The Combination of Beta-Blockers and ACE Inhibitors Across the Spectrum of Cardiovascular Diseases.

Cardiovascular disease is the leading cause of mortality worldwide, affecting a wide range of patients at different stages across the cardiovascular continuum. Hypertension is one of the earliest risk factors in this continuum and can be controlled in most patients with currently available antihypertensive agents. However, goals are often not met because treatments are not optimized in terms of tailoring therapy to individual patients based on their hypertension subclass and cardiovascular risk profile and initiating early use of adapted-dose, single-pill combinations. In this context, beta-blockers in combination with angiotensin-converting enzyme (ACE) inhibitors are of special interest as a result of their complementary actions on the sympathetic nervous system and renin-angiotensin-aldosterone system, two interlinked pathways that influence cardiovascular risk and disease outcomes. In addition to their antihypertensive actions, beta-blockers are used to manage arrhythmias and treat angina pectoris and heart failure, while ACE inhibitors provide cardioprotection in patients with acute coronary syndromes and treat congestive heart failure. A broad range of patients may therefore receive the combination in routine clinical practice. This paper examines the supporting evidence for beta-blockers and ACE inhibitors in each of the above indications and considers the rationale for combining these agents into a single pill, using data from bisoprolol and perindopril randomized controlled trials as supporting evidence. Combining these established antihypertensive agents into a single pill continues to provide effective blood pressure lowering and improved cardiovascular outcomes while allowing a greater proportion of patients to rapidly achieve treatment targets.

Apkinson: the smartphone application for telemonitoring Parkinson's patients through speech, gait and hands movement.

Aim: This paper introduces Apkinson, a mobile application for motor evaluation and monitoring of Parkinson's disease patients. Materials & methods: The App is based on previously reported methods, for instance, the evaluation of articulation and pronunciation in speech, regularity and freezing of gait in walking, and tapping accuracy in hand movement. Results: Preliminary experiments indicate that most of the measurements are suitable to discriminate patients and controls. Significance is evaluated through statistical tests. Conclusion: Although the reported results correspond to preliminary experiments, we think that Apkinson is a very useful App that can help patients, caregivers and clinicians, in performing a more accurate monitoring of the disease progression. Additionally, the mobile App can be a personal health assistant.

Comparison between angiotensin-converting enzyme inhibitor and angiotensin receptor blocker after percutaneous coronary intervention.

BACKGROUND: The inhibitors for renin-angiotensin-aldosterone system (RAAS) have different mechanisms of action in coronary artery disease (CAD). This study sought to compare the clinical outcomes between angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) therapy in patients with CAD undergoing contemporary percutaneous coronary intervention (PCI). METHODS: Based on the National Health Insurance claims data in South Korea, patients aged 18 years or older who had undergone PCI between July 2011 and June 2015 were enrolled. The study participants were classified either as patients with acute myocardial infarction (AMI, n = 21,747) or angina (n = 28,708). And according to the post PCI discharge medications, patients were categorized into ACEI and ARB therapy groups. The primary endpoint was all-cause death, and the two groups were compared using a propensity-score matching analysis. RESULTS: The study population had a median follow-up of 2.2 years (interquartile range, 1.2-3.2). In the propensity-score matched AMI group (8341 pairs), the occurrence of all-cause death was significantly lower in the ACEI group than in the ARB group (hazard ratio [HR] of ACEI, 0.823; 95% confidence interval [CI]: 0.715-0.947; p = 0.006). In the propensity-score matched angina group (10,878 pairs), there was no difference in the incidence of the primary endpoint between the ACEI and ARB groups (HR of ACEI, 1.113; 95% CI: 0.986-1.257; p = 0.084). CONCLUSIONS: In this nationwide Korean cohort study, ACEI therapy in patients with AMI and concomitant PCI showed a significant reduction in all-cause mortality rates when compared to that with ARB therapy.

Blood pressure reduction and clinical outcomes with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: protocol for a systematic review and meta-regression analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not-a phenomenon described as the 'ARB-MI paradox'. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP. METHODS: A comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists (two-tailed p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger's statistic. DISCUSSION: This systematic review will provide a detailed synthesis of evidence regarding the relationship between BP reduction and clinical outcomes with ACEi and ARBs. Greater understanding of the dependency of the effect of each class on BP reduction will advance insight into the nature of the ARB-MI paradox and guide the future usage of these agents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017072988.

The Divergent Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Adult Patients With Type 2 Diabetes Mellitus.

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT1) receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all-cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk.

Segmentation of gait sequences using inertial sensor data in hereditary spastic paraplegia.

Gait analysis is an important tool for diagnosis, monitoring and treatment of neurological diseases. Among these are hereditary spastic paraplegias (HSPs) whose main characteristic is heterogeneous gait disturbance. So far HSP gait has been analysed in a limited number of studies, and within a laboratory set up only. Although the rarity of orphan diseases often limits larger scale studies, the investigation of these diseases is still important, not only to the affect population, but also for other diseases which share gait characteristics.

Thermotoga maritima NusG: domain interaction mediates autoinhibition and thermostability.

NusG, the only universally conserved transcription factor, comprises an N- and a C-terminal domain (NTD, CTD) that are flexibly connected and move independently in Escherichia coli and other organisms. In NusG from the hyperthermophilic bacterium Thermotoga maritima (tmNusG), however, NTD and CTD interact tightly. This closed state stabilizes the CTD, but masks the binding sites for the interaction partners Rho, NusE and RNA polymerase (RNAP), suggesting that tmNusG is autoinhibited. Furthermore, tmNusG and some other bacterial NusGs have an additional domain, DII, of unknown function. Here we demonstrate that tmNusG is indeed autoinhibited and that binding to RNAP may stabilize the open conformation. We identified two interdomain salt bridges as well as Phe336 as major determinants of the domain interaction. By successive weakening of this interaction we show that after domain dissociation tmNusG-CTD can bind to Rho and NusE, similar to the Escherichia coli NusG-CTD, indicating that these interactions are conserved in bacteria. Furthermore, we show that tmNusG-DII interacts with RNAP as well as nucleic acids with a clear preference for double stranded DNA. We suggest that tmNusG-DII supports tmNusG recruitment to the transcription elongation complex and stabilizes the tmNusG:RNAP complex, a necessary adaptation to high temperatures.

Transcription is regulated by NusA:NusG interaction.

NusA and NusG are major regulators of bacterial transcription elongation, which act either in concert or antagonistically. Both bind to RNA polymerase (RNAP), regulating pausing as well as intrinsic and Rho-dependent termination. Here, we demonstrate by nuclear magnetic resonance spectroscopy that the Escherichia coli NusG amino-terminal domain forms a complex with the acidic repeat domain 2 (AR2) of NusA. The interaction surface of either transcription factor overlaps with the respective binding site for RNAP. We show that NusA-AR2 is able to remove NusG from RNAP. Our in vivo and in vitro results suggest that interaction between NusA and NusG could play various regulatory roles during transcription, including recruitment of NusG to RNAP, resynchronization of transcription:translation coupling, and modulation of termination efficiency.

Manipulating Crystallization of Organolead Mixed-Halide Thin Films in Antisolvent Baths for Wide-Bandgap Perovskite Solar Cells.

Wide-bandgap perovskite solar cells (PSCs) based on organolead (I, Br)-mixed halide perovskites (e.g., MAPbI2Br and MAPbIBr2 perovskite with bandgaps of 1.77 and 2.05 eV, respectively) are considered as promising low-cost alternatives for application in tandem or multijunction photovoltaics (PVs). Here, we demonstrate that manipulating the crystallization behavior of (I, Br)-mixed halide perovskites in antisolvent bath is critical for the formation of smooth, dense thin films of these perovskites. Since the growth of perovskite grains from a precursor solution tends to be more rapid with increasing Br content, further enhancement in the nucleation rate becomes necessary for the effective decoupling of the nucleation and the crystal-growth stages in Br-rich perovskites. This is enabled by introducing simple stirring during antisolvent-bathing, which induces enhanced advection transport of the extracted precursor-solvent into the bath environment. Consequently, wide-bandgap planar PSCs fabricated using these high quality mixed-halide perovskite thin films, Br-rich MAPbIBr2, in particular, show enhanced PV performance.

The Divergent Cardiovascular Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death.

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke - a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta-analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are "independent" of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects - ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients.

The two domains of Mycobacterium tuberculosis NusG protein are dynamically independent.

Transcription elongation factor NusG from Escherichia coli couples transcription and translation. It is the only conserved transcription factor in all three kingdoms of life, playing a variety of roles in gene expression. E. coli NusG consists of two non-interacting domains. While the N-terminal domain interacts with RNA polymerase, the C-terminal domain contacts NusE (S10), or the Rho transcription termination factor. The two corresponding domains of Thermotoga maritima NusG are mutually interacting. Therefore, NusG here forms an autoinhibited state, where the binding sites to RNAP, NusE, and the Rho factor are masked. Recent functional studies showed differences between NusG from E. coli and Mycobacterium tuberculosis. In contrast to E. coli NusG, M. tuberculosis NusG is able to stimulate intrinsic termination, but is not able to bind the Rho factor. To analyze whether this has structural reasons, we determined the solution structure of the carboxyterminal domain of M. tuberculosis NusG by nuclear magnetic resonance spectroscopy. Furthermore, we modeled the wild-type full-length protein, and present evidence that the two domains of this protein do not interact in solution by NMR dynamics measurements.

Determination of RNA polymerase binding surfaces of transcription factors by NMR spectroscopy.

In bacteria, RNA polymerase (RNAP), the central enzyme of transcription, is regulated by N-utilization substance (Nus) transcription factors. Several of these factors interact directly, and only transiently, with RNAP to modulate its function. As details of these interactions are largely unknown, we probed the RNAP binding surfaces of Escherichia coli (E. coli) Nus factors by nuclear magnetic resonance (NMR) spectroscopy. Perdeuterated factors with [(1)H,(13)C]-labeled methyl groups of Val, Leu, and Ile residues were titrated with protonated RNAP. After verification of this approach with the N-terminal domain (NTD) of NusG and RNAP we determined the RNAP binding site of NusE. It overlaps with the NusE interaction surface for the NusG C-terminal domain, indicating that RNAP and NusG compete for NusE and suggesting possible roles for the NusE:RNAP interaction, e.g. in antitermination and direct transcription:translation coupling. We solved the solution structure of NusA-NTD by NMR spectroscopy, identified its RNAP binding site with the same approach we used for NusG-NTD, and here present a detailed model of the NusA-NTD:RNAP:RNA complex.

Exploring RNA polymerase regulation by NMR spectroscopy.

RNA synthesis is a central process in all organisms, with RNA polymerase (RNAP) as the key enzyme. Multisubunit RNAPs are evolutionary related and are tightly regulated by a multitude of transcription factors. Although Escherichia coli RNAP has been studied extensively, only little information is available about its dynamics and transient interactions. This information, however, are crucial for the complete understanding of transcription regulation in atomic detail. To study RNAP by NMR spectroscopy we developed a highly efficient procedure for the assembly of active RNAP from separately expressed subunits that allows specific labeling of the individual constituents. We recorded [(1)H,(13)C] correlation spectra of isoleucine, leucine, and valine methyl groups of complete RNAP and the separately labeled ß' subunit within reconstituted RNAP. We further produced all RNAP subunits individually, established experiments to determine which RNAP subunit a certain regulator binds to, and identified the ß subunit to bind NusE.

Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles.

In continuation of our previous work, several 1-alkyl-2,3,5-tris(4-hydroxyphenyl)aryl-1H-pyrroles with chlorine or fluorine substituents in the aryl residues were synthesized and tested for estrogen receptor (ER) binding at isolated ERα/ERß receptors (HAP assay) and in transactivation assays using ERα-positive MCF-7/2a as well as U2-OS/ERα and U2-OS/ERß cells. In the competition experiment at ERα the compounds displayed very high relative binding affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ERα/ERß (8m) = 9). The highest estrogenic potency in ERα-positive MCF-7/2a cells was determined for 2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-propyl-1H-pyrrole 8m (EC(50) = 23 nM), while in U2-OS/ERα cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1-propyl-1H-pyrrole 8b (EC(50) = 0.12 nM) was the most potent agonist, only 30-fold less active than estradiol (E2, EC(50) = 0.004 nM). In U2-OS/ERß cells for all pyrroles no transactivation could be observed, which indicates that they are selective ERα agonists in cellular systems.