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This paper summarizes the challenges of identifying planetary-origin meteorites of non-igneous composition - particularly those of sedimentary origin. Evidence for putative sedimentary-origin (sed-type) meteorites and their potential parent bodies is reviewed, suggesting that the list of candidate parent bodies for sed-type meteorites includes, but is not limited to, Mars, Enceladus, Ganymede, Europa, Ceres, Vesta, and other hypothetical planets that existed between the orbits of Mars and Jupiter in the past. The extraterrestrial origin and probable parent body for sed-type meteorites should be assessed based on multiple lines of evidence, and not solely limited to tests of oxygen and noble gas isotopes, whose signatures may undergo terrestrial contamination and which may exhibit significant heterogeneity within both the Solar System and parent cosmic bodies. The observed fall of a cosmic body, evidence of hypervelocity fall, signs of impact, presence of fusion crust, melting, and/or shock deformation features in impactor fragments should be considered as priority signs of meteoritic origin. Keywords: 1908 Tunguska event, Sed-type meteorite, Mars, Enceladus, Icy moon, Parent body of meteorite

Introduction: Acute kidney injury (AKI) is a serious complication of cardiac surgery with cardiopulmonary bypass (CPB). Postoperative AKI develops in 30% to 52% of cardiac surgery patients and 2% to 5% of these patients require renal replacement therapy. Hypothesis: We hypothesized that nitric oxide treatment during cardiac surgery with CPB can decrease AKI incidence in adult patients. The aim of study was to evaluate the effects of nitric oxide supplementation to CPB circuit on the development of cardiac surgery-associated AKI. Methods: A prospective randomized controlled study included 96 patients with moderate risk of renal complications who underwent elective cardiac surgery with CPB. The study protocol was registered at www.clinicaltrials.gov (#NCT03527381). Patients were randomly assigned to either the nitric oxide supplementation to CPB circuit (NO-treatment group, n = 48) or the usual care (control group, n = 48). 40-ppm nitric oxide was administered in NO-treatment group during the entire CPB period. The primary outcome was AKI incidence. Results: Nitric oxide treatment was associated with a significant decrease in AKI incidence (10 (20.8%) versus 20 (41.6%); RR 0.5 (95% CI 0.26-0.95; p =0.023) and a higher urine output during CPB (2.6 [2.1;5.08] versus 1.7 [0.80;2.50] mL/kg/h; p = 0.0002). Urinary neutrophil gelatinase-associated lipocalin levels were significantly lower in NO-treatment group 4 h after surgery: 1.12 [0.75;5.8] versus 4.62 [2.02;34.55] ng/mL; p = 0.005. Concentrations of nitric oxide metabolites in NO-treatment group significantly increased at 5 min post-clamping, 5 min after declamping, and at the end of surgery. The concentrations of proinflammatory and anti-inflammatory mediators and free plasma hemoglobin did not significantly differ between groups. Conclusions: Nitric oxide administration to patients at moderate risk of renal complications undergoing elective cardiac surgery with CPB was associated with a decrease in AKI incidence. The implications of study for clinical practice expand the array of methods, which may be used for prevention of AKI in cardiac surgery patients.

A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

Objectives. This work aimed to study the efficacy of hybrid 99mTc-Pyrophosphate SPECT/CT for diagnosis of latent inflammatory processes in the myocardium of patients with atrial fibrillation (AF). Methods. The study comprised 34 patients aged 44 ± 9 years with AF of unknown etiology referred for radiofrequency ablation. The data were acquired using hybrid 99mTc-Pyrophosphate SPECT/CT. To evaluate and interpret the results of hybrid study and to determine localization of radiopharmaceutical accumulation, scintigraphic and CT images were fused. SPECT/CT results were compared with data of endomyocardial biopsy. Results. Sensitivity, specificity, and accuracy of 99mTc-Pyrophosphate SPECT/CT in diagnosing myocarditis were 91%, 100%, and 94%, respectively. Proposed diagnostic criteria for myocarditis comprised intensity of the radiopharmaceutical accumulation in the myocardium and the ratios of focus/lung, focus/vertebral column, and focus/LV pool. Minimum cutoff values for the histologically verified myocarditis were >1.47 for focus/lung index, >0.11 for focus/vertebral column ratio, and >1.26 for focus/lung index. Conclusions. SPECT/CT-based quantitative assessment of 99mTc-Pyrophosphate accumulation in the myocardium is a highly informative noninvasive method for diagnosis of inflammatory process in the heart in patients with AF of undefined etiology.

This article introduces a hypothesis on nanoparticle-mediated modulation of cholesterol crystal behaviour in the atherosclerotic plaques. The role of cholesterol crystals in progression of atherosclerosis is emphasized. Proposed mechanism of spontaneous cholesterol crystal formation in the organism is discussed. Mechanisms and factors associated with the nanoparticle-mediated modulation of cholesterol crystal behaviour are proposed. Authors hypothesize that specially designed nanoparticles may therapeutically modulate cholesterol crystal behaviour in atherosclerosis. Nano-sized agents used in stent coatings and imaging techniques can possibly prevent cholesterol crystallization in the diseased vessels. On the other hand, new nanotechnologies should be implemented with caution as certain types of nanoparticles could become crystal seeds for cholesterol deposited in the atherosclerotically damaged vascular walls causing destabilization of the plaques. Studying nanoparticle-induced alterations of cholesterol crystal formation requires multidisciplinary approach involving biomedical researchers, computer scientists, and physical chemists specializing in crystal growth. The proposed hypothesis on nanoparticle-mediated modulation of cholesterol crystal behaviour may be relevant to other medical conditions including gallbladder stones, arthritis, and ophthalmological diseases such as synchysis scintillans.

c-Jun N-terminal kinases (JNKs) are involved in the myocardial and aortic remodeling, increased arterial tone, and arterial blood pressure elevation associated with hypertension. The aim of the present study was to investigate the antihypertensive effect of a new JNK inhibitor, 1H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), on spontaneously hypertensive rats (SHRs). Experiments were performed using normotensive Wistar-Kyoto (WKY) rats and SHRs. Experimental groups of SHRs received IQ-1S intragastrically for 6 weeks in daily doses of 5 and 50 mg/kg; experimental groups of WKY rats received 50 mg/kg IQ-1S according to the same regimen. The IQ-1S administration regimen induced decreases in systolic blood pressure, mean arterial blood pressure, total peripheral resistance, blood viscosity, hematocrit, myocardial cell cross-sectional area, and aortic wall thickness in SHRs vs untreated SHRs. There were no significant differences in systolic blood pressure values between the control and experimental groups of WKY rats during the treatment period. A concentration-dependent decrease in the tone of carotid arterial rings isolated from SHRs was observed after JNK inhibitor application in vitro. Application of the JNK inhibitor diminished endothelin-1 secretion by human umbilical vein endothelial cells in vitro. The main mechanisms of the antihypertensive effect of IQ-1S included the attenuation of blood viscosity due to decreased hematocrit, a vasodilatory effect on arterial smooth muscle cells, and a decrease in endothelin-1 production by endothelial cells.

Objective Acute kidney injury (AKI) is a serious complication of cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study was to evaluate the effects of nitric oxide (NO) supplementation to the CPB circuit on the development of cardiac surgery–associated AKI. Methods This prospective randomized controlled study included 96 patients with moderate risk of renal complications who underwent elective cardiac surgery with CPB. The study protocol was registered at ClinicalTrials.gov (identifier NCT03527381 ). Patients were randomly allocated to either NO supplementation to the CPB bypass circuit (NO treatment group; n = 48) or usual care (control group; n = 48). In the NO treatment group, 40-ppm NO was administered during the entire CPB period. The primary outcome was the incidence of AKI. Results NO treatment was associated with a significant decrease in AKI incidence (10 cases [20.8%] vs 20 cases [41.6%] in the control group; relative risk, 0.5; 95% confidence interval, 0.26-0.95; P = .023) and a higher median urine output during CPB (2.6 mL/kg/h [interquartile range (IQR), 2.1-5.08 mL/kg/h] vs 1.7 mL/kg/h [IQR, 0.80-2.50 mL/kg/h]; P = .0002). The median urinary neutrophil gelatinase-associated lipocalin level at 4 hours after surgery was significantly lower in the NO treatment group (1.12 ng/mL [IQR, 0.75-5.8 ng/mL] vs 4.62 ng/mL [IQR, 2.02-34.55 ng/mL]; P = .005). In the NO treatment group, concentrations of NO metabolites were significantly increased at 5 minutes postclamping, at 5 minutes after declamping, and at the end of the operation. Concentrations of proinflammatory and anti-inflammatory mediators and free plasma hemoglobin did not differ significantly between the 2 groups. Conclusions NO administration in patients at moderate risk of renal complications undergoing elective cardiac surgery with CPB was associated with a lower incidence of AKI.

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5&prime, diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 &plusmn, 0.3 &mu, M) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

Background Salidroside is a biologically active compound derived from Rhodiola rosea L. Studies showed that salidroside after i.v. injection is extensively metabolized to p -tyrosol and only trace amounts of salidroside are found in the brain tissue. Objective The aim of the study was to investigate the neuroprotective effects of p -tyrosol in the global cerebral ischemia-reperfusion (GCI) model. Study design A total of 103 Wistar rats were assigned to groups of sham-operated (n = 10), control (n = 42), p -tyrosol-treated (n = 36), and pentoxifylline-treated (n = 15) animals. The rats of control, p -tyrosol-treated, and pentoxifylline-treated groups received intravenously 0.9% NaCl solution, 2% solution of p -tyrosol in doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg, and pentoxifylline in a dose of 100 mg/kg, respectively, daily for 5 days. Rats were examined at days 1, 3, and 5 after GCI. After evaluation of neurological deficit, animals were euthanized for morphological and biochemical characterization. Methods Rats of control, p -tyrosol-treated, and pentoxifylline-treated groups were exposed to three-vessel model of GCI. Neurological deficit, numeric density of neurons in hippocampal CA1 region, and percentage of neurons with focal and total chromatolysis were studied. Biochemical study assessed contents of conjugated dienes and fluorescent products in brain homogenate. Results In control group, only 50.0% of rats survived by day 5 after the GCI; 38.1% of survived animals had severe neurologic deficit. In brain tissue of PTX-treated rats, the levels of diene conjugates and fluorescent products were 79% and 73%, respectivley, at day 5 compared with control. Differences in diene conjugates were statistically significant compared with control. The survival rate of animals treated with 20 mg/kg p-tyrosol was 82.3% at day 5 after GCI. In p -tyrosol-treated GCI rats, the numeric density of neurons in the hippocampal CA1 region was higher by 31% compared with control. The percentage of neurons with focal and total chromatolysis decreased by 27% and 43%, respectively. At day 5 after GCI, the levels of conjugated dienes and fluorescent products were significantly lower (by 37% and 45%, respectively) in group of animals treated with 20 mg/kg p-tyrosol compared with control. Moderate neuroprotective effects of 5 mg/kg p -tyrosol administration were documented only at day 5 after GCI. In case of 10 mg/kg p -tyrosol administration, neuroprotection was documented sooner: at day 1 or 3 after GCI. However, administration of 5 and 10 mg/kg p -tyrosol did not affect animal survival. Conclusion Course administration of intravenous p -tyrosol in a dose of 20 mg/kg increased survival, reduced neurological deficit after GCI, attenuated neuronal damage in the hippocampus, and attenuated lipid peroxidation in brain tissue in animals subject to GCI with reperfusion.

Background Control of sympathetic hyperactivity is pivotal for treatment of heart failure (HF) in patients with coronary artery disease (CAD). Our earlier studies demonstrated that the auricular pulsed electrical stimulation of the vagus nerve (VNS) beneficially affected condition of CAD patients with HF. The aim of our study was to evaluate changes in heart rate (HR) and the levels of heat shock proteins in peripheral blood lymphocytes in patients with CAD in the course of VNS. Methods The study comprised 70 individuals aged 50–68 years with chronic coronary insufficiency, severe left ventricular dysfunction, and NYHA functional class (FC) III–IV HF. Main group included 63 patients who received VNS course (group 1). Control patients (n = 7) received sham therapy (group 2). Results According to the results of 6-minute walk test and 24-hour ECG monitoring, administration of VNS improved clinical condition of 58 of 63 patients, decreased HF FC, and attenuated HR. Clinical condition in sham therapy group did not change. Immunoenzyme method demonstrated that hsp70 and hsp60 contents in peripheral blood lymphocyte lysate increased by 58% and 48% (P 80 bpm. Conclusions Correction of autonomous nervous status by VNS attenuated HR and improved functional state of the heart in CAD patients. Cardiotropic effect of VNS was the most pronounced in patients with preserved endogenous stress-limiting systems associated with hsp60 and/or hsp70.

The article presents data on dependence of the myocardial electrical impedance on the temperature. These data have high clinical relevance because radio frequency energy-induced destruction of the myocardium in the course of surgical treatment of cardiac arrhythmias should be performed transmurally. Insufficient transmural myocardial damage results in recurrence of cardiac arrhythmias. Therefore, achieving transmural treatments of the myocardium is of high significance.Studies were performed by using 20 isolated hearts. To evaluate the effectiveness of radio frequency exposure, we studied two temperature settings: myocardial normothermia (36.6 °C) and myocardial hypothermia (20 °C). The depth of destruction as well as the temperatures of the epicardial, endocardial, and intramural myocardium at the points of impact were estimated. Data showed that lower temperature decreases tissue electrical impedance and results in a greater depth of damage.

An exotic meter-size quartzitic boulder known as John's Stone was found by John Anfinogenov in 1972 buried in permafrost close to the epicenter of the 1908 Tunguska blast in a region of Siberia dominated by Permian-Triassic Siberian Trap basalts. The boulder is made almost entirely of well-cemented quartz grains, mostly around 100 mu m in size; it contains zones with coarser or finer grain sizes. Rare zircon and rutile crystals are scattered within the quartz matrix. Quartz is often dissected by strain lamellae. The rock contains abundant scattered internal vugs rimmed by euhedral quartz crystals. We cannot exclude that John's Stone is a fragment of a Permian granite-derived sandstone unit. However, based on structure, mineralogy and chemistry the quartzitic boulder may have originated due to silica deposition from hydrothermal solutions that had reacted with basaltic rocks. Anfinogenov et al. (Anfinogenov, J. et al. [2014]. Icarus 243, 139-147) interpreted features observed in the permafrost at the base of the boulder as indicating it impacted from above, suggesting the boulder may be a meteorite, possibly of martian origin, given the reported presence on Mars of silica-rich deposits. Triple oxygen isotope ratios determined on two samples of the quartzite reveal a terrestrial rather than a martian meteorites composition. Oxygen isotope data suggest also that the precipitation of SiO2 could have occurred in equilibrium with hydrothermal water (delta O-18(w) approximate to -19.5 parts per thousand) at the temperature of about 50 degrees C. The thermal event that generated the quartzite may be related either to the century-old Tunguska Event, or, more probably, to Permian-Triassic Siberian Traps magmatism, although an extraterrestrial origin cannot be completely ruled out. (C) 2015 Elsevier Inc. All rights reserved.

Diabetes mellitus is a chronic disease requiring lifelong control with hypoglycemic agents that must demonstrate excellent efficacy and safety profiles. In patients taking glucose-lowering drugs, hypoglycemia is a common cause of death associated with arrhythmias, increased thrombus formation, and specific effects of catecholamines due to sympathoadrenal activation. Focus is now shifting from merely glycemic control to multifactorial approach. In the context of individual drugs and classes, this article reviews interdisciplinary strategies evaluating metabolic effects of drugs for treatment of chronic heart failure (CHF) which can mask characteristic hypoglycemia symptoms. Hypoglycemia unawareness and cardiac autonomic neuropathy are discussed. Data suggesting that hypoglycemia modulates immune response are reviewed. The potential role of gut microbiota in improving health of patients with diabetes and CHF is emphasized. Reports stating that nondiabetic CHF patients can have life-threatening hypoglycemia associated with imbalance of thyroid hormones are discussed. Regular glycemic control based on HbA1c measurements and adequate pharmacotherapy remain the priorities in diabetes management. New antihyperglycemic drugs with safer profiles should be preferred in vulnerable CHF patients. Multidrug interactions must be considered. Emerging therapies with reduced hypoglycemia risk, telemedicine, sensor technologies, and genetic testing predicting hypoglycemia risk may help solving the challenges of hypoglycemia in CHF patients with diabetes. Interdisciplinary work may involve cardiologists, diabetologists/endocrinologists, immunologists, gastroenterologists, microbiologists, nutritionists, imaging specialists, geneticists, telemedicine experts, and other relevant specialists. This review emphasizes that systematic knowledge on pathophysiology of hypoglycemia in diabetic patients with CHF is largely lacking and the gaps in our understanding require further discoveries.

The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.

The aim of this study was to discover remnants of the 1908 Tunguska meteorite. Field studies identified exotic rocks, furrows, and penetration funnels reported by the first eyewitnesses. Main methods included decoding of aerial survey photographs, systematic survey of epicenter area of the Tunguska explosion, exploratory excavations, reconstruction studies of the exotic rocks, mineralogical and spectral analysis of specimens, and experimental attempt of plasma-induced reproduction of fusion crust. The authors report the discovery of funnel-like structures and of an exotic boulder known as John’s Stone (JS) in the epicentral area. The article provides detailed description of JS, fresh furrows in the permafrost, multiple shear-fractured splinters, splinters with glassy coatings, evidence of high-speed impact of JS in the ground, and clear consistency in the geometry of spacial arrangements of all splinters, furrows, and cleaved pebbles. Pattern of permafrost destruction suggested about high-speed entry and lateral ricochet of JS in the ground with further deceleration and breakage. Calculated landing velocity of JS was at least 547 m/s. John’s Stone is composed of highly silicified gravelite sandstone (98.5% SiO 2 ) with grain size of 0.5–1.5 cm. Outer surface of several splinters showed continuous glassy coating similar to shiny fusion crust reminiscent of freshly applied enamel. Plasma-induced heating of John’s Stone specimen led to its explosive disintegration; residue presented with light-colored semi-transparent pumice-like grains and irregularly shaped fused particles. Overall, our data suggest that John’s Stone may be a fragment of the 1908 Tunguska meteorite and may represent a new type of meteorite.

Objectives The aim of this pilot study was to elucidate the effects of exogenous nitric oxide (NO) supply to the extracorporeal circulation circuit for cardioprotection against ischemia–reperfusion injury during coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Methods A total of 60 patients with coronary artery disease scheduled for CABG with CPB were enrolled in a prospective randomized study. Patients were allocated randomly to receive treatment according to standard or modified CPB protocol where 40-ppm NO was added to the CPB circuit during cardiac surgery. The primary endpoint was the measurement of cardiac troponin I (cTnI). The secondary end points consisted in the measurements of creatine kinase-muscle/brain fraction (CK-MB) and vasoactive inotropic score (VIS). Results NO delivered into the CPB circuit had a cardioprotective effect. The level of cTnI was significantly lower in NO-treated group compared with the control group 6 hours after surgery: 1.79 ± 0.39 ng/mL versus 2.41 ± 0.55 ng/mL, respectively (P = .001). The CK-MB value was significantly lower in NO-treated group compared with the control group 24 hours after surgery: 47.69 ± 8.08 U/L versus 62.25 ± 9.78 U/L, respectively (P = .001); and the VIS was significantly lower in the NO-treated group 6 hours after the intervention. Conclusions NO supply to the CPB circuit during CABG exerted a cardioprotective effect and was associated with lower levels of VIS and cardiospecific blood markers cTnI and CK-MB.

BACKGROUND Systemic arterial pressure (AP) depends on two physiological variables: cardiac output (CO) and total peripheral resistance (TPR). The latter depends on vascular hindrance and blood viscosity (BV). However, the relative contributions of the vascular and rheological factors to TPR remain unclear. OBJECTIVE The aim of our work was to study the haemodynamic and haemorheologic effects of a treatment course with pentoxifylline (PTX) in SHRs in an effort to assess the impact of the rheological factor on TPR and AP. METHODS The effects of the treatment course with PTX (100 mg/kg/day p.o. for six weeks) on BV, plasma viscosity, haematocrit, erythrocyte aggregation and deformability, mean AP (MAP), stroke volume (SV), CO, and TPR were studied in SHRs and in control Wistar Kyoto (WKY) rats. RESULTS PTX-treated SHRs had a lower BV, lower erythrocyte aggregation, and higher erythrocyte deformability index compared with the controls. The TPR level was higher by 43% compared with that in WKY rats and did not differ from the values obtained from control SHRs. In SHRs, moderate and strong positive correlations were found between BV and MAP and between BV and TPR. PTX-treated SHRs did not have any significant correlations between the above mentioned parameters. CONCLUSIONS Treatment with PTX attenuated whole blood viscosity, but did not affect the AP and hemodynamic parameters in the experimental SHRs compared with the control SHRs. The magnitude of the rheologic effects of PTX was insufficient to cause appreciable decreases in TPR and AP.

The vagus nerve is a major component of the autonomic nervous system and plays a critical role in many body functions including for example, speech, swallowing, heart rate and respiratory control, gastric secretion, and intestinal motility. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, with electrical stimulation being the most important. Implantable devices for VNS are approved therapy for refractory epilepsy and for treatment-resistant depression. In the case of heart disease applications, implantable VNS has been shown to be beneficial for treating heart failure in both preclinical and clinical studies. Adverse effects of implantable VNS therapy systems are generally associated with the implantation procedure or continuous on-off stimulation. The most serious implantation-associated adverse effect is infection. The effectiveness of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, heart failure, and other conditions remains under investigation. VNS merits further study for its potentially favorable effects on cardiovascular disease, especially heart failure.

The objective of this study was to determine whether Gq/11-coupled receptor activation can enhance the mechanosensitivity of a canonical transient receptor potential (TRPC)-like current and consequently the myogenic responsiveness of rat anterior cerebral arteries. Initial patch-clamp experiments revealed the presence of a basal cation current in isolated smooth muscle cells that displayed evidence of double rectification, which was blocked by trivalent cations (Gd3+ and La3+). PCR analysis identified the expression of TRPC1, 3, 6 and 7 mRNA and, characteristic of TRPC-like current, the whole-cell conductance was insensitive to a Na+-dependent transport (amiloride), TRP vanilloid (ruthenium red), and chloride channel (DIDS, niflumic acid, and flufenamate) inhibitors. One notable exception was tamoxifen, which elicited a dual effect, blocking or activating the TRPC-like current at 1 and 10 μM, respectively. This TRPC-like current was augmented by constrictor agonists (uridine 5′-triphosphate and U46619) or hyposmotic challenge (303 to 223 mOsm/l), a mechanical stimulus. Although each stimulus was effective alone, smooth muscle cells pretreated with agonist did not augment the whole-cell response to hyposmotic challenge. Consistent with these electrophysiological recordings, functional experiments revealed that neither UTP nor U46619 enhanced the sensitivity of intact cerebral arteries to hyposmotic challenge or elevated intravascular pressure. In summary, this study found no evidence that Gq/11-coupled receptor activation augments the mechanosensitivity of a TRPC-like current and consequently the myogenic responsiveness of anterior cerebral arteries.

This study examined whether elevated intravascular pressure stimulates asynchronous Ca2+ waves in cerebral arterial smooth muscle cells and if their generation contributes to myogenic tone development. The endothelium was removed from rat cerebral arteries, which were then mounted in an arteriograph, pressurized (20–100 mmHg) and examined under a variety of experimental conditions. Diameter and membrane potential (VM) were monitored using conventional techniques; Ca2+ wave generation and myosin light chain (MLC20)/MYPT1 (myosin phosphatase targeting subunit) phosphorylation were assessed by confocal microscopy and Western blot analysis, respectively. Elevating intravascular pressure increased the proportion of smooth muscle cells firing asynchronous Ca2+ waves as well as event frequency. Ca2+ wave augmentation occurred primarily at lower intravascular pressures (

Vascular smooth muscle tone plays a fundamental role in regulating blood pressure, blood flow, microcirculation, and other cardiovascular functions. The cellular and molecular mechanisms by which vascular smooth muscle contractility is regulated are not completely elucidated. Recent studies show that the actin cytoskeleton in smooth muscle is dynamic, which regulates force development. In this review, evidence for actin polymerization in smooth muscle upon external stimulation is summarized. Protein kinases such as Abelson tyrosine kinase, focal adhesion kinase, Src, and mitogen-activated protein kinase have been documented to coordinate actin polymerization in smooth muscle. Transmembrane integrins have also been reported to link to signaling pathways modulating actin dynamics. The roles of Rho family of the small proteins that bind to guanosine triphosphate (GTP), also known as GTPases, and the actin-regulatory proteins, including Crk-associated substrate, neuronal Wiskott-Aldrich Syndrome protein, the Arp2/3 complex, and profilin, and heat shock proteins in regulating actin assembly are discussed. These new findings promote our understanding on how smooth muscle contraction is regulated at cellular and molecular levels.

Previously, we reported that hyposmotic swelling evoked transient vascular smooth muscle cell (SMC) contraction that was completely abolished by L-type Ca(2+) channel blockers. In contrast, sustained contraction revealed in hyper- and isoosmotically-shrunken SMCs was insensitive to L-type channel blockers and was diminished in Ca(2+)-free medium by only 30-50%. Several research groups reported cell volume-dependent cytoskeleton network rearrangements. This study examines the role of cytoskeleton proteins in cell volume-dependent contraction of endothelium-denuded vascular smooth muscle rings (VSMR) from the rat thoracic aorta. Hyperosmotic shrinkage and hyposmotic swelling were triggered by modulation of medium osmolality; isosmotic shrinkage was induced by VSMR transfer from hypo- to isosmotic medium. The relative content of globular (G) and fibrillar (F) actin was estimated by fluorescence microscopy. Hyperosmotic shrinkage and hyposmotic swelling led to elevation of the F-actin/G-actin ratio by 2.5- and 1.8-fold respectively. Contraction of shrunken and swollen VSMR was insensitive to modulators of microtubules such as vinblastine, colchicine and docetaxel. Microfilament disassembly by cytochalasin B resulted in dramatic attenuation of the maximal amplitude of contraction of hyperosmotically-shrunken and hyposmotically-swollen VSMR, and almost completely abolished the contraction triggered by isosmotic shrinkage. These data suggest that both L-type Ca(2+) channel-mediated contraction of swollen vascular SMC and Ca(2+)(o)-insensitive contractions of shrunken cells are triggered by reorganization of the microfilament network caused by elevation of the F-actin/G-actin ratio.

The tyrosine phosphorylated protein Crk-associated substrate (CAS) has previously been shown to participate in the cellular processes regulating dynamic changes in the actin architecture and arterial constriction. In the present study, treatment of rat mesenteric arteries with phenylephrine (PE) led to the increase in CAS tyrosine phosphorylation and the association of CAS with the adapter protein CrkII. CAS phosphorylation was catalyzed by Abl in an in vitro study. To determine the role of Abl tyrosine kinase in arterial vessels, plasmids encoding Abl short hairpin RNA (shRNA) were transduced into mesenteric arteries by chemical loading plus liposomes. Abl silencing diminished increases in CAS phosphorylation on PE stimulation. Previous studies have shown that assembly of the multiprotein compound containing CrkII, neuronal Wiskott–Aldrich Syndrome Protein (N-WASP) and the Arp2/3 (Actin Related Protein) complex triggers actin polymerization in smooth muscle as well as in nonmuscle cells. In this study, Abl silencing attenuated the assembly of the multiprotein compound in resistance arteries on contractile stimulation. Furthermore, the increase in F/G-actin ratios (an index of actin assembly) and constriction on contractile stimulation were reduced in Abl-deficient arterial segments compared with control arteries. However, myosin regulatory light chain phosphorylation (MRLCP) elicited by contractile activation was not inhibited in Abl-deficient arteries. These results suggest that Abl may play a pivotal role in mediating CAS phosphorylation, the assembly of the multiprotein complex, actin assembly, and constriction in resistance arteries. Abl does not participate in the regulation of myosin activation in arterial vessels during contractile stimulation.

The aims of the study were to evaluate the effects of renal sympathetic denervation (RSD) on the heart and to identify the predictors of RSD efficacy in patients with resistant arterial hypertension. The study comprised 60 RSD patients (54.6 ± 9.5 years) who received full-dose antihypertensive therapy (4.1 drugs) including diuretics. Initially, 58.6 % of patients had abnormal left ventricular (LV) diastolic function. All patients received echocardiography before and 24 weeks after RSD. Renal sympathetic denervation was achieved through the endovascular radiofrequency ablation (RFA) of the renal arteries. Drug therapy continued for the entire period of observation. After RSD, all patients were retrospectively assigned to two groups: group 1 comprised patients (n = 22; 36.7 %) in whom the myocardial mass (MM) of the left ventricle decreased by more than 10 g after RSD; group 2 comprised patients (n = 38; 63.3 %) in whom LV MM increased or decreased by less than 10 g. Anthropometry, arterial blood pressure, heart rate, therapy, and LV end-diastolic dimensions (EDD) were comparable in these groups. After RSD, the values of office blood pressure significantly decreased and MM regressed by more than 10 g in 36.7 % of patients; LV diastolic function normalized in 31 % of patients, and diastolic dysfunction improved in 14 % of patients. The study found the associations between the initial LV wall dimensions and LV MM changes. Unlike LV EDD, arterial blood pressure, or heart rate, the initial values of LV wall thickness predicted LV MM regress. Trial registration: #NCT01499810 https://clinicaltrials.gov/ct2/show/NCT01499810 .

BACKGROUND: Control of sympathetic hyperactivity is pivotal for treatment of heart failure (HF) in patients with coronary artery disease (CAD). Our earlier studies demonstrated that the auricular pulsed electrical stimulation of the vagus nerve (VNS) beneficially affected condition of CAD patients with HF. The aim of our study was to evaluate changes in heart rate (HR) and the levels of heat shock proteins in peripheral blood lymphocytes in patients with CAD in the course of VNS. METHODS: The study comprised 70 individuals aged 50–68 years with chronic coronary insufficiency, severe left ventricular dysfunction, and NYHA functional class (FC) III–IV HF. Main group included 63 patients who received VNS course (group 1). Control patients (n = 7) received sham therapy (group 2). RESULTS: According to the results of 6‐minute walk test and 24‐hour ECG monitoring, administration of VNS improved clinical condition of 58 of 63 patients, decreased HF FC, and attenuated HR. Clinical condition in sham therapy group did not change. Immunoenzyme method demonstrated that hsp70 and hsp60 contents in peripheral blood lymphocyte lysate increased by 58% and 48% (P < 0.05), respectively, in patients who initially had HR < 80 bpm. The hsp70 level significantly increased and hsp60 level remained unchanged in patients with initial HR > 80 bpm. CONCLUSIONS: Correction of autonomous nervous status by VNS attenuated HR and improved functional state of the heart in CAD patients. Cardiotropic effect of VNS was the most pronounced in patients with preserved endogenous stress‐limiting systems associated with hsp60 and/or hsp70.

Here we review available data on nitric oxide (NO)-mediated signaling in skeletal muscle during physical exercise. Nitric oxide modulates skeletal myocyte function, hormone regulation, and local microcirculation. Nitric oxide underlies the therapeutic effects of physical activity whereas the pharmacological modulators of NO-mediated signaling are the promising therapeutic agents in different diseases. Nitric oxide production increases in skeletal muscle in response to physical activity. This molecule can alter energy supply in skeletal muscle through hormonal modulation. Mitochondria in skeletal muscle tissue are highly abundant and play a pivotal role in metabolism. Considering NO a plausible regulator of mitochondrial biogenesis that directly affects cellular respiration, we discuss the mechanisms of NO-induced mitochondrial biogenesis in the skeletal muscle cells. We also review available data on myokines, the molecules that are expressed and released by the muscle fibers and exert autocrine, paracrine and/or endocrine effects. The article suggests the presence of putative interplay between NO-mediated signaling and myokines in skeletal muscle. Data demonstrate an important role of NO in various diseases and suggest that physical training may improve health of patients with diabetes, chronic heart failure, and even degenerative muscle diseases. We conclude that NO-associated signaling represents a promising target for the treatment of various diseases and for the achievement of better athletic performance.

This article reviews the existing knowledge about the effects of physical exercise on nitric oxide (NO) production in the cardiopulmonary system. The authors review the sources of NO in the cardiopulmonary system; involvement of three forms of NO synthases (eNOS, nNOS, and iNOS) in exercise physiology; exercise-induced modulation of NO and/or NOS in physiological and pathophysiological conditions in human subjects and animal models in the absence and presence of pharmacological modulators; and significance of exercise-induced NO production in health and disease. The authors suggest that physical activity significantly improves functioning of the cardiovascular system through an increase in NO bioavailability, potentiation of antioxidant defense, and decrease in the expression of reactive oxygen species-forming enzymes. Regular physical exercises are considered a useful approach to treat cardiovascular diseases. Future studies should focus on detailed identification of (i) the exercise-mediated mechanisms of NO exchange; (ii) optimal exercise approaches to improve cardiovascular function in health and disease; and (iii) physical effort thresholds.

Phosphorylation and spatial reorganization of the vimentin network have been implicated in mediating smooth muscle contraction, cell migration, and cell mitosis. In this report, stimulation of cultured smooth muscle cells with 5-hydroxytryptamine (5-HT) induced PAK1 phosphorylation at Thr-423 (an indication of PAK activation). Treatment with PAK led to disassembly of wild type vimentin filaments, but not vimentin S56A (alanine substitution at serine-56) mutant filaments, as assessed by an in vitro filament assembly assay. Furthermore, stimulation with 5-HT resulted in the dissociation of Crk-associated substrate (CAS, an adapter protein associated with smooth muscle force development) from cytoskeletal vimentin. Expression of the vimentin S56A mutant in cells inhibited the increase in phosphorylation at Ser-56 and ratios of soluble vimentin to insoluble vimentin (an index of vimentin disassembly), and the dissociation of CAS from cytoskeletal vimentin in response to 5-HT activation as compared to cells expressing wild type vimentin. Because CAS may be involved in PAK activation, PAK phosphorylation was evaluated in cells expressing S56A vimentin mutant. Expression of vimentin S56A mutant depressed PAK phosphorylation at Thr-423 induced by 5-HT. The expression of the vimentin S56A mutant also inhibited the spatial reorientation of vimentin filaments in cells in response to 5-HT stimulation. Our results suggest that vimentin phosphorylation at Ser-56 may inversely regulate PAK activation possibly via the increase in the amount of soluble CAS upon agonist stimulation of smooth muscle cells. Additionally, vimentin phosphorylation at this position is critical for vimentin filament spatial rearrangement elicited by agonists.

This study elucidates the role of cell volume in contractions of endothelium-denuded vascular smooth muscle rings (VSMR) from the rat aorta. We observed that hyposmotic swelling as well as hyper- and isosmotic shrinkage led to VSMR contractions. Swelling-induced contractions were accompanied by activation of Ca2+ influx and were abolished by nifedipine and verapamil. In contrast, contractions of shrunken cells were insensitive to the presence of L-type channel inhibitors and occurred in the absence of Ca2+ o. Thirty minutes preincubation with bumetanide, a potent Na+, K+, CI- cotransport (NKCC) inhibitor, decreased Cl(-)i content, nifedipine-sensitive 45Ca uptake and contractions triggered by modest depolarization ([K+]o = 36 mM). Elevation of [K+]o to 66 mM completely abolished the effect of bumetanide on these parameters. Bumetanide almost completely abrogated phenylephrine-induced contraction, partially suppressed contractions triggered by hyperosmotic shrinkage, but potentiated contractions of isosmotically shrunken VSMR. Our results suggest that bumetanide suppresses contraction of modestly depolarized cells via NKCC inhibition and Cl(-)i-mediated membrane hyperpolarization, whereas augmented contraction of isosmotically shrunken VSMR by bumetanide is a consequence of suppression of NKCC-mediated regulatory volume increase. The mechanism of bumetanide inhibition of contraction of phenylephrine-treated and hyperosmotically shrunken VSMR should be examined further.

Non-invasive molecular imaging techniques can enhance diagnosis of neurological diseases to achieve their successful treatment. Positron emission tomography (PET) imaging can identify activated microglia and provide detailed functional information based on molecular biology. This imaging modality is based on detection of isotope labeled tracers, which emit positrons. The review summarizes the developments of various radiolabeled ligands for PET imaging of neuroinflammation.

This study examines the relative contributions of K-Cl cotransport and K+ channels to swelling-induced K+ fluxes in vascular smooth muscle cells (VSMC). DIOA known as a potent in

The aim of the study was the development and clinical application of patient selection algorithm for surgical treatment of longlasting persistent atrial fibrillation. The study included 235 patients with acquired heart disease and coronary artery disease, which in the period from 1999 to 2015 performed surgical treatment of long-term persistent atrial fibrillation (RF “MAZE III” procedure) in conjunction with the correction of the underlying heart disease. The patients were divided into 2 groups according to the method of operation: the group 1 – 135 patients (76 women and 59 men) who have applied an integrated approach to surgery for atrial fibrillation, including penetrating method of RF effects on atrial myocardium and the study of the function of the sinus node before and after the operation (these patients were operated on from 2008 to 2015). The group 2 – 100 patients (62 women and 38 men) with a “classical” method of monopolar RF “MAZE III”, which the sinus node function was not studied. We used the combined (epi- and endocardial) method of RF «MAZE». This algorithm is decreasing of possible permanent pacemaker postoperatively. The initial sinus node function in these patients, measured using the original method, the basic line of this algorithm was taken. The results showed that use this algorithm for selection of patients allows significantly reduce the possibility of pacemaker implantation in the postoperative period.

L-type Ca2+channels are broadly expressed in arterial smooth muscle cells, and their voltage-dependent properties are important in tone development. Recent studies have noted that these Ca2+channels are not singularly expressed in vascular tissue and that other subtypes are likely present. In this study, we ascertained which voltage-gated Ca2+channels are expressed in rat cerebral arterial smooth muscle and determined their contribution to the myogenic response. mRNA analysis revealed that the α1-subunit of L-type (Cav1.2) and T-type (Cav3.1 and Cav3.2) Ca2+channels are present in isolated smooth muscle cells. Western blot analysis subsequently confirmed protein expression in whole arteries. With the use of patch clamp electrophysiology, nifedipine-sensitive and -insensitive Ba2+currents were isolated and each were shown to retain electrical characteristics consistent with L- and T-type Ca2+channels. The nifedipine-insensitive Ba2+current was blocked by mibefradil, kurtoxin, and efonidpine, T-type Ca2+channel inhibitors. Pressure myography revealed that L-type Ca2+channel inhibition reduced tone at 20 and 80 mmHg, with the greatest effect at high pressure when the vessel is depolarized. In comparison, the effect of T-type Ca2+channel blockade on myogenic tone was more limited, with their greatest effect at low pressure where vessels are hyperpolarized. Blood flow modeling revealed that the vasomotor responses induced by T-type Ca2+blockade could alter arterial flow by ∼20–50%. Overall, our findings indicate that L- and T-type Ca2+channels are expressed in cerebral arterial smooth muscle and can be electrically isolated from one another. Both conductances contribute to myogenic tone, although their overall contribution is unequal.

This study examined whether elevated intravascular pressure stimulates asynchronous Ca2+ waves in cerebral arterial smooth muscle cells and if their generation contributes to myogenic tone development. The endothelium was removed from rat cerebral arteries, which were then mounted in an arteriograph, pressurized (20–100 mmHg) and examined under a variety of experimental conditions. Diameter and membrane potential (VM) were monitored using conventional techniques; Ca2+ wave generation and myosin light chain (MLC20)/MYPT1 (myosin phosphatase targeting subunit) phosphorylation were assessed by confocal microscopy and Western blot analysis, respectively. Elevating intravascular pressure increased the proportion of smooth muscle cells firing asynchronous Ca2+ waves as well as event frequency. Ca2+ wave augmentation occurred primarily at lower intravascular pressures (

This study examined whether elevated intravascular pressure stimulates asynchronous Ca(2+) waves in cerebral arterial smooth muscle cells and if their generation contributes to myogenic tone development. The endothelium was removed from rat cerebral arteries, which were then mounted in an arteriograph, pressurized (20-100 mmHg) and examined under a variety of experimental conditions. Diameter and membrane potential (V(M)) were monitored using conventional techniques; Ca(2+) wave generation and myosin light chain (MLC(20))/MYPT1 (myosin phosphatase targeting subunit) phosphorylation were assessed by confocal microscopy and Western blot analysis, respectively. Elevating intravascular pressure increased the proportion of smooth muscle cells firing asynchronous Ca(2+) waves as well as event frequency. Ca(2+) wave augmentation occurred primarily at lower intravascular pressures (60 mmHg) and ryanodine, a plant alkaloid that depletes the sarcoplasmic reticulum (SR) of Ca(2+), eliminated these events. Ca(2+) wave generation was voltage insensitive as Ca(2+) channel blockade and perturbations in extracellular [K(+)] had little effect on measured parameters. Ryanodine-induced inhibition of Ca(2+) waves attenuated myogenic tone and MLC(20) phosphorylation without altering arterial V(M). Thapsigargin, an SR Ca(2+)-ATPase inhibitor also attenuated Ca(2+) waves, pressure-induced constriction and MLC(20) phosphorylation. The SR-driven component of the myogenic response was proportionally greater at lower intravascular pressures and subsequent MYPT1 phosphorylation measures revealed that SR Ca(2+) waves facilitated pressure-induced MLC(20) phosphorylation through mechanisms that include myosin light chain phosphatase inhibition. Cumulatively, our findings show that mechanical stimuli augment Ca(2+) wave generation in arterial smooth muscle and that these transient events facilitate tone development particularly at lower intravascular pressures by providing a proportion of the Ca(2+) required to directly control MLC(20) phosphorylation.

Aim: The purpose of the study was to characterize transdermal delivery of xenon through rat skin from a lipophilic solution and from water. Methods: Sections of skin were obtained from