Over the past decade, since it was first observed in vivo, there has been an explosion in interest in the thin (approximately 500 nm), gel-like endothelial glycocalyx layer (EGL) that coats the ...luminal surface of blood vessels. In this review, we examine the mechanical and biochemical properties of the EGL and the latest studies on the interactions of this layer with red and white blood cells. This includes its deformation owing to fluid shear stress, its penetration by leukocyte microvilli, and its restorative response after the passage of a white cell in a tightly fitting capillary. We also examine recently discovered functions of the EGL in modulating the oncotic forces that regulate the exchange of water in microvessels and the role of the EGL in transducing fluid shear stress into the intracellular cytoskeleton of endothelial cells, in the initiation of intracellular signaling, and in the inflammatory response.
In recent years, the endothelial cell surface glycocalyx has emerged as a structure of fundamental importance to a broad range of phenomena that determine cardiovascular health and disease. This new ...understanding of the functional significance of the glycocalyx has been made possible through recently developed experimental techniques using intravital microscopy that are capable of directly probing the glycocalyx in vivo. Using fluorescent microparticle image velocimetry in venules and endothelialized cylindrical collagen microchannels, we show that the hydrodynamically relevant endothelial cell glycocalyx surface layer observed in microvessels in vivo (0.52+/-0.28 microm thickness), which is a fundamental determinant of the hydrodynamic and mechanical environment at the endothelial cell surface, is absent from human umbilical vein (0.03+/-0.04 microm thickness) and bovine aortic (0.02+/-0.04 microm thickness) endothelial cells grown and maintained under standard cell culture conditions in vitro. An endothelial surface-bound glycosaminoglycan layer, not necessarily indicative of but having similar hydrodynamic properties to the endothelial glycocalyx observed in vivo, was detected (0.21+/-0.27 microm thickness) only after hyaluronan and chondroitin sulfate were added to the cell culture media at hyperphysiological concentrations (0.2 mg/mL perfused for 75 minutes). The implications of this glycocalyx deficiency under standard cell culture conditions in these pervasive in vitro models broadly impact a myriad of studies involving endothelial cell monolayers in which inferences are made that may depend on endothelial cell surface chemistry. In light of these findings, conclusions drawn from such studies in the areas of microvascular permeability, inflammation, mechanotransduction, and atherosclerosis must be carefully reconsidered.
Automated control of blood glucose (BG) concentration is a long-sought goal for type 1 diabetes therapy. We have developed a closed-loop control system that uses frequent measurements of BG ...concentration along with subcutaneous delivery of both the fast-acting insulin analog lispro and glucagon (to imitate normal physiology) as directed by a computer algorithm. The algorithm responded only to BG concentrations and incorporated a pharmacokinetic model for lispro. Eleven subjects with type 1 diabetes and no endogenous insulin secretion were studied in 27-hour experiments, which included three carbohydrate-rich meals. In six subjects, the closed-loop system achieved a mean BG concentration of 140 mg/dl, which is below the mean BG concentration target of < or =154 mg/dl recommended by the American Diabetes Association. There were no instances of treatment-requiring hypoglycemia. Five other subjects exhibited hypoglycemia that required treatment; however, these individuals had slower lispro absorption kinetics than the six subjects that did not become hypoglycemic. The time-to-peak plasma lispro concentrations of subjects that exhibited hypoglycemia ranged from 71 to 191 min (mean, 117 +/- 48 min) versus 56 to 72 min (mean, 64 +/- 6 min) in the group that did not become hypoglycemic (aggregate mean of 84 min versus 31 min longer than the algorithm's assumption of 33 min, P = 0.07). In an additional set of experiments, adjustment of the algorithm's pharmacokinetic parameters (time-to-peak plasma lispro concentration set to 65 min) prevented hypoglycemia in both groups while achieving an aggregate mean BG concentration of 164 mg/dl. These results demonstrate the feasibility of safe BG control by a bihormonal artificial endocrine pancreas.
Compelling evidence continues to emerge suggesting that the glycocalyx surface layer on vascular endothelial cells plays a determining role in numerous physiological processes including inflammation, ...microvascular permeability, and endothelial mechanotransduction. Previous research has shown that enzymes degrade the glycocalyx, whereas inflammation causes shedding of the layer. To track the endogenous recovery of the glycocalyx in vivo, we used fluorescent microparticle image velocimetry (micro-PIV) in mouse cremaster muscle venules to estimate the hydrodynamically relevant glycocalyx thickness 1, 3, 5, and 7 days after enzymatic or cytokine-mediated degradation of the layer. Results indicate that after acute degradation of the glycocalyx, 5 to 7 days are required for the layer to endogenously restore itself to its native hydrodynamically relevant thickness in vivo. In light of these findings, and because demonstrable evidence has emerged that standard cell culture conditions are not conducive to providing the environment and/or cellular conditions necessary to produce and maintain a physiologically relevant cell surface glycocalyx in vitro, we sought to determine whether merely the passage of time would be sufficient to promote the production of a hydrodynamically relevant glycocalyx on a confluent monolayer of human umbilical vein endothelial cells (HUVECs). Using micro-PIV, we found that the hydrodynamically relevant glycocalyx was substantially absent 7 days postconfluence on HUVEC-lined cylindrical collagen microchannels maintained under standard culture conditions. Thus, it remains to be determined how a hydrodynamically relevant glycocalyx surface layer can be synthesized and maintained in culture before the endothelial cell culture model can be used to elucidate glycocalyx-mediated mechanisms of endothelial cell function.
The Cox maze III procedure has excellent long-term efficacy in curing atrial fibrillation. It has not been widely practiced because it is technically challenging and requires prolonged ...cardiopulmonary bypass. The aim of this study was to examine a simplified Cox maze III procedure that uses bipolar radiofrequency energy as an ablative source.
Beginning January 2002, a total of 40 consecutive patients underwent a modified Cox maze III procedure with bipolar radiofrequency energy. Nineteen had a lone maze procedure and 21 had a maze procedure plus a concomitant operation. One month after the operation, the first 8 patients were investigated with high-resolution magnetic resonance imaging. Patients were followed up monthly with clinical examination and electrocardiography.
There was no operative deaths. The crossclamp times were 47 ± 26 minutes for the modified lone Cox maze III procedure and 92 ± 37 minutes for the Cox maze III procedure plus concomitant procedures. These were significantly shorter than our previous times for the traditional Cox maze III procedure (93 ± 34 minutes and 122 ± 37 minutes, respectively,
P < .05). Follow-up magnetic resonance imaging showed no evidence of pulmonary vein stenosis, and atrial contractility was preserved in all patients. There were no late strokes. At 6-month follow-up, 91% of patients (21/23) were in sinus rhythm.
Bipolar radiofrequency ablation can be used to replace the surgical incisions of the Cox maze procedure. This energy source did not result in pulmonary vein stenosis. The modification of the Cox maze III procedure to use bipolar radiofrequency ablation simplified and shortened this procedure without sacrificing short-term efficacy.
At the beginning of the study, our hypothesis was that visiting certain microenvironments (MEs) is one of the most important determinants of personal exposure to ultrafine particles (UFP) and that ...moving between microenvironments significantly differentiates exposure. The overall aim of this study is to perform relevant exposure measurements to extend our knowledge on environmental exposure to UFP in urban environments. The UFP concentrations in different urban MEs were measured by personal monitoring in repeated sampling campaigns along a fixed route. The measurement runs were performed on one-week periods and at different times of day (AM: 08.00–10.30; PM: 16.00–18.30) and repeated in different periods of the year (winter, spring, summer, and autumn) for a total of 56 runs (>110 h). Measurements included on-line monitoring of the UFP particle number concentration (PNC), mean diameter (mean-d) and lung-deposited surface-area (LDSA). Additionally, the PNC, particle mass concentration (PMC) profiles for quasi-ultrafine particles (QUFP; PM0.25) were estimated. A significant seasonal difference in the PNC and PMC, mean diameter and surface area was observed as well as between different times of the day and days of the week. In addition, differences in the UFP concentrations were also found in each ME, and there were specific mean-diameter and surface area concentrations. In general, the mean particle diameters showed an inverse relationship with the PNC, while the LDSA had the opposite behaviour. Appreciable differences among all MEs and monitoring periods were observed; the concentration patterns and variations seemed related to the typical sources of urban pollutants (traffic), proximity to sources and time of day. The highest exposures were observed for walking or biking along high-trafficked routes and while using public buses. The UFP exposure levels in modern cars, equipped with high-efficiency filters and in air recirculation mode, were significantly lower.
•Ultrafine particles (UFP) personal exposure were measured in urban environments.•UFP were characterized by number, mass concentration, mean diameter and surface-area.•Appreciable differences among microenvironments and monitoring periods were observed.•Concentration patterns were related to typical sources of urban pollutants (traffic).•Temporal and microenvironmental patterns were determinants of UFP exposure.
The safety and efficacy of continuous, multiday, automated glycaemic management has not been tested in outpatient studies of preadolescent children with type 1 diabetes. We aimed to compare the ...safety and efficacy of a bihormonal bionic pancreas versus conventional insulin pump therapy in this population of patients in an outpatient setting.
In this randomised, open-label, crossover study, we enrolled preadolescent children (aged 6-11 years) with type 1 diabetes (diagnosed for ≥1 year) who were on insulin pump therapy, from two diabetes camps in the USA. With the use of sealed envelopes, participants were randomly assigned in blocks of two to either 5 days with the bionic pancreas or conventional insulin pump therapy (control) as the first intervention, followed by a 3 day washout period and then 5 days with the other intervention. Study allocation was not masked. The autonomously adaptive algorithm of the bionic pancreas received data from a continuous glucose monitoring (CGM) device to control subcutaneous delivery of insulin and glucagon. Conventional insulin pump therapy was administered by the camp physicians and other clinical staff in accordance with their established protocols; participants also wore a CGM device during the control period. The coprimary outcomes, analysed by intention to treat, were mean CGM-measured glucose concentration and the proportion of time with a CGM-measured glucose concentration below 3·3 mmol/L, on days 2-5. This study is registered with ClinicalTrials.gov, number NCT02105324.
Between July 20, and Aug 19, 2014, 19 children with a mean age of 9·8 years (SD 1·6) participated in and completed the study. The bionic pancreas period was associated with a lower mean CGM-measured glucose concentration on days 2-5 than was the control period (7·6 mmol/L SD 0·6 vs 9·3 mmol/L 1·7; p=0·00037) and a lower proportion of time with a CGM-measured glucose concentration below 3·3 mmol/L on days 2-5 (1·2% SD 1·1 vs 2·8% 1·2; p<0·0001). The median number of carbohydrate interventions given per participant for hypoglycaemia on days 1-5 (ie, glucose <3·9 mmol/L) was lower during the bionic pancreas period than during the control period (three range 0-8 vs five 0-14; p=0·037). No episodes of severe hypoglycaemia were recorded. Medium-to-large concentrations of ketones (range 0·6-3·6 mmol/dL) were reported on seven occasions in five participants during the control period and on no occasion during the bionic pancreas period (p=0·063).
The improved mean glycaemia and reduced hypoglycaemia with the bionic pancreas relative to insulin pump therapy in preadolescent children with type 1 diabetes in a diabetes camp setting is a promising finding. Studies of a longer duration during which children use the bionic pancreas during their normal routines at home and school should be done to investigate the potential for use of the bionic pancreas in real-world settings.
The Leona M and Harry B Helmsley Charitable Trust and the US National Institute of Diabetes and Digestive and Kidney Diseases.
Autism spectrum disorders (ASDs) and social anxiety disorder (SAD) are both characterized by social dysfunction, but no study to date has compared neural responses to social rewards in ASDs and SAD. ...Neural responses during social and non-social reward anticipation and outcomes were examined in individuals with ASD (n = 16), SAD (n = 15) and a control group (n = 19) via functional magnetic resonance imaging. Analyses modeling all three groups revealed increased nucleus accumbens (NAc) activation in SAD relative to ASD during monetary reward anticipation, whereas both the SAD and ASD group demonstrated decreased bilateral NAc activation relative to the control group during social reward anticipation. During reward outcomes, the SAD group did not differ significantly from the other two groups in ventromedial prefrontal cortex activation to either reward type. Analyses comparing only the ASD and SAD groups revealed greater bilateral amygdala activation to social rewards in SAD relative to ASD during both anticipation and outcome phases, and the magnitude of left amygdala hyperactivation in the SAD group during social reward anticipation was significantly correlated with the severity of trait anxiety symptoms. Results suggest reward network dysfunction to both monetary and social rewards in SAD and ASD during reward anticipation and outcomes, but that NAc hypoactivation during monetary reward anticipation differentiates ASD from SAD.
Locally compacting the mesh of a flow diverter by a dynamic push-pull technique can accelerate intracranial aneurysm healing. We asked how this deployment strategy compares with overlapping 2 flow ...diverters for aneurysmal flow reduction.
Using a high-fidelity virtual stent placement method, we simulated 3 flow-diverter strategies (single noncompacted, 2 overlapped, and single compacted) in 3 aneurysms (fusiform, large saccular, and medium saccular). Computational fluid dynamics analysis provided posttreatment hemodynamic parameters, including time-averaged inflow rate, aneurysm-averaged velocity, wall shear stress, total absolute circulation, and turnover time. We examined the relationship between the achieved degree of compaction and aneurysm orifice area.
Flow-diverter compaction resulted in a compaction coverage of 57%, 47%, and 22% over the orifice of the fusiform, large, and medium saccular aneurysm, respectively. Compaction coverage increased linearly with orifice area. In the fusiform aneurysm, the single compacted flow diverter accomplished more aneurysmal flow reduction than the other 2 strategies, as indicated by all 5 hemodynamic parameters. In the 2 saccular aneurysms, the overlapped flow diverters achieved the most flow reduction, followed by the single compacted and the noncompacted flow diverter.
Compacting a single flow diverter can outperform overlapping 2 flow diverters in aneurysmal flow reduction, provided that the compaction produces a mesh denser than 2 overlapped flow diverters and this denser mesh covers a sufficient portion of the aneurysm orifice area, for which we suggest a minimum of 50%. This strategy is most effective for aneurysms with large orifices, especially fusiform aneurysms.
We show that many salient hemodynamic flow properties, which have been difficult or impossible to assess in microvessels in vivo, can be estimated by using microviscometry and fluorescent ...microparticle image velocimetry in microvessels >20 μm in diameter. Radial distributions in blood viscosity, shear stress, and shear rate are obtained and used to predict axial pressure gradient, apparent viscosity, and endothelial-cell surface-layer thickness in vivo. Based solely on microparticle image velocimetry data, which are readily obtainable during the course of most intravital microscopy protocols from systemically injected particle tracers, we show that the microviscometric method consistently predicted a reduction in local and apparent blood viscosity after isovolemic hemodilution. Among its clinical applications, hemodilution is a procedure that is used to treat various pathologies that require reduction in peripheral vascular-flow resistance. Our results are directly relevant in this context because they suggest that the fractional decrease in systemic hematocrit is ≈25-35% greater than the accompanying fractional decrease in microvascular-flow resistance in vivo. In terms of its fundamental usefulness, the microviscometric method provides a comprehensive quantitative analysis of microvascular hemodynamics that has applications in broad areas of medicine and physiology and is particularly relevant to quantitative studies of angiogenesis, tumor growth, leukocyte adhesion, vascular-flow resistance, tissue perfusion, and endothelial-cell mechanotransduction.
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