A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren

Wu WP, Chang CH, Chiu YT, Ku CL, Wen MC, Shu KH, Wu MJ. A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren. Am J Physiol Renal Physiol 299: F929-F941, 2010. First published August 4, 2010; doi:10.1152/ajprenal.00192.2010.-The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with valsartan (15 mg . kg(-1) . day(-1)) and aliskiren (10 mg . kg(-1) . day(-1)), valsartan monotherapy (30 mg . kg(-1) . day(-1)), and aliskiren monotherapy (20 mg . kg(-1) . day(-1)) all significantly ameliorated the increase in blood urea nitrogen and the degree of hydronephrosis determined by the increase in weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent of the vasodilatory effect. There were no significant changes in serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO-related increases in the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, alpha-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-beta 1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and the (pro) renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro) renin receptor. In conclusion, a direct renin inhibitor in conjunction with an angiotensin II receptor blocker exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone

Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells

Aristolochic acid (AA) has been demonstrated to play a causal role in Chinese herbs nephropathy. However, the detailed mechanism for AA to induce apoptosis of renal tubular cells remains obscure. In this study, we show that AA evokes a rapid rise in the intracellular Ca2+ concentration of renal tubular cells through release of intracellular endoplasmic reticulum Ca2+ stores and influx of extracellular Ca2+, which in turn causes endoplasmic reticulum stress and mitochondria stress, resulting in activation of caspases and finally apoptosis. Ca2+ antagonists, including calbindin-D-28k (an intracellular Ca2+ buffering protein) and BAPTA-AM (a cell-permeable Ca2+ chelator), are capable of ameliorating endoplasmic reticulum stress and mitochondria stress, and thereby enhance the resistance of the cells to AA. Moreover, we show that overexpression of the anti-apoptotic protein Bcl-2 in combination with BAPTA-AM treatment can provide renal tubular cells with almost full protection against AA-induced cytotoxicity. In conclusion, our results demonstrate an impact of AA to intracellular Ca2+ concentration and its link with AA-induced cytotoxicity

Manganites at Quarter Filling: Role of Jahn-Teller Interactions

We have analyzed different correlation functions in a realistic spin-orbital model for half-doped manganites. Using a finite-temperature diagonalization technique the CE phase was found in the charge-ordered phase in the case of small antiferromagnetic interactions between $t_{2g}$ electrons. It is shown that a key ingredient responsible for stabilization of the CE-type spin and orbital-ordered state is the cooperative Jahn-Teller (JT) interaction between next-nearest Mn$^{+3}$ neighbors mediated by the breathing mode distortion of Mn$^{+4}$ octahedra and displacements of Mn$^{+4}$ ions. The topological phase factor in the Mn-Mn hopping leading to gap formation in one-dimensional models for the CE phase as well as the nearest neighbor JT coupling are not able to produce the zigzag chains typical for the CE phase in our model.Comment: 16 pages with 16 figures, contains a more detailed parameter estimate based on the structural data by Radaelli et al. (accepted for publication in Phys. Rev. B

Thirty-Day Clinical Outcome of Primary Percutaneous Intervention Versus Fibrinolysis Followed by Coronary Angiography in ST-Segment Elevation Myocardial Infarction

Background: Primary percutaneous coronary intervention (PCI)is the preferred reperfusion strategy in patients with ST-segment elevation myocardial infarction (STEMI). However, timely PCI cannot be offered to many patients. Objective: The purpose of this study was to compare the 30-day clinical outcome of primary PCI strategy and fibrinolysis followed by coronary angiography strategy in STEMI patients. Methods: This was a prospective, observational, single center study. All patients admitted for STEMI from 1 January 2016 to 30 November 2016 were screened for the study. Patients were divided into 2 reperfusion strategies: primary PCI or fibrinolysis followed by coronary angiography. Primary outcome was composite of all-cause mortality at 30 days. Results: A total of 178 patients were identified: 33 (18.5%) underwent primary PCI and 145 (81.5%) underwent fibrinolysis first. The median door-to-balloon time in the primary PCI group was 161.0 minutes (IQR 84.5). The median time from fibrinolysis-to-arrival at catheterization lab was 1738 minutes (IQR 901). The median total ischaemic time was 369 min (IQR 524) and 210 (IQR 247) for the primary PCI and fibrinolysis first group respectively (p=0.002). Kaplan-Meier survival analysis for 30-day all-cause mortality was 24.2% vs 9.7% respectively in primary PCI and fibrinolysis group p=0.018). Multivariate Linear Regression showed that Killip Class and LVEF were independent predictors of 30-day all-cause mortality. Reperfusion strategy was not associated with 30-day all-cause mortality (p=0.216). Conclusions: The clinical outcome of primary PCI strategy in STEMI is not better than fibrinolysis followed by coronary angiography strategy when timely PCI cannot be performed

Multi-spectral intravascular photoacoustic/ultrasound/optical coherence tomography tri-modality system with a fully-integrated 0.9-mm full field-of-view catheter for plaque vulnerability imaging

Myocardial infarctions are most often caused by the so-called vulnerable plaques, usually featured as non-obstructive lesions with a lipid-rich necrotic core, thin-cap fibroatheroma, and large plaque size. The identification and quantification of these characteristics are the keys to evaluate plaque vulnerability. However, single modality intravascular methods, such as intravascular ultrasound, optical coherence tomography and photoacoustic, can hardly achieve all the comprehensive information to satisfy clinical needs. In this paper, for the first time, we developed a novel multi-spectral intravascular tri-modality (MS-IVTM) imaging system, which can perform 360° continuous rotation and pull-backing with a 0.9-mm miniature catheter and achieve simultaneous acquisition of both morphological characteristics and pathological compositions. Intravascular tri-modality imaging demonstrates the ability of our MS-IVTM system to provide macroscopic and microscopic structural information of the vessel wall, with identity and quantification of lipids with multi-wavelength excitation. This study offers clinicians and researchers a novel imaging tool to facilitate the accurate diagnosis of vulnerable atherosclerotic plaques. It also has the potential of clinical translations to help better identify and evaluate high-risk plaques during coronary interventions

Comparison of Resting PD/PA with Fractional Flow Reserve Using a Monorail Pressure Catheter

Background: The RXi™ system (ACIST Medical Systems, MN, USA) is a new Fractional Flow Reserve (FFR) technology utilising an ultrathinmonorail microcatheter (Navvus®; ACIST Medical Systems) with an optical pressure sensor located close to the distal catheter tip. FFR measurement using monorail microcatheter is comparable to the conventional pressure wires. However, the predictive value of resting distal coronary artery pressure/aortic pressure (Pd/Pa) on hyperemic FFR value in the real world practice is unknown. Objective: To explore the diagnostic accuracy of resting Pd/Pa in relation to hyperemic FFR using the monorail pressure catheter. Methods: Resting Pd/Pa and FFR were measured using monorail pressure catheter in 67 consecutive patients with intermediate coronary artery lesions (30% to 80% diameter stenoses) between 01-03-2016 to 17-01-2017. Of 121 studied lesions, 29 (23.97%) were excluded because of no hyperemic FFR due to postive resting Pd/Pa (n=17), severe or non-critical stenosis (n=11) and suboptimal acquisition (n=1), leaving 92 lesions for final analysis. Hyperemic FFR was induced with intracoronary adenosine. The selection of coronary wire and the dose of intracoronary nitroglycerine were at the operators’ discretions. Results: Bland-Altman plots showed a moderate degree of scatter between Pd/Pa and FFR value. On average, Pd/Pa exceeded FFR by 0.066 (-0.09 to +0.22). Receiver-operating characteristic curves of the resting Pd/Pa with FFR≤0.80 as the reference variable showed an area under the curve of 0.78 (95% confidence intervals 0.680 to 0.881, pb0.001), with a diagnostic accuracy of 79.3% when the resting Pd/Pa was ≤0.86. Certain cutoff values of Pd/Pa can reliably predict whether hyperemic FFR was positive or negative (FFR cutoff≤0.80). Resting Pd/Pa value of N0.96 had a negative predictive value (NPV) of 100% and sensitivity of 100%; the resting Pd/Pa value of ≤0.82 had a positive predictive value (PPV) of 100% and specificity of 98.3%. These were consistent regardless of coronary vessel, location of lesion or degree of diameter stenosis. Conclusions: Certain range of resting Pd/Pa measured by monorail pressure catheter had excellent NPV and sensitivity or excellent PPV and specificity to predict hyperemic FFR. Clinical outcome studies are required to determine whether the results might obviate the need for hyperemia in selected patients

High-quality strong lens candidates in the final kilo-degree survey footprint

Large scale structure and cosmolog

Prognostic Value of N-terminal B-type Natriuretic Peptide in Patients with Acute Myocardial Infarction: A Multicenter Study

Background: Several models have been developed to help the clinician in risk stratification for Acute Coronary Syndrome (ACS),such as the TIMI and GRACE risk scores. However, there is conflicting evidence for the prognostic value of NT-ProBNP in acute myocardial infarction (AMI). Objective: (1) To explore the association of NT-proBNP with 30-day clinical outcome in AMI patients. (2) To compare the prognostic value of NT-proBNP with TIMI and GRACE risk scores in AMI patients. Methods: We conducted a multicenter, prospective observational study recruiting patients presented with AMI between 29-October-2015 and 14-January-2017, involving 1 cardiology referral centre and 4 non-cardiology hospitals. NT-proBNP level (Alere Triage®, US)was measured within 24 hours fromthe diagnosis of AMI. Patientswere followed-up for 1 month. Results: A total of 186 patients were recruited, 143 from tertiary cardiology centre and 43 from non-cardiology hospitals. Mean age was 54.7±10.0 years, 87.6% male and 64% were STEMI. The NT-proBNP level ranged from 60 to 16700pg/ml, with a median of 714pg/ml. Using the 75th centile as the cutoff, Kaplan-Meier survival analysis for the 30-day cardiac related mortality was significantly higher for patient with NT-proBNP level of ≥1600pg/ml (6.4% vs. 0.7%, p=0.02). Cox-regression analysis showed that NT-proBNP level of ≥1600pg/ml was an independent predictor of 30-day cardiac related mortality, regardless of TIMI risk score, GRACE score, LV ejection fraction and study hospitals (HR 9.274, p=0.054, 95%CI 0.965, 89.161). Readmission for heart failure at 30-day was also higher for patient with NT-proBNP level of ≥1600pg/ml (HR 9.308, p=0.053, 95%CI 0.969, 89.492). NT-proBNP level was not associated with all-cause mortality, risk of readmission for ACS, arrhythmia and stroke (pN0.05). By adding 50 score to GRACE risk score for NT-proBNP level of ≥1600pg/ml, combination of GraceNT-proBNP scores of more than 200 appeared to be a better independent predictor for 30-day cardiac related mortality (HR:28.28, p=0.004, 95%CI 2.94, 272.1). ROC analysis showed that this new score had 75% sensitivity and 91.2% specificity in predicting 30-day cardiac related mortality (AUC 0.791, p=0.046). Conclusions: NT-proBNP is a useful point-of-care risk stratification biomarker in AMI. It can be combined to the current risk score model for better risk stratification in AMI patients

Common variants at theCHEK2gene locus and risk of epithelial ovarian cancer

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.Other Research Uni