Biomedical subjects

C R Valeri

Publications and source records attributed to C R Valeri.

At least 55 records · Page 3Linked to original sources

PubMed1998

Patients with venous stasis ulceration have increased monocyte-platelet aggregation.

PURPOSE: Leukocyte activation has been implicated in the pathogenesis of venous stasis ulceration, but the involvement of activated platelets and leukocyte-platelet aggregates has not been previously investigated. The purpose of this study was to determine whether patients with venous stasis ulceration have increased platelet activation and a propensity toward formation of leukocyte-platelet aggregates. METHODS: Blood was drawn from the superficial veins of the leg just proximal to a venous stasis ulcer and from an antecubital vein in 14 patients with venous stasis ulceration. Blood was also drawn from the antecubital vein of 14 volunteers without evidence of venous disease. Whole-blood flow cytometry was used to analyze the samples before and after activation with a panel of agonists for evidence of platelet activation and the formation of leukocyte-platelet aggregates. RESULTS: Patients with venous stasis ulceration had a greater number of monocyte-platelet aggregates in both the arm and leg samples than did the control subjects (p < 0.01). Furthermore, antecubital blood samples from patients with venous stasis ulceration stimulated with either thrombin-receptor agonist peptide, adenosine diphosphate, or phorbol myristate acetate formed more monocyte-platelet aggregates than did control samples (p < 0.05). No differences in platelet activation or neutrophil-platelet aggregate formation were noted among the three sample groups. CONCLUSIONS: Patients with venous stasis ulceration have an increase in the number of monocyte-platelet aggregates in systemic venous blood as well as in venous blood adjacent to a venous stasis ulcer, implicating the monocyte as the leukocyte involved in the pathogenesis of venous stasis ulceration. No association was identified between the presence of a venous stasis ulcer and either neutrophil-platelet aggregation or the activation of individual platelets. Because platelet activation is necessary for the formation of monocyte-platelet aggregates, these data also suggest that monocyte-platelet aggregation is a more sensitive marker for in vivo platelet activation than is the identification of individual activated platelets.

Adenosine Diphosphate↗

PubMed1998

The red cell transfusion trigger: has a sin of commission now become a sin of omission?

The benefits of a Hct range of 30 to 35 percent include improved oxygen delivery and enhanced hemostasis, which help minimize complications in patients at high risk for ischemia and perioperative nonsurgical bleeding. In these settings, the conservative transfusion practice of using a lower Hct range should be replaced with a more aggressive approach. The known risks of blood transfusion would appear to be sufficiently low and the benefits sufficiently high to justify maintaining a Hct of at least 30 percent. An even higher Hct, of 35 percent, may be desirable in patients who have overt cardiopulmonary disease or who are at high risk for myocardial ischemia. Many retrospective studies have been conducted to persuade us that a conservative transfusion trigger is a safe and prudent practice, but retrospective studies are not what we need. What we need is a series of well-designed, prospective, randomized trials to evaluate the impact of a more aggressive transfusion policy on perioperative mortality, morbidity, and nonsurgical bleeding in patients with known cardiopulmonary disease or who are at high risk for myocardial and cerebrovascular ischemia.

Anemia↗

PubMed1998

Thermal and cardiovascular strain from hypohydration: influence of exercise intensity.

This study determined the effects of exercise intensity on the physiologic (thermal and cardiovascular) strain induced from hypohydration during heat stress. We hypothesized that the added thermal and cardiovascular strain induced by hypohydration would be greater during high intensity than low intensity exercise. Nine heat-acclimated men completed a matrix of nine trials: three exercise intensities, 25%, 45% and 65% VO2 max; and three hydration levels, euhydration and hypohydration at 3% and 5% body weight loss (BWL). During each trial, subjects attempted 50 min of treadmill exercise in a hot room (30 degrees C db, 50% rh) while body temperatures and cardiac output were measured. Hypohydration was achieved by exercise and fluid restriction the day preceding the trials. Core temperature increased (P<0.05) 0.12 degrees C per%BWL at each hypohydration level and was not affected by exercise intensity. Cardiac output was reduced (P<0.05) compared to euhydration levels and was reduced more during high compared to low intensity exercise after 5% BWL. It was concluded that: a) the thermal penalty (core temperature increase) accompanying hypohydration is not altered by exercise intensity; and b) at severe hypohydration levels, the cardiovascular penalty (cardiac output reduction) increases with exercise intensity.

Acclimatization↗

PubMed1997

Surface area and volume changes during maturation of reticulocytes in the circulation of the baboon.

Changes in the surface area and volume of reticulocytes were measured in vivo during late stage maturation. Baboons were treated with erythropoietin to produce mild reticulocytosis. Reticulocyte-rich cohorts of cells were obtained from whole blood by density gradient centrifugation. The cohorts were labeled with biotin, reinfused into the animal, and recovered from whole blood samples by panning on avidin supports. Changes in the surface area, volume, and membrane deformability were measured using micropipettes during the 2 to 6 weeks subsequent to reinfusion. For the entire cohort, the membrane area decreased by 10% to 15% and the cell volume decreased by approximately 8.5%, mostly within 24 hours after reinfusion. Estimates of the cellular dimensions of the reticulocyte subpopulation within this cohort indicated larger reductions in the mean cell area (12% to 30%) and mean cell volume (approximately 15%) of the reticulocytes themselves. Two weeks after reinfusion, the distribution of cell size for the cohort was indistinguishable from that of whole blood. There was evidence of slightly elevated membrane shear rigidity in some reticulocytes before reinfusion, but this slight increase disappeared within 24 hours after reinfusion. These are the first direct measurements of changes in the membrane physical properties of an identifiable cohort of reticulocytes as they mature in vivo.

Animals↗

PubMed1997

The volume of blood shed during the bleeding time correlates with the peripheral venous hematocrit.

The relation among the bleeding time, the peripheral venous hematocrit, and the amount of blood shed at the template bleeding time site has not been previously defined. We studied this relation in 227 persons: 26 were patients with idiopathic thrombocytopenic purpura (ITP), 137 were patients with a variety of other bleeding disorders, and 64 were healthy subjects. The bleeding time (mean +/- SD) for the healthy group was 7.1 +/- 1.2 minutes, and the amount of shed blood was 136.4 +/- 47.2 microL; in patients with ITP the bleeding time was 14.0 +/- 4.1 minutes and the shed blood was 508.1 +/- 387 microL; and in the group with other bleeding disorders, the mean bleeding time was 9.0 +/- 3.5 minutes, and the amount of shed blood was 224.7 +/- 184 microL. Bleeding times for all persons studied showed a significant correlation of 0.75 for the amount of shed blood on the filter paper and a significant correlation of 0.28 for the peripheral venous hematocrit. There was also a significant correlation between the bleeding time and the platelet count in patients with ITP. This study demonstrates that the volume of blood shed at the bleeding time site correlates with the peripheral venous hematocrit and emphasizes the contribution of the hematocrit to primary hemostasis in healthy subjects and patients with bleeding disorders.

Bleeding Time↗

PubMed1997

The effect of disinfection on viability and function of baboon red blood cells.

Methods that have been optimized for disinfection of red blood cells before transfusion must be evaluated for their effect on red blood cell viability and function in vitro and in vivo. This study evaluates (1) in vitro effects of Panavirocide treatment and benzoporphyrin (BPD) photosensitization on baboon and human red blood cell parameters and (2) in vivo effects of five disinfectant treatments on 24 h posttransfusion survival and cell lifetimes for baboon red blood cells. The in vitro studies showed that both disinfection methods resulted in a significant reduction in red blood cell potassium, suggesting that intracellular potassium is a sensitive measure of red cell injury during disinfection. The in vivo studies demonstrated significant reductions in the 24 h posttransfusion survival of baboon red blood cells and reductions in cell lifespan treated with a Panavirocide solution, BPD photosensitization and 15 mM nonactivated sodium chlorite. No effects were seen with 250 ppm formaldehyde, aluminum phthalocyanine photosensitization or activated sodium chlorite. These in vivo data showing effects of disinfection treatments support the use of baboons in studying disinfection procedures of autologous red blood cells before attempting studies in humans.

Animals↗

PubMed1996

In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function.

To examine the hypothesis that surface P-selectin-positive (degranulated) platelets are rapidly cleared from the circulation, we developed novel methods for tracking of platelets and measurement of platelet function in vivo. Washed platelets prepared from nonhuman primates (baboons) were labeled with PKH2 (a lipophilic fluorescent dye), thrombin-activated, washed, and reinfused into the same baboons. Three-color whole blood flow cytometry was used to simultaneously (i) identify platelets with a mAb directed against glycoprotein (GP)IIb-IIIa (integrin alpha 11b beta 3), (ii) distinguish infused platelets by their PKH2 fluorescence, and (iii) analyze platelet function with mAbs. Two hours after infusion of autologous thrombin-activated platelets (P-selectin-positive, PKH2-labeled), 95 +/- 1% (mean +/- SEM, n = 5) of the circulating PKH2-labeled platelets had become P-selectin-negative. Compared with platelets not activated with thrombin preinfusion, the recovery of these circulating PKH2-labeled, P-selectin-negative platelets was similar 24 h after infusion and only slightly less 48 h after infusion. The loss of platelet surface P-selectin was fully accounted for by a 67.1 +/- 16.7 ng/ml increase in the plasma concentration of soluble P-selectin. The circulating PKH2-labeled, P-selectin-negative platelets were still able to function in vivo, as determined by their (i) participation in platelet aggregates emerging from a bleeding time wound, (ii) binding to Dacron in an arteriovenous shunt, (iii) binding of mAb PAC1 (directed against the fibrinogen binding site on GPIIb-IIIa), and (iv) generation of procoagulant platelet-derived microparticles. In summary, (i) circulating degranulated platelets rapidly lose surface P-selectin to the plasma pool, but continue to circulate and function; and (ii) we have developed novel three-color whole blood flow cytometric methods for tracking of platelets and measurement of platelet function in vivo.

Animals↗

PubMed1996

Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis.

Highly reactive oxygen species rapidly inactivate nitric oxide (NO), and endothelial product which inhibits platelet activation. We studied platelet inhibition by NO in two brothers with a cerebral thrombotic disorder. Both children had hyperreactive platelets, as determined by whole blood platelet aggregometry and flow cytometric analysis of the platelet surface expression of P-selectin. Mixing experiments showed that the patients'platelets behaved normally in control plasma; however, control platelets suspended in patient plasma were not inhibited by NO. As determined by flow cytometry, in the presence of plasma from either patient there was normal inhibition of the thrombin-induced expression of platelet surface P-selectin by prostacyclin, but not NO. Using a scopoletin assay, we measured a 2.7-fold increase in plasma H2O2 generation in one patient and a 3.4-fold increase in the second patient, both compared woth control plasma. Glutathione peroxidase (GSH-Px) activity was decreased in the patients' plasmas compared with control plasma. The addition of exogenous GSH-Px led to restoration of platelet inhibition by NO. These data show that, in these patients' plasmas, impaired metabolism of reactive oxygen species reduces the bioavailability of NO and impairs normal platelet inhibitory mechanisms. These findings suggest that attenuated NO-mediated platelet inhibition produced by increased reactive oxygen species or impaired antioxidant defense may cause a thrombotic disorder in humans.

Cyclic GMP↗

PubMed1996

Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid.

UNLABELLED: Excessive postoperative bleeding after heart operations continues to be a source of morbidity. This prospective double-blind study evaluated epsilon-aminocaproic acid as an agent to reduce postoperative bleeding and investigated its mode of action. One hundred three patients were randomly assigned to receive either 30 gm epsilon-aminocaproic acid (51 patients) or an equivalent volume of placebo (52 patients). In a subset of these patients (14 epsilon-aminocaproic acid, 12 placebo), tests of platelet function and fibrinolysis were performed. RESULTS: By multivariate analysis, three factors were associated with decreased blood loss in the first 24 hours after operation: epsilon-aminocaproic acid versus placebo (647 ml versus 839 ml, p = 0.004), surgeon 1 versus all other surgeons (582 ml versus 978 ml, p = 0.002), and no intraaortic balloon versus intraaortic balloon pump use (664 ml versus 1410 ml, p = 0.02). No significant differences in platelet function could be demonstrated between the two groups. Inhibited fibrinolysis, as reflected by less depression of the euglobulin clot lysis and no rise in D-dimer levels, was significant in the epsilon-aminocaproic acid group compared with the placebo group. CONCLUSION: The intraoperative use of epsilon-aminocaproic acid reduces postoperative cardiac surgical bleeding.

Aminocaproic Acid↗

PubMed1996

P-selectin mediates intestinal ischemic injury by enhancing complement deposition.

BACKGROUND: Ischemia and reperfusion injury of rodent intestine is complement mediated. P-selectin antagonism reduces local injury, yet neutrophil depletion does not. This study tests the thesis that the protective mechanism of P-selectin antagonists involves complement inhibition. METHODS: We subjected rats (n = 86) to 50 minutes of complete mesenteric ischemia and 4 hours of reperfusion. Treatment with a monoclonal antibody (PB1.3) against P-selectin reduced intestinal injury as judged by 125I-albumin permeability index (7.33 +/- 0.40) compared with saline solution treatment (11.4 +/- 0.49) (p < 0.05). RESULTS: However, intestinal neutrophil sequestration assessed by myeloperoxidase assay was unchanged. Immunohistochemistry revealed that mucosal C5b-9 was deposited in animals treated with saline solution and was absent in the sham group. PB1.3 treatment reduced C5b-9 deposition in the intestinal mucosa compared with that in animals treated with saline solution (p < 0.05). Neutrophil-dependent remote lung injury assessed by 125I-albumin permeability and pulmonary myeloperoxidase assay were not significantly reduced by PB1.3. Treatment with a soluble form of P-selectin ligand, sialyl Lewisx (sLex), reduced intestinal myeloperoxidase (0.065 +/- 0.006) compared with saline solution treatment (0.136 +/- 0.02) (p < 0.05), but it did not reduce permeability. Remote lung permeability was reduced (4.52 +/- 0.65 x 10(-3)) by sLex compared with saline solution treatment (6.11 +/- 0.41 x 10(-3)) (p < 0.05). CONCLUSIONS: Antagonizing the lectin domain of P-selectin and thereby neutrophil adhesion was without local benefit in this model. In contrast, PB1.3 exerted a novel antagonism of P-selectin and reduced complement deposition.

Animals↗

PubMed1996

Effects of the temperature, the duration of frozen storage, and the freezing container on in vitro measurements in human peripheral blood mononuclear cells.

BACKGROUND: Bone marrow, peripheral blood, and umbilical cord blood have been used to prepare autologous and allogeneic pluripotential mononuclear cells for use in the repopulation of bone marrow. STUDY DESIGN AND METHODS: The purpose of this study was to evaluate how the temperature and duration of frozen storage of human peripheral blood mononuclear cells (PBMCs), as well as the freezing container, affected the in vitro recovery and viability of the mononuclear cells and their growth in colony-forming unit-granulocytic-erythroid-monocytic-megakaryocytic (CFU-GEMM) tissue culture assay. PBMCs were isolated from ficoll-hypaque-treated cellular residue obtained during the plateletpheresis of blood from 15 healthy donors. The PBMCs were treated with dimethyl sulfoxide (DMSO) to achieve a final DMSO concentration of 10 percent. Each unit was then separated into six aliquots: one stored in a polyvinylchloride (PVC) plastic bag, one in a polyolefin plastic bag, and four in polyethylene cryostorage vials. Each aliquot was frozen in a -80 degrees C mechanical freezer at a freezing rate of 2 to 4 degrees C per minute. The frozen PBMCs in PVC bags were stored in a -80 degrees C mechanical freezer and those in polyolefin bags in a -135 degrees C mechanical freezer. Each of the four frozen samples in a vial was stored at a different temperature: one in the -80 degrees C freezer, one in the -135 degrees C freezer, one in the vapor phase of liquid nitrogen at -150 degrees C, and one in liquid nitrogen at -197 degrees C. Some of the frozen PBMCs were stored for periods of 1 to 1.5 years and others for 2 to 2.4 years, after which they were thawed, washed, and tested. RESULTS: The samples stored in PVC bags and those stored in polyolefin bags exhibited in vitro recoveries that were 90 percent of the recovery of fresh PBMCs and viabilities of 90 percent after 2.4 years of frozen storage. The PBMCs stored in PVC bags exhibited no loss of CFU-GEMM activity after 1 to 1.5 years, but a 40-percent loss of activity was observed after 2 to 2.4 years. PBMCs stored in polyolefin bags, however, exhibited no loss of CFU-GEMM activity, even after 2 to 2.4 years of storage. In vitro recovery was significantly lower in PBMCs stored in vials at -80 degrees C or -135 degrees C than in cells stored in PVC or polyolefin bags at these temperatures, both in the 1- to 1.5-year and the 2- to 2.4-year time frames. In vitro recovery and viability were similar in PBMCs stored in vials at -80 degrees C, -135 degrees C, -150 degrees C, and -197 degrees C. The growth patterns in the CFU-GEMM assay in PBMCs stored in vials were significantly lower after storage at -80 degrees C than after storage at -135 degrees C, -150 degrees C, or -197 degrees C. CONCLUSION: PBMCs isolated by leukapheresis and ficoll-hypaque treatment can be frozen with 10-percent DMSO in a -80 degrees C mechanical freezer. When a PVC bag is used for freezing and storage of PBMCs at -80 degrees C, the duration of frozen storage should not exceed 1.5 years, whereas PBMCs frozen in a polyolefin bag can be stored in a -135 degrees C freezer for as long as 2.4 years. When these guidelines were followed, in vitro recovery was 90 percent that of fresh PBMCs, viability was 90 percent, and growth in the CFU-GEMM tissue culture assay was similar to that of fresh PBMCs. The PBMCs frozen and stored in PVC or polyolefin bags exhibited satisfactory results, whereas those stored in cryostorage vials did not.

Blood Preservation↗

PubMed1996

Anti-selectin therapy modifies skeletal muscle ischemia and reperfusion injury.

Restoration of blood flow to ischemic skeletal muscle results in a reperfusion injury characterized by permeability edema in part mediated by neutrophils that adhere via the selectin family of adhesion molecules. Rats underwent 4 h of hindlimb tourniquet ischemia followed by 4 h reperfusion. The role of neutrophils was determined by rendering one group of animals neutropenic before ischemia. In additional experimental groups, selectins were blocked with either a soluble form of the selectin counter-receptor, sialyl-Lewis X (SLX) or a monoclonal antibody directed against P-selectin (PB1.3). Neutrophil depletion resulted in a 36.1% reduction in hindlimb permeability (p < .05). SLX reduced hindlimb permeability index (PI) 23.9% at 1 mg/kg and 36.1% at 10 mg/kg compared to a nonfucosylated oligosaccharide, sialyl-N-acetylactosamine (p < .05). SLX also reduced neutrophil sequestration by 48.6% (p < .05). PB1.3 reduced hindlimb injury by 26.5% (p < .05) but did not reduce leukosequestration. We interpret these data to indicate that ischemia and reperfusion lead to selectin-mediated neutrophil sequestration. The oligosaccharide SLX, while moderately effective in limiting neutrophil sequestration was as effective as neutrophil depletion in reducing hindlimb permeability. The lack of concordance between the ability of SLX and PB1.3 in limiting neutrophil sequestration and permeability indicate mechanisms of action of these two agents that are in addition to the blocking of adhesion.

Animals↗

PubMed1996

Effect of heparin on fibrinolytic activity and platelet function in vivo.

Heparin, a polyanionic glycosaminoglycan, is used routinely before the induction of cardiopulmonary bypass. Earlier observations in our laboratory suggested that the postoperative bleeding that occurs, despite neutralization of heparin with protamine, is secondary to hypothermia and dilutional anemia during bypass. An additional, potential mechanism for excessive bleeding following cardiopulmonary bypass is that heparin activates the fibrinolytic system, which may, in turn, adversely affect hemostasis. To understand better the effects of heparin administration on the fibrinolytic system in vivo, we simulated the anticoagulant regimen of cardiopulmonary bypass by administering increasing doses of intravenous heparin to five adult baboons over 60 min. We measured fibrinolytic parameters serially following heparinization and demonstrated that heparin induces activation of the fibrinolytic system. We showed that the fibrinolytic system was activated in vivo as evidenced by an increase in plasmin activity and immunoreactive plasmin light chain, as well as an increase in immunoreactive fibrinogen fragment E in vitro. These results demonstrate that the fibrinolytic system is activated in vivo by the administration of heparin during cardiopulmonary bypass. These data suggest that, despite administration of a neutralizing agent such as protamine, heparin may contribute to postoperative bleeding complications following cardiopulmonary bypass surgery owing principally to its longer lived effects on the fibrinolytic system.

Animals↗

PubMed1996

Effects of erythrocyte infusion on VO2max at high altitude.

This study investigated whether autologous erythrocyte infusion would ameliorate the decrement in maximal O2 uptake (VO2max) experienced by lowlanders when they ascend to high altitude. VO2max was measured in 16 men (treadmill running) at sea level (SL) and on the 1st (HA1) and 9th (HA9) days of high-altitude (4,300 m) residence. After VO2max was measured at SL, subjects were divided into two matched groups (n = 8). Twenty-four hours before ascent to high altitude, the experimental group received a 700-ml infusion of autologous erythrocytes and saline (42% hematocrit), whereas the control group received only saline. The VO2max of erythrocyte-infused [54 +/- 1 (SE) ml.kg-1.min-1] and control subjects (52 +/- 2 ml.kg-1.min-1) did not differ at SL before infusion. The decrement in VO2max on HA1 did not differ between groups, averaging 26% overall, despite higher (P < 0.01) arterial hematocrit, hemoglobin concentration, and arterial O2 content in the erythrocyte-infused subjects. By HA9, there were no longer any differences in hematocrit, hemoglobin concentration, or arterial O2 content between groups. No change in VO2max occurred between HA1 and HA9 for either group. Thus, despite increasing arterial O2-carrying capacity, autologous erythrocyte infusion did not ameliorate the decrement in VO2max at 4,300-m altitude.

Acclimatization↗

PubMed1996

Altitude acclimatization and blood volume: effects of exogenous erythrocyte volume expansion.

We studied sea-level residents during 13 days of altitude acclimatization to determine 1) altitude acclimatization effects on erythrocyte volume and plasma volume, 2) if exogenous erythrocyte volume expansion alters subsequent erythrocyte volume and plasma volume adaptations, 3) if an increased blood oxygen content alters erythropoietin responses during altitude acclimatization, and 4) mechanisms responsible for plasma loss at altitude. Sixteen healthy men had a series of hematologic measurements made at sea level, on the first and ninth days of altitude (4,300 m) residence, and after returning to sea level. Twenty-four hours before the ascent to altitude, one group received a 700-ml infusion of autologous erythrocytes (42% hematocrit), whereas the other group received only a saline infusion. Erythrocyte infusion increased erythrocyte volume by approximately 10%, whereas saline infusion had no effect; in addition, initially at altitude, blood oxygen content was 8% higher in erythrocyte-infused than in saline-infused subjects. The new findings regarding altitude acclimatization are summarized as follows: 1) erythrocyte volume does not change during the first 13 days and is not affected by prior exogenous expansion, 2) a modest increase in blood oxygen content does not modify erythropoietin responses, 3) plasma losses are related to vascular protein losses, and 4) exogenous erythrocyte volume expansion coincides with transient increases in plasma loss, vascular protein loss, and mean arterial pressure elevation. These findings better define human blood volume responses during altitude acclimatization.

Acclimatization↗

PubMed1996

Effects of nitric oxide inhibition on systemic and renal hemodynamics in the hemorrhaged rat.

The systemic and renal hemodynamic responses to nitric oxide (NO) inhibition with L-Name were compared in both normotensive, normovolemic rats and in rats following acute hemorrhagic hypotension. The mean arterial blood pressure increased in normovolemic as well as in hemorrhaged, hypotensive rats. The systemic vascular resistance also increased in both groups, but the increase was greater in normotensive rats (104 +/- 11%) than in hypotensive rats (64 +/- 14%). The renal vascular resistance also increased more in normotensive rats (189 +/- 20%) than in hypotensive rats (102 +/- 19%; p < 0.05). The glomerular filtration rate was markedly reduced by L-Name in normovolemic rats (from 3.0 +/- 0.1 to 2.1 +/- 0.1 ml/min/300 g), but increased in hemorrhaged rats following L-Name (from 1.8 +/- 0.2 to 2.5 +/- 0.2 ml/min/300 g). In summary, the L-Name-induced increase in vascular resistance is markedly reduced following hemorrhage, suggesting that NO production or availability is reduced. However, the NO production continues in the hemorrhaged rat and contributes substantially to the hypotension and functional renal insufficiency associated with acute severe volume depletion.

Animals↗

PubMed1995

Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease.

Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.

Animals↗

PubMed1995

Hemoglobin-spectrin complexes: interference with spectrin tetramer assembly as a mechanism for compartmentalization of band 1 and band 2 complexes.

The irreducible complexation of hemoglobin with spectrin is a natural phenomenon of red blood cell aging, positively correlating with increasing cell density and decreasing cell deformability. The current study begins to address the role of these complexes in the disruption of membrane skeletal physiology and structure. The effect of bound hemoglobin on spectrin dimer self-association was investigated in vitro. The extent of conversion of isolated spectrin dimers to tetramers was evaluated as a function of peroxide-induced globin complexation before the conversion incubations. The incremental accumulation of tetramer was observed to decrease with increasing peroxide concentration used in the globin complexation step. The role of oxidized heme in this process was made apparent by the inability of carboxyhemoglobin to inhibit tetramer accumulation. A Western blot analysis of naturally formed globin-spectrin conjugates demonstrated irreducible complexes of globin with both bands 1 and 2. The complexes are tentatively designated "h1" and "h2". This analysis also demonstrated that h1 is completely extractable from cell ghosts, whereas h2 is only 50% extractable. These findings are incorporated into a hypothesis linking globin-spectrin complexation and the consequent inhibition of spectrin dimer self-association to the clustered band 3 senescence antigen (Low et al, Science 227:531, 1985).

Carboxyhemoglobin↗