Ursodeoxycholic acid as a means of preventing atherosclerosis,steatosis and liver fibrosis in patients with nonalcoholic fatty liver disease

BACKGROUNDAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Weight loss is a key factor for successful NAFLD and CVD therapy. Ursodeoxycholic acid (UDCA), which is one of the first-line therapeutic agents for treatment of NAFLD, is reported to have a beneficial effect on dyslipidemia and ASCVD risk because of antioxidant properties.AIMTo evaluate the effects of 6 mo of UDCA treatment on hepatic function tests, lipid profile, hepatic steatosis and fibrosis, atherogenesis, and ASCVD risk in men and women with NAFLD, as well as to assess the impact of > 5% weight reduction on these parameters.METHODSAn open-label, multicenter, international noncomparative trial was carried out at primary health care settings and included 174 patients with ultrasound-diagnosed NAFLD who received 15 mg/kg/d UDCA for 6 mo and were prescribed lifestyle modification with diet and exercise. The efficacy criteria were liver enzymes, lipid profile, fatty liver index (FLI), noninvasive liver fibrosis tests (nonalcoholic fatty liver disease fibrosis score and liver fibrosis index), carotid intima-media thickness (CIMT), and ASCVD risk score. To test statistical hypotheses, the Wilcoxon test, paired t-test, Fisher’s exact test, and Pearson''s chi-squared test were used. RESULTSThe alanine aminotransferase (ALT) level changed by -14.1 U/L (-31.0; -5.3) from baseline to 3 mo and by -6.5 U/L (-14.0; 0.1) from 3 to 6 mo. The magnitude of ALT, aspartate transaminase, and glutamyltransferase decrease was greater during the first 3 mo of treatment compared to the subsequent 3 mo (P < 0.001, P < 0.01, P < 0.001, respectively). At 6 mo, in the total sample, we observed a statistically significant decrease in body weight and levels of FLI: 84.9 ± 10.4 vs 72.3 ± 17.6, P < 0.001, total cholesterol: 6.03 ± 1.36 vs 5.76 ± 1.21, Р < 0.001, low-density lipoprotein: 3.86 ± 1.01 vs 3.66 ± 0.91, Р < 0.001, and triglyceride: 3.18 (2.00; 4.29) vs 2.04 (1.40; 3.16), Р < 0.001. No effect on nonalcoholic fatty liver disease fibrosis score or liver fibrosis index was found. The CIMT decreased significantly in the total sample (0.985 ± 0.243 vs 0.968 ± 0.237, P = 0.013), whereas the high-density lipoprotein (Р = 0.036) and 10-year ASCVD risk (Р = 0.003) improved significantly only in women. Fifty-four patients (31%) achieved > 5% weight loss. At the end of the study, the FLI decreased significantly in patients with (88.3 ± 10.2 vs 71.4 ± 19.6, P < 0.001) and without > 5% weight loss (83.5 ± 10.3 vs 72.8 ± 16.7, P < 0.001). The changes in ALT, aspartate transaminase, glutamyltransferase, total cholesterol, and low-density lipoprotein levels were similar between the subgroups.CONCLUSIONUDCA normalizes liver enzymes greatly within the first 3 mo of treatment, improves lipid profile and hepatic steatosis independent of weight loss, and has a positive effect on CIMT in the total sample and 10-year ASCVD risk in women after 6 mo of treatment.     

Systematic biopsy should not be omitted in the era of combined magnetic resonance imaging/ultrasound fusion-guided biopsies of the prostate

Purpose

To evaluate prostate cancer detection rates with classical trans-rectal ultrasound-guided systematic 10-core biopsies (SB), targeted biopsies (TB) guided by magnetic resonance (MR)/US fusion imaging and their combination in biopsy-naïve and patients with previously negative prostate biopsies. We compared pathology results after radical prostatectomy with biopsy findings.

Methods

Consecutive patients with prostate imaging-reporting and data system lesions grade?≥?3 submitted to MRI/US-guided TB and subsequent standard 10-core SB between December 2015 and June 2019 were analyzed.

Results

Detection rate (TB- or SB-positive) in 563 included patients (192 naïve, 371 with previous biopsies) was 56.7% (67.7% for the first, 50.9% for repeated biopsies). With TB (disregarding SB), the rates were 41.4%, 52.1% and 35.8%, respectively. With SB (disregarding TB), the rates were 49.1%, 63.0% and 41.8%, respectively. Eventually, 118 patients underwent surgery and clinically significant cancer was found in 111 (94.1%) specimens. Of those, 23 (20.7%) would have been missed had we relied upon a negative TB and 14 (12.6%) would have been missed had we relied upon a negative SB, disregarding a positive finding on the alternative biopsy template.

Conclusion

SB should not be omitted since TB and SB combination have higher detection rate of clinically relevant prostate cancer than either procedure alone.

     

Tritium in well waters, streams and atomic lakes in the East Kazakhstan Oblast of the Semipalatinsk Nuclear Test Site.

The concentration of tritium has been determined in well waters, streams and atomic lakes in the Sarzhal, Tel'kem, Balapan and Degelen Mountains areas of the Semipalatinsk Test Site. The data show that levels of tritium in domestic well waters within the settlement of Sarzhal are extremely low at the present time with a median value of 4.4 Bq dm(-3) (95% confidence interval:4.1-4.7 Bq dm(-3)). These levels are only marginally above the background tritium content in surface waters globally. Levels in the atomic craters at Tel'kem 1 and Tel'kem 2 are between one and two orders of magnitude higher, while the level in Lake Balapan is approximately 12,600 Bq dm(-3). Significantly, levels in streams and test-tunnel waters sourced in the Degelen Mountains, the site of approximately 215 underground nuclear tests, are a further order of magnitude higher, being in the range 133,000--235,500 Bq dm(-3). No evidence was adduced which indicates that domestic wells in Sarzhal are contaminated by tritium-rich waters sourced in the Degelen massif, suggesting that the latter are not connected hydrologically to the near-surface groundwater recharging the Sarzhal wells. Annual doses to humans arising from the ingestion of tritium in these well waters are very low at the present time and are of no radiological significance.     

Effect of Heat Treatment on the Mechanical and Corrosion Properties of Mg–Zn–Ga Biodegradable Mg Alloys

Mg alloys have mechanical properties similar to those of human bones, and have been studied extensively because of their potential use in biodegradable medical implants. In this study, the influence of different heat treatment regimens on the microstructure and mechanical and corrosion properties of biodegradable Mg–Zn–Ga alloys was investigated, because Ga is effective in the treatment of disorders associated with accelerated bone loss. Solid–solution heat treatment (SSHT) enhanced the mechanical properties of these alloys, and a low corrosion rate in Hanks’ solution was achieved because of the decrease in the cathodic-phase content after SSHT. Thus, the Mg–4 wt.% Zn–4 wt.% Ga–0.5 wt.% Y alloy after 18 h of SSHT at 350 °C (ultimate tensile strength: 207 MPa; yield strength: 97 MPa; elongation at fracture: 7.5%; corrosion rate: 0.27 mm/year) was recommended for low-loaded orthopedic implants.     

Usefulness of changes in left ventricular wall thickness to predict full or partial pressure reperfusion in ST-elevation acute myocardial infarction

Experimental studies have shown that if an acute transmural myocardial infarction is reperfused at full pressure there is an immediate and persisting increase in end-diastolic wall thickness (EDWT) due to massive intramural edema, with the amount of edema inversely related to the residual stenosis in the infarct-related artery. This study investigated if these findings are paralleled in the clinical setting and whether the resultant myocardial substrate differs after percutaneous coronary intervention (PCI) versus thrombolysis (the latter having a higher incidence of residual flow limiting stenosis in the culprit vessel). Eighty-eight consecutive patients with ST-elevation myocardial infarction were enrolled. Twenty-seven patients underwent primary PCI, 23 had rescue PCI, and 38 had thrombolysis. Standard M-mode and 2-dimensional echocardiographies were performed within 12 hours. Regional EDWT was measured in 904 infarct-related segments after the different reperfusion strategies and compared with 504 remote noninfarcted segments. EDWT of infarct-related segments after primary PCI was significantly increased compared with normal segments. At follow-up, after 6 months, EDWT of these segments was significantly decreased, indicating transmural infarction. EDWT of infarct-related segments after thrombolysis did not differ from that of normal segments. After rescue PCI, EDWT of infarct-related segments was significantly decreased compared with that of normal segments. In conclusion, full-pressure restoration of epicardial blood flow after transmural myocardial infarction causes an immediate increase in EDWT, easily detected by echocardiography. In contrast, pressure-limiting reperfusion (typical for thrombolysis) resultsin normal EDWT. This confirms experimental data that PCI and thrombolysis can differ in their resultant myocardial substrate.     

MIP-2 causes differential activation of RhoA in mouse aortic versus pulmonary artery endothelial cells

Previously, we have shown that endothelial cell chemotaxis to the proangiogenic chemokine MIP-2 (macrophage inflammatory protein-2) is much greater in mouse aortic endothelial cells (EC) than pulmonary arterial endothelial cells (PA EC). This was true despite the observation that both cell types display comparable levels of the ligand receptor, CXCR(2) (8). Since the systemic arterial circulation is proangiogenic in the adult lung and the pulmonary circulation is relatively resistant to neovascularization, we questioned whether the observed functional heterogeneity is related to inherent differences in cell signaling cascades of the two EC subtypes. Specifically, we measured activation of Rac1 and RhoA, both thought to be involved in EC cell migration. Rac1 showed inconsistent and minimal changes in both cell types after MIP-2 treatment (p>0.05). However, activated RhoA was increased upon exposure to MIP-2 only in aortic EC (61% increase; p<0.05). Decreased RhoA activation after treatment of aortic EC with specific siRNA for RhoA resulted in a functional decrease in EC chemotaxis to MIP-2 (17% increase; p<0.05). Additionally, increased RhoA activation in PA EC with adenoviral infection of RhoA caused an increase in PA EC chemotaxis to MIP-2 (46% increase; p<0.05). Inhibition of RhoA activity with the Rho kinase inhibitor, Y27632, blocked aortic EC chemotaxis and stress fiber formation. Thus, RhoA activation is increased after MIP-2 treatment in mouse aortic endothelial cells but not in pulmonary artery endothelial cells. We conclude that RhoA is part of a signaling pathway essential for aortic cell migration after CXCR(2) ligation. This result provides one explanation for the difference in chemotaxis observed in these two endothelial subtypes that express similar levels of CXCR(2).