Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.

Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons.

1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.

[Localized Nodular Pulmonary Amyloidosis after Resection of Lung Cancer;Report of a Case].

A 79-year-old man had undergone endoscopic colorectal resection for colon cancer and partial resection of right S2 for lung cancer in 2007. Two years later, enlargement of a small nodule in the right S10 detected by chest computed tomography was noted. Partial lung resection was performed in April 2009, and the pathological diagnosis was localized nodular pulmonary amyloidosis.

The relationship of fibroblast growth factors 21 and 23 and α-Klotho with platelet activity measured by platelet volume indices.

BACKGROUND: Subjects with high fibroblast growth factor 21(FGF21) and 23 (FGF23), endocrine hormones that regulate insulin sensitivity and phosphate metabolism, respectively, are reported to have a higher risk for adverse cardiovascular outcome. Therefore, the relationship of FGF21, FGF23, and α-Klotho (co-receptor for FGF23 signaling) with mean platelet volume (MPV) and platelet distribution width (PDW), two platelet volume indices that reflect platelet activity, was investigated. METHODS: Data from 156 patients admitted to the cardiology department were analyzed. MPV and PDW were measured by an automatic blood counter, and serum FGF21, FGF23, and α-Klotho concentrations were measured by an enzyme-linked immunoassay. RESULTS: Log(FGF21) was significantly correlated with serum triglycerides but did not differ according to the use of non-use of antidiabetic or lipid-lowering drugs. MPV and PDW were significantly correlated (R=0.475, p<0.001). MPV was significantly correlated with log(FGF21) (R=-0.167, p<0.05) and log(FGF23) (R=0.351, p<0.001) but not with log(α-Klotho). Linear regression analysis showed a negative and positive association of log(FGF21) and log(FGF23), respectively, with MPV that was independent of possible confounders including sex, age, renal function, and antithrombotic drug use. In addition, log(FGF23) was found to have a significant independent positive association with PDW. CONCLUSIONS: Among cardiac patients, FGF21 had a negative association with MPV, whereas FGF23 had a positive association. Future studies of serum FGF23/FGF21 concentrations and the incidence of thromboembolic disorders are warranted.

Platelet volume indices are associated with systolic and diastolic cardiac dysfunction, and left ventricular hypertrophy.

BACKGROUND: Mean platelet volume (MPV) and platelet distribution width (PDW) are indices that reflect platelet activity. We investigated the association between these platelet indices and left ventricular hypertrophy and cardiac function. METHODS: We analyzed the data of 1241 patients who were admitted to the Cardiology Department. RESULTS: Both MPV and PDW were selected as independent factors associated with left ventricular systolic and diastolic dysfunction, and left ventricular hypertrophy. The highest tertile of MPV and PDW was associated with left ventricular systolic dysfunction (left ventricular ejection fraction of <50 %) with an odds ratio of 1.53 and 2.03, respectively, when the respective lowest tertile was used as reference. The highest PDW tertile was associated with left ventricular hypertrophy with an odds ratio of 1.56 (95 % CI, 1.13-2.15) and with dysfunction with an odds ratio of 3.34 (95 % CI, 1.54-7.25). CONCLUSIONS: Indices of platelet activation (MPV and/or PDW) were independently associated positively with left ventricular hypertrophy and left ventricular systolic and diastolic dysfunction. Whether these platelet indices represent useful markers for identifying individuals at higher risk for thromboembolic disease and organ damage among cardiac patients awaits further investigation.

[A New Method of Analyzing the Closing Volume (CV) Curve: "N2 First Derivative Wave Method"].

Evaluation of the lung function involves the measurement of many factors. The closing volume (CV) curve is clinically important as an index of uneven alveolar ventilation and airway closure. Although conventional methods for CV measurement are usually based on the pattern of the exhaled nitrogen (N2) concentration curve with respect to the lung volume, it is often difficult to measure the steep pattern of patients with chronic obstructive pulmonary disease (COPD). In this paper, we proposed a new method called the "N2 first derivative (fdN) wave method" for measuring CV. The N2 concentration of the CV curve was transformed to a derivative with respect to the lung volume, which revealed the existence of cardiogenic oscillations. Discrimination between phases III and IV was straightforward based on the difference in the slope or in the amplitude of oscillations of the fdN wave. Our new method was able to distinguish phase IV from phase III using the difference in amplitude of the oscillation of the fdN wave even in the presence of COPD with steep patterns of the CV curve. Close relationships were seen among normal subjects including COPD patients in both the slope of the alveolar plateau (ΔN2) and the CV values measured with the conventional and new methods. In conclusion, the new method we propose in this paper was able to provide measurements of CV for all subjects including those with COPD. [Original]

Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters.

The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 µm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, ß-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea.

Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes.

Fulminant type 1 diabetes, established in 2000, is defined as a novel subtype of diabetes mellitus that results from remarkably acute and almost complete destruction of pancreatic beta cells at the disease onset. In this study, we aimed to clarify the pathogenesis of fulminant type 1 diabetes with special reference to insulitis and viral infection. We examined pancreatic autopsy samples from three patients who had died soon after the onset of disease and analyzed these by immunohistochemistry and in situ-hybridization. The results were that both beta and alpha cell areas were significantly decreased in comparison with those of normal controls. Mean beta cell area of the patients just after the onset was only 0.00256 % while that of normal control was 1.745 %. Macrophages and T cells-but no natural killer cells-had infiltrated the islets and the exocrine pancreas. Although both of them had massively infiltrated, macrophages dominated islet infiltration and were detected in 92.6 % of the patients' islets. Toll-like receptor (TLR) 3, a sensor of viral components, was detected in 84.7+/- 7.0 % of T cells and 62.7+/- 32.3 % of macrophages (mean+/- SD) in all three patients. TLR7 and TLR9 were also detected in the pancreas of all three patients. Enterovirus RNA was detected in beta-cell positive islets in one of the three patients by in situ-hybridization. In conclusion, our results suggest that macrophage-dominated insulitis rather than T cell autoimmunity contributes to beta cell destruction in fulminant type 1 diabetes.

Type B3 thymoma with marked neuroendocrine differentiation: Report of a case.

Thymomas are tumors originating from the thymus epithelial cells and are the most common tumors of the anterior mediastinum. They have been classified into types A, AB, B1, B2, and B3 by the World Health Organization. Type B3 thymoma is composed of epithelial cell sheets with mild to moderate atypia and scant lymphocytes. An association between thymic carcinoma and neuroendocrine differentiation has been observed by some authors. However, cases of type B3 thymoma with neuroendocrine differentiation are very rarely discussed in the literature. A 68-year-old woman was referred to our hospital with an abnormal shadow on a chest roentgenogram. Chest computed tomography showed that the lesion was located in the anterior mediastinum. She underwent surgery, and the tumor was diagnosed as a type B3 thymoma with neuroendocrine differentiation. An extremely rare case of a type B3 thymoma showing neuroendocrine differentiation is presented herein.

Mean platelet component and mean platelet volume as useful screening markers for myelodysplastic syndrome.

BACKGROUND: Hematologic disorders, including myelodysplastic syndrome (MDS), are difficult to identify in routine hematologic examinations using automated hematology analyzers. However, the practical uses of mean platelet component and mean platelet volume (MPV) measured by these analyzers as screening markers for MDS, remain unclear. METHODS: Mean platelet component and MPV values were measured in the peripheral blood of patients with MDS, aplastic anemia, idiopathic thrombocytopenic purpura, myeloproliferative neoplasms, and in healthy controls using an automated hematologic analyzer. Cutoff values for discriminating between the MDS group and healthy controls were determined by recursive partitioning analysis. RESULTS: Mean platelet component was significantly lower in MDS patients compared with controls, while MPV was significantly higher. Combined cutoff values for MDS diagnosis of <25.3 g/dL for mean platelet component and >10.0 fL for MPV showed a specificity and positive predictive value of 99.9% and 99.1%, respectively. These cutoff values also differentiated between MDS and diagnoses of aplastic anemia, idiopathic thrombocytopenic purpura, and myeloproliferative neoplasms. CONCLUSION: Mean platelet component and MPV may, thus, be useful and convenient screening markers for MDS.

Angiotensin II receptor blocker reduces oxidative stress and attenuates hypoxia-induced left ventricular remodeling in apolipoprotein E-knockout mice.

Elevated superoxide formation in cardiac extracts of apolipoprotein E-knockout (apoE-KO) mice has been reported. In addition, we previously reported that hypoxia increased oxidative stress in the aortas of apoE-KO mice, although we did not examine the effect of hypoxia on the heart. The aim of this study was to investigate the effect of chronic hypoxia on the left ventricular (LV) remodeling in apoE-KO mice treated with or without an angiotensin II receptor blocker. Male apoE-KO mice (n=83) and wild-type mice (n=34) at 15 weeks of age were kept under hypoxic conditions (oxygen, 10.0+/-0.5%) and treated with olmesartan (3 mg/kg/day) or vehicle for 3 weeks. Although LV pressure was not changed, hypoxia caused hypertrophy of cardiomyocytes and increased interstitial fibrosis in the LV myocardium. Furthermore, nuclear factor-kappaB (NF-kappaB) and matrix metalloproteinase (MMP)-9 activities were increased in apoE-KO mice exposed to chronic hypoxia. Olmesartan effectively suppressed the 4-hydroxy-2-nonenal protein expression and NF-kappaB and MMP-9 activities, and preserved the fine structure of the LV myocardium without affecting the LV pressure. In conclusion, olmesartan reduced oxidative stress, and attenuated the hypoxia-induced LV remodeling, in part through the inhibition of NF-kappaB and MMP-9 activities, in apoE-KO mice.

Manual laparoscopy-assisted intraoperative reduction for adult ileocolic intussusception with ileal adenoma: A case report.

INTRODUCTION: Adult intussusception is a rare condition with a pathological lead point. Intraoperative reduction of adult intussusception can eliminate the need for extensive or invasive resection. We safely performed a manual laparoscopy-assisted intraoperative reduction that allowed functional preservation of tissue. PRESENTATION OF CASE: A 70-year-old woman with dull right lumbar pain at regular intervals and right lower quadrant abdominal tenderness was admitted to our hospital. The ileum exhibited enhanced wall thickening and invagination into the ascending colon on computed tomography. Emergency laparoscopic surgery was chosen to treat the ileocolic intussusception. First, the right colon was mobilized. Second, the ileocecal region was pulled through a 4-cm right pararectus incision. Third, the edge of the intussusceptum was gently manipulated back upstream without tearing. After reduction, a soft mass was recognized on palpation at the lead point, located 10cm proximal to the ileocecal valve. Ileocecal resection was performed, and a laterally spreading tumor was observed in the resected specimen. The histological diagnosis was high-grade tubular adenoma. The postoperative course was uneventful. DISCUSSION: Adult intussusception has a pathological lead point, and curative treatment generally includes resection of the lesion. Complete or partial intraoperative reduction can avoid or shorten bowel resection and allow functional preservation of the tissue. CONCLUSION: Manual laparoscopy-assisted intraoperative reduction with a minilaparotomy was safely performed, which eliminated the need for extensive or invasive resection.

Fatal cardiac anomaly of unguarded mitral orifice with asplenia syndrome.

We report the case of a newborn baby with an unguarded mitral orifice associated with asplenia syndrome, double-outlet right ventricle, dysplastic tricuspid valve, and pulmonary stenosis. This case was accompanied by severe tricuspid regurgitation and severe right ventricular hypertrophy. The patient had a fatal clinical course due to severe hypoxia and congestive heart failure. Unguarded mitral orifice is a rare disease in which there has been no previous report of lethal clinical course during the neonatal period. Prior reports stated that unguarded mitral orifice was a new constellation of defects and that its etiology and embryology could be classified in the same category because of similar associated malformations of double-outlet right ventricle and pulmonary stenosis or atresia. However, the present case was diagnosed on autopsy as also having asplenia syndrome. Therefore, it is possible that the genetic etiology of unguarded mitral orifice in this case was different from cases of non-heterotaxy. .

Capillary Degeneration and Right Ventricular Remodeling Due to Hypoxic Stress with Sugen5416.

BACKGROUND: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients. OBJECTIVE: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group). RESULTS: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed. CONCLUSION: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.

Extramedullary Plasmacytoma Arising From the Anterior Mediastinum.

Plasmacytomas are a localized proliferation of plasma cells in the bone marrow and soft tissue. Extramedullary plasmacytomas are rare and typically solitary plasma cell neoplasms originating from extraosseous organs and tissues. A 31-year-old woman was referred to our hospital with a rapidly growing abnormal shadow on a chest roentgenogram. Chest computed tomography showed that the lesion was located in the anterior mediastinum. She underwent surgery, and the tumor was diagnosed as an extramedullary plasmacytoma. She remains well 2 years postoperatively without recurrence. An extremely rare case of an anterior mediastinal extramedullary plasmacytoma is presented.

Anatomical hepatectomy for liver metastasis from rectal adenocarcinoma presenting with intrabiliary extension: a case report.

Liver metastases from colorectal carcinoma commonly form nodular lesions in the liver parenchyma. We report a case of liver metastasis from rectal adenocarcinoma that extended predominantly into the bile duct. A 62-year-old Japanese man underwent low anterior resection for rectal adenocarcinoma 9 years ago. Approximately 3 years later, he underwent radiofrequency ablation therapy for a metastatic liver tumor. Nine years after surgery, a tumor in liver segment III exhibiting intrabiliary extension was discovered; it was unclear if this was a metastatic liver tumor or intrahepatic cholangiocarcinoma. Accordingly, we performed a left hepatectomy with lymph node dissection. The tumor was negative for cytokeratins 7 and 20, and was histologically similar to the primary rectal adenocarcinoma; it was diagnosed as rectal carcinoma metastasis. The patient has survived for 3 years after the hepatic surgery, for 9 years after radiofrequency ablation therapy, and for 12 years after the primary surgery. This case shows that liver metastasis from colorectal carcinoma can present as a predominantly intrabiliary growth that mimics intrahepatic cholangiocarcinoma on imaging. Moreover, our case provides evidence for the superiority of anatomical hepatectomy over partial hepatectomy for metastatic liver tumors with intrabiliary growth arising from rectal adenocarcinomas.

Bronchial artery aneurysm suggested to be caused by metalic tracheal stent migration.

Occurrence of bronchial artery aneurysm is rare, and it has been detected in less than 1 % of all selective bronchial arteriography cases. Here, we present a case of a bronchial artery aneurysm caused by a tracheal stent migration. A 59-year-old man was operated on for esophageal cancer, where an esophageal-tracheal fistula occurred 1 week after operation. Surgical repair of the esophageal-tracheal fistula was performed using a muscle flap, but this not results in fistula closure. Consequently, a self-expanding covered metallic tracheal stent was implanted for rescue, and this resulted in fistula closure. After 1 year, there was frequent hemoptysis caused by migration of the stent. He was referred to our hospital where removal of the stent was planned. A sudden occurrence of massive bleeding from trachea occurred, and extracorporeal membrane oxygenation (ECMO) was used. Although removal of tracheal stent was performed successfully, the patient subsequently died from multi-organ failure. Post-mortem autopsy revealed that the massive bleeding is originated from the rupture of a bronchial artery aneurysm.

Chronic hypoxia accelerates the progression of atherosclerosis in apolipoprotein E-knockout mice.

The aim of this study was to investigate the effect of chronic hypoxia on the development and progression of atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. Male and female apoE-KO mice (6 weeks old) and age- and sex-matched wild-type mice were kept under hypoxic conditions (10.0 +/- 0.5% O2) in a gas chamber or in room air for 3 weeks. Aortic atherosclerotic plaque was not observed in wild-type mice under normoxic or hypoxic conditions. In the apoE-KO mice, however, hypoxia induced proliferation of smooth muscle cells and plaque formation in the aorta, which were not observed under normoxic conditions. Although sexual dimorphism of the response to hypoxia was not observed, these hypoxia-induced atherogenic changes were accompanied by a significant increase of plasma low density lipoprotein (LDL) cholesterol and NADPH-dependent vascular superoxide (O2-) production. Furthermore, matrix metalloproteinase (MMP)-9 was activated in the aorta of apoE-KO mice. In conclusion, chronic hypoxia accelerated the development of atherosclerosis in apoE-KO mice, along with increased O2- production and activated MMP-9 in the aorta.

A case of vulvar superficial angiomyxoma with necrotizing angiitis-like lesions and expression of granulocyte-colony stimulating factor.

A vulvar tumor of 3-year-old girl was resected. The tumor had a pedunculated polypoid appearance with a multinodular surface and was covered by normal colored skin. Histologically, the tumor was lobulated and consisted of sparse stellate- or spindle-shaped tumor cells with a large amount of edematous stroma admixed with myxomatous areas. The tumor was rich in blood vessels of various sizes. Several blood vessels showed fibrinoid necrosis. There was a diffuse neutrophilic infiltration in the stroma. The tumor was diagnosed as a superficial angiomyxoma. Immunohistochemically, the tumor cells diffusely expressed vimentin, focally alpha-smooth muscle actin and desmin. Both estrogen and progesterone receptors were negative. Occasionally, they expressed CD34. Most of the tumor cells expressed granulocyte-colony stimulating factor (G-CSF). Endothelial cells of tumor blood vessels occasionally expressed intercellular adhesion molecule-1 or E-selectin. Some endothelial cells in the tumor were immunolabeled by anti-vascular endothelial growth factor (VEGF) antibody along their luminal surfaces. In the present case, G-CSF and adhesion molecules to neutrophils may have played some roles in neutrophilic infiltration into the tumor and in fibrinoid necrosis of the blood vessels. In addition to these molecules, VEGF may have contributed to vascular growth, leading to edematous stroma.

Multiple infectious pseudoaneurysms: An autopsy case.

A 47-year-old Japanese woman died unexpectedly 11 days after admission due to acute cerebellar infarction. The patient had a history of Sjögren syndrome with long-term steroid therapy, hypertension, thalamic infarction and amphetamine psychosis. Multiple pseudoaneurysms in both the aorta and coronary artery were found at autopsy, and one located in the aortic root had ruptured into the pericardium resulting in sudden unexpected death. The detailed examination suggested that the pseudoaneurysms resulted from microbial infection to the arterial wall via the vasa vasorum. Immunosuppression induced by the long-term steroid therapy and abused drug injection could have influenced the formation of pseudoaneurysms.