The interaction of vasoactive substances during exercise modulates platelet aggregation in hypertension and coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Acute vigorous exercise, associated with increased release of plasma catecholamines, transiently increases the risk of primary cardiac arrest. We tested the effect of acute submaximal exercise on vasoactive substances and their combined result on platelet function.</p> <p>Methods</p> <p>Healthy volunteers, hypertensive patients and patients with coronary artery disease (CAD) performed a modified treadmill exercise test. We determined plasma catecholamines, thromboxane A₂, prostacyclin, endothelin-1 and platelet aggregation induced by adenosine diphosphate (ADP) and collagen at rest and during exercise.</p> <p>Results</p> <p>Our results during exercise showed a) platelet activation (increased thromboxane B₂, TXB₂), b) increased prostacyclin release from endothelium and c) decreased platelet aggregation in all groups, significantly more in healthy volunteers than in patients with CAD (with hypertensives lying in between these two groups).</p> <p>Conclusion</p> <p>Despite the pronounced activation of Sympathetic Nervous System (SNS) and increased TXB₂levels during acute exercise platelet aggregation decreases, possibly to counterbalance the prothrombotic state. Since this effect seems to be mediated by the normal endothelium (through prostacyclin and nitric oxide), in conditions characterized by endothelial dysfunction (hypertension, CAD) reduced platelet aggregation is attenuated, thus posing such patients in increased risk for thrombotic complications.</p

Protein Conformation and Supercharging with DMSO from Aqueous Solution

The efficacy of dimethyl sulfoxide (DMSO) as a supercharging reagent for protein ions formed by electrospray ionization from aqueous solution and the mechanism for supercharging were investigated. Addition of small amounts of DMSO to aqueous solutions containing hen egg white lysozyme or equine myoglobin results in a lowering of charge, whereas a significant increase in charge occurs at higher concentrations. Results from both near-UV circular dichroism spectroscopy and solution-phase hydrogen/deuterium exchange mass spectrometry indicate that DMSO causes a compaction of the native structure of these proteins at low concentration, but significant unfolding occurs at ~63% and ~43% DMSO for lysozyme and myoglobin, respectively. The DMSO concentrations required to denature these two proteins in bulk solution are ~3–5 times higher than the concentrations required for the onset of supercharging, consistent with a significantly increased concentration of this high boiling point supercharging reagent in the ESI droplet as preferential evaporation of water occurs. DMSO is slightly more basic than m-nitrobenzyl alcohol and sulfolane, two other supercharging reagents, based on calculated proton affinity and gas-phase basicity values both at the B3LYP and MP2 levels of theory, and all three of these supercharging reagents are significantly more basic than water. These results provide additional evidence that the origin of supercharging from aqueous solution is the result of chemical and/or thermal denaturation that occurs in the ESI droplet as the concentration of these supercharging reagents increases, and that proton transfer reactivity does not play a significant role in the charge enhancement observed

Achieved systolic blood pressure in older people: A systematic review and meta-analysis

Background: It remains unclear into which level the systolic blood pressure (SBP) should be lowered in order to provide the best cardiovascular protection among older people. Hypertension guidelines recommendation on attaining SBP levels 33,600 participants) were included. Compared with attaining SBP levels ≥140 mmHg, levels of 130 to <140 mmHg were not associated with lower risk of outcomes in the meta-analysis of RCTs, whereas there was an associated reduction of cardiovascular mortality (RR 0.72, 95% CI 0.59-0.88) and all-cause mortality (RR 0.86, 95% CI 0.75-0.99) in the meta-analysis of post-hoc analyses or subanalyses of RCTs. Limited and conflicting data were available for the SBP levels of <130 mmHg and 140 to <150 mmHg. Conclusions: Among older people, there is suggestive evidence that achieving SBP levels of 130 to <140 mmHg is associated with lower risks of cardiovascular and all-cause mortality. Future trials are required to confirm these findings and to provide additional evidence regarding the <130 and 140 to <150 mmHg SBP levels

Подготовка ИТ-консультантов в российских вузах в разрезе проблематики консалтинга

Differences in clinical effectiveness between angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in the primary treatment of hypertension are unknown. The aim of this retrospective cohort study was to assess the prevention of type 2 diabetes and cardiovascular disease (CVD) in patients treated with ARBs or ACEis. Patients initiated on enalapril or candesartan treatment in 71 Swedish primary care centers between 1999 and 2007 were included. Medical records data were extracted and linked with nationwide hospital discharge and cause of death registers. The 11 725 patients initiated on enalapril and 4265 on candesartan had similar baseline characteristics. During a mean follow-up of 1.84 years, 36 482 patient-years, the risk of new diabetes onset was lower in the candesartan group (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69-0.96, P = 0.01) compared with the enalapril group. No difference between the groups was observed in CVD risk (HR 0.99, 95% CI 0.87-1.13, P = 0.86). More patients discontinued treatment in the enalapril group (38.1%) vs the candesartan group (27.2%). In a clinical setting, patients initiated on candesartan treatment had a lower risk of new-onset type 2 diabetes and lower rates of drug discontinuation compared with patients initiated on enalapril. No differences in CVD risk were observed

Nucleobindin Co-Localizes and Associates with Cyclooxygenase (COX)-2 in Human Neutrophils

The inducible cyclooxygenase isoform (COX-2) is associated with inflammation, tumorigenesis, as well as with physiological events. Despite efforts deployed in order to understand the biology of this multi-faceted enzyme, much remains to be understood. Nucleobindin (Nuc), a ubiquitous Ca2+-binding protein, possesses a putative COX-binding domain. In this study, we investigated its expression and subcellular localization in human neutrophils, its affinity for COX-2 as well as its possible impact on PGE2 biosynthesis. Complementary subcellular localization approaches including nitrogen cavitation coupled to Percoll fractionation, immunofluorescence, confocal and electron microscopy collectively placed Nuc, COX-2, and all of the main enzymes involved in prostanoid synthesis, in the Golgi apparatus and endoplasmic reticulum of human neutrophils. Immunoprecipitation experiments indicated a high affinity between Nuc and COX-2. Addition of human recombinant (hr) Nuc to purified hrCOX-2 dose-dependently caused an increase in PGE2 biosynthesis in response to arachidonic acid. Co-incubation of Nuc with COX-2-expressing neutrophil lysates also increased their capacity to produce PGE2. Moreover, neutrophil transfection with hrNuc specifically enhanced PGE2 biosynthesis. Together, these results identify a COX-2-associated protein which may have an impact in prostanoid biosynthesis

Lipocalin 2 modulates the cellular response to amyloid beta

The production, accumulation and aggregation of amyloid beta (Aß) peptides in Alzheimer's disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Aß aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Aß1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Aß1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Aß toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.Cell Death and Differentiation advance online publication, 23 May 2014; doi:10.1038/cdd.2014.68.We thank Dr. Ioannis Sotiropoulos for reagents and comments. Sandro Da Mesquita and Ana Catarina Ferreira are recipients of PhD fellowships and Fernanda Marques is recipient of a postdoctoral fellowship by the Fundacao para a Ciencia e Tecnologia (FCT, Portugal)/FEDER. This work was supported by a grant from FCT/FEDER (EXPL/NEUOSD/2196/2013)

Genomic comparisons reveal biogeographic and anthropogenic impacts in the koala (Phascolarctos cinereus): a dietary-specialist species distributed across heterogeneous environments

The Australian koala is an iconic marsupial with highly specific dietary requirements distributed across heterogeneous environments, over a large geographic range. The distribution and genetic structure of koala populations has been heavily influenced by human actions, specifically habitat modification, hunting and translocation of koalas. There is currently limited information on population diversity and gene flow at a species-wide scale, or with consideration to the potential impacts of local adaptation. Using species-wide sampling across heterogeneous environments, and high-density genome-wide markers (SNPs and PAVs), we show that most koala populations display levels of diversity comparable to other outbred species, except for those populations impacted by population reductions. Genetic clustering analysis and phylogenetic reconstruction reveals a lack of support for current taxonomic classification of three koala subspecies, with only a single evolutionary significant unit supported. Furthermore, similar to 70% of genetic variance is accounted for at the individual level. The Sydney Basin region is highlighted as a unique reservoir of genetic diversity, having higher diversity levels (i.e., Blue Mountains region; AvHe(corr)-0.20, PL% = 68.6). Broad-scale population differentiation is primarily driven by an isolation by distance genetic structure model (49% of genetic variance), with clinal local adaptation corresponding to habitat bioregions. Signatures of selection were detected between bioregions, with no single region returning evidence of strong selection. The results of this study show that although the koala is widely considered to be a dietary-specialist species, this apparent specialisation has not limited the koala's ability to maintain gene flow and adapt across divergent environments as long as the required food source is available