhagic stroke. Arterial pressure in R+/A+ mice increased progressively during high-salt diet and L-NAME. In R+/A+ and control mice, high-salt diet or L-NAME alone did not increase arterial pressure.We now describe the first model of spontaneous hemorrhagic strokes in hypertensive mice. The type and locations of stroke are reasonably similar to those observed in patients with hypertension.