Fibrosis biomarkers as predictors of left atrial appendage thrombosis in patients with nonvalvular atrial fibrillation

Aim. To compare clinical, echocardiographic characteristics and blood biomarkers in patients with nonvalvular atrial fibrillation (AF) depending on the presence of left atrial appendage (LAA) thrombus and to identify independent predictors of LAA thrombosis.Material and methods. Patients with nonvalvular AF subjected to transesopha geal echocardiography before catheter ablation were divided into 2 groups comparable by sex and age: group 1 (n=45) — with LAA throm bosis; group 2 (n=97) — without LAA thrombosis. The patients underwent transthoracic and transesophageal echocardiography. In addition, the following blood biomarkers were analyzed: NT-proBNP (pg/ml), GDF-15 (pg/ml), TGF-β1 (pg/ml), PIIINP (ng/ml), high-sensitivity C-reactive protein (hsCRP) (mg/l), cystatin C (mg/l).Results. In group 1, persistent AF, coronary artery disease, heart failure were more often noted. In addition, group 1 patients had higher volume indices of both atria, left ventricular mass index and pulmonary artery systolic pressure, as well as lower left ventricular ejection fraction and blood flow velocity in the LAA. There were no differences in the groups in terms of the mean CHA2DS2VASc score, the proportion of patients taking oral anticoagulants (OAC), and the OAC spectrum. In group 1, higher levels of NT-proBNP (p=0,0001), GDF15 (p=0,0001), PIIINP (p=0,0002) were found with no differences in the levels of TGF-β1, hsCRP and cystatin C. A stepwise logistic regression revealed independent predictors of LAA thrombosis: LA volume index (ml/m2) — odds ratio (OR)=1,084, 95% confidence interval (CI) 1,028-1,143 (p=0,003); GDF15 ≥933 pg/ml — OR=3,054, 95% CI, 1,260-7,403 (p=0,013); PIIINP ≥68 pg/ml — OR=5,865, 95% CI, 2,404-14,308 (p<0,001). There were following model quality parameters: AUC=0,815 (p<0,001), specificity, 74,4%, sensitivity, 72,7%.Conclusion. In patients with nonvalvular atrial fibrillation taking OAC, serum levels of fibrosis biomarkers PIIINP ≥68 pg/mL and GDF-15 ≥933 pg/mL, along with the left atrial volume index, were independent predictors of LAA thrombosis

Validation of ozone measurements from the Atmospheric Chemistry Experiment (ACE)

This paper presents extensive bias determination analyses of ozone observations from the Atmospheric Chemistry Experiment (ACE) satellite instruments: the ACE Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instrument. Here we compare the latest ozone data products from ACE-FTS and ACE-MAESTRO with coincident observations from nearly 20 satellite-borne, airborne, balloon-borne and ground-based instruments, by analysing volume mixing ratio profiles and partial column densities. The ACE-FTS version 2.2 Ozone Update product reports more ozone than most correlative measurements from the upper troposphere to the lower mesosphere. At altitude levels from 16 to 44 km, the average values of the mean relative differences are nearly all within +1 to +8%. At higher altitudes (45 60 km), the ACE-FTS ozone amounts are significantly larger than those of the comparison instruments, with mean relative differences of up to +40% (about + 20% on average). For the ACE-MAESTRO version 1.2 ozone data product, mean relative differences are within +/- 10% (average values within +/- 6%) between 18 and 40 km for both the sunrise and sunset measurements. At higher altitudes (similar to 35-55 km), systematic biases of opposite sign are found between the ACE-MAESTRO sunrise and sunset observations. While ozone amounts derived from the ACE-MAESTRO sunrise occultation data are often smaller than the coincident observations (with mean relative differences down to -10%), the sunset occultation profiles for ACE-MAESTRO show results that are qualitatively similar to ACE-FTS, indicating a large positive bias (mean relative differences within +10 to +30%) in the 45-55 km altitude range. In contrast, there is no significant systematic difference in bias found for the ACE-FTS sunrise and sunset measurements

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Синдром хронічної втоми та стан клітинної і гуморальної ланок системного імунітету

Chronic fatigue syndrome is associated with a dysfunction of the cellular component of systemic immunity at the expense of a decrease of the absolute and relative number of TCD3+-lymphocytes, including active variants; a deep deficiency of the absolute and relative number of immunoregulatory T-lymphocytes (TCD4+ and TCD8+); a reduction of the immunoregulatory and effector indices and an increase of the leuko-T-cellular index, the absolute and relative number of mature B-lymphocytes (BCD22+), the concentration of immunoglobulins of the principal classes (IgM, IgG, IgA), circulating immune complexes essentially elevate in the peripheral blood, allergization of the patients organism, immune reactivity enhance. The immunoglobulin-secretory function of B-lymphocytes from the production of IgM and IgG, the titer of normal (natural) antibodies and the activity of the complement system lower at this background.Синдром хронической усталости ассоциируется с дисфункцией клеточного звена системного иммунитета за счет выраженного уменьшения абсолютного и относительного количества ТCD3+-лимфоцитов, в том числе и активных вариантов; глубоким дефицитом абсолютного и относительного количества иммунорегуляторных Т-лимфоцитов (ТCD4+ и ТCD8+); снижением иммунорегуляторного и эффекторного индексов и ростом лейкоТ-клеточного индекса, существенно возрастает в периферической крови абсолютное и относительное количество зрелых В-лимфоцитов (ВCD22+), концентрация иммуноглобулинов основных классов (IgM, IgG , IgA), циркулирующих иммунных комплексов, повышается аллергизация организма пациентов, иммунная реактивность. На этом фоне снижается иммуноглобулинсекреторная функция В-лимфоцитов по продукции IgM и IgG, титр нормальных (естественных) антител и активность системы комплемента.Синдром хронічної втоми асоціюється із дисфункцією клітинної ланки системного імунітету за рахунок вираженого зменшення абсолютної і відносної кількості ТCD3+-лімфоцитів; глибоким дефіцитом абсолютної та відносної кількості імунорегуляторних Тлімфоцитів (ТCD4+ і ТCD8+); зниженням імунорегуляторного та ефекторного індексів і зростанням лейко-Тклітинного індексу, суттєво зростає в периферичній крові абсолютна і відносна кількість зрілих Влімфоцитів (ВCD22+), концентрація імуноглобулінів основних класів (IgM, IgG, IgA), циркулюючих імунних комплексів, підвищується алергізація організму пацієнтів, імунна реактивність. На цьому тлі знижується імуноглобулінсекреторна функція В-лімфоцитів із продукції IgM та IgG, титр нормальних (природних) антитіл та активність системи комплементу

Validation of Odin/OSIRIS stratospheric NO₂ profiles

This paper presents the validation study of stratospheric NO2 profiles retrieved from Odin/OSIRIS measurements of limb-scattered sunlight (version 2.4). The Optical Spectrograph and Infrared Imager System (OSIRIS) NO2 data set is compared to coincident solar occultation measurements by the Halogen Occultation Experiment (HALOE), Stratospheric Aerosol and Gas Experiment (SAGE) II, SAGE III, and Polar Ozone and Aerosol Measurement (POAM) III during the 2002–2004 period. Comparisons with seven Systeme d'Analyse par Observation Zenithal (SAOZ) balloon measurements are also presented. All comparisons show good agreement, with differences, both random and systematic, of less than 20% between 25 km and 35 km. Inconsistencies with SAGE III below 25 km are found to be caused primarily by diurnal effects from varying NO2 concentrations along the SAGE III line-of-sight. On the basis of the differences, the OSIRIS random uncertainty is estimated to be 16% between 15 km and 25 km, 6% between 25 km and 35 km, and 9% between 35 km and 40 km. The estimated systematic uncertainty is about 22% between 15 and 25 km, 11–21% between 25 km and 35 km, and 11–31% between 35 km and 40 km. The uncertainties for AM (sunrise) profiles are generally largest and systematic deviations are found to be larger at equatorial latitudes. The results of this validation study show that the OSIRIS NO2 profiles are well behaved, with reasonable uncertainty estimates between 15 km and 40 km. This unique NO2 data set, with more than hemispheric coverage and high vertical resolution will be of particular interest for studies of nitrogen chemistry in the middle atmosphere, which is closely linked to ozone depletion

Comparison of ozone profiles measured by the Odin satellite instruments and ground-based, airborne, satellite experiments and model computations

The Odin satellite carries two instruments measuring ozone spectra from which strato- spheric ozone profiles are retrieved. Onboard Odin, the Sub-Millimeter Radiometer (SMR) measures an ozone spectral line at 501.4 GHz. Forward model and inversion codes using the Optimal Estimation Method permit the retrieval of vertical profiles in the altitude range 20-65 km. The UV-visible spectrograph of the OSIRIS instru- ment measures ozone absorption limb spectra in the ranges 300-340 and 400-700 nm. A code based on the technique described by Flittner et al. (2000) and McPeters et al. (2000) provides vertical profiles from 20 to 60 km. This work presents a comparison of Odin ozone profiles with those obtained by ground-based measurements from primary or complementary stations of the Network for the Detection of Stratospheric Change (NDSC) such as lidars, microwave radiometers and ozonesondes. Some additional comparisons are also performed with ozone profiles obtained by balloon flights, air- craft experiments, other satellite measurements and model computations. These largesets of comparisons is also used to confirm the soundness of the Odin ozone measure- ments