Do the Effects of Secondary Prevention of Cardiovascular Events in PAD Patients Differ from Other Atherosclerotic Disease?

Atherosclerosis is considered a generalized disease. Similar or identical etiopathogenetic mechanisms and risk factors are involved in various atherosclerotic diseases, and the positive effects of preventive measures on atherogenesis in different parts of the arterial system were shown. However, until know, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease (CHD), while less attention has been devoted to the management of peripheral arterial disease (PAD), despite its significant morbidity and mortality. Data on the efficacy of preventive measures in PAD patients have mostly been gained from subgroup analyses from studies devoted primarily to the management of coronary patients. These data have shown that treatment of risk factors for atherosclerosis with drugs can reduce cardiovascular events also in patients with PAD. The effects of some preventive procedures in PAD patients differ from coronary patients. Aspirin as a basic antiplatelet drug has been shown to be less effective in PAD patients than in coronary patients. The latest Antithrombotic Trialists’ Collaboration (ATC) meta-analysis demonstrates no benefit of aspirin in reducing cardiovascular events in PAD. Statins reduce cardiovascular events in all three of the most frequently presented cardiovascular diseases, including PAD to a comparable extent. Recent studies indicate that in PAD patients, in addition to a reduction in cardiovascular events, statins may have some hemodynamic effects. They prolong walking distance and improve quality of life. Similarly, angiotensin enzyme inhibitors are also effective in the prevention of cardiovascular events in coronary, cerebrovascular, as well as PAD patients and show positive effects on the walking capacity of patients with intermittent claudication. In PAD patients, the treatment of hypertension and diabetes also effectively prevents cardiovascular morbidity and mortality. As PAD patients are at a highest risk of cardiovascular complications, the risk factors of atherosclerosis should be treated intensively in this group of patients. Most of the preventive measures, including the drugs used for prevention of CHD, are also effective in PAD patients.     

Fibroblast Growth Factor-21 and the Beneficial Effects of Long-Chain n-3 Polyunsaturated Fatty Acids

Long‐chain n‐3 polyunsaturated fatty acids (LC n‐3 PUFA) in the diet protect against insulin resistance and obesity. Fibroblast growth factor‐21 (Fgf21) is a hormonal factor released mainly by the liver that has powerful anti‐diabetic effects. Here, we tested whether the beneficial metabolic effects of LC n‐3 PUFA involve the induction of Fgf21. C57BL/6 J mice were exposed to an obesogenic, corn‐oil‐based, high‐fat diet (cHF), or a diet in which corn oil was replaced with a fish‐derived LC n‐3 PUFA concentrate (cHF + F) using two experimental settings: short‐term (3 weeks) and long‐term treatment (8 weeks). CHF + F reduced body weight gain, insulinemia, and triglyceridemia compared to cHF. cHF increased plasma Fgf21 levels and hepatic Fgf21 gene expression compared with controls, but these effects were less pronounced or absent in cHF + F‐fed mice. In contrast, hepatic expression of peroxisome proliferator‐activated receptor (PPAR)‐α target genes were more strongly induced by cHF + F than cHF, especially in the short‐term treatment setting. The expression of genes encoding Fgf21, its receptors, and Fgf21 targets was unaltered by short‐term LC n‐3 PUFA treatment, with the exception of Ucp1 (uncoupling protein 1) and adiponectin genes, which were specifically up‐regulated in white fat. In the long‐term treatment setting, the expression of Fgf21 target genes and receptors was not differentially affected by LC n‐3 PUFA. Collectively, our findings indicate that increased Fgf21 levels do not appear to be a major mechanism through which LC n‐3 PUFA ameliorates high‐fat‐diet‐associated metabolic disorders.     

Some issues related to the energy sources in the Czech Republic

Although the Czech Republic is a relatively small country it is faced with the problem of balancing energy production against the available resources of energy-producing raw materials. The Czech Republic is atypical of the EU countries because it is one of a few countries that presently exports electric energy and, at the same time, is still producing uranium ores. Resources of all the essential energy-producing raw materials exist in the Czech Republic, though, temporarily, only brown coal and bituminous coal reserves cover the immediate needs of energy production, while uranium ores are sufficient to satisfy the demands for a long period in the future. This paper provides data on the deposits of raw materials useful for energy production in the Czech Republic and their lifetimes, as well as the proportions of different energy sources.     

BH3 Mimetics in Hematologic Malignancies

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy-refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action—direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.     

Spectrum shifting as a mechanism to improve performance of VHTRs with advanced actinide fuels

Reprocessing of spent LWR fuel is an intrinsic part of the closed fuel cycle. While current technologies treat recovered minor actinides as high level wastes, the primary objective of one of the U.S. DOE Nuclear Energy Research Initiative (NERI) projects is to assess the possibility, advantages and limitations of designing a single-batch (no-refueling) very high temperature reactor (VHTR) configuration that utilizes transuranic nuclides (TRU) as a fuel component. Since both VHTR core design concepts, pebble bed and prismatic block assembly, permit flexibility in component configuration, fuel utilization and management, it is possible to improve fissile properties by neutron spectrum shifting through configuration adjustments. The presented analysis is focused on the TRU-impact on the single-batch mode (no-refueling) VHTR core lifetime. As a result of the analysis, promising performance characteristics have been demonstrated. The TRU-core configurations are expected to be suitable for long-term autonomous operation without intermediate refueling.     

Flexible conversion ratio fast reactors: Overview

Conceptual designs of lead-cooled and liquid salt-cooled fast flexible conversion ratio reactors were developed. The performance achievable by the unity conversion ratio cores of these reactors was compared to an existing supercritical carbon dioxide-cooled (S-CO₂) fast reactor design and an uprated version of an existing sodium-cooled fast reactor. All concepts have cores rated at 2400 MWt. The cores of the liquid-cooled reactors are placed in a large-pool-type vessel with dual-free level, which also contains four intermediate heat exchangers (IHXs) coupling a primary coolant to a compact and efficient supercritical CO₂ Brayton cycle power conversion system. The S-CO₂ reactor is directly coupled to the S-CO₂ Brayton cycle power conversion system. Decay heat is removed passively using an enhanced reactor vessel auxiliary cooling system (RVACS) and a passive secondary auxiliary cooling system (PSACS). The selection of the water-cooled versus air-cooled heat sink for the PSACS as well as the analysis of the probability that the PSACS may fail to complete its mission was performed using risk-informed methodology. In addition to these features, all reactors were designed to be self-controllable. Further, the liquid-cooled reactors utilized common passive decay heat removal systems whereas the S-CO₂ uses reliable battery powered blowers for post-LOCA decay heat removal to provide flow in well defined regimes and to accommodate inadvertent bypass flows. The multiple design limits and challenges which constrained the execution of the four fast reactor concepts are elaborated. These include principally neutronics and materials challenges. The neutronic challenges are the large positive coolant reactivity feedback, small fuel temperature coefficient, small effective delayed neutron fraction, large reactivity swing and the transition between different conversion ratio cores. The burnup, temperature and fluence constraints on fuels, cladding and vessel materials are elaborated for three categories of material - materials currently available, available on a relatively short time scale and available only with significant development effort. The selected fuels are the metallic U-TRU-Zr (10% Zr) for unity conversion ratio and TRU-Zr (75% Zr) for zero conversion ratio. The principal selected cladding and vessel materials are HT-9 and A533 or A508, respectively, for current availability, T-91 and 9Cr-1Mo steel for relatively short-term availability and oxide dispersion strengthened ferritic steel (ODS) available only with significant development.     

Decay heat in fast reactors with transuranic fuels

In this work, we performed an evaluation of decay heat power of advanced, fast spectrum, lead and molten salt-cooled reactors, with flexible conversion ratio. The decay heat power was calculated using the BGCore computer code, which explicitly tracks over 1700 isotopes in the fuel throughout its burnup and subsequent decay. In the first stage, the capability of the BGCore code to accurately predict the decay heat power was verified by performing a benchmark calculation for a typical UO₂ fuel in a Pressurized Water Reactor environment against the (ANSI/ANS-5.1-2005, “Decay Heat Power in Light Water Reactors,” American National Standard) standard. Very good agreement (within 5%) between the two methods was obtained. Once BGCore calculation capabilities were verified, we calculated decay power for fast reactors with different coolants and conversion ratios, for which no standard procedure is currently available. Notable differences were observed for the decay power of the advanced reactor as compared with the conventional UO₂ LWR. The importance of the observed differences was demonstrated by performing a simulation of a Station Blackout transient with the RELAP5 computer code for a lead-cooled fast reactor. The simulation was performed twice: using the code-default ANS-79 decay heat curve and using the curve calculated specifically for the studied core by BGCore code. The differences in the decay heat power resulted in failure to meet maximum cladding temperature limit criteria by ∼100 °C in the latter case, while in the transient simulation with the ANS-79 decay heat curve, all safety limits were satisfied. The results of this study show that the design of new reactor safety systems must be based on decay power curves specific to each individual case in order to assure the desired performance of these systems.     

Patterns of Lake Balkhash water level changes and their climatic correlates during 1992–2010 period

The variation in Lake Balkhash water levels during the period from 1992 to 2010 and their relationship with climate dynamics were investigated in this study, using satellite altimetry data and meteorological records from climate stations located in the lake catchment basin. The altimetry‐derived water level demonstrated a general water level increase, reaching a mean value of 8.1 cm year^?1 in July 2005, with a maximum value of 342.52 m. The increased Lake Balkhash water level was accompanied by an overall upward trend in precipitation and temperature in the catchment basin during the study period. A strong increase in the winter and spring temperature was the main contributor to the general upward temperature trend, whereas a significant change of summer and autumn precipitation was the major contributor to the annual precipitation trend. Neither precipitation nor temperature increased uniformly across the entire lake drainage basin. The study results identified the most pronounced climate change occurring in the mountainous part (>2000 m above sea level) of the basin, in the upper reaches of the Ili river, which is the main water inflow to the lake. Statistical analysis indicated the Lake Balkhash water level is strongly correlated with both precipitation and temperature. The correlations were investigated for three altitudinal strata (<1000 m, 1000–2000 m, >2000 m) corresponding to the lower, middle and upper reaches of the Ili river. The best correlations were obtained for the upper reaches of the Ili river, indicating a changing snow cover and glacier equilibrium are the main factors controlling the water level trends in Lake Balkhash.     

Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity

Antibiotic-resistant bacteria are recognized as one of the leading causes of death in the world. We proposed and successfully tested peptides with a new mechanism of antimicrobial action “protein silencing” based on directed co-aggregation. The amyloidogenic antimicrobial peptide (AAMP) interacts with the target protein of model or pathogenic bacteria and forms aggregates, thereby knocking out the protein from its working condition. In this review, we consider antimicrobial effects of the designed peptides on two model organisms, E. coli and T. thermophilus, and two pathogenic organisms, P. aeruginosa and S. aureus. We compare the amino acid composition of proteomes and especially S1 ribosomal proteins. Since this protein is inherent only in bacterial cells, it is a good target for studying the process of co-aggregation. This review presents a bioinformatics analysis of these proteins. We sum up all the peptides predicted as amyloidogenic by several programs and synthesized by us. For the four organisms we studied, we show how amyloidogenicity correlates with antibacterial properties. Let us especially dwell on peptides that have demonstrated themselves as AMPs for two pathogenic organisms that cause dangerous hospital infections, and in which the minimal inhibitory concentration (MIC) turned out to be comparable to the MIC of gentamicin sulfate. All this makes our study encouraging for the further development of AAMP. The hybrid peptides may thus provide a starting point for the antibacterial application of amyloidogenic peptides.