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BACKGROUND: Determining reversible aspects of the platelet storage lesion may result in improved function and survival of transfused platelets. STUDY DESIGN AND METHODS: Using a model of high-dose (apheresis-derived) platelet concentrates (PC), functional changes imposed by transient adverse metabolic conditions (pH < 6.0 for 1-2 hr) that could be reversed by autologous plasma rescue followed by standard platelet storage were investigated. Whole-blood-derived PCs were transfused into a small number of normal volunteers to determine platelet recovery and survival. RESULTS: Without rescue, high-dose PCs developed severe in vitro functional derangements at the time of the pH nadir including 1) loss of resting morphology; 2) complete abrogation of osmotic recovery and platelet aggregation and glycoprotein IIb/IIIa up-regulation to agonist; and 3) decreased α-granule release. By contrast, spontaneous and agonist-induced binding of annexin V were unaffected by adverse metabolic conditions. Plasma rescue to an optimal pH improved morphology scores, stabilized osmotic recovery, and completely restored platelet secretory responses, as measured by aggregation, glycoprotein IIb/IIIa up-regulation, and α-granule release. In a limited number of studies, plasma rescue was accompanied by preserved in vivo platelet recovery and survival after autologous transfusion after 5 days of storage. CONCLUSION: Transient derangement of platelet metabolism, which does not increase membrane phosphatidylserine exposure, causes in vitro functional abnormalities that are fully reversed or stabilized by metabolic rescue. Preliminary data suggest that such rescued platelets may have normal posttransfusion recovery and survival.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX-2, the enzyme that mediates inflammatory responses. Meloxicam is a relatively COX-2-selective anti-arthritis drug that shows significant TxA2 inhibition, albeit less than traditional NSAIDs. A randomized, double-blind, placebo-controlled trial was conducted in 79 healthy adults to compare the effects of once-daily therapeutic (7.5 mg, 15 mg) and supratherapeutic (30 mg) doses of meloxicam with extended-release indomethacin (Indo-ER 75 mg once daily) on bleeding time, TxA2 formation, and platelet aggregation. The authors measured platelet aggregation to COX-1-dependent (ADP arachidonate) and COX-1-independent (high-dose collagen) agonists, bleeding time, serum TxB2, and clotting times (aPTT and PT) after 8 days' administration and at 3 and 6 hours after steady-state dosing. Meloxicam significantly decreased TxB2 production compared with placebo in a dose-dependent fashion, reaching a peak of 77% inhibition 6 hours after 30 mg meloxicam; Indo-ER blocked TxB2 formation by 96% at the same time point. However, neither acute nor 8 days' administration of meloxicam at any dose caused a significant increase in bleeding time or inhibition of platelet aggregation to any agonist when compared with placebo. By contrast, Indo-ER significantly increased the bleeding time and inhibited platelet aggregation to COX-1-dependent agonists 6 hours after dosing. Clotting times were unaffected by any drug. It was concluded that unlike nonselective NSAIDs, meloxicam's blockade of TxA2 formation (even at supratherapeutic doses) does not reach levels that result in decreased in vivo platelet function, as measured by bleeding time and aggregometry. In this study of healthy subjects, meloxicam did not interfere with platelet-mediated hemostasis.

UNLABELLED Platelet dysfunction contributes to blood loss after cardiopulmonary bypass. This study examined the antiplatelet effects of heparin, protamine, and varying heparin/protamine ratios in an in vitro physiologic model and further elucidated the mechanism of the antiplatelet and anticoagulant effects of protamine. We used the Clot Signature Analyzer (CSA(TM)), a system that analyzes coagulation in flowing whole blood, to test two aspects of platelet function, with different concentrations of heparin and protamine, under conditions simulating arterial flow: collagen-induced thrombus formation (CITF) under moderate shear and high shear platelet activation, platelet hemostasis time (PHT). In addition, platelet aggregometry, celite activated clotting time (Hepcon(TM) ACT), prothrombin time (PT), and partial thromboplastin time (PTT) were measured. Both PHT and the CITF were prolonged by heparin at 20 microg/mL, protamine at 20 and 40 microg/mL, and heparin/protamine ratios of 1:1 and 1:2, but not at 1:1.5. The Hepcon ACT was prolonged by heparin 20 microg/mL and protamine alone at 20 and 40 microg/mL, was normal at a ratio of 1:1, and was prolonged at 1:1.5 and 1:2. Protamine 80 microg/mL prolonged the PT and PTT. Dependency on thrombin, protein kinase C activation, and nonspecific charge effects were examined. The direct thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone prolonged the PHT and ACT, but not the CITF, whereas the polycationic molecules polyarginine and polylysine prolonged the CITF, but not the PHT. The effect of protamine on the PTT, but not PT, could be shortened by the addition of excess phospholipid. Therefore, heparin inhibits both high shear collagen-independent and moderate shear collagen-dependent platelet activation; however, the latter is not mediated by its antithrombin activity. Protamine's antithrombin effect may explain its inhibition of platelet activation at high shear stress. Protamine's nonspecific charge effects are more important for inhibiting moderate shear collagen-induced platelet activation. IMPLICATIONS This study suggests that protamine reversal of heparin's antiplatelet effect occurs within a narrow window because of the direct antiplatelet effects of protamine. Antithrombin effects may explain the inhibition of shear activation of platelets by both heparin and protamine. Nonspecific charge effects of protamine may explain the inhibition of collagen platelet activation in the presence of medium shear.

Objective: Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. Methods: In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. Results: Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. Conclusions: The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit. (J Thorac Cardiovasc Surg 1999;118:460-6)

SummaryThe risk of serious bleeding in patients with immune thrombocytopenic purpura (ITP) appears to be less than in comparably thrombocytopenic patients with megakaryocytic hypoplasia. It has been proposed that this difference is due to enhanced hemostatic activity of young platelets, which are increased in the circulation during ITP. We examined α-granule release in reticulated platelets (RP), which are thought to be the youngest circulating platelets, and in older non-reticulated platelets (non-RP) in normal human controls and ITP patients. Normal controls had a mean RP of 7%, compared with 42% in ITP patients. The mean concentration of thrombin receptor agonist peptide (TRAP) causing 50% of control RP to express CD62P (EC50) was 0.82 ± 0.08 μM (SEM), significantly higher than the TRAP CD62P EC50 for RP in ITP, 0.57 ± 0.06 uM (p = 0.04). Similarly, the TRAP EC 50 for non-RP in controls, 0.84 ± 0.09 μM, was significantly higher than in ITP, 0.56 ± 0.07 μM (p = 0.03), suggesting that all platelets in ITP have an enhanced α-granule threshold response to TRAP compared with controls, while RP and older platelets within each patient group have similar threshold sensitivities to TRAP. By contrast, high-dose TRAP caused RP to express twice as much mean and total CD62P as non-RP in both ITP patients and controls (p

Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin–dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications.

Determining reversible aspects of the platelet storage lesion may result in improved function and survival of transfused platelets.Using a model of high-dose (apheresis-derived) platelet concentrates (PC), functional changes imposed by transient adverse metabolic conditions (pH6.0 for 1-2 hr) that could be reversed by autologous plasma rescue followed by standard platelet storage were investigated. Whole-blood-derived PCs were transfused into a small number of normal volunteers to determine platelet recovery and survival.Without rescue, high-dose PCs developed severe in vitro functional derangements at the time of the pH nadir including 1) loss of resting morphology; 2) complete abrogation of osmotic recovery and platelet aggregation and glycoprotein IIb/IIIa up-regulation to agonist; and 3) decreased alpha-granule release. By contrast, spontaneous and agonist-induced binding of annexin V were unaffected by adverse metabolic conditions. Plasma rescue to an optimal pH improved morphology scores, stabilized osmotic recovery, and completely restored platelet secretory responses, as measured by aggregation, glycoprotein IIb/IIIa up-regulation, and alpha-granule release. In a limited number of studies, plasma rescue was accompanied by preserved in vivo platelet recovery and survival after autologous transfusion after 5 days of storage.Transient derangement of platelet metabolism, which does not increase membrane phosphatidylserine exposure, causes in vitro functional abnormalities that are fully reversed or stabilized by metabolic rescue. Preliminary data suggest that such rescued platelets may have normal posttransfusion recovery and survival.

Interpersonal psychotherapy (IPT) has demonstrated efficacy in protecting against a recurrence of major depression in elderly subjects when used alone on a monthly basis and when combined with antidepressant medication. The authors summarize their experience using IPT over the past 10 years and discuss a variety of treatment correlates. In addition, preliminary results using IPT combined with paroxetine in depressed elders reveals no difference in remission rates between cognitively intact and cognitively impaired depressed elders.

The study of megakaryocytopoiesis has been based largely on in vitro assays. We characterize an in vivo model of megakaryocyte and platelet development in which human peripheral blood stem cells (PBSCs) differentiate along megakaryocytic as well as myeloid/lymphoid lineages in sublethally irradiated nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice. Human hematopoiesis preferentially occurs in the bone marrow of the murine recipients, and engraftment is independent of exogenous cytokines. Human colony-forming units–megakaryocyte (CFU-MK) develop predominantly in the bone marrow, and their presence correlates with the overall degree of human cell engraftment. Using a sensitive and specific flow cytometric assay, human platelets are detected in the peripheral blood from weeks 1 to 8 after transplantation. The number of circulating human platelets peaks at week 3 with a mean of 20 × 109/L. These human platelets are functional as assessed by CD62P expression in response to thrombin stimulation in vitro. Exogenous cytokines have a detrimental effect on CFU-MK production after 2 weeks, and animals treated with these cytokines have no circulating platelets 8 weeks after transplantation. Although cytokine stimulation of human PBSCs ex vivo led to a significant increase in CFU-MK, CD34+/41+, and CD41+ cells, these ex vivo expanded cells provided only delayed and transient platelet production in vivo, and no CFU-MK developed in vivo after transplantation. In conclusion, xenogeneic transplantation of human PBSCs into NOD/SCID mice provides an excellent in vivo model to study human megakaryocytopoiesis and platelet production.

Background —We previously demonstrated that inhibiting formation of terminal complement components (C5a and C5b-9) prevents platelet and neutrophil (PMN) but not monocyte activation during simulated extracorporeal circulation (SECC). This study examined whether earlier complement inhibition during SECC, blocking C3a formation, would additionally prevent monocyte activation. Methods and Results —SECC was established by recirculating heparinized whole blood from human volunteers on a membrane oxygenator. CAB-2, a chimeric protein constructed from genes encoding the complement regulatory proteins CD46 and CD55, inactivates the C3/C5 convertases and blocks in vitro generation of C3a, C5a, and C5b-9. CAB-2 was used in 4 experiments at a final concentration of 300 μg/mL and 4 experiments at 30 μg/mL; 4 control runs used vehicle alone. Samples were assayed for C3a and C5b-9, monocyte activation (CD11b upregulation), PMN activation (CD11b upregulation and elastase release), and platelet activation (P-selectin expression and monocyte-platelet conjugate formation). CAB-2 at both doses significantly inhibited formation of C3a and C5b-9 during SECC. High-dose CAB-2 significantly blocked monocyte and PMN CD11b upregulation and PMN elastase release. CAB-2 also inhibited formation of platelet activation–dependent monocyte–platelet conjugates. Conclusions —Blockade of complement activation early in the common pathway inhibited monocyte CD11b upregulation during SECC, suggesting that early complement components contribute most to monocyte activation during SECC. As expected, PMN and platelet activation were blocked by terminal complement inhibition. This investigation further elucidates the relation between complement and blood cell activation during simulated cardiopulmonary bypass.

The risk of serious bleeding in patients with immune thrombocytopenic purpura (ITP) appears to be less than in comparably thrombocytopenic patients with megakaryocytic hypoplasia. It has been proposed that this difference is due to enhanced hemostatic activity of young platelets, which are increased in the circulation during ITP. We examined alpha-granule release in reticulated platelets (RP), which are thought to be the youngest circulating platelets, and in older non-reticulated platelets (non-RP) in normal human controls and ITP patients. Normal controls had a mean RP of 7%, compared with 42% in ITP patients. The mean concentration of thrombin receptor agonist peptide (TRAP) causing 50% of control RP to express CD62P (EC50) was 0.82+/-0.08 microM (SEM), significantly higher than the TRAP CD62P EC50 for RP in ITP, 0.57+/-0.06 microM (p = 0.04). Similarly, the TRAP EC50 for non-RP in controls, 0.84+/-0.09 microM, was significantly higher than in ITP, 0.56+/-0.07 microM (p = 0.03), suggesting that all platelets in ITP have an enhanced alpha-granule threshold response to TRAP compared with controls, while RP and older platelets within each patient group have similar threshold sensitivities to TRAP. By contrast, high-dose TRAP caused RP to express twice as much mean and total CD62P as non-RP in both ITP patients and controls (p0.05 for both comparisons). We conclude that compared with controls, all platelets in ITP are primed to undergo alpha-granule release to TRAP, while in both ITP and controls, the newly circulating, reticulated platelets have the potential to contribute greater amounts of CD62P surface ligand compared with older platelets (non-RP) after stimulation. Both the increased RP% and enhanced platelet response to agonist in ITP may contribute to maintenance of hemostasis despite thrombocytopenia.

Complications of cardiopulmonary bypass (CPB) may be associated with either immune suppression or immune activation, but the specific effects of CPB on many lymphocyte and monocyte subsets are unclear. In addition, the increasing age of patients undergoing cardiac surgery raises the possibility of even greater effects on the immune system in elderly patients. We measured immunophenotypic alterations of circulating lymphocytes and monocytes after CPB in male and female cardiac surgery patients who were either younger than 60 or older than 75 years of age. The total lymphocyte counts in all patients decreased postoperatively; older patients had significantly lower counts at all time points. The absolute decline was greatest among T cells and particularly CD4+ T cells, which reached an average nadir of 251 cells/microl on postoperative day 1 in the older patients. The percentages of CD8+, CD4+CD45RA+, and CD4+CD45RO+ T cells did not change significantly, whereas the percentages of B cells and natural killer cells increased. Both T and B lymphocytes and monocytes showed evidence of activation, with increased percentages of CD3+HLADr+, CD3+IL2R+, and CD19+CD23+ lymphocytes and increased expression of CD11b on monocytes. By contrast, expression of class II major histocompatibility antigen (HLADr) monocytes decreased significantly. We conclude that CPB produces a profound alteration in the pool of circulating lymphocytes and monocytes, evidenced by decreased numbers of lymphocyte subsets including CD4+ cells and decreased expression of monocyte surface membrane proteins important for antigen presentation; CPB also activates a variety of specific circulating mononuclear cell subsets. Older patients showed patterns of lymphocyte and monocyte activation comparable to those of younger patients; however, they had consistently lower lymphocyte numbers and a trend toward decreased monocyte HLADr expression, potentially placing them at greater risk for infectious complications. Gender had no effect.

The adhesive characteristics of hematopoietic stem and progenitor cells may partly regulate their proliferation and differentiation and may be critical in the homing of transplanted stem cells. Using quantitative adhesion assays, we have examined the characteristics of activated platelet adhesion to CD34+ cells in human blood and to the KG1a cell line. Approximately 85-95% of CD34+ cells from both sources bound thrombin-activated platelets; like mature neutrophils, activated platelet binding was maximal within 2 minutes of coincubation. Activated platelet adhesion to CD34+ cells was completely inhibited by chelation of calcium or by preincubation with the G1 blocking monoclonal antibody (MoAb) to platelet P-selectin. Using MoAbs to P-selectin glycoprotein ligand-1 (PSGL-1), we demonstrated that PSGL-1 was present on the surface of CD34+ cells; preincubation of CD34+ cells with the PL1 blocking MoAb to PSGL-1 completely inhibited activated platelet adhesion to CD34+ cells. Furthermore, treatment of CD34+ cells with O-sialoglycoprotein endopeptidase, which destroyed the PL1 epitope of PSGL-1, also abolished activated platelet-CD34+ cell binding. By contrast, MoAb directed against control epitopes of PSGL-1 or endopeptidase-sensitive epitopes of the CD34 molecule had no effect on activated platelet adhesion to CD34+ cells. Unlike mature neutrophils that, when activated, decrease P-selectin-dependent platelet adhesion because of redistribution of PSGL-1, phorbol ester treatment of CD34+ cells had no effect on their ability to bind activated platelets or PSGL-1 MoAbs. This study identifies PSGL-1 on CD34+ cells as the ligand for platelet P-selectin and suggests functional differences between mature and precursor hematopoietic cells in the regulation of surface PSGL-1 expression.

BACKGROUND The time course and reversibility of sodium nitroprusside's in vivo inhibition of platelet function are unclear. METHODS Platelet aggregation and P-selectin expression as measures of platelet dense and alpha-granule release, respectively, were examined before and after administration of sodium nitroprusside (18 mg) to human volunteers and in in vitro studies. Hypotension occurring with sodium nitroprusside administration was treated with intravenous crystalloid and/or phenylephrine. RESULTS Compared with preinfusion studies, platelet aggregation to epinephrine was significantly inhibited immediately and 4 min after discontinuation of the sodium nitroprusside infusion but returned to baseline at 8 and 12 min after discontinuing sodium nitroprusside. However, both dense and alpha-granule release to adenosine diphosphate after in vivo sodium nitroprusside were never significantly inhibited even at the time when sodium nitroprusside infusion was maximal. In contrast to our in vivo findings, in vitro incubation of platelet-rich plasma with sodium nitroprusside resulted in significant inhibition of dense and alpha-granule release to adenosine diphosphate. These in vitro inhibitory effects of sodium nitroprusside were reversed by pretreatment with epinephrine but not phenylephrine. CONCLUSIONS In normal volunteers, sodium nitroprusside inhibits platelet aggregation to epinephrine but not adenosine diphosphate; inhibition was reversed within 8-12 min after discontinuing sodium nitroprusside. Sodium nitroprusside in vitro inhibition of platelet function to adenosine diphosphate was reversed by epinephrine pretreatment. Because of the rapid reversibility of its antiplatelet effect, sodium nitroprusside may be clinically useful even when there is the potential for impaired coagulation.

Hydrocarbons, stable aorganochlorines, metals and radionuclides are widespread in the freshwaters of the Canadian Arctic. Petroleum-associated hydrocarbon sources include natural seepage, wastes and effluents from exploration, production and refining at Norman Wells and spills. Hydrocarbons also originate from combustion of carbon-based fuels, generally at lower latitudes and then reach the Arctic with air movements. Organochlorine compounds also move throughout the hemisphere by aerial pathways and have become distributed widely in Arctic fish. The organochlorine at highest concentration in Arctic freshwater is α-HCH, while those generally at highest concentrations in the fish are toxaphene, PCBs and chlordane. Metals are ubiquitous in Arctic freshwaters, with inputs of several metals by precipitation superimposed on natural geologic backgrounds. Mercury is found in muscle of fish from Arctic freshwaters at concentrations up to about 0.5 ppm. Radionuclides are also widespread at levels below those acceptable in food, with some local elevations near former mines. The implications of these contaminants for the northern ecosystems and the people dependent upon them are still not clear. Preliminary studies of inducible enzymes in fish suggest that the thresholds for biological damage have not been reached.

Potentially toxic organic compounds, acids, metals and radionuclides in the northern polar region are a matter of concern as it becomes evident that long-range transport of pollution on hemispheric to global scales is damaging this part of the world. In this review and assessment of sources, occurrence, history and pathways of these substances in the north, the state of knowledge of the transport media--the ocean and atmospheric circulation--is also examined. A five-compartment model of the northern region is developed with the intent of assessing the pathways of northern contaminants. It shows that we know most about pathways of acids, metals and radionuclides and least about those of complex synthetic organic compounds. Of the total annual inputs of anthropogenic acidic sulphur and the metals lead and cadmium to the Arctic via the atmosphere, an estimated 10-14% are deposited. A water mass budget for the surface layer of the Arctic Ocean, the most biologically active part of that sea, is constructed to examine the mass budget for one of the major persistent organochlorine compound groups found in remote regions, hexachlorocyclohexanes (HCH), one isomer of which is lindane. It is concluded that both the atmosphere and the ocean are important transport media. Even for the HCH substances which are relatively easily measured and simple in composition compared to other synthetic organics, we know little about the occurrence and environmental physical/chemical characteristics that determine pathways into the food chain. More environmental measurements, chemical characterization studies and environmental chemical transport modelling are needed, as is better knowledge of the circulation of the Arctic Ocean and the marine food web.

Limited data have been collected on the presence of contaminants in the Arctic terrestrial ecosystem, with the exception of radioactive fallout from atmospheric weapons testing. Although southern and temperate biological systems have largely cleansed themselves of radioactive fallout deposited during the 1950s and 1960s, Arctic environments have not. Lichens accumulate radioactivity more than many other plants because of their large surface area and long life span; the presence and persistence of radioisotopes in the Arctic is of concern because of the lichen → reindeer → human ecosystem. Effective biological half-life of cesium 137 is reckoned to be substantially less than its physical half-life. The database on organochlorines in Canadian Arctic terrestrial mammals and birds is very limited, but indications are that the air/plant/animal contaminant pathway is the major route of these compounds into the terrestrial food chain. For terrestrial herbivores, the most abundant organochlorine is usually hexachlorobenzene followed by hexachlorocyclohexane isomers. PCB accumulation favours the hexachlorobiphenyl, pentachlorobiphenyl and heptachlorobiphenyl homologous series. The concentrations of the various classes of organochlorine compounds are substantially lower in terrestrial herbivore tissues than in marine mammal tissues. PCBs and DDT are the most abundant residues in peregrine falcons (a terrestrial carnivore) reaching average levels of 9.2 and 10.4 μg · g −1 , respectively, more than 10 times higher than other organochlorines and higher than in marine mammals, including the polar bear. Contaminants from local sources include metals from mining activities, hydrocarbons and waste drilling fluids from oil and gas exploration and production, wastes from DEW line sites, naturally occurring radionuclides associated with uranium mineralization, and smoke containing SO 2 and H 2 SO 4 aerosol from the Smoking Hills at Cape Bathurst, N.W.T.

One indicator of older women's economic status among industrial nations is the value of old-age pensions relative to prior income. This study examines the impact of program changes and wage levels on old-age pension replacement rates (benefit amount divided by previous year's wage) for women in ten industrial countries from 1960 to 1980. The findings suggest that greater attention needs to be given to how women pension beneficiaries are affected by policy decisions and that a replacement rate index is a viable means of measuring such change.

The nucleotide sequence for the Rhodobacter sphaeroides form II ribulose 1, 5-bisphosphate car☐ylase/oxygenase was determined. The deduced product is highly homologous with the form II-like enzyme of Rhodospirillum rubrum , but appears to be more distantly related to the large subunit of the L 8 S 8 enzyme found in autotrophic bacteria, cyanobacteria and higher plants. Several regions highly conserved among L 8 S 8 and L X enzymes correspond with regions previously implicated in catalytic activity and subunit interactions. An imperfect palindrome and a stem loop structure were identified in the 5′ and 3′ flanking sequences, respectively, of R. sphaeroides rbpL .

Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.