Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity

Received 22 July 2012; revised 29 January 2013; accepted 4 March 2013Aims Aldosterone plays a crucial role in cardiovascular disease. ‘Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the ‘endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis. Methods and results C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high ‘endogenous' aldosterone) and in ‘exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR. Conclusion Obesity-induced endothelial dysfunction depends on the ‘endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complication

Ribociclib-induced liver injury: a case report

BackgroundIdiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib.Case presentationA 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering.ConclusionThis case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation

Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation

Aims Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. Methods and results Eight-week-old male apolipoprotein E knockout (ApoE−/−) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n−3 long chain fatty acids (LC n−3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. Conclusion Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n−3 F

Genomic analysis of focal nodular hyperplasia with associated hepatocellular carcinoma unveils its malignant potential: a case report.

Background Focal nodular hyperplasia (FNH) is typically considered a benign tumor of the liver without malignant potential. The co-occurrence of FNH and hepatocellular carcinoma (HCC) has been reported in rare cases. In this study we sought to investigate the clonal relationship between these lesions in a patient with FNH-HCC co-occurrence. Methods A 74-year-old female patient underwent liver tumor resection. The resected nodule was subjected to histologic analyses using hematoxylin and eosin stain and immunohistochemistry. DNA extracted from microdissected FNH and HCC regions was subjected to whole exome sequencing. Clonality analysis were performed using PyClone. Results Histologic analysis reveals that the nodule consists of an FNH and two adjoining HCC components with distinct histopathological features. Immunophenotypic characterization and genomic analyses suggest that the FNH is clonally related to the HCC components, and is composed of multiple clones at diagnosis, that are likely to have progressed to HCC through clonal selection and/or the acquisition of additional genetic events. Conclusion To the best of our knowledge, our work is the first study showing a clonal relationship between FNH and HCC. We show that FNH may possess the capability to undergo malignant transformation and to progress to HCC in very rare cases

Echocardiography does not predict mortality in hemodynamically stable elderly patients with acute pulmonary embolism.

BACKGROUND The evidence on the prognostic value of transthoracic echocardiography (TTE) in elderly, hemodynamically stable patients with Pulmonary Embolism (PE) is limited. OBJECTIVES To evaluate the prevalence of common echocardiographic signs of right ventricular (RV) dysfunction and their prognostic impact in hemodynamically stable patients aged ≥65years with acute PE in a prospective multicenter cohort. METHODS TTE was performed by cardiologists. We defined RV dysfunction as a RV/left ventricular ratio >0.9 or RV hypokinesis (primary definition) or the presence of ≥1 or ≥2 of 6 predefined echocardiographic signs (secondary definitions). Outcomes were overall mortality and mortality/non-fatal recurrent venous thromboembolism (VTE) at 30days, adjusting for the Pulmonary Embolism Severity Index risk score and highly sensitive troponin T values. RESULTS Of 400 patients, 36% had RV dysfunction based on our primary definition, and 81% (≥1 sign) and 53% (≥2 signs) based on our secondary definitions, respectively. Using our primary definition, there was no association between RV dysfunction and mortality (adjusted HR 0.90, 95% CI 0.31-2.58) and mortality/non-fatal VTE (adjusted HR 1.09, 95% CI 0.40-2.98). Similarly, there was no statistically significant association between the presence of ≥1 or ≥2 echocardiographic signs (secondary definitions) and clinical outcomes. CONCLUSION The prevalence of echocardiographic RV dysfunction varied widely depending upon the definition used. There was no association between RV dysfunction and clinical outcomes. Thus, TTE may not be suitable as a stand-alone risk assessment tool in elderly patients with acute PE. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov. Identifier: NCT00973596

Permanent storage of carbon dioxide in geological reservoirs by mineral carbonation

Anthropogenic greenhouse-gas emissions continue to increase rapidly despite efforts aimed at curbing the release of such gases. One potentially long-term solution for offsetting these emissions is the capture and storage of carbon dioxide. In principle, fluid or gaseous carbon dioxide can be injected into the Earth's crust and locked up as carbonate minerals through chemical reactions with calcium and magnesium ions supplied by silicate minerals. This process can lead to near-permanent and secure sequestration, but its feasibility depends on the ease and vigour of the reactions. Laboratory studies as well as natural analogues indicate that the rate of carbonate mineral formation is much higher in host rocks that are rich in magnesium- and calcium-bearing minerals. Such rocks include, for example, basalts and magnesium-rich mantle rocks that have been emplaced on the continents. Carbonate mineral precipitation could quickly clog up existing voids, presenting a challenge to this approach. However, field and laboratory observations suggest that the stress induced by rapid precipitation may lead to fracturing and subsequent increase in pore space. Future work should rigorously test the feasibility of this approach by addressing reaction kinetics, the evolution of permeability and field-scale injection methods

Multitracer determinatin of apparent groundwater ages in peridotite aquifers within the Samail ophiolite, Sultanate of Oman

CO2 sequestration in the form of carbonate minerals via alteration of oceanic crust and upper mantle is an important part of the global carbon cycle, but the annual rate of CO2 mineralization is not well quantified. This study aimed to constrain groundwater ages within the Samail ophiolite, Sultanate of Oman. Such ages could provide upper bounds on the time required for ongoing low temperature CO2 mineralization. While we were able to estimate apparent groundwater ages for modern waters, results from hyperalkaline boreholes and springs were disappointing. Waters from boreholes and hyperalkaline springs within the ophiolite were characterized using multiple environmental tracers including tritium (3H), noble gases (3He, 4He, Ne, Ar, Kr, Xe), stable isotopes (δ18O, δ2H), and chemical parameters (pH, Ca, Mg, DIC, etc.). Shallow peridotite groundwater and samples from boreholes near the mantle transition zone have a pH < 9.3, are 4-40 yrs old, have little to no non-atmospheric He accumulation, NGTs (noble gas temperatures) equivalent to the modern mean annual ground temperature, and stable isotopes within the range of current local precipitation. In contrast, hyperalkaline springs and deeper samples from peridotite boreholes have pH > 10, are pre-H-bomb (older than 1952), have significant non-atmospheric helium accumulation (30-70% of dissolved helium), often are isotopically heavier (enriched in δ18O), and can have NGTs 6-7 °C lower than the modern ground temperature. These differences suggest that groundwater in deep (>50 m) peridotite aquifers is considerably older than shallow groundwater in peridotite and water in deeper aquifers near the mantle transition zone. Unfortunately, how much older remains an open question. The low NGT of groundwater from one deep (300 m) peridotite borehole indicates it is probably glacial in origin. If so, it must date back to at least the late Pleistocene, the most recent glacial period; He accumulation suggests it could be from 20-220 ka. The inefficacy of this suite of environmental tracers to quantitatively estimate apparent groundwater age for hyperalkaline fluids necessitates the use of different techniques. Future work to constrain groundwater ages should utilize a packer system to isolate discrete depth intervals within boreholes and less common environmental tracers such as 39Ar and 81Kr

Reaction path modeling of enhanced in situ CO2 mineralization for carbon sequestration in the peridotite of the Samail Ophiolite, Sultanate of Oman

The peridotite section of the Samail Ophiolite in the Sultanate of Oman offers insight into the feasibility of mineral carbonation for engineered, in situ geological CO2 storage in mantle peridotites. Naturally occurring CO2 sequestration via mineral carbonation is well-developed in the peridotite; however, the natural process captures and sequesters CO2 too slowly to significantly impact the concentration of CO2 in the atmosphere. A reaction path model was developed to simulate in situ CO2 mineralization through carbonation of fresh peridotite, with its composition based on that of mantle peridotite in the Samail Ophiolite and including dissolution kinetics for primary minerals. The model employs a two-stage technique, beginning with an open system and progressing to three different closed system scenarios- a natural system at 30 °C, an engineered CO2 injection scenario at 30 °C, and an engineered CO2 injection scenario at 90 °C. The natural system model reproduces measured aqueous solute concentrations in the target water, signifying the model is a close approximation of the natural process. Natural system model results suggest that the open system achieves steady state within a few decades, while the closed system may take up to 6,500 years to reach observed fluid compositions. The model also identifies the supply of dissolved inorganic carbon as the limiting factor for natural CO2 mineralization in the deep subsurface. Engineered system models indicate that injecting CO2 at depth could enhance the rate of CO2 mineralization by a factor of over 16,000. CO2 injection could also increase mineralization efficiency – kilograms of CO2 sequestered per kilogram of peridotite – by a factor of over 350. These model estimates do not include the effects of precipitation kinetics or changes in permeability and reactive surface area due to secondary mineral precipitation. Nonetheless, the faster rate of mineralization in the CO2 injection models implies that enhanced in situ peridotite carbonation could be a significant sink for atmospheric CO2