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The paper investigates the educational leadership management practices as a perspective to educational transformation. The descriptive correlation research design is utilized in the study to quantify and measure the profile of the respondents, contribution of effective style educational leadership management and practices, and educational transformation perspective of the educational management practices of the respondents. Likewise, purposive quota sampling employs in the study to define the criteria for the sample size. The study comprised fifty (50) respondents only. Results show that the contribution of effective style educational leadership management and practices of the respondents involves democratic leaders where they yield with a high morale environment to generate and motivate creative solutions of effective leadership style in school organization, show that instructional leadership involves on planning practice, coordination, evaluation, and teaching improvement learning, show that authoritative leaders ensure that the systems are in order, and quick in the decision process and control the organization, show that coaching leadership involves behavior, attitude, work performance, evaluation, process of the work, and the policies in the school organization, and show that transformational leaderships is an essential element in the organization to be imposed for good, better, and best because all employees in the school organization are determinant for the process. Hence, educational transformation perspective of the educational management practices of the respondents explores career, advocacy, and policy in pursuing equity in education, contributes to the school system in the organization, reveals significant effect on positive and negative effects of the transformational leadership process, maintains school culture and identity for the diverse and challenging condition strength of school organization and setting, and supports the innovation of learning in the school organization and supports advanced flexible learning technology.

Cardiomyopathies are ascribed to a variety of etiologies, present with diverse clinical phenotypes, and lack disease-modifying treatments. Mounting evidence implicates dysregulated activin receptor signaling in heart disease and highlights inhibition of this pathway as a potential therapeutic target. Here, we explored the effects of activin ligand inhibition using ActRIIB:ALK4-Fc, a heterodimeric receptor fusion protein, in two mechanistically distinct murine models of cardiomyopathy. Treatment with ActRIIB:ALK4-Fc significantly improved systolic or diastolic function in cardiomyopathy induced by neuromuscular disease or diabetes mellitus. Moreover, ActRIIB:ALK4-Fc corrected Ca

Introduction: Pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (PH-HFpEF) is the most prevalent form of WHO Group 2 PH but lacks effective treatment options. We previously found that sequestration of activins and growth differentiation factors with the sotatercept analog RAP-011, an activin receptor type IIA-Fc fusion protein, reverses pathological remodeling of pulmonary arteries and the right ventricle (RV) in experimental models of pulmonary arterial hypertension (PAH, Group 1 PH). This strategy of selective multi-ligand neutralization offers a promising new approach for treating patients with PAH and is under active clinical evaluation (PULSAR, SPECTRA, and STELLAR). Here, we compared the cardiopulmonary effects of therapeutic treatment with RAP-011 to those of sildenafil in a rat model of PH-HFpEF. Methods: PH was induced in adult male obese ZSF1 rats by a single subcutaneous injection of SU5416 (100 mg/kg). To model the timeline of diagnosis and treatment for Group 2 PH patients, we initiated treatment with RAP-011 and sildenafil 8 weeks post SU5416 administration—at which point RV dysfunction is prominent—and continued treatment for 8 weeks. RV systolic pressure (RVSP), pulmonary artery acceleration time (PAAT), RV hypertrophy, and tricuspid annular plane systolic excursion (TAPSE) were evaluated by right heart catheterization and echocardiography following the 8-week treatment regimen. Results: Obese ZSF1 rats treated with SU5416 displayed significantly increased RVSP (P < 0.0001) and decreased PAAT (P < 0.0001). RAP-011 treatment fully reversed changes in RVSP (P < 0.0001) and PAAT (P < 0.0001), whereas sildenafil treatment improved RVSP by 19% (P < 0.05) and PAAT by 36% (P < 0.001). Treatment with RAP-011, but not sildenafil, normalized RV hypertrophy (P < 0.0001) and increased TAPSE (P < 0.0001). Conclusions: Therapeutic treatment with the sotatercept analog RAP-011 exerted beneficial cardiopulmonary effects in a ZSF1 rat model of PH-HFpEF that were significantly greater than those produced by sildenafil, fully normalizing PH and RV hypertrophy and improving RV function. These findings support evaluation of sotatercept in patients with PH-HFpEF (Group 2 PH).

Rationale αv integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvβ6) and fibroblasts (αvβ1) in fibrotic lungs. Objectives We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. Methods Selective αvβ6 and αvβ1, dual αvβ6/αvβ1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual αvβ6/αvβ1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. Measurements and main results Inhibition of integrins αvβ6 and αvβ1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvβ6/αvβ1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. Conclusions In the fibrotic lung, dual inhibition of integrins αvβ6 and αvβ1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.

Background: Seaweeds and kelps, also known as macroalgae, have long been common in the East-Asian diet. During recent years, macroalgae have entered the global food market, and a variety of macroalgae products are now available for consumers. Some macroalgae species are known to be particularly rich in iodine, but little data regarding the iodine content of macroalgae-containing foods exists. Objective: The aim of this research study was to analyse the iodine content in a large variety of commercially available macroalgae-containing foods and supplements and to evaluate whether such products are sources of adequate dietary iodine. Design: Ninety-six different products were collected after surveying the Norwegian market for commercially available macroalgae products, collected from three categories: 1) wholefood macroalgae products (n = 43), 2) macroalgae-containing foods (n = 39), and 3) dietary supplements containing macroalgae (n = 14). All products were analysed for iodine content by inductively coupled plasma-mass spectrometry (ICP-MS). Results: The iodine content in one portion of wholefood macroalgae products ranged from 128 to 62,400 µg. In macroalgae-containing foods, the iodine content ranged from 30 to 25,300 µg per portion, and in supplements it ranged from 5 to 5,600 µg per daily dose. The species with the highest analysed iodine content were oarweed, sugarkelp and kombu, with mean iodine levels of 7,800, 4,469 and 2,276 µg/g, respectively. For 54 products, the intake of one portion or dose would exceed the tolerable upper intake level (UL) for iodine. Discussion and conclusion: The iodine content in the included products was variable and for most products high, exceeding the tolerable upper intake level (UL) if consumed as a serving or portion size. The labelling of macroalgae species included, and declaration of iodine content, were inadequate or inaccurate for several products. As macroalgae-containing products are unreliable iodine sources, inclusion of such products in the diet may pose a risk of consuming excessive amounts of iodine. This research study is financially supported by the Insti- tute of Marine Research.

Havforskningsinstituttet begynte med en systematisk registrering av innrapporterte funn av strandet krill i 2014. Antall tilfeller var få fra 2014 til 2017, men økte kraftig i 2018 og har siden holdt seg på dette nivået. Det er vanskelig å vite om dette skyldes at krill har drevet i land oftere de siste tre årene enn tidligere, eller om flere nå melder ifra om funn. Antallet innrapporterte tilfeller økte akkurat da bruken av kjemiske avlusingsmidler i landet som helhet minket kraftig, mens antallet innrapporterte tilfeller var relativt lavt i de årene der bruken av avlusingsmidler var høyest. Hyppigheten av strandet krill kan også ha en sammenheng med mengden krill i sjøen. Mars, august, september og oktober skiller seg klart ut som månedene med flest funn. De aller fleste funnene er fra Rogaland og gamle Hordaland fylke. De eneste områdene i landet hvor det ikke er rapportert om funn av strandet krill, er Finnmark og Skagerakkysten.

IIntroduction: Right ventricular (RV) failure is the primary cause of death in patients with pulmonary arterial hypertension (PAH). Beneficial effects of sotatercept - an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors - have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We have reported that therapeutic treatment with sotatercept analog RAP-011 reverses RV remodeling and function in rats with severe angio-obliterative PAH, providing benefits on top of standard care. Hypothesis: To determine whether RAP-011 exerts a direct cardioprotective effect in a mouse model of pressure overload-induced RV failure. Methods: RV failure was induced in male C57BL/6 mice by pulmonary artery banding (PAB). RAP-011 or vehicle were administered subcutaneously twice weekly for 3 weeks beginning one day post surgery. RV remodeling and function were assessed by echocardiography and RV pressure measured by catheterization. RV fibrosis was assessed by Masson’s trichrome staining. Results: PAB caused RV hypertrophy and increased RV wall thickness in comparison to sham surgery. RAP-011 treatment markedly attenuated these PAB-induced changes (by 72% and 41%, respectively; P < 0.0001). PAB significantly reduced tricuspid annular plane systolic excursion (0.68 ± 0.03 vs. 0.98 ± 0.03 mm), which was partially restored by RAP-011 (0.84 ± 0.04 mm; P < 0.01). In addition, the PAB-induced increase in myocardial performance index was reversed by RAP-011 (1.86 vs. 1.48, P < 0.0001). RAP-011 attenuated PAB-induced RV developed pressure (by 82%, P < 0.0001) and partially normalized peak rates of RV pressure change (+dP/dt max and -dP/dt min , P < 0.05). RAP-011 also reduced the extent of PAB-induced RV fibrosis (19.5% vs. 10.5%, P < 0.001). Conclusions: Consistent with our previous findings in a rat model of severe angio-obliterative PAH, RAP-011 treatment reduces RV remodeling and improves function in a PAB model, thus implicating direct cardioprotective actions of RAP-011 as an important component of its therapeutic effects in severe experimental PAH.

Background: Beneficial effects of sotatercept – an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that traps multiple members of the TGF-β superfamily, including activins and growth differentiation factors – have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We previously reported that therapeutic treatment with a rodent analog of sotatercept (RAP-011) reverses vascular modeling in rats with established severe angio-obliterative PAH. Aims: To investigate: 1) whether RAP-011 adds therapeutic benefit when combined with sildenafil compared to sildenafil alone and 2) whether benefits of RAP-011 persist after monotherapy cessation. Methods: Sugen-hypoxia-normoxia rats were treated with RAP-011 or sildenafil as monotherapies, or in combination therapy, from weeks 5 to 9, after established disease. We evaluated structural and functional parameters for the pulmonary vasculature and right ventricle (RV) at week 9 and 4 weeks after treatment cessation. Results: Compared to vehicle controls, combination therapy yielded greater improvement than sildenafil alone for RV systolic pressure (↓65% vs 12%, P Conclusions: Our results indicate that combination therapy with RAP-011 exerts effects superior to sildenafil alone and that benefits of RAP-011 persist 4 weeks after cessation of monotherapy.

Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl3 injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED50) of thrombus formation was 0.003 mg/kg/h compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., >1250-fold ED50 levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. Our study demonstrates that compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke.

Integrin αVβ6 (epithelial cell) and αVβ1 (fibroblast)-mediated activation of TGF-β have been shown to promote fibrosis in the bleomycin lung injury model, and elevated levels of αVβ6 have been found in human IPF lung tissue. Through the development of novel immuno- and cell adhesion assays, we confirmed significantly elevated levels of αVβ1 in IPF lung tissue and demonstrated αVβ1-specific binding of human lung fibroblasts to latent TGF-β. We then compared a dual-specific small molecule inhibitor of αVβ6/αVβ1 (PLN-74809) to a pan-αV inhibitor and specific inhibitors of αVβ6 and αVβ1 in the bleomycin mouse model or precision cut lung slices (PCLS; bleomycin-injured mouse/human IPF tissue) to assess which integrin inhibition strategy was most effective at blocking fibrogenesis. Characterization of inhibitor potency, selectivity, and functional activity was performed by ligand-binding and TGF-β reporter cell-based assays. Prophylactic dosing of PLN-74809 and a pan-αV inhibitor via minipump had similar plateau effects in the bleomycin model, reducing total lung hydroxyproline (OHP) and collagen gene expression by 40%. Oral therapeutic dosing of PLN-74809 also resulted in dose-dependent inhibition of OHP levels. Comparison of single and dual inhibitors in murine PCLS showed an additive effect of dual αVβ6/αVβ1 inhibition vs αVβ6 or αVβ1 inhibition alone, and PLN-74809 potency was higher than that of nintedanib or pirfenidone. PLN-74809 was also confirmed to inhibit collagen gene expression in PCLS from IPF patient tissue (p

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

This thesis investigates whether multivariate machine learning forecasting methods, using information extracted from Automatic Identification System (AIS) data, add additional information in predicting short-term freight rates. The focus in this thesis is the Liquid Petroleum Gas (LPG) shipping market, directed on the prediction of the Mont Belvieu propane spot price. Forecasting LPG spot prices is challenging due to a comparatively small fleet, niche trading patterns and cargo bases, creating high volatility. Nonetheless, anticipating fluctuations in freight rates is a crucial element to long-term profitability for both operators and shipowners. A thorough literature review is presented to investigate the state-of-the-art within the topic. The data used in this research is provided by the Norwegian Coastal Authorities and Equinor. Several methods are proposed to extract and create predictive features. A significant amount of market specific features are generated and tested with selection methods to identify the most powerful predictors of the Mont Belvieu propane spot price. Two machine learning models are employed; the Multilayer Perceptron (MLP) and Long Short-Term Memory (LSTM) neural networks. To baseline the results, the no-change persistence model and the Vector Autoregressive (VAR) model are utilized, where the latter is widely used for multivariate forecasting in maritime econometrics. By optimizing the neural network architectures with a genetic algorithm, the LSTM-model is identified to perform better than the baseline model and the traditional multivariate VAR-model. Moreover, the results indicate that both the machine learning and traditional models with information extracted from AIS data are able to predict short-term fluctuations in freight rates more accurately than without this information. In conclusion, there is evidence in favor of using information extracted from AIS data in short-term freight rate prediction. Furthermore, the results also suggest favorability of using multivariate machine learning forecasting models over traditional models. This thesis suggests that further work within the use of AIS data in the context of maritime econometrics is recommended. After surveying the performance in the case study, it is finally recommended to investigate whether the approach used in this study can be readily applied to other ocean freight industries.

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Background It is well accepted that functional activity of platelet integrin αIIbβ3 is crucial for hemostasis and thrombosis. The β3 subunit of the complex undergoes tyrosine phosphorylation shown to be critical for outside-in integrin signaling and platelet clot retraction ex vivo. However, the role of this important signaling event in other aspects of prothrombotic platelet function is unknown. Method Here, we assess the role of β3 tyrosine phosphorylation in platelet function regulation with a knock-in mouse strain, where two β3 cytoplasmic tyrosines are mutated to phenylalanine (DiYF). We employed platelet transfusion technique and intravital microscopy for observing the cellular events involved in specific steps of thrombus growth to investigate in detail the role of β3 tyrosine phosphorylation in arterial thrombosis in vivo. Results Upon injury, DiYF mice exhibited delayed arterial occlusion and unstable thrombus formation. The mean thrombus volume in DiYF mice formed on collagen was only 50% of that in WT. This effect was attributed to DiYF platelets but not to other blood cells and endothelium, which also carry these mutations. Transfusion of isolated DiYF but not WT platelets into irradiated WT mice resulted in reversal of the thrombotic phenotype and significantly prolonged blood vessel occlusion times. DiYF platelets exhibited reduced adhesion to collagen under in vitro shear conditions compared to WT platelets. Decreased platelet microparticle release after activation, both in vitro and in vivo, were observed in DiYF mice compared to WT mice. Conclusion β3 tyrosine phosphorylation of platelet αIIbβ3 regulates both platelet pro-thrombotic activity and the formation of a stable platelet thrombus, as well as arterial microparticle release.

Platelets assume two main functions that lead to opposite outcomes. In one instance, they support hemostatic plug formation and prevent bleeding at sites of vascular breach. Alternatively, their uncontrolled recruitment at sites of plaque erosion/rupture in arteries can lead to ischemic events and death. Antiplatelet agents have been developed to successfully treat or prevent arterial thrombotic events, but their use is inevitably associated with bleeding complications. These agents target platelet receptors (i.e., P2Y12, the ADP receptor mediating aggregation and thrombus stability; αIIbβ3, the fibrinogen and vWF receptor mediating platelet aggregation/thrombus growth; PAR1, the high-affinity platelet thrombin receptor) or the cyclooxygenase 1 (COX1) enzyme that promotes TxA2 synthesis (another platelet-derived endogenous agonist of platelet aggregation). Evidences have emerged showing that these pathways are complementary as combinations of drugs provide additive protection. Signaling pathways downstream of the glycoprotein receptors have been well characterized and indicate that inhibition of effectors (specific to a pathway or ubiquitous) could provide significant protection from thrombosis. In this chapter, we will review the biology associated with genetic and pharmacologic modulation of platelet effectors and report their effects on thrombosis and primary hemostasis.

The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An I max and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA‐mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.

Objective— The goal of this study was to investigate the potential crosstalk between Rap1 and Rac1, 2 small GTPases central to platelet activation, particularly downstream of the collagen receptor GPVI. Methods and Results— We compared the activation response of platelets with impaired Rap signaling (double knock-out; deficient in both the guanine nucleotide exchange factor, CalDAG-GEFI, and the Gi-coupled receptor for ADP, P2Y12), to that of wild-type platelets treated with a small-molecule Rac inhibitor, EHT 1864 (wild-type /EHT). We found that Rac1 is sequentially activated downstream of Rap1 on stimulation via GPVI. In return, Rac1 provides important feedback for both CalDAG-GEFI– and P2Y12-dependent activation of Rap1. When analyzing platelet responses controlled by Rac1, we observed (1) impaired lamellipodia formation, clot retraction, and granule release in both double knock-out and EHT 1864-treated wild-type platelets; and (2) reduced calcium store release in EHT 1864-treated wild-type but not double knock-out platelets. Consistent with the latter finding, we identified 2 pools of Rac1, one activated immediately downstream of GPVI and 1 activated downstream of Rap1. Conclusion— We demonstrate important crosstalk between Rap1 and Rac1 downstream of GPVI. Whereas Rap1 signaling directly controls sustained Rac1 activation, Rac1 affects CalDAG-GEFI– and P2Y12-dependent Rap1 activation via its role in calcium mobilization and granule/ADP release, respectively.

It is known that hepatic metabolism limits the antiaggregatory activity of clopidogrel and, as a consequence, its clinical benefits. In this study, we investigated whether other factors exist that could account for clopidogrel's suboptimal antithrombotic activity. Using an in vivo murine FeCl(3) thrombosis model coupled with intravital microscopy, we found that at equivalent, maximal levels of inhibition of ADP-induced platelet aggregation, clopidogrel (50 mg/kg p.o.) failed to reproduce the phenotype associated with P2Y(12) deficiency. However, elinogrel (60 mg/kg p.o.), a direct-acting reversible P2Y(12) antagonist, achieved maximal levels of inhibition in vivo, and its administration (1 mg/kg i.v.) abolished residual thrombosis associated with clopidogrel dosing. Because elinogrel is constantly present in the plasma, whereas the active metabolite of clopidogrel exists for ∼2 h, we evaluated whether an intracellular pool of P2Y(12) exists that would be inaccessible to clopidogrel and contribute to its limited antithrombotic activity. Using saturation [(3)H]2-(methylthio)ADP ([(3)H]2MeSADP) binding studies, we first demonstrated that platelet stimulation with thrombin and convulxin (mouse) and thrombin receptor activating peptide (TRAP) (human) significantly increased surface expression of P2Y(12) relative to that of resting platelets. We next found that clopidogrel dose-dependently inhibited ADP-induced aggregation, signaling (cAMP), and surface P2Y(12) on resting mouse platelets, achieving complete inhibition at the highest dose (50 mg/kg), but failed to block this inducible pool. Thus, an inducible pool of P2Y(12) exists on platelets that can be exposed upon platelet activation by strong agonists. This inducible pool is not blocked completely by clopidogrel, contributes to thrombosis in vivo, and can be blocked by elinogrel.

Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y(12) and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl(3)-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y(12)(-/-) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y(12). Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y(12)(-/-) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y(12) activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y(12)-independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.

Using data from the US Department of Housing and Urban Development (HUD) concerning Housing Choice Voucher (HCV, formerly called Section 8) recipients, the authors provide a spatial analysis in Cincinnati, Ohio, USA. ‘Hot spot’ analysis is utilized to detect areas with significant densities of voucher recipients compared with the surrounding environs. Results show that the implementation of Cincinnati's HCV program between 2000 and 2005 in conjunction with public housing transformation has not led to a greater dispersion of voucher recipients and either poverty or racial deconcentration. Many HCV households remain concentrated in hot spots. The implications for US low-income housing policy are discussed.

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Background— Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (α M β 2 , CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise α M β 2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified. Methods and Results— Our previous studies have established the P 201 -K 217 sequence in the α M I domain as the binding site for platelet glycoprotein (GP) Ibα. Here we report that antibody targeting of α M (P 201 -K 217 ) reduced α M β 2 -dependent adhesion to GP Ibα but not other α M β 2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-α M (P 201 -K 217 ) inhibited the firm adhesion of both human and murine leukocytes to adherent platelets under laminar flow conditions. In a mouse femoral artery wire injury model, antibody targeting of α M (P 201 -K 217 ) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening. Conclusions— This study demonstrates that GP Ibα is a physiologically relevant ligand for α M β 2 and that integrin engagement of GP Ibα is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.

During the past decade, interrelationships between inflammation and thrombosis have been the subject of extensive works, and it is now commonly recognized that inflammation (notably leucocyte recruitment) directly affects thrombosis, and that thrombosis also constitutes a pro-inflammatory event. This tight link is partly attributable to P-selectin, which is functional not only when expressed on the surface of activated platelets and endothelial cells, but also when shed, generating its soluble form, termed sP-selectin. In this review, we will provide an overview of the relative roles of the different compartments of P-selectin (platelet, endothelial cell, plasma) in haemostasis and vascular pathologies, and the potential therapeutic benefits achievable in targeting this molecule.

The critical role for ADP in arterial thrombogenesis was established by the clinical success of P2Y12 antagonists, currently used at doses that block 40–50% of the P2Y12 on platelets. This study was designed to determine the role of P2Y12 in platelet thrombosis and how its complete absence affects the thrombotic process. P2Y12-null mice were generated by a gene-targeting strategy. Using an in vivo mesenteric artery injury model and real-time continuous analysis of the thrombotic process, we observed that the time for appearance of first thrombus was delayed and that only small, unstable thrombi formed in P2Y12–/– mice without reaching occlusive size, in the absence of aspirin. Platelet adhesion to vWF was impaired in P2Y12–/– platelets. While adhesion to fibrinogen and collagen appeared normal, the platelets in thrombi from P2Y12–/– mice on collagen were less dense and less activated than their WT counterparts. P2Y12–/– platelet activation was also reduced in response to ADP or a PAR-4–activating peptide. Thus, P2Y12 is involved in several key steps of thrombosis: platelet adhesion/activation, thrombus growth, and stability. The data suggest that more aggressive strategies of P2Y12 antagonism will be antithrombotic without the requirement of aspirin cotherapy and may provide benefits even to the aspirin-nonresponder population.

To explore the possible role of a residual or variant alphaIIbbeta3 integrin (alphaIIbbeta3) in thrombogenesis, we used a new ex vivo perfusion chamber model to examine blood from patients with different subtypes of Glanzmann's thrombasthenia (GT). Non-anticoagulated blood was perfused through capillaries coated with type III collagen for 4.5 min (shear rate: 1600/s). Platelet deposition was quantified as platelet adhesion and mean thrombus size volume; fibrin and von Willebrand Factor (VWF) were specifically revealed by immunohistochemistry. In two patients with variant and in one patient with type II GT, platelet adhesion was maximal and we observed an unexpected formation of thrombi that were smaller than normal in size. These thrombi were surrounded by a thick meshwork that displayed a strong staining for fibrin and VWF. In two patients with heterozygous GT, platelet adhesion and thrombogenesis were normal. In two patients with type I GT, there was no thrombus formation, although platelet adhesion was also maximal. These data suggest the existence of a substitute pathway for thrombogenesis mediated by fibrin and possibly alphaIIbbeta3 (alphaIIbbeta3 at a reduced level, as in type II, and/or abnormal) as this fibrin network was not observed in type I GT with no alphaIIbbeta3. These interactions might facilitate haemostasis and even lead to thrombosis under certain favourable conditions. Furthermore, these data might have pharmacological relevance to the development of anti-alphaIIbbeta3 antithrombotic agents.

Studies focusing on cellular and molecular mechanisms that regulate atherosclerosis have fed scientific journals for decades, nearly as long as it takes an atherosclerotic plaque to grow, rupture, and eventually induce vascular occlusive events. See p 981 Three closely linked lines of research have now merged. In the 1980s, concepts crystallized on the role of lipids (eg, oxidized LDL, elevated cholesterol) in the genesis of atherosclerotic plaque. In the 1990s, use of antiplatelet agents proved that platelet aggregation caused thrombotic ischemic events resulting from the rupture of plaques in advanced lesions and from the vascular injuries inflicted by percutaneous interventions (PCI). Now, atherosclerosis is recognized as an inflammation-mediated disease involving multiple interactions between leukocytes, cells of the vessel wall, and platelets. Indeed, recent studies of predictors of cardiovascular risk rank markers of inflammation (eg, high-sensitive C-reactive protein) as comparable to markers of cholesterol (eg, total cholesterol/HDL cholesterol). Emerging data suggest that CD40L may be at the heart of the atherosclerotic process. What makes CD40L so unique? Its localization and its multifunctionality (Figure 1). CD40L is a surprisingly abundant protein in platelets and may have roles in the inflammatory aspects of atherosclerotic lesion progression, thrombosis, and now, as implied by the work of Urbich et al1 in this issue of Circulation , in restenosis. Figure 1. Three functions of sCD40L released from platelets during thrombosis. sCD40L is released from platelet-rich thrombi and contributes to various steps in atherosclerotic lesion progression: (1) Inflammation. sCD40L induces the production and release of proinflammatory cytokines from vascular cells and matrix metalloproteinases from resident cells in the atheroma. (2) Thrombosis. sCD40L stabilizes platelet-rich thrombi. (3) Restenosis. sCD40L inhibits the reendothelialization of the injured vessel, potentially leading to the activation and proliferation of smooth muscle cells. CD40L is a trimeric, transmembrane protein of the tumor necrosis …