Asymmetry in genitalia does not increase the rate of their evolution.

Left-right asymmetry is a frequently encountered phenomenon in the copulation organs of insects. While various causes have been proposed for genital asymmetry, we raise the question of whether asymmetry might facilitate, or even accelerate, morphological divergence of genitalia between species. We tested this hypothesis in the scarab chafer genus Schizonycha, which comprises species with symmetric as well as asymmetric male genitalia. Morphometric analyses were conducted in the context of their phylogeny, inferred from mitochondrial and nuclear ribosomal DNA sequence data (cox1, rrnL, and 28S) for a sample of 99 South African specimens, including 34 species and 5 outgroup taxa. Trees were reconstructed with maximum likelihood and Bayesian analysis. The extent of asymmetry and the variation of male copulation organs were analyzed with Generalized Procrustes analysis (GPA), by quantifying shape divergence of the parameres. We found a continuous transition in the degree of asymmetry among the investigated species. Ancestral state reconstruction revealed multiple origins and a high degree of evolutionary plasticity of paramere asymmetry in Schizonycha. However, no significant correlation between evolutionary rates of paramere shape divergence and the degree of paramere asymmetry was found, and so we conclude that asymmetric genitalia in Schizonycha do not increase the rate of genital shape divergence.

Observation of Wakefields and Resonances in Coherent Synchrotron Radiation.

We report on high resolution measurements of resonances in the spectrum of coherent synchrotron radiation (CSR) at the Canadian Light Source (CLS). The resonances permeate the spectrum at wave number intervals of 0.074 cm(-1), and are highly stable under changes in the machine setup (energy, bucket filling pattern, CSR in bursting or continuous mode). Analogous resonances were predicted long ago in an idealized theory as eigenmodes of a smooth toroidal vacuum chamber driven by a bunched beam moving on a circular orbit. A corollary of peaks in the spectrum is the presence of pulses in the wakefield of the bunch at well-defined spatial intervals. Through experiments and further calculations we elucidate the resonance and wakefield mechanisms in the CLS vacuum chamber, which has a fluted form much different from a smooth torus. The wakefield is observed directly in the 30-110 GHz range by rf diodes, and indirectly by an interferometer in the THz range. The wake pulse sequence found by diodes is less regular than in the toroidal model, and depends on the point of observation, but is accounted for in a simulation of fields in the fluted chamber. Attention is paid to polarization of the observed fields, and possible coherence of fields produced in adjacent bending magnets. Low frequency wakefield production appears to be mainly local in a single bend, but multibend effects cannot be excluded entirely, and could play a role in high frequency resonances. New simulation techniques have been developed, which should be invaluable in further work.

Febrile non-haemolytic transfusion reaction occurrence and potential risk factors among the U.S. elderly transfused in the inpatient setting, as recorded in Medicare databases during 2011-2012.

BACKGROUND AND OBJECTIVES: Febrile non-haemolytic transfusion reaction (FNHTR) is an acute transfusion complication resulting in fever, chills and/or rigours. Study's objective was to assess FNHTR occurrence and potential risk factors among inpatient U.S. elderly Medicare beneficiaries, ages 65 and older, during 2011-2012. MATERIALS AND METHODS: Our retrospective claims-based study utilized large Medicare administrative databases. FNHTR was ascertained via ICD-9-CM diagnosis code, and transfusions were identified by recorded procedure and revenue centre codes. The study ascertained FNHTR rates among the inpatient elderly overall and by age, gender, race, blood components and units transfused. Multivariate logistic regression analyses were used to assess potential risk factors. RESULTS: Among 4 336 338 inpatient transfusion stays for elderly during 2011-2012, 2517 had FNHTR diagnosis recorded, an overall rate of 58.0 per 100,000 stays. FNHTR rates (per 100,000 stays) varied by age, gender, number of units and blood components transfused. FNHTR rates were substantially higher for RBCs- and platelets-containing transfusions as compared to plasma only. Significantly higher odds of FNHTR were identified with greater number of units transfused (P < 0.01), for females vs. males (OR = 1.15, 95% CI 1.04-1.27), and with 1-year histories of transfusion (OR = 1.25, 95% CI 1.10-1.42), lymphoma (OR = 1.22, 95% CI 1.02-1.46), leukaemia (OR = 1.90, 95% CI 1.56-2.31) and other diseases. CONCLUSIONS: Our study shows increased FNHTR occurrence among elderly with greater number of units and with RBCs- and platelets-containing transfusions, suggesting need to evaluate effectiveness of prestorage leucoreduction in elderly. The study also suggests importance of prior recipient alloimmunization and underlying health conditions in the development of FNHTR.

Transfusion-associated circulatory overload (TACO) and potential risk factors among the inpatient US elderly as recorded in Medicare administrative databases during 2011.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) is a serious transfusion complication resulting in respiratory distress. The study's objective was to assess TACO occurrence and potential risk factors among elderly Medicare beneficiaries (ages 65 and older) in the inpatient setting during 2011. MATERIALS AND METHODS: This retrospective claims-based study utilized Medicare administrative databases in coordination with Centers for Medicare & Medicaid Services. Transfusions were identified by recorded procedure and revenue centre codes, while TACO was ascertained via ICD-9-CM diagnosis code. We evaluated TACO diagnosis code rates overall and by age, gender, race, number of units and blood components transfused. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 2,147,038 inpatient transfusion stays for elderly in 2011, 1340 had TACO diagnosis code, overall rate of 62·4 per 100,000 stays. TACO rates increased significantly with age and units transfused (P < 0·0001). After adjustment for confounding, significantly higher odds of TACO were found for women vs. men (OR = 1·40, 95% CI 1·26-1·60), White people vs. non-White people (OR = 1·38, 95% CI 1·20-1·62) and persons with congestive heart failure (OR = 1·61, 95% CI 1·44-1·88), chronic pulmonary disease (OR = 1·19, 95% CI 1·08-1·32) and different anaemias. CONCLUSION: Our study identified largest number of potential TACO cases to date and showed a substantial increase in TACO occurrence with age and number of units transfused. The study suggested increased TACO risk in elderly with congestive heart failure, chronic pulmonary disease and anaemias. Overall, study shows importance of large administrative databases as an additional epidemiological tool.

A model describing stable coherent synchrotron radiation in storage rings.

We present a model describing high power stable broadband coherent synchrotron radiation (CSR) in the terahertz frequency region in an electron storage ring. The model includes distortion of bunch shape from the synchrotron radiation (SR), which enhances higher frequency coherent emission, and limits to stable emission due to an instability excited by the SR wakefield. It gives a quantitative explanation of several features of the recent observations of CSR at the BESSY II storage ring. We also use this model to optimize the performance of a source for stable CSR emission.

Applications of eTag trade mark assay platform to systems biology approaches in molecular oncology and toxicology studies.

We have developed a universal eTag trade mark multiplex assay platform that can be uniquely applied to survey the molecule profiles of biologic systems in sub-global large-scale analyses. The effectiveness of eTag trade mark assays when applied to focused system biology studies in molecular oncology and predictive toxicology is herein described while reviewing the current methods commonly used. The multi-analyte and multi-parameter assay approach for parallel analysis will form the basis of an emerging paradigm of multiplexed molecular profiling for signaling pathway networks and various aspects of drug development processes.

Bursts of coherent synchrotron radiation in electron storage rings: a dynamical model.

Evidence of coherent synchrotron radiation has been reported recently at the electron storage rings of several light source facilities. The main features of the observations are (i) a radiation wavelength short compared to the nominal bunch length, and (ii) a coherent signal showing recurrent bursts of duration much shorter than the radiation damping time, but with spacing equal to a substantial fraction of the damping time. We present a model of beam longitudinal dynamics that reproduces these features.

The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules.

Chemokines have been hypothesized to contribute to the selectivity of lymphocyte trafficking not only as chemoattractants, but also by triggering integrin-dependent sticking (arrest) of circulating lymphocytes at venular sites of extravasation. We show that T cells roll on most Peyer's patch high endothelial venules (PP-HEVs), but preferentially arrest in segments displaying high levels of luminal secondary lymphoid tissue chemokine (SLC) (6Ckine, Exodus-2, thymus-derived chemotactic agent 4 [TCA-4]). This arrest is selectively inhibited by functional deletion (desensitization) of CC chemokine receptor 7 (CCR7), the receptor for SLC and for macrophage inflammatory protein (MIP)-3beta (EBV-induced molecule 1 ligand chemokine [ELC]), and does not occur in mutant DDD/1 mice that are deficient in these CCR7 ligands. In contrast, pertussis toxin-sensitive B cell sticking does not require SLC or MIP-3beta signaling, and occurs efficiently in SLC(low/-) HEV segments in wild-type mice, and in the SLC-negative HEVs of DDD/1 mice. Remarkably, sites of T and B cell firm adhesion are segregated in PPs, with HEVs supporting B cell accumulation concentrated in or near follicles, the target domain of most B cells entering PPs, whereas T cells preferentially accumulate in interfollicular HEVs. Our findings reveal a fundamental difference in signaling requirements for PP-HEV recognition by T and B cells, and describe an unexpected level of specialization of HEVs that may allow differential, segmental control of lymphocyte subset recruitment into functionally distinct lymphoid microenvironments in vivo.

Molecular mechanisms of lymphocyte homing to peripheral lymph nodes.

To characterize the adhesion cascade that directs lymphocyte homing to peripheral lymph nodes (PLNs), we investigated the molecular mechanisms of lymphocyte interactions with the microvasculature of subiliac lymph nodes. We found that endogenous white blood cells and adoptively transferred lymph node lymphocytes (LNCs) tethered and rolled in postcapillary high endothelial venules (HEVs) and to a lesser extent in collecting venules. Similarly, firm arrest occurred nearly exclusively in the paracortical HEVs. Endogenous polymorphonuclear (PMNs) and mononuclear leukocytes (MNLs) attached and rolled in HEVs at similar frequencies, but only MNLs arrested suggesting that the events downstream of primary rolling interactions critically determine the specificity of lymphocyte recruitment. Antibody inhibition studies revealed that L-selectin was responsible for attachment and rolling of LNCs, and that LFA-1 was essential for sticking. LFA-1-dependent arrest was also abolished by pertussis toxin, implicating a requirement for G alpha i--protein-linked signaling. alpha 4 integrins, which play a critical role in lymphocyte homing to Peyer's Patches, made no significant contribution to attachment, rolling, or sticking in resting PLNs. Velocity analysis of interacting LNCs revealed no detectable contribution by LFA-1 to rolling. Taken together, our results suggest that lymphocyte- HEV interactions within PLNs are almost exclusively initiated by L-selectin followed by a G protein-coupled lymphocyte-specific activation event and activation-induced engagement of LFA-1. These events constitute a unique adhesion cascade that dictates the specificity of lymphocyte homing to PLNs.

Platelet-mediated lymphocyte delivery to high endothelial venules.

Circulating lymphocytes gain access to lymph nodes owing to their ability to initiate rolling along specialized high endothelial venules (HEVs). One mechanism of rolling involves L-selectin binding to peripheral node addressin (PNAd) on HEVs. Activated platelets are shown to bind to circulating lymphocytes and to mediate rolling in HEVs, in vivo, through another molecule, P-selectin, which also interacts with PNAd. In vitro, activated platelets enhanced tethering of lymphocytes to PNAd and sustained lymphocyte rolling, even in the absence of functional L-selectin. Thus, a platelet pathway operating through P-selectin provides a second mechanism for lymphocyte delivery to HEVs.

Cell surface P- and E-selectin support shear-dependent rolling of bovine gamma/delta T cells.

The vascular selectins P- and E-selectin are inducible adhesion proteins expressed by endothelial cells that have been shown to support shear-dependent rolling of myeloid cells. This interaction is thought to be a prerequisite event for subsequent steps, such as tight adhesion/aggregation and transendothelial cell migration, involved in the accumulation of leukocytes into tissues. Certain lymphocyte subsets have also been shown to bind the vascular selectins, but the importance of this interaction in mediating shear-dependent rolling, as described for myeloid cells, has not been demonstrated. We expand on our earlier observation that bovine gamma/delta T cells bind E-selectin by showing that this interaction leads to a reproducible rolling event in assays done under shear forces that approximate those that occur in vivo. E-selectin, expressed by L cell transfectants or cytokine-stimulated human and bovine endothelial cells, equally supports the shear-dependent rolling interaction. The lymphocyte adhesion proteins L-selectin, CD44, and CD2 do not contribute to this event. Neuraminidase treatment of the gamma/delta T cells or addition of EDTA to the assay completely blocks the rolling interaction. We further show for the first time that P-selectin expressed by thrombin-activated platelets or a soluble P-selectin/human Ig chimera specifically binds gamma/delta T cells. The P-selectin interaction is similar to the rolling event mediated by E-selectin--it requires divalent cations and sialic acid on the lymphocyte, it lacks involvement of L-selectin and CD44, and rolling occurs under physiologic shear conditions. These results provide the documentation that the vascular selectins can support shear-dependent rolling of a lymphocyte subset and that P-selectin mediates the adhesion of gamma/delta T cells.

Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor.

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.

Comparison of L-selectin and E-selectin ligand specificities: the L-selectin can bind the E-selectin ligands sialyl Le(x) and sialyl Le(a).

The L- and E-selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-selectin, like E-selectin, can interact with synthetic neoglycoproteins containing Sialyl Le(x) (Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc beta-R), or Sialyl Le(a) (Neu5Ac-alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta-R). Additionally, both the E-selectin and L-selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-selectin. Despite overlapping interactions, the L- and E-selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-selectin; and furthermore, L-selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-selectin found on a subset of lymphocytes associated with the skin.

The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1.

A skin-associated population of memory T lymphocytes, defined by expression of the cutaneous lymphocyte antigen (CLA), binds selectively and avidly to the vascular lectin endothelial cell-leukocyte adhesion molecule 1 (ELAM-1), an interaction that may be involved in targeting of CLA+ T cells to cutaneous sites of chronic inflammation. Here we present evidence that CLA itself is the (or a) lymphocyte homing receptor for ELAM-1. Antigen isolated with anti-CLA monoclonal antibody HECA-452 from human tonsillar lysates avidly binds ELAM-1 transfected mouse cells. Anti-CLA antibody blocks T lymphocyte binding to ELAM-1 transfectants. HECA-452 and ELAM-1 binding to lymphocytes or to isolated tonsillar HECA-452 antigen is abrogated by neuraminidase treatment implying a prominent role for sialic acid in CLA structure and function. The dominant form of CLA on T cells is immunologically distinct from the major neutrophil ELAM-1 ligand, the sialyl Lewis x (sLex) antigen (NeuAc alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc), which is absent, weakly expressed, or masked on T cells. However, neuraminidase treatment of CLA+ T cells, but not of CLA- T cells, reveals Lewis x (CD15) structures. In combination with the known requirement for terminal NeuAc alpha 2-3Gal and fucose residues attached to N-acetylglucosamine for ELAM-1 and HECA-452 binding, this finding suggests that CLA may comprise an additionally sialylated or otherwise modified form of sLex. The identification of a lymphocyte homing receptor for skin may permit novel approaches to the diagnosis and therapy of cutaneous and inflammatory disorders.

The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140.

LECAM-1 (leukocyte-endothelial cell adhesion molecule 1), the lymphocyte lectin ("selectin") homing receptor for peripheral lymph nodes (PLNs), participates in the earliest interactions of polymorphonuclear neutrophilic leukocytes (PMNs) with inflamed venules. Here, we present evidence that LECAM-1 mediates this function through a novel mechanism--presentation of oligosaccharide ligands to the inducible vascular selectins endothelial-leukocyte adhesion molecule (ELAM-1) and granule membrane protein 140 (GMP-140). PMN, but not lymphocyte, LECAM-1 is modified with the vascular selectin ligand sialyl Lewis x (sLex) and specifically binds ELAM-1-transfected cells. Although only a small fraction of total cell surface sLex, LECAM-1-associated sLex appears to play a prominent role in PMN interactions with cell-associated ELAM-1 and GMP-140, as anti-LECAM-1 monoclonal antibodies or selective removal of cell surface LECAM-1 inhibits PMN binding to vascular selectin transfectants by up to 70%. The enhanced function of LECAM-1-associated sLex may reflect the striking concentration, shown here, of LECAM-1 on PMN surface microvilli, the site of initial cellular contact.

Antibodies against human neutrophil LECAM-1 (LAM-1/Leu-8/DREG-56 antigen) and endothelial cell ELAM-1 inhibit a common CD18-independent adhesion pathway in vitro.

Neutrophil adhesion to interleukin-1 (IL-1)-stimulated human umbilical vein endothelial cells (HUVEC) involves the CD18 family of leukocyte integrins (lymphocyte function-associated antigen-1 [LFA-1], Mac-1, and p150,95) and LECAM-1 (DREG-56/LEU-8/LAM-1 antigen) on neutrophils and intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1) on the endothelium. In this study, we compare CD18-independent adhesion pathways mediated by neutrophil LECAM-1 and endothelial ELAM-1 and find that these two pathways overlap in a variety of assays: (1) anti-LECAM-1 and anti-ELAM-1 monoclonal antibody (MoAb) inhibit neutrophil binding to HUVEC, and the inhibitory effect is not additive; (2) anti-LECAM-1 MoAb, like anti-ELAM-1 MoAb, inhibits neutrophil binding to HUVEC stimulated for 3 hours with IL-1, but not to HUVEC stimulated for 8 hours, by which time ELAM-1 expression is downregulated; (3) anti-ELAM-1 MoAb has no effect on transendothelial migration, a CD18-dependent, LECAM-1-independent neutrophil function. Interestingly, anti-ELAM MoAb has a reduced but significant inhibitory effect on the adhesion of activated neutrophils that have shed their cell-surface LECAM-1. We also show that neutrophil binding to ELAM-1-transfected L cells is inhibited not only by anti-ELAM-1 but also by anti-LECAM-1 MoAb. These results suggest that LECAM-1 and ELAM-1 can operate in the same adhesion pathway, possibly as a receptor-counterreceptor pair. LECAM-1 and ELAM-1 are likely to interact with other ligands as well, perhaps through carbohydrate determinants that modify more than one glycoprotein.

The human peripheral lymph node vascular addressin is a ligand for LECAM-1, the peripheral lymph node homing receptor.

The trafficking of lymphocytes from the blood and into lymphoid organs is controlled by tissue-selective lymphocyte interactions with specialized endothelial cells lining post capillary venules, in particular the high endothelial venules (HEV) found in lymphoid tissues and sites of chronic inflammation. Lymphocyte interactions with HEV are mediated in part by lymphocyte homing receptors and tissue-specific HEV determinants, the vascular addressins. A peripheral lymph node addressin (PNAd) has been detected immunohistologically in mouse and man by monoclonal antibody MECA-79, which inhibits lymphocyte homing to lymph nodes and lymphocyte binding to lymph node and tonsillar HEV. The human MECA-79 antigen, PNAd, is molecularly distinct from the 65-kD mucosal vascular addressin. The most abundant iodinated species by SDS-PAGE is 105 kD. When affinity isolated and immobilized on glass slides, MECA-79 immunoisolated material binds human and mouse lymphocytes avidly in a calcium dependent manner. Binding is blocked by mAb MECA-79, by antibodies against mouse or human LECAM-1 (the peripheral lymph node homing receptor, the MEL-14 antigen, LAM-1), and by treatment of PNAd with neuraminidase. Expression of LECAM-1 cDNA confers PNAd binding ability on a transfected B cell line. We conclude that LECAM-1 mediates lymphocyte binding to PNAd, an interaction that involves the lectin activity of LECAM-1 and carbohydrate determinants on the addressin.

ELAM-1 is an adhesion molecule for skin-homing T cells.

Endothelial cell leukocyte adhesion molecule-1 (ELAM-1) has been described as an inducible endothelial cell-adhesion molecule for neutrophils, and is believed to have a key role in the extravasation of these cells at sites of acute inflammation. Here we report that ELAM-1-transfected COS cells also bind a unique skin-associated subset of circulating memory T cells defined by the expression of the cutaneous lymphocyte-associated antigen. T cells expressing this antigen bind at least as well as neutrophils to expressed ELAM-1, whereas other lymphocytes in the peripheral blood bind poorly, or not at all. Immunohistological survey of chronically inflamed tissue specimens revealed that vascular expression of ELAM-1 occurs at cutaneous sites in preference to noncutaneous sites. We conclude that at sites of chronic inflammation, ELAM-1 may function as a skin vascular addressin, a tissue-selective endothelial cell-adhesion molecule for skin-homing memory T lymphocytes.

Mechanism of the stimulation of prostaglandin H synthase and prostacyclin synthase by the antithrombotic and antimetastatic agent, nafazatrom.

Nafazatrom, an antithrombotic and antimetastatic agent containing a pyrazolone functionality, is a reducing substrate for the peroxidase activity of prostaglandin H (PGH) synthase. Nafazatrom inhibits the hydroperoxide-dependent oxidation of phenylbutazone, stimulates the reduction of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, and is oxidized by microsomal or purified enzyme preparations from ram seminal vesicles. Consonant with the effects of other peroxidase-reducing substrates, nafazatrom stimulates the oxygenation of arachidonic acid to prostaglandin endoperoxides by the cyclooxygenase component of PGH synthase. In addition, nafazatrom causes an elevation in the levels of 6-keto-prostaglandin F1 alpha, the non-enzymatic hydrolysis product of prostacyclin (PGI2) biosynthesized from arachidonic acid by ram seminal vesicle microsomes. Elevation of PGI2 biosynthetic capacity by nafazatrom occurs under conditions in which prostaglandin endoperoxide biosynthesis is maximal, suggesting that nafazatrom has a stimulatory effect on the conversion of prostaglandin endoperoxides to PGI2. Nafazatrom has no effect on the ability of ram seminal vesicle microsomes to convert PGH2 to PGI2 but protects microsomal PGI2 synthase from inactivation by 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid. Nafazatrom stimulates PGI2 biosynthesis in ram seminal vesicle microsomes by acting as a substrate for the peroxidase-catalyzed reduction of hydroperoxy fatty acids that are irreversible inactivators of PGI2 synthase. Several other compounds, including dipyridamole and triiodothyronine, exert similar effects. This may contribute to the reported ability of nafazatrom and related compounds to elevate the levels of bioassayable PGI2 in vivo and to the antithrombotic and antimetastatic activities of nafazatrom.