The madness of history

In this novel, the main character/narrator is used as a vehicle to make sense of the atrocities in the former Yugoslavia

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors

Lack of Renal 11 Beta-Hydroxysteroid Dehydrogenase Type 2 at Birth, a Targeted Temporal Window for Neonatal Glucocorticoid Action in Human and Mice

International audienceBackground Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Methods Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. Results We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. Conclusions We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Cleaner bioprocesses for promoting zero-emission biofuels production in Vojvodina

In this study, the policy, market conditions and food security of biomass energy sources are assessed for supplying the future needs of Vojvodina. The Autonomous Province of Vojvodina is an autonomous province in Serbia, containing about 27% of its total population according to the 2002 Census. It is located in the northern part of the country, in the Pannonia plain, in southeastern Europe. Vojvodina is an energy-deficient province. The incentives to invest human and financial resources in the research and development of cleaner bioprocesses are high, considering the benefits which might be achieved in terms of environment protection and manufacturing costs. In the near and medium tenu, the development of bioprocesses for waste recycling and resource recovery might be one of the most viable options, considering much research work has already been done. In Vojvodina, there are technological solutions that biofuels produced in a closed cycle, so that the quantity of waste reduced to a minimum. These solutions include the stillage (remainder after distillation) used for fattening cattle, and cattle excrement to produce biogas and manure as fertilizer. The energy required for the production of bioethanol is obtained combustion lignocelullose residual waste from the production of basic raw materials starch, or biogas. Ash from the burned biomass returned to soil as a source of minerals for plants and replacement of mineral fertilizer. Such a closed cycle is economical for small farms in Vojvodina.Biotechnology Biofuels Cleaner production Environment Vojvodina

Potential development of bioethanol production in Vojvodina

The Autonomous Province of Vojvodina is an Autonomous Province in Serbia, containing about 27% of its total population according to the 2002 Census. Contribution of renewable energy sources in total energy consumption of Vojvodina contemporary amounts to less than 1%, apropos 280 GWh/year. By combining of methods of introduction of new and renewable sources, systematic application of methods for increasing of energetic efficacy, as well as of introduction of the new technologies, percentage of contribution of the non-conventional energy sources in Vojvodina could be increased to as much as 20%. This paper presents the potential of development of bioethanol production in Vojvodina. Production of bioethanol on small farms can be successfully applied for processing of only 30 kg of corn per day, with obtaining of crude ethanol in the so-called "brandy ladle" and use of lygnocellulosic agricultural wastes as an energy source. In a case of construction of a larger number of such plants, the only possible solution is seen in the principle of construction of the so-called "satellite plants", which will on small farm produce crude ethanol, with obtaining and consumption of stillage for animal feeding, and consumption of agricultural wastes as energetic fuels. If stillage is to be used as feed in wet feeding, it is estimated that, because of restrictions established by the magnitude of animal farm, the upper limit of capacity of such enterprises that process is at some 10-15 tons of corn per day, and production of 3000-3500 hL of absolute ethanol per day. In such a case, for animal feeding necessary is to have herd with 1300-1700 of milking cows or 5000-25,000 heads of sheep and/or pigs. Technological model of separate grain processing ad bioethanol production from dextrose hydrolysates of starch is interesting for countries possessing plants for bioethanol production from molasses and plants for cereals processing into starch and dextrose hydrolysates of starch.Bioenergy Bioethanol Corn Farm Vojvodina

Perspectives of sustainable development in countries of Southeastern Europe

Countries of SE Europe are at very beginning of planning of their development in accordance with theoretical concept of sustainable development. Sustainable development is defined as the basic imperative and the only model of development in a longer period of time. The basic indicators of sustainable development represent a very useful and quality way for measuring and monitoring the state of sustainable development, as in every country individually so as in the regions and globally as a whole. Values of the indicators of all four subsystems in observed countries are within expectation. Also the current level of development of every country separately is taken into account and in accordance to that it is defined the current position of any country in respect to its international requests. The special value is given by the comparison of obtained results of the state in the developed EU countries, according to which there is an impression of equal degree of sustainable development in France and Germany, whereas the data regarding the state of sustainable development in Greece and at Slovenia has been improved between two analysis. Taking into account the results of the previous and current research there is a clear need for regular observation of the state of every indicator individually but also the need to observe the relationship among them as a whole. The special attention needs to be given to the intensive monitoring of indicators of economic and ecological subsystem. The research showed, among other things, to the fragile relationship of values of indicators of economic and ecological subsystem, by which any change in values of one indicator consequently leads to the changes in the final result. Both conducted researches point to the fact that the value of the mentioned indicators changes at the fastest pace.Sustainable development Indicators Southeastern Europe