Interaction between inflammation and thrombosis in acute coronary syndrome

BACKGROUND: Inflammation and thrombosis are important in the pathogenesis of acute coronary syndrome (ACS). Cytokines [interleukin-1beta (IL-1beta) and interleukin-6 (IL-6)] are inflammation markers which play a major role in the development of coronary heart disease. Experimental data documented that an increase of cytokine and von Willebrand factor (vWF) levels in unstable angina (UA) and non-Q wave myocardial infarction (MI) predicts an adverse outcome. AIM: To examine the correlation between the IL-1beta, IL-6 and vWF levels in patients with ACS. METHODS: We examined 92 patients (74 men, 18 women, aged from 43 to 76) divided into 3 groups. The first group included 43 patients with a Q-wave MI, the second group - 33 with a non-Q-wave MI, and the third group - 18 with UA. All patients were given 125-250 mg of aspirin and bolus of 5.000 units of unfractionated heparin, followed by heparin infusion titrated to maintain an activated partial thromboplastin time of 50-75 s. Patients with a Q-wave MI received thrombolytic therapy 1.5 million units of streptokinase. The IL-1b, IL-6 and vWF levels was measured on admission and 7 as well as 21 days later. Fifteen patients with stable angina served as the control group. RESULTS: The levels of cytokines and vWF were significantly higher in patients with ACS than in control subjects. A significant correlation between vWF and IL-6 levels, measured on admission and 7 days later, was found in patients with UA (r=+0.74 and r=+0.55, respectively). Also, a significant correlation was found between vWF and IL-1beta levels measured on admission in patients with either Q-wave or non-Q wave MI (r=+0.7 and r=+0.61, respectively). CONCLUSIONS: Our data suggest that there is a positive correlation between inflammation and thrombosis markers in patients with ACS.     

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes’ epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redox-dead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO₂-OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO₂-OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO₂-OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.Soluble epoxide hydrolase (sEH) has a conserved cysteine (Cys521) proximal to its catalytic center. This cysteine can undergo Michael addition with electrophilic lipids, which inhibits hydrolysis of the enzyme’s epoxyeicosatrienoic acid (EET) substrates (1). This in turn elevates EET levels, which mediate blood vessel dilation and lowers blood pressure (BP), especially in the setting of hypertension (2, 3). Diverse sEH inhibitors limit injury in a variety of diseases (4), providing broad cardiovascular protection (5) against hypertension (6, 7), ischemia and reperfusion injury (8, 9), hypertrophy, and heart failure (10), as well as inflammation (11, 12). Consistent with the therapeutic potential of hydrolase inhibitors, sEH null mice are protected from pathological interventions (13). Conversely, genetic alterations that promote enhanced hydrolase activity are a risk factor for human heart failure (14).The endogenous lipid electrophile 10-nitrooctadec-9-enoic acid (nitro-oleic acid, NO₂-OA) inhibits sEH in vitro (1). NO₂-OA and other fatty acid nitroalkenes appear to signal via pleiotropic mechanisms including targeting and activating peroxisome proliferator-activated receptor gamma (PPARγ), the Kelch-like erythroid cell-derived protein with CNC homology (EHC)-associated protein-1 (Keap1), and nuclear factor (erythroid-derived)-like-2 (Nrf2)-regulated antioxidant response genes and inhibiting proinflammatory gene expression regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (15, 16). Nitroalkenes are produced by radical addition of nitrogen dioxide (·NO₂) to one or more of the olefinic carbons of an unsaturated fatty acid. Nitrogen dioxide is both a product of oxidative inflammatory reactions involving nitric oxide (NO) and nitrite and the acidification nitrite. When the electron-withdrawing nitro group is bonded to alkenyl groups, this confers an electrophilic reactivity to fatty acids (17, 18). Thus, fatty acid nitroalkenes can modify proteins covalently via reversible Michael addition reactions that overall serves to link cellular metabolic and redox homeostasis with the posttranslational regulation of target protein function.Nitro fatty acids, which have been detected endogenously in plasma and urine of humans, animal models, and plants (19–21), mediate salutary cardiovascular signaling actions (22). For example they relax blood vessels, attenuate platelet activation, and reduce inflammation via cyclic guanosine monophosphate (cGMP)-independent mechanisms (23, 24). Of relevance, the Mediterranean diet is characterized by high consumption of unsaturated fatty acids, especially from olive oil and fish rich in oleic and linoleic acid, together with vegetables rich in nitrite and nitrate (25). The acidic and low-oxygen conditions in the stomach provide an environment for efficient nitration of such unsaturated fatty acids by nitrite (26).NO₂-OA normalizes blood pressure in an angiotensin (Ang) II-induced murine model of hypertension via undefined mechanisms (27). This was notable as pharmacological inhibitors of sEH also lower BP in murine hypertension, including salt- or Ang II-induced models (6, 7). As NO₂-OA inhibits sEH, we hypothesized that this mechanism may account for BP lowering in the setting of hypertension. Furthermore, as the Mediterranean diet both contains nitro fatty acids and can elevate their endogenous generation, this mechanism may contribute to dietary-induced BP decreases that in turn will reduce the risk of adverse cardiovascular event (28).Given the complexity of causally establishing whether nitro fatty acids lower BP by inhibiting sEH, especially in the setting of dietary-induced endogenous fatty acid nitration, we generated a Cys521Ser sEH knockin (KI) mouse. This “redox-inactive” sEH thiol mutant, rendered insensitive to adductive inhibition by lipid electrophiles in vitro, provided a novel model system for testing the impact of lipid nitroalkenes on sEH hydrolysis of vasoactive EET species and downstream physiological responses (1). The data reveal that nitro fatty acids, applied exogenously as a pharmacological agent or generated endogenously as part of the Mediterranean diet, inhibit sEH to elevate plasma EETs, which in turn lower BP.     

Effectiveness of inhaled hypertonic saline application for sputum induction to improve Mycobacterium tuberculosis identification in patients with pulmonary tuberculosis

Wiener Medizinische Wochenschrift - This study assessed the effectiveness and diagnostic significance of hypertonic saline sputum induction for improving Mycobacterium tuberculosis (MTB) detection....     

Influence of Modified Epoxy Resins on Peroxide Curing,Mechanical Properties and Adhesion of SBR,NBR and XNBR to Silver Wires—Part II: Application of Carboxy-Containing Peroxy Oligomer (CPO)

This research was aimed at verifying the effect of carboxy-containing peroxy oligomer (CPO) addition on the possibility of rubber crosslinking and a subsequent adhesion of the modified rubber to silver wires. Three commonly industrially used rubbers were selected for the study: styrene–butadiene rubber (SBR), acrylonitrile–butadiene rubber (NBR) and carboxylated acrylonitrile–butadiene rubber (XNBR), together with carboxy-containing peroxy oligomer (CPO). An improvement in the adhesion of rubbers to silver wires was observed when applying the oligomeric peroxide with functional groups, with no deterioration of mechanical properties of the vulcanizates. Crosslinking synergy between dicumyl peroxide (DCP) and the modifier could hardly be observed. Nevertheless, the studies demonstrated, that to a small extent, even the CPO itself can crosslink NBR and especially XNBR, resulting in a material of notable elasticity and adhesion to silver wires.     

Usability and acceptability by a younger and older user group regarding a mobile robot-supported gait rehabilitation system

The aim of the study was to identify differences regarding usability, acceptability, and barriers of usage of a robot-supported gait rehabilitation system between a younger and older group of patients with gait impairments. A mobile robot-supported gait rehabilitation prototype was tested on a group of geriatric patients aged 60 and above, and on a group of young patients aged 59 and below in a clinical setting during five therapy sessions. The involved therapists received 2 days training with the system and could test it profoundly. Data on usability, acceptability, and barriers to system usage were collected with questionnaires and structured interviews with the patients. The robotic system received overall moderate usability and good acceptability ratings; it was rated as clearly structured, practical, and safe. Analyses identified a few barriers, such as time-intensive setup of the system or tight leg shells, which can be minimized with regular training and system adaptations. Differences between the two user groups could be revealed and will be used for future investigation. This study showed the potential of the mobile robot-supported system for gait rehabilitation, but also pointed out further need for action. Efficacy studies are the next step in the evaluation process.