Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance.

Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents.

Relationship of postcontrast myocardial T1 value and delayed enhancement to reduced cardiac function and serious arrhythmia in dilated cardiomyopathy with left ventricular ejection fraction less than 35.

BACKGROUND: Dilated cardiomyopathy (DCM) is often associated with progressive heart failure or ventricular arrhythmia. Look-Locker magnetic resonance imaging (MRI) allows quantitative evaluation of interstitial fibrosis by measuring the myocardial T1 value, and delayed enhancement (DE) MRI visualizes myocardial scar. PURPOSE: To determine the relationship of postcontrast myocardial T1 value or DE to reduced cardiac function or sustained ventricular tachycardia (SVT) in DCM patients with a left ventricular ejection fraction (LVEF) <35%. MATERIAL AND METHODS: We enrolled 41 patients with DCM. Correlations between the cardiac function parameters and postcontrast myocardial T1 value or extent of DE were evaluated. The relationship between SVT and the T1 values or extent of DE was assessed. The correlation between the extent of DE and the T1 value was also examined. RESULTS: The postcontrast myocardial T1 value was significantly correlated with the LVEF (P < 0.05; r = 0.31) and end-diastolic volume (P < 0.01; r = -0.40) in 40 patients with LVEF <35%. DE was not correlated with the cardiac function, but provided a high negative predictive value of 94.7% for SVT. No correlation was found between the myocardial T1 value and extent of DE. CONCLUSION: In DCM patients with LVEF <35%, the postcontrast myocardial T1 value correlated with the severity of cardiac dysfunction, and the absence of DE indicated the low risk of SVT. Both MRI parameters should be estimated because they may reflect discrete forms of myocardial damages in patients with DCM.

Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A.

ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required.

Myocardial fibrosis evaluated by Look-Locker and late gadolinium enhancement magnetic resonance imaging in apical hypertrophic cardiomyopathy: association with ventricular tachyarrhythmia and risk factors.

PURPOSE: To evaluate the distribution and extent of myocardial fibrosis identified by either contrast-enhanced Look-Locker or late gadolinium enhancement magnetic resonance imaging (LGE MRI) and their relationships between ventricular tachyarrhythmia or risk factors in apical hypertrophic cardiomyopathy (APH). MATERIALS AND METHODS: Twenty-five APH patients were examined using a 3.0 T or 1.5 T instrument. We used MRI to evaluate myocardial T1 values and scar. We compared the myocardial fibrosis assessed by contrast-enhanced Look-Locker or LGE MRI with ventricular tachyarrhythmia or risk factors for hypertrophic cardiomyopathy. RESULTS: Myocardial scar was present in 17 of the 25 patients with APH. Myocardial scar was distributed predominantly in the apical myocardium (P < 0.01), whereas myocardial T1 values did not differ between the apical, midventricular, and basal septum. The extent of myocardial scar according to 16-segment model and ejection fraction were related to ventricular tachyarrhythmia or risk factors in APH (P < 0.05 for both). The myocardial T1 value was not associated with the tachyarrhythmia or risk factors. CONCLUSION: In APH, the extent of myocardial scar on LGE MRI is associated with ventricular tachyarrhythmia and risk factors. Quantification of the myocardial T1 value is not necessary for its risk stratification.

Contribution of extrahepatic collaterals to liver parenchymal circulation after proper hepatic artery embolization.

BACKGROUND AND AIM: To retrospectively evaluate proper hepatic artery embolization, with respect to the development of extrahepatic collaterals. METHODS: Proper hepatic artery embolization was performed in 18 patients with hemorrhagic arterial lesions in the hepatic hilum. Post-procedural development of extrahepatic collaterals was evaluated by computed tomography or angiography. Embolization data and liver function tests were assessed. The correlation of outcomes with portal venous stenosis, hepatic failure prior to embolization, elevation of prothrombin time, and insufficient collateral development were analyzed. RESULTS: Postoperative bleeding occurred in 17/18 patients, and one was treated for an idiopathic aneurysm of the proper hepatic artery; all treatments achieved technical success. Extrahepatic collaterals were confirmed in 13 patients. Elevations of liver function test values were transient and returned to baseline within 14 days in patients with collateral development (n = 13), but were unimproved in patients without collaterals (n = 5) (P < 0.001). Portal venous stenosis; prior hepatic failure; unrecovered, elevation of prothrombin time; and insufficient collateral development were significantly correlated with poor outcomes (P < 0.05, respectively). CONCLUSIONS: Proper hepatic artery embolization is effective for hemostasis, and extrahepatic collateral development is expected. Therefore, this is a safe treatment without prolonged hepatic ischemic damage, especially in patients without severe portal venous stenosis or prior hepatic failure.

Delayed enhancement magnetic resonance imaging in hypertrophic cardiomyopathy with Basal septal hypertrophy and preserved ejection fraction: relationship with ventricular tachyarrhythmia.

OBJECTIVE: This study aimed to determine the relationship between delayed enhancement magnetic resonance imaging (DE MRI) and ventricular tachyarrhythmia in patients with hypertrophic cardiomyopathy (HCM) with basal septal hypertrophy and preserved ejection fraction (EF). METHODS: One hundred seven patients with HCM with basal septal hypertrophy and EF greater than 50% underwent cine and DE MRI. Myocardial scar was identified with DE MRI. We assessed whether patient,s background, cine MRI findings, presence of myocardial scar, or number of scarred myocardial segments was related to the occurrence of ventricular tachyarrhythmia. RESULTS: Patient,s age, family history of HCM, and number of scarred segments differed between the patients with and without the arrhythmia. A family history of HCM and number of scarred segments were significantly related to ventricular tachyarrhythmia (P < 0.01). CONCLUSIONS: The number of scarred segments is the significant DE MRI parameter related to ventricular tachyarrhythmia in HCM with basal septal hypertrophy and preserved EF.

Anatomical relationship between the common carotid artery and the internal jugular vein during head rotation.

This study investigated the anatomical relationship between the common carotid artery and internal jugular vein during head rotation for the effective performance of percutaneous transjugular procedures. The subjects included 30 volunteers who had never undergone internal jugular vein cannulation. In the supine position, two-dimensional ultrasonographic images of the right internal jugular vein and common carotid artery were obtained, 2 and 4 cm above the clavicle, along the lateral border of the sternal head of the sternocleidomastoid muscle. Ultrasonographic images were examined for head rotation at 0°, 15°, 30°, 45°, 60°, and 75° from the midline to the left. The percentage of overlap of the common carotid artery by the internal jugular vein and the flattening of the internal jugular vein at each head rotation position were measured and evaluated. The overlap of the common carotid artery by the internal jugular vein significantly increased at ≥45° of head rotation 2 cm above the clavicle (P < 0.01) and at ≥30° of head rotation 4 cm above the clavicle (P < 0.01), compared with that observed in the neutral position. The flattening of the internal jugular vein significantly decreased at ≥45° of head rotation 2 cm above the clavicle (P < 0.01) and at ≥30° of head rotation 4 cm above the clavicle (P < 0.01). Head rotation should be kept to <45° at 2 cm above the clavicle and <30° at 4 cm above the clavicle to decrease the risk of accidental puncture of the common carotid artery during internal jugular vein puncture. Moreover, flattening of the internal jugular vein gradually decreases during head rotation to the side.

MRI differentiation of cardiomyopathy showing left ventricular hypertrophy and heart failure: differentiation between cardiac amyloidosis, hypertrophic cardiomyopathy, and hypertensive heart disease.

PURPOSE: To evaluate the capability of MRI to differentiate cardiac amyloidosis (CA), end-stage hypertrophic cardiomyopathy (HCM), and hypertensive heart disease (HHD), which are important etiologies of left ventricular hypertrophy (LVH) and heart failure. MATERIALS AND METHODS: We enrolled 26 patients presenting with both LVH and heart failure: six with CA, nine with end-stage HCM, and 11 with HHD. Cardiac function, presence of pericardial or pleural effusion, and the extent and patterns of late gadolinium enhancement (LGE) were compared among the three diseases. RESULTS: Myocardial LGE was observed in all six CA patients, eight end-stage HCM patients, and six HHD patients. The number of LGE segments was significantly greater in CA than in HCM or HHD (p = 0.02 for both), and all patients with CA showed a global endocardial pattern of LGE. There were significant differences among CA, HCM, and HHD in ejection fraction and end-diastolic and end-systolic volume indices (p < 0.05 for all). Pericardial effusion was observed more frequently in CA than in HCM or HHD (p = 0.04 or 0.01, respectively). CONCLUSION: MRI is valuable for distinguishing among CA, end-stage HCM, and HHD, all of which present with LVH and heart failure.

Anemia and the risk of contrast-induced nephropathy in patients with renal insufficiency undergoing contrast-enhanced MDCT.

PURPOSE: The purpose of this study was to assess the effect of anemia on the incidence of contrast-induced nephropathy (CIN) in patients with renal impairment undergoing MDCT. MATERIALS AND METHODS: Institutional review board approval was waived for this retrospective review of 843 patients with stable renal insufficiency (eGFR between 15 and 60 mL/min) who had undergone contrast-enhanced MDCT. Baseline hematocrit and hemoglobin values were measured. Serum creatinine (SCr) was assessed at the baseline and at 48-72 h after contrast administration. RESULTS: The overall incidence of CIN in the patient population with renal insufficiency was 6.9%. CIN developed in 7.8% (54 of 695) of anemic patients, and in 2.8% (4 of 148) of non-anemic patients (P=.027). After adjustment for confounders, low hemoglobin and low hematocrit values remained independent predictors of CIN (odds ratio 4.6, 95% CI 1.0-20.5, P=.046). CONCLUSIONS: Anemia is associated with a higher incidence of CIN in patients with renal insufficiency. Anemia is a potentially modifiable risk factor for CIN, and has an unfavorable impact on prognosis in patients with renal insufficiency undergoing contrast-enhanced MDCT.

CT, MRI, and PET findings of gastric schwannoma.

Gastric schwannoma is a rare tumor that accounts for only 0.2 % of all gastric tumors. We report a case of gastric schwannoma that underwent computed tomography (CT), magnetic resonance imaging (MRI), and [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and its histological confirmation was acquired. Gastric schwannoma showed high intensity on T2-weighted and diffusion-weighted MRI and high maximum standardized uptake on [(18)F]-FDG-PET. Lymphadenopathy close to the tumor was also found. Although diffusion-weighted MRI, [(18)F]-FDG-PET, and the presence of lymphadenopathy could suggest malignant tumors, the detail interpretation of the other CT and MRI findings may give a clue for the diagnosis of gastric schwannoma.

Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice.

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.