The effect of intermittent operation on a wind-powered membrane system for brackish water desalination.

Renewable energy powered membrane systems that are directly-connected must take account of both the inherent fluctuations and the intermittency of the energy resource. In order to determine the effect of intermittent operation, a membrane system was tested with variables of (i) amplitude from 60 to 300 W and (ii) length of time with no power from 0.5 to 3 min. This was performed over one hour periods with six on/off cycles to simulate the system operating under intermittent operation for short periods of time when directly-connected to a small wind turbine. The setup used a Filmtec BW30-4040 brackish water reverse osmosis membrane with feed waters of 2,750 mg/L and 5,500 mg/L NaCl. The results showed that the membrane system produced potable water under the majority of intermittency experiments performed. There was a relatively large increase in the average salt concentration of the permeate, especially when the system was off for shorter periods of time (0.5-1 min). Longer periods of no power (1-3 min) did not have as significant an effect on the average water quality. This is important when the need for energy buffering or short term storage is considered for these systems as it shows the potential for improving the overall flux and water quality using temporary energy storage.

Plasmin inhibition of platelet function and of arachidonic acid metabolism.

To study interactions between platelets and the fibrinolytic system, we examined the effects of human plasmin on human platelets washed by gel filtration. Plasmin concentrations that did not affect platelet shape change, release, or aggregation (less than 1.0 caseinolytic units [CU]/ml) caused a dose- and time-dependent inhibition of platelet aggregation in response to thrombin, ionophore A23187, and collagen. Complete loss of aggregation occurred at 0.1-0.5 CU/ml of plasmin. In a parallel dose-dependent manner, plasmin likewise inhibited thrombin, ionophore, and collagen-stimulated thromboxane B2 production. In contrast, neither aggregation nor thromboxane B2 formation induced by arachidonate was inhibited by plasmin pretreatment of the platelets. Plasmin blocked the thrombin-induced release of [3H]arachidonic acid from platelet membrane phospholipids and the thrombin-induced platelet oxygen burst. However, plasmin did not inhibit the arachidonate-induced oxygen burst. Inhibition of arachidonic acid release by plasmin was not mediated by increase in platelet cyclic AMP. These results suggest that plasmin inhibits platelet function, at least in part, by blocking the mobilization of arachidonic acid from membrane phospholipid pools. The effects of plasmin on platelets may contribute to the hemostatic abnormalities seen in pathologic and pharmacologic fibrinolysis.

Unidirectional transfer of prostaglandin endoperoxides between platelets and endothelial cells.

An important determinant of platelet-vessel wall interactions is the local balance of production of endothelial prostacyclin (PGI2) and platelet thromboxane (TX) A2, labile eicosanoids with opposing effects on hemostasis. Disputed evidence suggests that platelet-derived prostaglandin endoperoxide intermediates may be utilized as substrates for vascular PGI2 synthesis. Using several different approaches, we have found that platelets can transfer endoperoxides to cultured endothelial cells for efficient conversion to PGI2, but a reciprocal transfer of endothelial endoperoxides for utilization by platelet thromboxane synthetase does not occur under the same experimental conditions. However, platelets can utilize arachidonic acid released by endothelial cells for lipoxygenase metabolism. We have directly demonstrated the production of [3H]6-keto-PGF1 alpha (the breakdown product of [3H]PGI2) by aspirin-treated endothelial cells in the presence of platelets stimulated with [3H]arachidonic acid. In coincubation experiments using either arachidonate or ionophore A23187 as a stimulus, radioimmunoassay of the net production of arachidonic acid metabolites showed that 6-keto-PGF1 alpha generation by aspirin-treated endothelial cells in the presence of platelets may actually exceed its generation by uninhibited endothelial cells alone. In functional assays, platelet aggregation was inhibited in the presence of aspirin-treated endothelial cells after stimulation with either arachidonate or ionophore A23187. In contrast, the inverse experiments, using aspirin-treated platelets and uninhibited endothelial cells, failed to demonstrate platelet utilization of endothelial endoperoxides for TXA2 production by any of the above methods. These studies thus provide evidence that efficient unidirectional transfer and utilization of platelet-derived endoperoxides for endothelial PGI2 production can occur. This process may serve to amplify PGI2 generation adjacent to areas of vascular injury and permit tight localization of platelet plug formation at these sites.

Leukotriene B4 stimulates polymorphonuclear leukocyte adhesion to cultured vascular endothelial cells.

Adhesion of polymorphonuclear leukocytes (PMN) to the endothelial lining of blood vessels is an essential component of the inflammatory response. We have examined the effects of various lipoxygenase metabolites of arachidonic acid on PMN adhesion to cultured vascular endothelial cells, using a quantitative monolayer adhesion assay. Our results indicated that leukotriene B4 (LTB4) could effectively stimulate PMN adhesion to endothelial cell surfaces, in contrast to the sulfidopeptide leukotrienes C4, D4, and E4, and the monohydroxyacid lipoxygenase products of leukocytes and platelets, 5S-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid and 12S-hydroxy-5,8-cis,10-trans,14-cis-eicosatetraenoic acid, respectively. LTB4-stimulation of PMN-endothelial adhesion did not appear to be dependent upon the generation of cyclooxygenase metabolites, nor was it inhibited by exogenous prostacyclin. Enhanced PMN adhesion was observed with endothelial cells that were cultured from different types of large vessels (arteries and veins) in several species. These findings suggest an important pathophysiologic role for LTB4 in regulating leukocyte-vessel wall interactions.

Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells.

Both nitric oxide (NO) and carbon monoxide (CO) are vessel wall-derived messenger molecules that cause platelet inhibition and vasodilation by activating guanylyl cyclase in target cells. Since vascular smooth muscle cells (SMCs) are exposed to shear and tensile stresses, this study examined the effects of these hemodynamic forces on the enzymes that generate NO and CO in SMCs. Monolayers of cultured rat aortic SMCs were subjected to shear stress using a modified cone and plate viscometer, or cyclic elongational stretch using a compliant silastic culture membrane. Shear stress stimulated time-dependent increases in mRNA and protein for inducible heme oxygenase-1 (HO-1), the enzyme which forms CO as a byproduct of heme degradation. The threshold level of shear necessary to induce HO-1 expression was between 5 and 10 dynes/cm2. In contrast, shear stress did not stimulate inducible NO synthase (iNOS) expression. Cyclic stretch also induced the expression of HO-1 but not of iNOS mRNA. Exposure of vascular SMCs to shear stress stimulated the production and release of CO as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets. In addition, ADP-stimulated aggregation was inhibited in platelets exposed to sheared SMCs but not in platelets exposed to untreated control SMCs. Treatment of sheared SMCs with the HO-1 inhibitor, tin protoporphyrin-IX, blocked the antiaggregatory effect of the cells, whereas the iNOS inhibitor, methyl--arginine, had no effect. These results indicate that hemodynamic forces induce HO-1 gene expression and CO production in vascular SMCs, and that SMC-derived CO inhibits platelet aggregation. Thus, CO is a novel endogenous vessel wall-derived messenger molecule that may be selectively induced by hemodynamic forces to inhibit platelet reactivity and preserve blood fluidity at sites of vascular injury.

von Willebrand factor binding to platelet GpIb initiates signals for platelet activation.

The hypothesis that von Willebrand factor (vWF) binding to platelet membrane glycoprotein Ib (GpIb) initiates intracellular pathways of platelet activation was studied. We measured the biochemical responses of intact human platelets treated with ristocetin plus vWF multimers purified from human cryoprecipitate. vWF plus ristocetin causes the breakdown of phosphatidylinositol 4,5-bisphosphate, the production of phosphatidic acid (PA), the activation of protein kinase C (PKC), increase of ionized cytoplasmic calcium ([Ca2+]i), and the synthesis of thromboxane A2. PA production, PKC activation, and the rise of [Ca2+]i stimulated by the ristocetin-induced binding of vWF multimers to platelets are inhibited by an anti-GpIb monoclonal antibody, but are unaffected by anti-GpIIb-IIIa monoclonal antibodies. Indomethacin also inhibits these responses without impairing platelet aggregation induced by vWF plus ristocetin. These results indicate that vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb. This signal then causes PKC activation and increases of [Ca2+]i, which promote platelet secretion and potentiate aggregation.

Platelet protein phosphorylation, elevation of cytosolic calcium, and inositol phospholipid breakdown in platelet activation induced by plasmin.

Studies have been performed on the biochemical mechanism of platelet activation induced by the fibrinolytic protease plasmin. In washed human platelets, greater than or equal to 1.0 caseinolytic units (CU/ml plasmin induced aggregation. Platelet [14C]serotonin release was stimulated by 1.0 CU/ml plasmin to an extent comparable to that induced by 1.0 U/ml thrombin. A dose- and time-dependent phosphorylation of the platelet 47,000- and 20,000-kD proteins was noted in 32PO4-labeled platelets incubated with plasmin; phosphorylation was not affected by extracellular Ca2+, but was completely inhibited by an increase in platelet cyclic AMP. Phosphorylation of these platelet proteins suggested that plasmin may act on platelets by stimulating a rise in cytosolic calcium concentration ([Cai2+]) and activating inositol phospholipid-dependent phospholipase C and protein kinase C. Using both quin2 fluorescence and aequorin luminescence as indicators, plasmin was found to elevate platelet [Cai2+] in the presence or absence of extracellular Ca2+. Phospholipase C activation was shown by the generation of [3H]diglyceride in [3H]arachidonic acid-labeled platelets and [32P]phosphatidic acid in 32PO4 labeled platelets exposed to plasmin. Plasmin did not induce formation of thromboxane A2 (TXA2). Only small amounts of this eicosanoid were detected late in the time course after plasmin stimulation. Our results indicate that plasmin causes platelet aggregation and secretion associated with phosphorylation of the 47,000- and 20,000-kD proteins, Ca2+ mobilization, and phospholipase C and protein kinase C activation.

Preferential incorporation of eicosanoid precursor fatty acids into human umbilical vein endothelial cell phospholipids.

We have examined the preferential incorporation of specific fatty acids into phospholipid classes of cultured human umbilical vein endothelial cells. Pulse-labeling of human umbilical vein endothelial cell phospholipids with radiolabeled fatty acids and inhibition of radiolabeled fatty acid incorporation by competition with excess, unlabeled fatty acids in pair-wise combinations revealed two distinct classes of esterification systems into human umbilical vein endothelial cell phospholipids. The eicosanoid precursor fatty acids, including arachidonate, 8,11,14-eicosatrienoate (ETA) and 5,8,11,14,17-eicosapentaenoate (EPA), exhibited high affinity incorporation into total phospholipids, whereas other fatty acids, including docosahexaenoate and monohydroxy eicosatetraenoates, showed low affinity incorporation. The relative degree of incorporation of eicosanoid precursor fatty acids into phospholipid classes was phosphatidylcholine (PC) greater than phosphatidylethanolamine (PE) greater than phosphatidylinositol (PI) greater than phosphatidylserine (PS). The specific activity of [14C]arachidonic acid-labeled PI was two times higher than that of any other radiolabeled phospholipids. When competitive incorporation of eicosanoid precursor fatty acids into phospholipid classes was studied, they were found to be acylated into different phospholipid classes at different rates. Although eicosanoid precursor fatty acids were not preferentially incorporated into PC, arachidonic acid was preferentially incorporated into the other phospholipids and exhibited particular selectivity in comparison with the other eicosanoid precursor fatty acids for incorporation into PI. These results demonstrate that human umbilical vein endothelial cells possess selective incorporation mechanisms for specific fatty acids into various phospholipids via the deacylation-reacylation pathway.

Control of platelet protein kinase C activation by cyclic AMP.

Experiments were performed to elucidate the role of adenosine 3': 5'-cyclic monophosphate (cAMP) in the control of platelet protein kinase C (PKC) activation. Platelet aggregation and secretion in response to 4 beta-phorbol 12-myristate 13-acetate (PMA) or 1-oleoyl-2-acetylglycerol (OAG) were inhibited by dibutyryl cAMP in a dose-dependent manner. Inhibition of these functional activities paralleled a decrease in the PMA-induced phosphorylation of the Mr 47,000 substrate (p47) of PKC by pre-incubation of platelets with dibutyryl cAMP. These changes were also observed when platelet cAMP was increased by prostacyclin (PGI2), forskolin, or theophylline. The ADP scavenger creatine phosphate/creatine phosphokinase (CP/CPK) and the cyclooxygenase inhibitor indomethacin also diminished the aggregation and p47 phosphorylation responses to PMA or OAG. Pre-incubation of platelets with dibutyryl cAMP significantly potentiated the inhibition of aggregation and p47 phosphorylation effected by CP/CPK and indomethacin. These results are consistent with the model that PMA- or OAG-induced activation of platelets is amplified by secreted ADP and that the response to secreted ADP is inhibited by cAMP. Furthermore, the findings that increased intracellular cAMP inhibits PMA- or OAG-induced p47 phosphorylation in excess of that due solely to CP/CPK, and that cAMP significantly potentiates the effects of ADP removal and inhibition of cyclooxygenase in blocking p47 phosphorylation suggest that cAMP also exerts non-ADP-mediated inhibitory effects on PKC in intact platelets.

Regulation of the phosphoinositide cycle by Na+/H+ exchange and intracellular pH in human platelets.

We have found that thrombin-induced activation of protein kinase C (PKC) in platelets, measured by phosphorylation of the 47 kDa protein, is synergistically enhanced by the amiloride analogue ethylisopropylamiloride (EIA), a specific inhibitor of Na+/H+ exchange. This EIA effect was further synergistically enhanced by lowering intracellular pH (pHi) with either nigericin or sodium propionate, and reversed by raising pHi with monensin or ammonium chloride. The synergistic enhancement of thrombin-activated PKC by EIA plus nigericin was not observed when PKC was directly activated by phorbol esters. EIA and EIA plus nigericin caused a 3- to 6-fold increase in thrombin-induced diacylglycerol (DAG), but not phosphatidic acid (PA), production. EIA and nigericin also caused a marked increase in thrombin-induced breakdown and inhibition of resynthesis of phosphatidylinositol 4,5-bisphosphate (PIP2). In summary, we have presented evidence that inhibition of Na+/H+ exchange causes primarily a H(+)-mediated interruption of the phosphoinositide cycle in activated platelets, including the accumulation of DAG associated with the enhancement of PKC activation, the inhibition of conversion of DAG to PA, and increased PIP2 breakdown. These data suggest a model in which Na+/H+ and pHi play an important regulatory role in permitting the phosphoinositide cycle to proceed in thrombin-activated platelets.

Platelet lipoxygenase-dependent oxygen burst. Evidence for differential activation of lipoxygenase in intact and disrupted human platelets.

The metabolism of arachidonic acid in platelets by both cyclooxygenase and lipoxygenase involves the rapid consumption of molecular oxygen. However, selective inhibition of cyclooxygenase completely abolishes the arachidonate-induced oxygen burst in intact platelets. This is in contrast to platelet lysates, in which approximately 50% of the arachidonate-induced oxygen burst remains detectable following inhibition of cyclooxygenase with acetylsalicylic acid. This lipoxygenase oxygen burst is blocked by preincubation of the platelets with ETYA, which inhibits both cyclooxygenase and lipoxygenase. In cell-free 100000 x g supernatants of platelet lysates, which contain only lipoxygenase activity, arachidonate induces an oxygen burst which is not blunted by preincubation with aspirin but is completely abolished by preincubation with ETYA. The finding of a lipoxygenase-dependent oxygen burst in platelet lysates but not in intact platelet suspensions suggests differential activation or differential availability of platelet lipoxygenase in intact and disrupted platelets. This was confirmed by a 5 min lag in the generation of [14C]HETE (the major lipoxygenase product) from [14C]arachidonic acid in intact platelets, but an almost immediate initiation of [14C]HETE production in platelet lysates. In contrast, the synthesis of [14C]thromboxane B2 (the major cyclooxygenase product) from [14C]arachidonic acid began immediately in both intact and disrupted platelet preparations and peaked within 5 min. These observations provide new insight into factors controlling platelet hydroxy acid production and help to explain the nature of the platelet oxygen burst.

Monoclonal antibody AG-1 initiates platelet activation by a pathway dependent on glycoprotein IIb-IIIa and extracellular calcium.

The biochemical responses of intact human platelets to the monoclonal antibody (mAb) AG-1 were investigated. AG-1 is a murine IgG mAb that recognizes a series of platelet membrane glycoproteins (Gp) from M(r) 21,000 to 29,000, one of which is the M(r) 24,000 (p24) receptor for anti-CD9 mAbs. AG-1 causes platelet aggregation and secretion. Platelets binding AG-1 demonstrate a dose- and time-dependent breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2), production of diacylglycerol, and generation of phosphatidic acid (PA). These events are associated with the activation of protein kinase C (PKC), an increase in intracellular calcium, and fibrinogen binding. Platelet PA generation and PKC activation in response to AG-1 are inhibited by mAbs to platelet GpIIb-IIIa or by extracellular EGTA, but not by a mAb to platelet GpIb or by inhibiting platelet Na+/H+ exchange with 5-(N-ethyl-N-isopropyl)amiloride. Platelet cytoplasmic free calcium ([Ca2+]i) is elevated in response to AG-1, and this elevation is inhibited by mAbs to GpIIb-IIIa, an RGDS peptide or by chelating extracellular calcium. These results suggest that AG-1 binding to a unique platelet-surface glycoprotein initiates platelet responses through the activation of PIP2-specific phospholipase C, and that this occurs through a signal pathway that is dependent on GpIIb-IIIa and extracellular calcium.

Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: role in polyamine and collagen synthesis.

BACKGROUND: Transforming growth factor-beta(1) (TGF-beta(1)) contributes to arterial remodeling by stimulating vascular smooth muscle cell (VSMC) growth and collagen synthesis at sites of vascular injury. Because L-arginine is metabolized to growth-stimulatory polyamines and to the essential collagen precursor L-proline, we examined whether TGF-beta(1) regulates the transcellular transport and metabolism of L-arginine by VSMCs. METHODS AND RESULTS: TGF-beta(1) increased L-arginine uptake, and this was associated with a selective increase in cationic amino acid transporter-1 (CAT-1) mRNA. In addition, TGF-beta(1) stimulated L-arginine metabolism by inducing arginase I mRNA and arginase activity. TGF-beta(1) also stimulated L-ornithine catabolism by elevating ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activity. TGF-beta(1) markedly increased the capacity of VSMCs to generate the polyamine putrescine and L-proline from extracellular L-arginine. The TGF-beta(1)-mediated increase in putrescine and L-proline production was reversed by methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by hydroxy-L-arginine, an arginase inhibitor. Furthermore, the formation of putrescine was inhibited by the ODC inhibitor alpha-difluoromethylornithine, and L-proline generation was blocked by the OAT inhibitor L-canaline. L-Canaline also inhibited TGF-beta(1)-stimulated type I collagen synthesis. CONCLUSIONS: These results demonstrate that TGF-beta(1) stimulates polyamine and L-proline synthesis by inducing the genes that regulate the transport and metabolism of L-arginine. In addition, they show that TGF-beta(1)-stimulated collagen production is dependent on L-proline formation. The ability of TGF-beta(1) to upregulate L-arginine transport and direct its metabolism to polyamines and L-proline may contribute to arterial remodeling at sites of vascular damage.

Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation.

BACKGROUND: Recent studies have demonstrated that systemic pharmacological induction of heme oxygenase-1 (HO-1), the inducible isoform of the initial and rate-limiting enzyme for heme catabolism, attenuates neointima formation after experimental vascular injury. We have now investigated the ability of localized adenovirus-mediated HO-1 (Ad-HO-1) gene delivery to modify arterial remodeling after balloon angioplasty. METHODS AND RESULTS: Two weeks after balloon angioplasty in the rat carotid artery, elevated HO-1 protein was observed in the Ad-HO-1 arteries compared with those exposed to empty adenovirus (Ad-E) or to PBS. The arteries exposed to Ad-HO-1 exhibited significantly reduced neointimal area, medial wall area, neointimal area/medial wall area ratio, and neointimal thickness compared with arteries exposed to Ad-E. The Ad-E vessels showed subtle reductions in each morphometric parameter compared with PBS vessels. In a separate group of animals, concomitant treatment of Ad-HO-1 with the HO-1 inhibitor tin protoporphyrin completely restored each morphometric parameter to control levels. Arteries exposed to Ad-HO-1 demonstrated significantly increased TUNEL labeling of apoptotic nuclei and significantly decreased PCNA labeling of DNA synthesis in the medial wall 48 hours after injury. CONCLUSIONS: These results indicate that HO-1 represents an important in vivo vasoprotective mediator that is capable of attenuating the pathophysiological remodeling response to endovascular injury and suggest that HO-1 may be a novel target for the treatment of vascular disease.

A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials.

Aspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials.

Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries.

Recent studies indicate that systemic induction of heme oxygenase-1 (HO-1), which oxidatively degrades heme into iron, biliverdin, and carbon monoxide (CO), or adenoviral-mediated gene transfer of HO-1 inhibits neointima formation after experimental vascular injury. In the present study, we investigated whether the acute, local administration of the HO-1 product, CO, regulates the arterial remodeling response following injury. Immediately after balloon injury of rat carotid arteries, a saturated solution of CO or nitrogen (N2), or phosphate buffered saline (PBS) was incubated luminally within the injured vessels for 30 min. Two weeks after injury, arteries exposed to CO exhibited significantly reduced neointimal area, neointimal area/medial wall area ratio, neointimal thickness, and medial wall area compared to arteries exposed to N2 or PBS. Arteries exposed to CO also demonstrated significantly reduced DNA synthesis in the medial wall two days after injury as suggested by proliferating cell nuclear antigen immunostaining, and this was associated with a decrease in the protein expression of the G1 cyclins, cyclin E and A, and transforming growth factor-beta1. These results indicate that the acute, local delivery of CO blocks the pathophysiological remodeling response to vascular injury, and identifies CO as a potentially important therapeutic agent in the treatment of vasculoproliferative disease.

Steroid estrogens in ocean sediments.

This paper gives results from a study measuring the abundance of steroid hormones in ocean sediments in the proximity of a deep ocean sewage outfall. The outfall is discharge point for an enhanced primary sewage treatment plant and sediment samples were taken adjacent and 7 km from the outfall. All samples contained steroid estrogens at nanogram per gram levels with higher concentrations at the 7 km sampling site. The concentration of estrone ranged from (0.16-1.17 ng/g), 17beta-estradiol (0.22-2.48 ng/g) and the synthetic 17alpha-ethinylestradiol (<0.05-0.5 ng/g). The values detected correspond with estimates based on the proportion of estrogens sorbed to particles in the effluent and the expected proportion of particles originating from sewage in the ocean sediments. The results suggest that estrogens associated with the particulate fraction aggregate on contact with high ionic strength seawater and settle to the seafloor after discharge through deep ocean outfalls.

Teratogenic effects of antileukemic chemotherapy.

The clinical teratogenicity of the new antileukemic chemotherapeutic agents administered to mothers early in the first trimester of pregnancy is not well defined. Cytarabine and thioguanine were given in identical doses to the same mother during the first trimester of two separate pregnancies. Both pregnancies resulted in viable babies, one with and one without congenital malformations. This case illustrates the highly unpredictable clinical effects on the fetus of chemotherapy early in pregnancy.

Antithrombotic therapy in patients with acute coronary syndromes.

The potential armamentarium of agents used in the treatment of acute coronary syndromes continues to expand, including such well-tested agents as aspirin, unfractionated heparin, and earlier-generation fibrinolytic agents, and newer agents such as low-molecular-weight heparins, direct thrombin inhibitors, thienopyridines, platelet glycoprotein IIb/IIIa receptor inhibitors, and bolus-administration fibrinolytic agents. Older and newer antithrombotic agents have undergone and continue to undergo intensive clinical investigation in patients with the clinical spectrum of acute coronary syndromes, which includes unstable angina, non-Q-wave (non-ST-segment elevation) myocardial infarction, and ST-segment elevation myocardial infarction. These studies, often conducted on an international scope and involving thousands of patients, provide data allowing practitioners to optimize the care of patients with acute coronary syndromes. In this article, studies of these established and newer agents in the treatment of patients with acute coronary syndromes are reviewed critically and summarized. Recommendations regarding use of antithrombotic agents in patients with acute coronary syndromes are then given.

Long-term efficacy of deferoxamine iron chelation therapy in adults with acquired transfusional iron overload.

Transfusional iron overload in adult patients with acquired anemias may result in widespread organ dysfunction. Long-term deferoxamine mesylate therapy was administered by continuous subcutaneous infusion to six such patients, who have been followed up for up to 66 months of therapy while continuing to be transfusion-dependent. During deferoxamine therapy, liver density by computed tomographic scan decreased in four of five patients, liver iron content decreased in two of three patients, and liver function normalized in two patients. Plasma cortisol response to insulin-induced hypoglycemia improved in three of five patients receiving therapy. Pituitary growth hormone reserve normalized in two patients and remained normal in the other three tested. One patient, treated concurrently with ascorbic acid, died suddenly. The other five patients have had no cardiac deterioration by noninvasive testing. We conclude that long-term deferoxamine iron chelation therapy is effective not only in retarding but, in some cases, even reversing organ damage caused by transfusional iron overload.