The impact of early rehabilitation in intensive care unit for COVID-19 patients.

PURPOSE: To evaluate the impact of early rehabilitation in intensive care unit (ICU) on the survival and functional outcomes of COVID-19 patients admitted to ICU at acute phase. MATERIALS AND METHODS: We conducted a prospective quasi-experimental study including 346 eligible COVID-19 patients from all admitted cases in an ICU in Vietnam, divided into three groups: no rehabilitation (n = 32), late rehabilitation (n = 109), and early rehabilitation (n = 205). Baseline characteristics and survival information of patient were collected with BORG-CR10 scale and PFIT; the data were collected at different time points: before intervention, when switching to oxygen-therapy, and at discharge. RESULTS: The control group (patients not using rehabilitation therapy) has worse survival than both early rehabilitation group (hazard ratio [HR] 0.553; 95% confidence interval [CI] 0.380-0.806; p value < 0.001) and late rehabilitation group (HR 0.374; CI 0.235-0.594; p value < 0.001). Regarding functional improvement, during the first five days, rehabilitation did not make a significant impact on the patients (p value > 0.05), however if continued from day 5 to day 20, the early-rehabilitation patients obtained a statistically significant improvement for BORG-CR10 (p value < 0.01). No clear association was found for PFIT (p value > 0.05). CONCLUSION: The research emphasises the benefits of the early rehabilitation in ICU for COVID-19 patients.

Rehabilitation for severe COVID-19 patients in the intensive care unit (ICU) can improve patient survival during the ICU stay.This study suggests the benefit of early rehabilitation in ICU for COVID-19 patients.Early rehabilitation shows statistically significant improvement for exertion in patients who underwent rehabilitation at least 5 d.

First description of congenital toxoplasmosis after maternal coinfection with Toxoplasma gondii and severe acute respiratory syndrome coronavirus 2: a case report.

BACKGROUND: Congenital toxoplasmosis can be associated with serious clinical consequences from fetus to adulthood. Hence, early detection is required to minimize severe sequelae through appropriate therapy. We describe the first case of a congenital toxoplasmosis after maternal coinfection with Toxoplasma gondii and severe acute respiratory syndrome coronavirus 2 and the challenging serological diagnosis of the disease in this context. CASE PRESENTATION: A Caucasian boy was born at 27 weeks 2 days of gestation by cesarean section due to maternal COVID-19-related respiratory failure. Postpartum serological screening of the mother revealed a previously unrecognized active Toxoplasma gondii infection. The premature child initially tested negative for anti- Toxoplasma gondii immunoglobulin A and M antibodies 1, 2 and 4 weeks after birth, whereas immunoglobulin G antibodies were only weakly positive with no evidence of child-specific production. Neither neurological nor ophthalmological abnormalities were detected. Approximately 3 months after birth, serological testing indicated a congenital toxoplasmosis by presence of immunoglobulin A and M, in combination with a child-specific immunoglobulin G synthesis. Additionally, cerebrospinal fluid was tested positive for Toxoplasma gondii DNA. Although no clinical manifestations of congenital toxoplasmosis were detected, an antiparasitic therapy was initiated to minimize the risk of late sequelae. There were no hints for a transplacental transmission of severe acute respiratory syndrome coronavirus 2. CONCLUSION: This case raises the awareness of possible coinfections with the risk of transplacental transmission in cases of maternal coronavirus disease 2019. The report emphasizes the need for screening vulnerable patients for toxoplasmosis in general and especially in the context of pregnancy. It becomes evident that prematurity can complicate the serological diagnosis of congenital toxoplasmosis due to a delayed antibody response. Repeated testing is recommended to carefully monitor children at risk and especially those with a history of preterm birth.

Composite Structural Supercapacitors: High-Performance Carbon Nanotube Supercapacitors through Ionic Liquid Localisation.

Composite structural supercapacitors (SSC) are an attractive technology for aerospace vehicles; however, maintaining strength whilst adding energy storage to composite structures has been difficult. Here, SSCs were manufactured using aerospace-grade composite materials and CNT mat electrodes. A new design methodology was explored where the supercapacitor electrolyte was localised within the composite structure, achieving good electrochemical performance within the active region, whilst maintaining excellent mechanical performance elsewhere. The morphologies of these localised SSC designs were characterised with synchrotron X-ray fluorescence microscopy and synchrotron X-ray micro-computed tomography and could be directly correlated with both electrochemical and mechanical performance. One configuration used an ionogel with an ionic liquid (IL) electrolyte, which assisted localisation and achieved 2640 mW h kg-1 at 8.37 W kg-1 with a corresponding short beam shear (SBS) strength of 71.5 MPa in the active area. A separate configuration with only IL electrolyte achieved 758 mW h kg-1 at 7.87 W kg-1 with SBS strength of 106 MPa in the active area. Both configurations provide a combined energy and strength superior to results previously reported in the literature for composite SSCs.

Churn prediction in telecommunication industry using kernel Support Vector Machines.

In this age of fierce competitions, customer retention is one of the most important tasks for many companies. Many previous works proposed models to predict customer churn based on various machine learning techniques. In this study, we proposed an advanced churn prediction model using kernel Support Vector Machines (SVM) algorithm for a telecom company. Baseline SVM models were initially built to find out the most suitable kernel types and will be used to make comparison with other approaches. Dimension reduction strategies such as Sequential Forward Selection (SFS) and Sequential Backward Selection (SBS) were applied to the dataset to find out the most important features. Furthermore, resampling techniques to deal with imbalanced data such as Synthetic Minority Oversampling Technique Tomek Link (SMOTE Tomek) and Synthetic Minority Oversampling Technique ENN (SMOTE ENN) were used on the dataset. Using the above-mentioned techniques, we have obtained better results compared to those obtained from previous works, we achieved an F1-score and accuracy of 99% and 98.9% respectively.

Mapping the wildland-urban interface in California using remote sensing data.

Due to the mixed distribution of buildings and vegetation, wildland-urban interface (WUI) areas are characterized by complex fuel distributions and geographical environments. The behavior of wildfires occurring in the WUI often leads to severe hazards and significant damage to man-made structures. Therefore, WUI areas warrant more attention during the wildfire season. Due to the ever-changing dynamic nature of California's population and housing, the update frequency and resolution of WUI maps that are currently used can no longer meet the needs and challenges of wildfire management and resource allocation for suppression and mitigation efforts. Recent developments in remote sensing technology and data analysis algorithms pose new opportunities for improving WUI mapping methods. WUI areas in California were directly mapped using building footprints extracted from remote sensing data by Microsoft along with the fuel vegetation cover from the LANDFIRE dataset in this study. To accommodate the new type of datasets, we developed a threshold criteria for mapping WUI based on statistical analysis, as opposed to using more ad-hoc criteria as used in previous mapping approaches. This method removes the reliance on census data in WUI mapping, and does not require the calculation of housing density. Moreover, this approach designates the adjacent areas of each building with large and dense parcels of vegetation as WUI, which can not only refine the scope and resolution of the WUI areas to individual buildings, but also avoids zoning issues and uncertainties in housing density calculation. Besides, the new method has the capability of updating the WUI map in real-time according to the operational needs. Therefore, this method is suitable for local governments to map local WUI areas, as well as formulating detailed wildfire emergency plans, evacuation routes, and management measures.

Nitric Oxide Synthase Inhibitors into the Clinic at Last.

The 1998 Nobel Prize in Medicine and Physiology for the discovery of nitric oxide, a nitrogen containing reactive oxygen species (also termed reactive nitrogen or reactive nitrogen/oxygen species) stirred great hopes. Clinical applications, however, have so far pertained exclusively to the downstream signaling of cGMP enhancing drugs such as phosphodiesterase inhibitors and soluble guanylate cyclase stimulators. All clinical attempts, so far, to inhibit NOS have failed even though preclinical models were strikingly positive and clinical biomarkers correlated perfectly. This rather casts doubt on our current way of target identification in drug discovery in general and our way of patient stratification based on correlating but not causal biomarkers or symptoms. The opposite, NO donors, nitrite and enhancing NO synthesis by eNOS/NOS3 recoupling in situations of NO deficiency, are rapidly declining in clinical relevance or hold promise but need yet to enter formal therapeutic guidelines, respectively. Nevertheless, NOS inhibition in situations of NO overproduction often jointly with enhanced superoxide (or hydrogen peroxide production) still holds promise, but most likely only in acute conditions such as neurotrauma (Stover et al., J Neurotrauma 31(19):1599-1606, 2014) and stroke (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016; Casas et al., Proc Natl Acad Sci U S A 116(14):7129-7136, 2019). Conversely, in chronic conditions, long-term inhibition of NOS might be too risky because of off-target effects on eNOS/NOS3 in particular for patients with cardiovascular risks or metabolic and renal diseases. Nitric oxide synthases (NOS) and their role in health (green) and disease (red). Only neuronal/type 1 NOS (NOS1) has a high degree of clinical validation and is in late stage development for traumatic brain injury, followed by a phase II safety/efficacy trial in ischemic stroke. The pathophysiology of NOS1 (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016) is likely to be related to parallel superoxide or hydrogen peroxide formation (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016; Casas et al., Proc Natl Acad Sci U S A 114(46):12315-12320, 2017; Casas et al., Proc Natl Acad Sci U S A 116(14):7129-7136, 2019) leading to peroxynitrite and protein nitration, etc. Endothelial/type 3 NOS (NOS3) is considered protective only and its inhibition should be avoided. The preclinical evidence for a role of high-output inducible/type 2 NOS (NOS2) isoform in sepsis, asthma, rheumatic arthritis, etc. was high, but all clinical development trials in these indications were neutral despite target engagement being validated. This casts doubt on the role of NOS2 in humans in health and disease (hence the neutral, black coloring).

Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease.

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This effect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.

Generation of highly porous silver nanowire networks by plasma treatment and their direct application as supercapacitor electrodes.

Exposure to plasma can significantly increase the surface area of silver species and their resistance to oxidation. While some work investigating plasma-treated silver has been done, limited morphologies and applications have been explored. We hereby explore this effect on silver nanowires (AgNWs) through medium-vacuum air plasma exposure time ranging between 30 s to 60 min. These plasma-treated AgNW networks are directly applied as supercapacitor electrodes, without any carbon or polymer additives that are typically employed alongside silver in energy storage applications. The plasma treatment consequently affected the electrochemical performance of AgNWs, where longer treatment times resulted in higher energy storage capacity. An increase in resistance was observed for plasma treatment times greater than or equal to 5 min, due to the switch from the percolation threshold of the metallic Ag phase to the Ag2O phase. Despite an initial drop in stored energy, an overall improvement in energy storage capacity was observed throughout cycling, where the optimal plasma treatment time of 5 min resulted in an increase of 320% of its starting value with near 100% coulombic efficiency, through the development of stable redox-active surface nanostructures.

Enhanced Flocculation Efficiency in a High-Ionic-Strength Environment by the Aid of Anionic ABA Triblock Copolymers.

The flocculation efficiency of polyelectrolytes in a high-ionic-strength environment is often affected and reduced due to shielding of the active ionizable functional groups, as well as changes in the surface chemistry of the solid slurry. To address this problem, a series of well-defined novel ABA triblock copolymers were employed for the flocculation of high-ionic-strength kaolin slurries at three different Ca2+ concentrations (0.05, 0.10, and 0.50 M). The primary focus was on the advancement in the polymer architecture, where the anionic functionalities were localized at the terminal ends. Typical commercial flocculants tend to have anionic functionalities randomly distributed throughout the polymer chain and hence a higher propensity toward condensed conformation and formation of insoluble species. In comparison to a control random copolymer, the ABA triblock copolymers were able to flocculate kaolin slurries to give faster settlement rates, particularly at the high Ca2+ concentrations of 0.10 and 0.50 M. In addition, these polymers had significantly better clarification ability at higher Ca2+ concentrations compared to the control random copolymer. The ABA triblock copolymer architecture may therefore have potential as a flocculant in high-ionic-strength applications.

Isoform-selective NADPH oxidase inhibitor panel for pharmacological target validation.

Dysfunctional reactive oxygen species (ROS) signaling is considered an important disease mechanism. Therapeutically, non-selective scavenging of ROS by antioxidants, however, has failed in multiple clinical trials to provide patient benefit. Instead, pharmacological modulation of disease-relevant, enzymatic sources of ROS appears to be an alternative, more promising and meanwhile successfully validated approach. With respect to targets, the family of NADPH oxidases (NOX) stands out as main and dedicated ROS sources. Validation of the different NOX isoforms has been mainly through genetically modified rodent models and is lagging behind in other species. It is unclear whether the different NOX isoforms are sufficiently distinct to allow selective pharmacological modulation. Here we show for five widely used NOX inhibitors that isoform selectivity can be achieved, although individual compound specificity is as yet insufficient. NOX1 was most potently (IC50) targeted by ML171 (0.1 µM); NOX2, by VAS2870 (0.7 µM); NOX4, by M13 (0.01 µM) and NOX5, by ML090 (0.01 µM). In addition, some non-specific antioxidant and assay artefacts may limit the interpretation of data, which included, surprisingly, the clinically advanced NOX inhibitor, GKT136901. In a human ischemic blood-brain barrier hyperpermeability model where genetic target validation is not an option, we provide proof-of-principle that pharmacological target validation for different NOX isoforms is possible by applying an inhibitor panel at IC50 concentrations. Moreover, our findings encourage further lead optimization and development efforts for isoform-selective NOX inhibitors in different indications.

Light-In-Flight Imaging by a Silicon Image Sensor: Toward the Theoretical Highest Frame Rate.

Light in flight was captured by a single shot of a newly developed backside-illuminated multi-collection-gate image sensor at a frame interval of 10 ns without high-speed gating devices such as a streak camera or post data processes. This paper reports the achievement and further evolution of the image sensor toward the theoretical temporal resolution limit of 11.1 ps derived by the authors. The theoretical analysis revealed the conditions to minimize the temporal resolution. Simulations show that the image sensor designed following the specified conditions and fabricated by existing technology will achieve a frame interval of 50 ps. The sensor, 200 times faster than our latest sensor will innovate advanced analytical apparatuses using time-of-flight or lifetime measurements, such as imaging TOF-MS, FLIM, pulse neutron tomography, PET, LIDAR, and more, beyond these known applications.

An Image Signal Accumulation Multi-Collection-Gate Image Sensor Operating at 25 Mfps with 32 × 32 Pixels and 1220 In-Pixel Frame Memory.

The paper presents an ultra-high-speed image sensor for motion pictures of reproducible events emitting very weak light. The sensor is backside-illuminated. Each pixel is equipped with multiple collection gates (MCG) at the center of the front side. Each collection gate is connected to an in-pixel large memory unit, which can accumulate image signals captured by repetitive imaging. The combination of the backside illumination, image signal accumulation, and slow readout from the in-pixel signal storage after an image capturing operation offers a very high sensitivity. Pipeline signal transfer from the the multiple collection gates (MCG) to the in-pixel memory units enables the sensor to achieve a large frame count and a very high frame rate at the same time. A test sensor was fabricated with a pixel count of 32 × 32 pixels. Each pixel is equipped with four collection gates, each connected to a memory unit with 305 elements; thus, with a total frame count of 1220 (305 × 4) frames. The test camera achieved 25 Mfps, while the sensor was designed to operate at 50 Mfps.

Toward the Ultimate-High-Speed Image Sensor: From 10 ns to 50 ps.

The paper summarizes the evolution of the Backside-Illuminated Multi-Collection-Gate (BSI MCG) image sensors from the proposed fundamental structure to the development of a practical ultimate-high-speed silicon image sensor. A test chip of the BSI MCG image sensor achieves the temporal resolution of 10 ns. The authors have derived the expression of the temporal resolution limit of photoelectron conversion layers. For silicon image sensors, the limit is 11.1 ps. By considering the theoretical derivation, a high-speed image sensor designed can achieve the frame rate close to the theoretical limit. However, some of the conditions conflict with performance indices other than the frame rate, such as sensitivity and crosstalk. After adjusting these trade-offs, a simple pixel model of the image sensor is designed and evaluated by simulations. The results reveal that the sensor can achieve a temporal resolution of 50 ps with the existing technology.

A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection.

Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease-disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.

The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non-allergic angio-oedema.

BACKGROUND AND PURPOSE: Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B2 receptors). The aim of this study was to investigate whether activation of B2 receptors by endogenous bradykinin contributes to physiological extravasation. This may shed new light on the assumption that treatment with an angiotensin converting enzyme inhibitor (ACEi) results in an alteration in the vascular barrier function predisposing to non-allergic angio-oedema. EXPERIMENTAL APPROACH: We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B2 receptor (B2tg ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2tg mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2n ). KEY RESULTS: Overexpression of B2 receptors was functional in conductance vessels and resistance vessels as evidenced by B2 receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2tg respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2tg as compared with B2n . However, neither endothelial overexpression of B2 receptors nor treatment with the ACEi moexipril or B2 antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy. CONCLUSIONS AND IMPLICATIONS: Activation of B2 receptors does not appear to be involved in spontaneous extravasation. Therefore, the assumption that treatment with an ACEi results in an alteration in the physiological vascular barrier function predisposing to non-allergic angio-oedema is not supported by our findings.

Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors.

Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity.

Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation.

AIMS: Vascular oxidative stress generated by endothelial NO synthase (eNOS) was observed in experimental and clinical cardiovascular disease, but its relative importance for vascular pathologies is unclear. We investigated the impact of eNOS-dependent vascular oxidative stress on endothelial function and on neointimal hyperplasia. RESULTS: A dimer-destabilized mutant of bovine eNOS where cysteine 101 was replaced by alanine was cloned and introduced into an eNOS-deficient mouse strain (eNOS-KO) in an endothelial-specific manner. Destabilization of mutant eNOS in cells and eNOS-KO was confirmed by the reduced dimer/monomer ratio. Purified mutant eNOS and transfected cells generated less citrulline and NO, respectively, while superoxide generation was enhanced. In eNOS-KO, introduction of mutant eNOS caused a 2.3-3.7-fold increase in superoxide and peroxynitrite formation in the aorta and myocardium. This was completely blunted by an NOS inhibitor. Nevertheless, expression of mutant eNOS in eNOS-KO completely restored maximal aortic endothelium-dependent relaxation to acetylcholine. Neointimal hyperplasia induced by carotid binding was much larger in eNOS-KO than in mutant eNOS-KO and C57BL/6, while the latter strains showed comparable hyperplasia. Likewise, vascular remodeling was blunted in eNOS-KO only. INNOVATION: Our results provide the first in vivo evidence that eNOS-dependent oxidative stress is unlikely to be an initial cause of impaired endothelium-dependent vasodilation and/or a pathologic factor promoting intimal hyperplasia. These findings highlight the importance of other sources of vascular oxidative stress in cardiovascular disease. CONCLUSION: eNOS-dependent oxidative stress is unlikely to induce functional vascular damage as long as concomitant generation of NO is preserved. This underlines the importance of current and new therapeutic strategies in improving endothelial NO generation.

Nitric oxide and the CABG patient.

The post surgery success of coronary artery bypass grafting (CABG) is counteracted by thrombosis and de-endothelialization, intimal hyperplasia and, over the long term, atherosclerosis. There are many reasons to assume that in CABG patients vascular bioavailability of NO generated by the endothelium plays an important role for graft function. This holds true for factors such as graft type, harvesting and storage, the type of surgery, non-pharmacologic prevention of risk factors, for example, regular physical activity (if feasible), and drug therapy. Although the precise role of graft endothelial NO bioavailability for graft patency and clinical endpoints is still uncertain, current data rather speak in favor of NO indicating that the potential of vasoprotective activities of NO in the CABG patient deserves further investigation.

Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification.

In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS(++)). When compared with transgene negative controls (eNOS(n)), eNOS(++)-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-α1 and sGC-ß1 subunits in eNOS(n) and eNOS(++). In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS(++). Semiquantitative evaluation of sGC-ß1-S-nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS(++), a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO-dependent posttranslational regulation of vascular sGC in mammals involving S-nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction.

Catalase activity prevents exercise-induced up-regulation of vasoprotective proteins in venous tissue.

Physical activity induces favourable changes of arterial gene expression and protein activity, although little is known about its effect in venous tissue. Although our understanding of the initiating molecular signals is still incomplete, increased expression of endothelial nitric oxide synthase (eNOS) is considered a key event. This study sought to investigate the effects of two different training protocols on the expression of eNOS and extracellular superoxide dismutase (ecSOD) in venous and lung tissue and to evaluate the underlying molecular mechanisms. C57Bl/6 mice underwent voluntary exercise or forced physical activity. Changes of vascular mRNA and protein levels and activity of eNOS, ecSOD and catalase were determined in aorta, heart, lung and vena cava. Both training protocols similarly increased relative heart weight and resulted in up-regulation of aortic and myocardial eNOS. In striking contrast, eNOS expression in vena cava and lung remained unchanged. Likewise, exercise up-regulated ecSOD in the aorta and in left ventricular tissue but remained unchanged in lung tissue. Catalase expression in lung tissue and vena cava of exercised mice exceeded that in aorta by 6.9- and 10-fold, respectively, suggesting a lack of stimulatory effects of hydrogen peroxide. In accordance, treatment of mice with the catalase inhibitor aminotriazole for 6 weeks resulted in significant up-regulation of eNOS and ecSOD in vena cava. These data suggest that physiological venous catalase activity prevents exercise-induced up-regulation of eNOS and ecSOD. Furthermore, therapeutic inhibition of vascular catalase might improve pulmonary rehabilitation.