Annalisa Scognamiglio

Monoclonal Antibody Against Tissue Factor Shortens Tissue Plasminogen Activator Lysis Time and Prevents Reocclusion in a Rabbit Model of Carotid Artery Thrombosis

BACKGROUNDnTissue factor (TF)-dependent activation of the coagulation is important in the pathophysiology of intravascular thrombus formation. We tested the effects of a monoclonal antibody against TF (AP-1) on lysis time induced by tissue-type plasminogen activator (TPA) and on reocclusion rate in a rabbit model of carotid artery thrombosis.nnnMETHODS AND RESULTSnIntravascular thrombosis was obtained by placing an external constrictor around carotid arteries with endothelial injury. Carotid blood flow velocity ws measured continuously with a Doppler flow probe. Thirty minutes after thrombus formation, the rabbits received either AP-1 (0.15 mg/kg IV, n=8) or placebo (n=8). All rabbits also received TPA (80 microg/kg bolus plus 8 microg x kg(-1) x min(-1) infusion for up to 90 minutes or until reperfusion was achieved) and heparin (200 U/kg IV as a bolus). At reperfusion, TPA was discontinued, and the rabbits were followed for an additional 90 minutes. AP-1 shortened lysis time from 44+/-8 minutes (mean+/-SEM) in control rabbits to 26+/-7 minutes in AP-1 rabbits (P<.01). Reocclusion occurred in all control rabbits in 10+/-3 minutes, whereas it occurred in only two of eight AP-1 treated rabbits in 72 and 55 minutes (P<.01). No changes in prothrombin time and ex vivo platelet aggregation in response to various agonists were observed after AP-1 administration, indicating the absence of systemic effects by this antibody.nnnCONCLUSIONSnTF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.

Endogenous Tissue Factor Pathway Inhibitor Modulates Thrombus Formation in an In Vivo Model of Rabbit Carotid Artery Stenosis and Endothelial Injury

BACKGROUNDnTissue factor pathway inhibitor (TFPI) is the sole known inhibitor of the extrinsic coagulation pathway of physiological importance; however, its role in modulating thrombosis in vivo is still unclear.nnnMETHODS AND RESULTSnIntravascular thrombosis was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries (n=10). Carotid blood flow velocity was measured by a Doppler flow probe. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent thrombosis, developed at the site of stenosis. Transstenotic TFPI plasma activity was measured in blood samples before induction of CFRs and after 30, 60, and 180 minutes of CFRs. TFPI plasma activity distal to the site of thrombosis was significantly lower than the corresponding proximal values at 30, 60, and 180 minutes of CFRs. In addition, a progressive decrease in TFPI plasma activity was observed in both the proximal and the distal samples, indicating consumption of TFPI during thrombus formation. In 10 additional rabbits, CFRs were abolished by administration of aspirin (10 mg/kg). In the animals in which aspirin abolished CFRs, endogenous TFPI was depleted by a bolus of a polyclonal antibody against rabbit TFPI, and the effects on restoration of CFRs were monitored. In 5 of 6 animals in which aspirin abolished CFRs, depletion of endogenous TFPI activity caused full restoration of CFRs.nnnCONCLUSIONSnThe data of the present study support the involvement of endogenous TFPI in the process of thrombus formation in vivo and its active role in modulating arterial thrombosis.

Career Risk and Market Discipline in Asset Management

We establish that the labor market helps discipline asset managers via the impact of fund liquidations on their careers. Using hand-collected data on 1,948 professionals, we find that top managers working for funds liquidated after persistently poor relative performance suffer demotion coupled with a significant loss in imputed compensation. Scarring effects are absent when liquidations are preceded by normal relative performance or involve mid-level employees. Seen through the lens of a model with moral hazard and adverse selection, these scarring effects can be ascribed to a drop in asset managers’ reputation. The findings suggest that performance-induced liquidations supplement compensation-based incentives.

Property Tax and Property Values: Evidence from the 2012 Italian Tax Reform

This paper assesses the extent to which property taxes are capitalized into property values, exploiting the 2012 Italian tax reform. Municipal-level variation in the level of the property tax rates is instrumented using the exogenous staggered timing of local elections. We show that the incumbent local governments with upcoming elections in 2013 shifted the composition of fiscal revenues towards lower property tax. Our 2SLS estimate shows that a one standard deviation increase in municipal-level property tax intensity leads to a 2.7% reduction of municipal property values in the year of the reform. We elicit information on the characteristics of the compliers and show that these municipalities feature inefficient public spending and low social capital.

713-3 β-Blocker Agents Prevent Oxygen Radical-induced Human Apolipoprotein-B100Oxidation

Oxygen radicals may induce both peroxidation of polyunsaturated lipids and protein alterations in low density lipoprotein (LDL). Oxidized LDL taken up by macrophages via the “scavenger” receptor may contribute to formation of foam cells. Previous studies have shown that β -blocker agents reduce experimental atherosclerosis in primates. In addition, we have previously shown that β -blocker agents inhibit oxygen radical-induced lipid peroxidation. Thus, in this study we have investigated whether β -blockers may prevent oxidative modifications induced by oxygen radicals on apolipoprotein-B 100 (apo-B 100 ) of LDL. Purified human LDL was exposed to oxygen radicals generated by CuSO 4 (15xa0 μ M for 20 hs at 37° C) under control conditioincubation with propranolol (P: 1–10μmM). The index of peroxidation malonildihaldehyde, by thiobarbiturate method, was 2.1xa0±xa00.5* nmoles/mg of protein in native LDL, 34.5xa0±xa04.1 in control LDL and decreased to 6.5xa0±xa01.8* in LDL incubated with P (*pxa0lxa00.01 vs controls). When oxidized LDL was run on SDS-polyacrylamide electrophoresis (SDS-PAGE: 5 to 10% gradient) extensive apo-B 100 fragmentation was observed. Addition of P prevented the apo-B 100 fragmentation (mean reduction from 12 to 3 bands of low molecular weight). Moreover, oxidized LDL had increased mobility on 0.8% agarose gel electrophoresis (2.8xa0±xa00.4 time than controls). Similarly, incubation with P reduced LDL mobility to 0.8xa0±xa00.2 fold in respect to controls (pxa0lxa00.05). These data demostrate protection by propranonol on apo-B 100 oxidation in vitro, at clinically relevant concentrations. Although β -blockers are known to adversely affect lipid metabolism, inhibition of both LDL peroxidation and apo-B 100 fragmentation may reduce uptake of oxidized LDL by macrophages and hence foam cell formation.