Atherothrombosis as a Leading Cause of Acute Coronary Syndromes and Stroke: The Main Killers in Developed Countries

Worldwide, cardiovascular incidents are estimated to cause 17.5 million deaths, 80% of which are ischemic strokes or acute coronary syndromes. Cardiovascular disease results in a significant financial burden for healthcare system—namely, in 2009, it was 9% of the gross health service expenditure in the European Union. Therefore, the development of the knowledge about atherosclerosis—initially thought to be solely degenerative disorder but now considered a multifactorial inflammatory state—is essential. Acute coronary syndrome (ACS) is usually a manifestation of severe reduction in coronary blood flow caused by atherosclerotic plaque and thrombus. The pathology of the atherosclerotic plaque is complex. Essentially, it is disease of the arterial intima that, through subsequent stages, results to luminal narrowing. Over the years, various theories regarding the genesis growth and vulnerability of atherosclerotic lesions have been promoted, usually focusing on endothelial injury, smooth muscle cell proliferation, lipid accumulation, and, more recently, inflammatory reactions

Heterogeneities in electricity grids strongly enhance non-Gaussian features of frequency fluctuations under stochastic power input

Stochastic feed-in of fluctuating renewable energies is steadily increasing in modern electricity grids and this becomes an important risk factor for maintaining power grid stability. Here we study the impact of wind power feed-in on the short-term frequency fluctuations in power grids based on an IEEE test grid structure, the swing equation for the dynamics of voltage phase angles, and a series of measured wind speed data. External control measures are accounted for by adjusting the grid state to the average power feed-in on a time scale of one minute. The wind power is injected at a single node by replacing one of the conventional generator nodes in the test grid by a wind farm. We determine histograms of local frequencies for a large number of one-minute wind speed sequences taken from the measured data and for different injection nodes. These histograms exhibit a common type of shape, which can be described by a Gaussian distribution for small frequencies and a nearly exponentially decaying tail part. Non-Gaussian features become particularly pronounced for wind power injection at locations, which are weakly connected to the main grid structure. This effect is only present when taking into account the heterogeneities in transmission line and node properties of the grid, while it disappears upon homogenizing of these features. The standard deviation of the frequency fluctuations increases linearly with the average injected wind power.Comment: 9 pages, 7 figure

On-line power system inertia calculation using wide area measurements

Future developments in power systems, e.g. relatively larger generator sets, the virtual power plant and synthetic inertia concept and connection of generation assets over inverters, will cause the system inertia to vary significantly. During system operation, if the inertia of the system is significantly lower than anticipated at the planning stage, then the existing, deterministic protection and control may fail to ensure system stability. Therefore, the ability to accurately determine the inertia of individual system areas, and the system as a whole, online would be very useful. In this paper, an Inertia Calculation Application (ICA), which could be implemented as part of a Wide Area Monitoring Protection and Control scheme, is presented. The necessary wide area measurements must be processed during large disturbances to the active power balance of the system. The ICA has been validated by using computer simulations, under laboratory conditions and by using real-life data recorded by a transmission system operator

The resuscitation-promoting factors of Mycobacterium tuberculosis are required for virulence and resuscitation from dormancy but are collectively dispensable for growth in situ

Mycobacterium tuberculosis contains five resuscitation-promoting factor (Rpf)-like proteins, RpfA-E, that are implicated in resuscitation of this organism from dormancy via a mechanism involving hydrolysis of the peptidoglycan by Rpfs and partnering proteins. In this study, the rpfA-E genes were shown to be collectively dispensable for growth of M. tuberculosis in broth culture. The defect in resuscitation of multiple mutants from a ‘non-culturable’ state induced by starvation under anoxia was reversed by genetic complementation or addition of culture filtrate from wild-type organisms confirming that the phenotype was associated with rpf-like gene loss and that the ‘non-culturable’ cells of the mutant strains were viable. Other phenotypes uncovered by sequential deletion mutagenesis revealed a functional differentiation within this protein family. The quintuple mutant and its parent that retained only rpfD displayed delayed colony formation and hypersensitivity to detergent, effects not observed for mutants retaining only rpfE or rpfB. Furthermore, mutants retaining rpfD or rpfE were highly attenuated for growth in mice with the latter persisting better than the former in late-stage infection. In conjunction, these results are indicative of a hierarchy in terms of function and/or potency with the Rpf family, with RpfB and RpfE ranking above RpfD

An Input-to-State Stability Approach to Verify Almost Global Stability of a Synchronous-Machine-Infinite-Bus System

Conditions for almost global stability of an operating point of a realistic model of a synchronous generator with constant field current connected to an infinite bus are derived. The analysis is conducted by employing the recently proposed concept of input-to-state stability (ISS)–Leonov functions, which is an extension of the powerful cell structure principle developed by Leonov and Noldus to the ISS framework. Compared with the original ideas of Leonov and Noldus, the ISS–Leonov approach has the advantage of providing additional robustness guarantees. The efficiency of the derived sufficient conditions is illustrated via numerical experiments

Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy

The emergence of drug resistance in M. tuberculosis undermines the efficacy of tuberculosis (TB) treatment in individuals and of TB control programs in populations. Multiple drug resistance is often attributed to sequential functional monotherapy, and standard initial treatment regimens have therefore been designed to include simultaneous use of four different antibiotics. Despite the widespread use of combination therapy, highly resistant M. tb strains have emerged in many settings. Here we use a stochastic birth-death model to estimate the probability of the emergence of multidrug resistance during the growth of a population of initially drug sensitive TB bacilli within an infected host. We find that the probability of the emergence of resistance to the two principal anti-TB drugs before initiation of therapy ranges from 10−5 to 10−4; while rare, this is several orders of magnitude higher than previous estimates. This finding suggests that multidrug resistant M. tb may not be an entirely “man-made” phenomenon and may help explain how highly drug resistant forms of TB have independently emerged in many settings

Opicapone as adjunct to levodopa in treated Parkinson\u27s disease without motor complications: A randomized clinical trial

\ua9 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.Background: Catechol-O-methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson\u27s disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa-treated patients without motor complications. Methods: This was a randomized, double-blind, 24-week, placebo-controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa-treated patients without motor complications were randomized to 24 weeks of double-blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society-Unified Parkinson\u27s Disease Rating Scale Part III (MDS-UPDRS-III) total score. Results: A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double-blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS-UPDRS-III subscore was −6.5 [−7.9, −5.2] in the opicapone group versus −4.3 [−5.7, 3.0] in the placebo group resulting in a significant difference of −2.2 [−3.9, −0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%). Conclusions: Treatment with once-daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications

VapC Toxins from Mycobacterium tuberculosis Are Ribonucleases that Differentially Inhibit Growth and Are Neutralized by Cognate VapB Antitoxins

The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as ‘non-toxic’. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of ‘non-toxic’ VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617 – VapC proteins with similarity to Rv0549c and Rv3320c, respectively – these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism

Opicapone as adjunct to levodopa in treated Parkinson's disease without motor complications: A randomized clinical trial

BACKGROUND: Catechol-O-methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa-treated patients without motor complications. METHODS: This was a randomized, double-blind, 24-week, placebo-controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa-treated patients without motor complications were randomized to 24 weeks of double-blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) total score. RESULTS: A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double-blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS-UPDRS-III subscore was -6.5 [-7.9, -5.2] in the opicapone group versus -4.3 [-5.7, 3.0] in the placebo group resulting in a significant difference of -2.2 [-3.9, -0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%). CONCLUSIONS: Treatment with once-daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications