The effects of oral adsorbent (AST-120) in the experimental model of chronic renal failure--pathophysiological study on renal function, glomerular hypertrophy, mesangial function and glomerular histology

Oral adsorbent (AST-120) reduces blood levels of urea and creatinine in experimental studies. It has also been shown to retard the progression of chronic renal failure in clinical studies. In the present study, the effect of AST-120 was examined in the rat model of subtotal nephrectomy (sNPX). This experimental model of chronic renal failure is characterized by glomerular hyperfunction, glomerular hypertrophy, increased mesangial trapment of macromolecules and subsequent glomerular sclerosis. We report the effect of AST-120 on glomerular hyperfunction, glomerular hypertrophy and mesangial trapment of macromolecules in the early stage and glomerular function and histology in the late stage of the rat model of sNPX. From 2 days after sNPX, rats were fed regular rat chow with (AST group: AST) or without (control) AST-120. At 2 weeks, iron dextran (ID) was injected intravenously. Three days after the injection, mesangial trapment of ID was largely ameliorated in AST when compared with control (p less than 0.02). The value of mean planar area of glomerulus (PAmean) in AST was significantly lower than that in control (p less than 0.05). At 2 and 9 weeks, the values of GFR and RPF in AST were all statistically higher than those in control. At 9 weeks, whereas average glomerular sclerosis index (SI: 0-4 scale) was 1.07 in control, significantly lower SI (0.57) was noted in AST (p less than 0.05). Thus, AST-120 has effects on glomerular hypertrophy, increased mesangial trapment of macromoleculus and finally the progression of chronic renal failure in the rat model of sNPX. The effects are not through reducing glomerular hyperfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.     

P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A

A series of different human MDR (multidrug-resistant) cell lines including a HeLa-MDR1 transfectant which exhibit high overexpression of the MDR1/P-glycoprotein gene, but no enhanced expression of the MRP (multidrug resistance associated protein) gene, showed different ratios of relative resistances to the taxanes taxol and taxotere. Using these cell lines the chemosensitizing efficacies of several structurally different chemosensitizers, i.e. the dihydropyridine dexniguldipine-HC1 (B8509-035), its main pyridine metabolite M1 (B8909-008), the cyclic peptide cyclosporin A, or the phenylalkylamine dexverapamil-HCl, were examined applying a 72 h tetrazolium based colorimetric MTT-assay, or a 96 h sulforhodamine B assay. Remarkably, we observed in some instances that the modulating efficacy of a particular chemosensitizer was strongly dependent on the cell line used for experimentation. Thus, dexniguldipine-HCl efficiently modulated taxane resistances of the ovarian carcinoma MDR cell line 2780AD in the submicromolar concentration range, whereas cyclosporin A and the other chemosensitizers were rather ineffective. Dexniguldipine-HCl or cyclosporin A, however, both showed a similarly strong modulating activity on the HeLa-MDR1 transfectant in clear contrast to the effects observed using the pyridine B8909-008, or dexverapamil-HCl, respectively, at the same final concentrations. Our results point to additional, as yet unidentified factors beyond the expression levels of P-glycoprotein which could contribute to the susceptibility of MDR cells to a combined treatment using taxanes and different chemosensitizing compounds. This result appears to be important considering the clinical application of chemosensitizers for combination therapy of tumors of different origin.     

Chronological observation of surgically‐treated granuloma faciale implies the necessity of circumspect management for perinasal nodular subset

Granuloma faciale (GF) is a rare chronic dermatosis with still unknown etiopathology, which usually presents a solitary, asymptomatic, smooth reddish‐brown to violaceous plaques or nodules on the face. Various therapeutic approaches, including topical application of corticosteroid or tacrolimus and removal with laser, cryotherapy and surgery have been attempted; however, the outcome has been inconsistent. Herein, we report a case of perinasal nodular GF who repeatedly underwent surgical excisions after the failure of laser treatment. Despite its nomenclature, GF does not manifest granulomatous tissue and the lesion is histopathologically characterized by dense dermal cell infiltration devoid of granulomatous changes and not distinguished by a clear border, which partially explains the difficulty of complete removal in our case. Review of the published work delineated that GF could be largely divided into two clinical subsets: plaque and nodular types. The plaque type GF could be responsive to topical tacrolimus, an approach preferentially adopted nowadays, while nodular type GF was often resistant to topical therapies and required surgical or laser removal. The latter subset often arose around the nose. For this location, surgical excision with sufficient removal margin is sometimes technically difficult when an aesthetically acceptable outcome is expected, explaining the basis for local recurrence. Postoperative recurrence could be observed after years of disease‐free period. These observations indicated that the need for respective treatment strategies for the management of distinctive GF subsets. Of note, a multidisciplinary approach combining radical resection and additional supportive intervention with long‐term follow up may be required for perinasal and nodular GF.     

Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.     

Evaluation of the input site and characteristics of the antegrade fast pathway based on three-dimensional bi-atrial stimulus-ventricle mapping

Journal of Interventional Cardiac Electrophysiology - Previous studies examined the right atrial (RA) input site of the antegrade fast pathway (AFp) (AFpI). However, the left atrial (LA) input to...