An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized

Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised? A pulsed fluoroscopic investigation

Objectives: Throughout the 20th Century, it has been postulated that the knee moves on the basis of a four-bar link mechanism composed of the cruciate ligaments, the femur and the tibia. As a consequence, the femur has been thought to roll back with flexion, and total knee arthroplasty (TKA) prostheses have been designed on this basis. Recent work, however, has proposed that at a position of between 0° and 120° the medial femoral condyle does not move anteroposteriorly whereas the lateral femoral condyle tends, but is not obliged, to roll back - a combination of movements which equates to tibial internal/femoral external rotation with flexion. The aim of this paper was to assess if the articular geometry of the GMK Sphere TKA could recreate the natural knee movements in situ/in vivo. Methods: The pattern of knee movement was studied in 15 patients (six male: nine female; one male with bilateral TKAs) with 16 GMK Sphere implants, at a mean age of 66 years (53 to 76) with a mean BMI of 30 kg/m2 (20 to 35). The motions of all 16 knees were observed using pulsed fluoroscopy during a number of weight-bearing and non-weight-bearing static and dynamic activities. Results: During maximally flexed kneeling and lunging activities, the mean tibial internal rotation was 8° (standard deviation (SD) 6). At a mean 112° flexion (SD 16) during lunging, the medial and lateral condyles were a mean of 2 mm (SD 3) and 8 mm (SD 4) posterior to a transverse line passing through the centre of the medial tibial concavity. With a mean flexion of 117° (SD 14) during kneeling, the medial and lateral condyles were a mean of 1 mm (SD 4) anterior and 6 mm (SD 4) posterior to the same line. During dynamic stair and pivoting activities, there was a mean anteroposterior translation of 0 mm to 2 mm of the medial femoral condyle. Backward lateral condylar translation occurred and was linearly related to tibial rotation. Conclusion: The GMK Sphere TKA in our study group shows movements similar in pattern, although reduced in magnitude, to those in recent reports relating to normal knees during several activities. Specifically, little or no translation of the medial femoral condyle was observed during flexion, but there was posterior roll-back of the lateral femoral condyle, equating to tibiofemoral rotation. We conclude that the GMK Sphere is anteroposteriorly stable medially and permits rotation about the medial compartment

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro. Abou El Hassan MA, Verheul HM, Jorna AS, Schalkwijk C, van Bezu J, van der Vijgh WJ, Bast A. Department of Medical Oncology, Free University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. [email protected] Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) doxorubicin with(out) monoHER (0.2-1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC(50)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (< or =25 micro M, P<0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in viv

Sustainability of the whole-community project '10,000 Steps': a longitudinal study

<p>Abstract</p> <p>Background</p> <p>In the dissemination and implementation literature, there is a dearth of information on the sustainability of community-wide physical activity (PA) programs in general and of the '10,000 Steps' project in particular. This paper reports a longitudinal evaluation of organizational and individual sustainability indicators of '10,000 Steps'.</p> <p>Methods</p> <p>Among project adopters, department heads of 24 public services were surveyed 1.5 years after initially reported project implementation to assess continuation, institutionalization, sustained implementation of intervention components, and adaptations. Barriers and facilitators of project sustainability were explored. Citizens (<it>n </it>= 483) living near the adopting organizations were interviewed to measure maintenance of PA differences between citizens aware and unaware of '10,000 Steps'. Independent-samples <it>t</it>, Mann-Whitney <it>U</it>, and chi-square tests were used to compare organizations for representativeness and individual PA differences.</p> <p>Results</p> <p>Of all organizations, 50% continued '10,000 Steps' (mostly in cycles) and continuation was independent of organizational characteristics. Level of intervention institutionalization was low to moderate on evaluations of routinization and moderate for project saturation. The global implementation score (58%) remained stable and three of nine project components were continued by less than half of organizations (posters, street signs and variants, personalized contact). Considerable independent adaptations of the project were reported (e.g. campaign image). Citizens aware of '10,000 Steps' remained more active during leisure time than those unaware (227 ± 235 and 176 ± 198 min/week, respectively; <it>t </it>= -2.6; p < .05), and reported more household-related (464 ± 397 and 389 ± 346 min/week, respectively; <it>t </it>= -2.2; p < .05) and moderate-intensity-PA (664 ± 424 and 586 ± 408 min/week, respectively; <it>t </it>= -2.0; p < .05). Facilitators of project sustainability included an organizational leader supporting the project, availability of funding or external support, and ready-for-use materials with ample room for adaptation. Barriers included insufficient synchronization between regional and community policy levels and preference for other PA projects.</p> <p>Conclusions</p> <p>'10,000 Steps' could remain sustainable but design, organizational, and contextual barriers need consideration. Sustainability of '10,000 Steps' in organizations can occur in cycles rather than in ongoing projects. Future research should compare sustainability other whole-community PA projects with '10,000 Steps' to contrast sustainability of alternative models of whole-community PA projects. This would allow optimization of project elements and methods to support decisions of choice for practitioners.</p

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER)

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

Conscious thought beats deliberation without attention in diagnostic decision-making: at least when you are an expert

Contrary to what common sense makes us believe, deliberation without attention has recently been suggested to produce better decisions in complex situations than deliberation with attention. Based on differences between cognitive processes of experts and novices, we hypothesized that experts make in fact better decisions after consciously thinking about complex problems whereas novices may benefit from deliberation-without-attention. These hypotheses were confirmed in a study among doctors and medical students. They diagnosed complex and routine problems under three conditions, an immediate-decision condition and two delayed conditions: conscious thought and deliberation-without-attention. Doctors did better with conscious deliberation when problems were complex, whereas reasoning mode did not matter in simple problems. In contrast, deliberation-without-attention improved novices’ decisions, but only in simple problems. Experts benefit from consciously thinking about complex problems; for novices thinking does not help in those cases

Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.

N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition

A Membrane-Bound Vertebrate Globin

The family of vertebrate globins includes hemoglobin, myoglobin, and other O2-binding proteins of yet unclear functions. Among these, globin X is restricted to fish and amphibians. Zebrafish (Danio rerio) globin X is expressed at low levels in neurons of the central nervous system and appears to be associated with the sensory system. The protein harbors a unique N-terminal extension with putative N-myristoylation and S-palmitoylation sites, suggesting membrane-association. Intracellular localization and transport of globin X was studied in 3T3 cells employing green fluorescence protein fusion constructs. Both myristoylation and palmitoylation sites are required for correct targeting and membrane localization of globin X. To the best of our knowledge, this is the first time that a vertebrate globin has been identified as component of the cell membrane. Globin X has a hexacoordinate binding scheme and displays cooperative O2 binding with a variable affinity (P50∼1.3–12.5 torr), depending on buffer conditions. A respiratory function of globin X is unlikely, but analogous to some prokaryotic membrane-globins it may either protect the lipids in cell membrane from oxidation or may act as a redox-sensing or signaling protein