Effect of erythrocyte aggregation at normal human levels on functional capillary density in rat spinotrapezius muscle.
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Previous studies have shown that functional capillary density (FCD) is substantially reduced by erythrocyte aggregation. However, only supranormal levels of aggregability were studied. To investigate the effect of erythrocyte aggregability at the level seen in healthy humans, the FCD of selected capillary fields in rat spinotrapezius muscle was determined with high-speed video microscopy under normal (nonaggregating) conditions and after induction of erythrocyte aggregation with Dextran 500 (200 mg/kg). To examine shear rate dependence, the effect was studied both at normal and reduced arterial pressures (50 and 25 mmHg), the latter achieved by short periods of hemorrhage. In a separate study, volume flow was determined in arterioles (52.1 +/- 3.7 microm) under the same conditions. Before Dextran 500 infusion, FCD fell to 91% and 76% of control values, respectively, when arterial pressure was reduced to 50 and 25 mmHg. After Dextran 500 infusion, FCD was 96% at normal arterial pressure and fell to 79% and 37% of normal control values at 50 and 25 mmHg. All FCD values were significantly lower after dextran infusion. FCD reduction after lowering arterial pressure or dextran infusion appeared to be due to plasma skimming rather than capillary plugging. Reduction of FCD by dextran at reduced pressure was compensated by increased red blood cell flux in capillaries with red blood cell flow. We conclude that the level of aggregability seen in healthy humans is an important determinant of FCD only at reduced arterial pressure. (+info)
Increase in erythrocyte disaggregation shear stress in hypertension.
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The aggregation and disaggregation behaviors of red blood cells were investigated in 17 normotensive and 21 hypertensive subjects with a laser reflectometry technique, and simultaneous measurements were taken of blood viscosity with a coaxial viscometer. Increased red blood cell aggregation (26%, p less than 0.001) and disaggregation shear rate (20%, p less than 0.01) and shear stress (18%, p less than 0.01) were observed in hypertensive subjects when compared with normotensive subjects. Similar elevations in hypertensive subjects were found when the hematocrit was adjusted to 40%. Variation of red blood cell concentration caused the red blood cell disaggregation shear rate to change in an opposite direction but did not modify red blood cell aggregability and disaggregation shear stress. The increase of the reversible aggregation of red blood cells was associated with higher fibrinogen and plasma protein concentrations in hypertension. An increase in red blood cell aggregability and in the shear resistance of red blood cell aggregates may play a role in the development of the cardiovascular complication in hypertension. The quantification of red blood cell disaggregation shear stress, which represents the hydrodynamic force required to disperse the aggregates, may provide a useful parameter for clinical investigations. (+info)
Relation of haemofilter type to venous catheter resistance is crucial for filtration performance and haemocompatibility in CVVH--an in vitro study.
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BACKGROUND: Main factors for the overall performance of haemofilters (HF) are membrane features and filter durability without clogging/clotting of capillaries. However, the venous line resistance (Pv) is a powerful force for net filtrate flux resulting in haemoconcentration and thus is enhancing the phenomenon of membrane clogging. Therefore, we hypothesized that catheter type, as it is associated with Pv-levels, contributes to the extent in which filter longevity and filtration performance are restricted due to blocked hollow fibres. METHODS: Heparinized porcine blood (5 IU/ml) was circulated in an in vitro system for haemofiltration (FH6S-filters were used, Ca. Gambro). Three different sizes of catheters for peripheral vein access (Vygonuele V, Ca. Vygon) were alternately inserted into the circuit for blood return from the filter to the reservoir. To produce Pv-levels lower than commonly induced by Shaldon catheters, a 14G-vygonuele was used. Pv-levels standard for 11-12 French catheters were provided by using a 16G-vygonuele. To produce Pv-levels common for low-French or tri-lumen catheters, a shortened 18G-vygonuele was used. The respective Pv-levels attained were compared with respect to the overall filtration performance (system pressures, haemocompatibility and sieving coefficients). RESULTS: Catheters of 14 and 16G enabled transiently maximal blood flow (Qb)/filtration rates (Qf) of 300/60 ml/min and continuous filtration with Qb/Qf of 200/40 ml/min. The shortened 18G catheter reduced maximal flow rates down to Qb/Qf of 200/40 ml/min, and continuous flow rates down to Qb/Qf of 125/25 ml/min. At the end, median values for blocked hollow fibres were, 35% in the 14G-group, 40% in the 18G-group and 70% in the 16G-group. Haemocompatibility appeared to be higher in the 14G-group with respect to various parameters when compared with the other groups. CONCLUSIONS: The flow resistance by the catheter chosen for haemofiltration clearly influenced the filtration performance. Thus, investigations focused on compatibility of catheter type as it related to Pv-levels with the particular method of renal replacement therapy that should be performed. This point could be crucial in reducing filter clogging and haemostasis during CVVH. (+info)
Characterization of acatalasemic erythrocytes treated with low and high dose hydrogen peroxide. Hemolysis and aggregation.
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The effects of hydrogen peroxide on normal and acatalasemic erythrocytes were examined. Severe hemolysis of acatalasemic erythrocytes and a small tyrosine radical signal (g = 2.005) associated with the formation of ferryl hemoglobin were observed upon the addition of less than 0.25 mM hydrogen peroxide. However, when the concentration of hydrogen peroxide was increased to 0.5 mM, acatalasemic erythrocytes became insoluble in water and increased the tyrosine radical signal. Polymerization of hemoglobin and aggregation of the erythrocytes were observed. On the other hand, normal erythrocytes exhibited only mild hemolysis by the addition of hydrogen peroxide under similar conditions. From these results, the scavenging of hydrogen peroxide by hemoglobin generates the ferryl hemoglobin species (H-Hb-Fe(IV)=O) plus protein-based radicals (*Hb-Fe(IV)=O). These species induce hemolysis of erythrocytes, polymerization of hemoglobin, and aggregation of the acatalasemic erythrocytes. A mechanism for the onset of Takarara disease is proposed. (+info)
Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease.
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OBJECTIVES: This study sought to determine the relationship between blood viscosity and iron deficiency and their impact on symptoms and exercise function in adults with cyanotic congenital heart disease. BACKGROUND: Iron deficiency is believed to raise whole blood viscosity in cyanotic congenital heart disease, although available data are inconsistent. METHODS: Thirty-nine cyanotic adults were prospectively assessed for iron deficiency (transferrin saturation < or =5%), hyperviscosity symptoms, and exercise capacity. Same-day measurement of whole blood viscosity and hematocrit (Hct) adjusted viscosity (cells resuspended in autologous plasma to Hct of 45%) was performed at shear rates ranging from 0.277 s(-1) to 128.5 s(-1). RESULTS: Viscosity did not differ between patients with iron deficiency (n = 14) and those without (n = 25). Whole blood viscosity correlated with Hct (r = 0.63, p < 0.001 at low shear and r = 0.84, p < 0.001 at high shear) but not with red blood cell size or iron indices. Hyperviscosity symptoms were independent of iron indices but directly correlated with increased Hct-adjusted viscosity (r = 0.41, p = 0.01). Exercise capacity did not differ in iron-deficient patients. However, peak oxygen consumption was higher in those with Hct > or = 65% (12.6 +/- 3.4 ml/kg/m2 vs. 9.8 +/- 2.6 ml/kg/m2, mean +/- SD, p = 0.036) despite higher whole blood viscosity in these same individuals (p < 0.01 for all shear rates). CONCLUSIONS: Iron deficiency is common in cyanotic adults but does not alter viscosity. Hyperviscosity symptoms are associated with a higher Hct-adjusted viscosity independent of cell size or iron stores. Higher Hct is associated with better exercise capacity. Further work to understand the origin of hyperviscosity symptoms is warranted. (+info)
Hemorheologic abnormalities associated with HIV infection: altered erythrocyte aggregation and deformability.
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PURPOSE: To investigate possible alterations of erythrocyte aggregation and deformability, which are factors that can influence blood flow, in human immunodeficiency virus (HIV)-infected individuals and to determine whether these factors are related to the severity of immunodeficiency. METHODS: Laboratory evaluations were performed on 46 HIV-infected individuals and 44 HIV-negative control subjects. Current and nadir (lowest previous) CD4+ T-lymphocyte counts were identified for each subject. Erythrocyte aggregation was measured using a fully automatic erythrocyte aggregometer. Factors related to erythrocyte aggregation were also determined: erythrocyte sedimentation rate (ESR), zeta sedimentation ratio (ZSR), and plasma fibrinogen levels. Erythrocyte deformability was observed at various fluid shear stress levels, with a laser diffraction ektacytometer. Correlations were sought between each of these measures and current or nadir CD4+ T-lymphocyte counts, and each measure was compared between three subgroups based on current and nadir CD4+ T-lymphocyte counts (severely immunosuppressed, immune reconstituted, never severely immunosuppressed). RESULTS: The following parameters were significantly different between HIV-infected subjects and controls: increased erythrocyte aggregation, at stasis (P < 0.001) and low shear stress (P < 0.001), increased ESR (P < 0.001), increased ZSR (P < 0.028), increased serum fibrinogen (P = 0.015), and decreased erythrocyte deformability (P < 0.001). Only erythrocyte aggregation at stasis correlated significantly with current CD4+ T-lymphocyte count (r = - 0.344, P = 0.022). None of the parameters was significantly different between HIV-infected subgroups. CONCLUSIONS: Increased aggregation and decreased deformability of erythrocytes are associated with HIV-infection regardless of the severity of immunodeficiency. HIV-infected individuals may be at risk for progressive retinal microvascular damage from persistent hemorheologic abnormalities, despite immune reconstitution associated with potent antiretroviral drug therapies. (+info)
Hemorheologic abnormalities associated with HIV infection: in vivo assessment of retinal microvascular blood flow.
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PURPOSE: To evaluate retinal microvascular blood flow in human immunodeficiency virus (HIV)-infected individuals using scanning laser Doppler flowmetry (SLDF) and to seek correlations between flow and various laboratory measures that may predict alterations in flow. METHODS: The Heidelberg Retina Flowmeter and SLDF software were used to acquire in vivo retinal blood flow data from 24 HIV-infected individuals and 16 HIV-negative control subjects. In each subject, separate scans were performed in each of six retinal regions: nasal parapapillary retina; macula; and the superior, nasal, inferior, and temporal periphery. Erythrocyte aggregation (assessed in vitro by a fully automatic erythrocyte aggregometer and by zeta sedimentation ratio [ZSR, a hematocrit-independent sedimentation rate]), serum fibrinogen level, plasma viscosity, and leukocyte rigidity (assessed in vitro with a cell transit analyzer) were compared with flow in selected regions. RESULTS: Flow was significantly higher in the periphery (superior, nasal, inferior, temporal) than in the posterior retina (nasal parapapillary retina, macula). Flow was highest in the temporal periphery for both HIV-infected subjects and control subjects. Flow in the posterior retina was significantly lower in HIV-infected subjects than in control subjects (P < 0.0001). Among HIV-infected individuals, flow in the macula correlated negatively with ZSR (r = -0.397, P = 0.0547) and leukocyte rigidity (r = -0.505, P = 0.0119). CONCLUSIONS: Microvascular blood flow in the posterior retina is reduced in HIV-infected individuals. Both increased erythrocyte aggregation and increased leukocyte rigidity contribute to this hemorheologic abnormality. (+info)
Physicochemical and biological characterization of targeted, nucleic acid-containing nanoparticles.
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Nucleic acid-based therapeutics have the potential to provide potent and highly specific treatments for a variety of human ailments. However, systemic delivery continues to be a significant hurdle to success. Multifunctional nanoparticles are being investigated as systemic, nonviral delivery systems, and here, we describe the physicochemical and biological characterization of cyclodextrin-containing polycations (CDP) and their nanoparticles formed with nucleic acids including plasmid DNA (pDNA) and small interfering RNA (siRNA). These polycation/nucleic acid complexes can be tuned by formulation conditions to yield particles with sizes ranging from 60 to 150 nm, zeta potentials from 10 to 30 mV, and molecular weights from approximately 7 x 107 to 1 x 109 g mol-1 as determined by light scattering techniques. Inclusion complexes formed between adamantane (AD)-containing molecules and the beta-cyclodextrin molecules enable the modular attachment of poly(ethylene glycol) (AD-PEG) conjugates for steric stabilization and targeting ligands (AD-PEG-transferrin) for cell-specific targeting. A 70 nm particle can contain approximately 10 000 CDP polymer chains, approximately 2000 siRNA molecules, approximately 4000 AD-PEG5000 molecules, and approximately 100 AD-PEG5000-Tf molecules; this represents a significant payload of siRNA and a large ratio of siRNA to targeting ligand (20:1). The particles protect the nucleic acid payload from nuclease degradation, do not aggregate at physiological salt concentrations, and cause minimal erythrocyte aggregation and complement fixation at the concentrations typically used for in vivo application. Uptake of the nucleic acid-containing particles by HeLa cells is measured by flow cytometry and visualized by confocal microscopy. Competitive uptake experiments show that the transferrin-targeted particles display enhanced affinity for the transferrin receptor through avidity effects (multiligand binding). Functional efficacy of the delivered pDNA and siRNA is demonstrated through luciferase reporter protein expression and knockdown, respectively. The analysis of the CDP delivery vehicle provides insights that can be applied to the design of targeted nucleic acid delivery vehicles in general. (+info)