Metro Mapping:development of an innovative methodology to co-design care paths to support shared decision making in oncology

Treatment decision-making can be complex, notably when there are multiple treatments available, with different (probabilities of) benefits and harms, for example, survival and side effects.1 It is precisely in these complex situations that the preferences of the patient are of utmost importance, as the trade-offs of benefits and harms are subjective and concern patients' lives.2 In such trade-offs, shared decision making (SDM) has gained momentum as a strategy to include both the best available evidence and the patient's preferences.3</p

Unrestricted somatic stem cells (USSC) from human umbilical cord blood display uncommitted epigenetic signatures of the major stem cell pluripotency genes

AbstractUnrestricted somatic stem cells (USSC) from human cord blood display a broad differentiation potential for ectodermal, mesodermal, and endodermal cell types. The molecular basis for these stem cell properties is unclear and unlike embryonic stem cells (ESC) none of the major stem cell factors OCT4, SOX2, and NANOG exhibits significant expression in USSC. Here, we report that these key stem cell genes hold an epigenetic state in between that of an ESC and a terminally differentiated cell type. DNA methylation analysis exhibits partial demethylation of the regulatory region of OCT4 and a demethylated state of the NANOG and SOX2 promoter/enhancer regions. Further genome-wide DNA methylation profiling identified a partially demethylated state of the telomerase gene hTERT. Moreover, none of the pluripotency factors exhibited a repressive histone signature. Notably, SOX2 exhibits a bivalent histone signature consisting of the opposing histone marks dimeH3K4 and trimeH3K27, which is typically found on genes that are "poised" for transcription. Consequently, ectopic expression of OCT4 in USSC led to rapid induction of expression of its known target gene SOX2. Our data suggest that incomplete epigenetic repression and a "poised" epigenetic status of pluripotency genes preserves the USSC potential to be able to react adequately to distinct differentiation and reprogramming cues

Comparison of four mathematical models to analyze indicator-dilution curves in the coronary circulation

While several models have proven to result in accurate estimations when measuring cardiac output using indicator dilution, the mono-exponential model has primarily been chosen for deriving coronary blood/plasma volume. In this study, we compared four models to derive coronary plasma volume using indicator dilution; the mono-exponential, power-law, gamma-variate, and local density random walk (LDRW) model. In anesthetized goats (N = 14), we determined the distribution volume of high molecular weight (2,000 kDa) dextrans. A bolus injection (1.0 ml, 0.65 mg/ml) was given intracoronary and coronary venous blood samples were taken every 0.5–1.0 s; outflow curves were analyzed using the four aforementioned models. Measurements were done at baseline and during adenosine infusion. Absolute coronary plasma volume estimates varied by ~25% between models, while the relative volume increase during adenosine infusion was similar for all models. The gamma-variate, LDRW, and mono-exponential model resulted in volumes corresponding with literature, whereas the power-model seemed to overestimate the coronary plasma volume. The gamma-variate and LDRW model appear to be suitable alternative models to the mono-exponential model to analyze coronary indicator-dilution curves, particularly since these models are minimally influenced by outliers and do not depend on data of the descending slope of the curve only

Agonist-induced impairment of glycocalyx exclusion properties: contribution to coronary effects of adenosine

The endothelial glycocalyx is the negatively charged, gel-like mesh residing at the luminal side of the vascular endothelium and forming the interface between the flowing blood and the vessel wall. The vast majority of glycocalyx volume resides in the microcirculation, particularly in the capillaries. Intravital microscopic observations of capillaries in striated muscle preparations illustrate that under resting conditions, the glycocalyx is not accessible for flowing red blood cells and greatly hinders plasma flow in the axial direction, causing a significant reduction in functionally perfused capillary volume. Glycocalyx exclusion properties have been shown to be reduced by adenosine and other vasoactive substances. A diminished exclusion of circulating blood by the glycocalyx may facilitate nutrient exchange since it is associated with an increase in functionally perfused blood volume and surface area in the capillaries. Our recent studies have focused on the effect of adenosine on glycocalyx exclusion in the coronary circulation and demonstrate an important role for this mechanism in the increase in circulating coronary blood volume during administration of this vasodilator. The current review elaborates on the glycocalyx as a blood-excluding intravascular layer and how it can be modulated by various agonists. Further, the potential role of adenosine-induced modulation of glycocalyx exclusion properties in coupling increases in blood flow and circulating blood volume in the coronary circulation is discussed. Finally, we consider how degradation of the glycocalyx may impact on coronary blood volume regulation, thereby providing new opportunities to diagnose glycocalyx damage in the clinical settin

IHS Book Roundtable: The Moderate Bolshevik: Mikhail Tomsky from the Factory to the Kremlin, 1880-1936

Histor

Endothelial glycocalyx: sweet shield of blood vessels

At the time that the term glycocalyx ("sweet husk") was introduced as a description of the extracellular polysaccharide coating on cells (Bennett HS: 1963. Morphological aspects of extracellular polysaccharides. J Hist Cytochem 11:14-23.), early electron microscopic observations had shown that anionic polysaccharides were also presented by the inner surface of blood vessels but the length of these structures was considered to be small and their functional significance was unknown. Research in the past decades in the glycocalyx field has evolved, and recent estimations indicate that the endothelial glycocalyx constitutes a voluminous intravascular compartment that plays an important role in vascular wall homeostasis. Pathologic loss of glycocalyx may be associated with an impaired vascular wall protection throughout the circulatory system, whereas agonist-induced modulation of glycocalyx accessibility for circulating blood may constitute a physiologically relevant mechanism to regulate functionally perfused volume and exchange area at the microvascular level. Both aspects are discussed in the current revie

Prevalence and determinants of insufficient work ability in older HIV-positive and HIV-negative workers.

To explore whether the prevalence and determinants of insufficient work ability (WA) of older HIV-positive workers differ from a comparable group of HIV-negative workers. Cross-sectional data from 359 HIV-negative and 264 HIV-positive middle-aged individuals (45-65 years) participating in paid labor, collected within the AGEhIV Cohort Study between October 2010-September 2012, were selected. Data were collected by self-administered questionnaires and physical examination. Participants self-rated their current WA, ranging from 0 to 10. WA was dichotomized into insufficient ( <6) and sufficient (≥6). Using univariable and multivariable logistic regression, we studied the independent effect of HIV status on insufficient WA and determinants of insufficient WA. Overall, 8% of participants reported insufficient WA (HIV-positive 9 vs. HIV-negative 7%, P = 0.20). Twice as many HIV-positive as HIV-negative individuals were declared partly unfit for work (6 vs. 3%, P = 0.02). HIV status itself was not associated with WA in univariable and multivariable analyses. Multivariable analyses revealed that low educational level, working fewer hours, being partly unfit for work, experiencing a high need for recovery after work, staying home from work ≥2 times in the past 6 months, and reporting depressive symptoms were associated with insufficient WA, independent of HIV status. HIV-positive individuals aged 45-65 years participating in paid labor seem to function as well at work as HIV-negative individuals. HIV-positive participants were more often formally declared partly unfit for work, but percentages were low in both groups. Knowledge of determinants of insufficient WA may help employers and professionals to optimize W

Effect of acute hyaluronidase treatment of the glycocalyx on tracer-based whole body vascular volume estimates in mice

The endothelial glycocalyx forms a hyaluronan-containing interface between the flowing blood and the endothelium throughout the body. By comparing the systemic distribution of a small glycocalyx-accessible tracer vs. a large circulating plasma tracer, the size-selective barrier properties of the glycocalyx have recently been utilized to estimate whole body glycocalyx volumes in humans and animals, but a comprehensive validation of this approach has been lacking at the moment. In the present study, we compared, in anesthetized, ventilated C57Bl/6 mice, the whole body distribution of small (40 kDa) dextrans (Texas Red labeled; Dex40) vs. that of intermediate (70 kDa) and large (500 kDa) dextrans (both FITC labeled; Dex70 and Dex500, respectively) using tracer dilution and vs. that of circulating plasma, as derived from the dilution of fluorescein-labeled red blood cells and large-vessel hematocrit. The contribution of the glycocalyx was evaluated by intravenous infusion of a bolus of the enzyme hyaluronidase. In saline-treated control mice, distribution volume (in ml) differed between tracers (P Dex70 (0.90 ± 0.04) > Dex500 (0.81 ± 0.10) > plasma (0.71 ± 0.02), resulting in an inaccessible vascular volume, i.e., compared with the distribution volume of Dex40, of 0.03 ± 0.01, 0.15 ± 0.04, and 0.31 ± 0.05 ml for Dex70, Dex500, and plasma, respectively. In hyaluronidase-treated mice, Dex70 and Dex40 volumes were not different from each other, and inaccessible vascular volumes for Dex500 (0.03 ± 0.03) and plasma (0.14 ± 0.05) were smaller (P < 0.05) than those in control animals. Clearance of Dex70 and Dex500 from the circulation was enhanced (P < 0.05) in hyaluronidase-treated vs. control mice. These results indicate that the glycocalyx contributes to size-dependent differences in whole body vascular distribution of plasma solutes in mice. Whole body vascular volume measurements based on the differential distribution of glycocalyx-selective tracers appear appropriate for the detection of generalized glycocalyx degradation in experimental animals and human

Heparin impairs glycocalyx barrier properties and attenuates shear dependent vasodilation in mice

The endothelial glycocalyx is a hydrated mesh of polysaccharides and adsorbed plasma proteins that forms the true interface between the flowing blood and the endothelium. We hypothesized in the present study that competitive binding of heparin to glycocalyx-associated proteins would affect glycocalyx barrier properties and mechanotransduction of shear stress to the endothelium. In anesthetized mice, the clearance of 70-kDa dextrans from the circulation was increased (P <0.05 versus saline) 1 hour after heparin (1.25 U) and glycocalyx degradation with hyaluronidase (35 U; amount cleared in 30 minutes after saline: 11+/-5%; after heparin: 45+/-8%; after hyaluronidase: 30+/-3%). Clearance of 40-kDa dextrans increased (P <0.05 versus saline) to a lesser extent after both treatments (saline: 46+/-3%; heparin: 60+/-5%; hyaluronidase: 60+/-2%). The dilator response of second-order arterioles in cremaster muscle during reactive hyperemia was reduced for < or =90 minutes after heparin as reflected by a decrease (P=0.008) in t(50) of diameter recovery, and this effect was associated with a diminished NO bioavailability. Infusion of hyaluronidase resulted in reductions (P <0.05) in baseline and peak reactive hyperemic diameter, whereas, despite an increase in wall shear rate at the beginning of reactive hyperemia, t(50) of diameter recovery was not affected. In conclusion, our data in mice show that a heparin challenge is associated with increased vascular leakage of dextrans and impaired arteriolar vasodilation during reactive hyperemia. Our data suggest that protein-heparan sulfate interactions are important for a functional glycocaly