bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: Experience in the standard clinical setting
Authors: Santagostino Elena , Faradji Albert , Iorio Alfonso , Meer Jan van der , Ingerslev Jørgen , Lambert Thierry , Maas-Enriquez Monika , Gorina Eduard , Musso Roberto ,   for the KOGENATE® Bayer European PMS Study Group
Published: December 2007

The safety of full-length sucrose-formulated recombinant factor VIII (rFVIII-FS; KOGENATE® FS) for up to 24 months of use was evaluated in a postmarketing observational study in Europe. Long-term safety and efficacy data were available for 212 patients with severe haemophilia A, including 13 previously untreated patients (PUPs) and 12 patients with 1–19 exposure days (EDs). Patients accumulated a mean (± SD) of 187 (121) EDs to rFVIII-FS and received a total of 39,627 infusions, mainly for prophylaxis and for the treatment of 4,283 spontaneous or trauma-related bleeds during an average observation time of 710 (136) days. Of these bleeding episodes, 85.4% were successfully treated with one or two infusions of rFVIII-FS. Haemostasis was also evaluated during 46 minor to major surgical pro- cedures, and the response to infusion was “excellent” or “good” in all cases. FVIII inhibitor formation was observed in six patients (two de novo; four persistent or recurrent). The de novo cases represent 8.0% (2 of 25) of patients who reported 0–19 previous EDs at study entry. Four of the five patients who reported possible drug-related adverse effects developed inhibitors. The results of this observational study demonstrate the efficacy and safety of rFVIII-FS during normal clinical use in the treatment of patients with severe haemophilia A. Furthermore, these findings are consistent with those of previous phase III clinical studies with rFVIII-FS, particularly with regard to its efficacy and low incidence of inhibitor formation.
Effects of primary and secondary prophylaxis on the clinical expression of joint damage in children with severe haemophilia A
Authors: Kurnik Karin , Friedrichs Frauke , Halimeh Susan , Krümpel Anne , Bidlingmaier Christoph , Schobess Rosemarie , Nowak-Göttl Ulrike
Published: December 2007

Patients with severe haemophilia A (HA) can either be treated by regular FVIII infusions twice or three times per week (prophylaxis), or only in case of bleeding episodes (on-demand). Whereas prophylaxis reduces the number of bleeding episodes and may therefore prevent the development of haemophilic arthropathy, there is still a lot of controversy surrounding recommendations on age and dose at start of prophylactic regimens. The present database study was performed to investigate the role of primary versus secondary prophylaxis in HA children. The outcome variable was imaging-proven haemophilic joint damage. Forty-two children were initially treated with primary prophylaxis following the first bleeding episode, and were frequency-matched (year of birth, catchment area) to 67 pa- tients receiving “on-demand” therapy with an early switch to “secondary prophylaxis”. In multivariate analysis adjusted for the HA mutation type and the presence or absence of thrombophilia, the Pettersson score investigated at a median age of 12.5 years in joints with at least one documented bleeding episode was not significantly different between the two patient groups (p=0.944),and no statistically significant differences were found in patients with target joints (p=0.3), nor in children in whom synovitis had occurred (p=0.77). No conclusion can be drawn from the data presented herein whether primary prophylaxis or an early start of secondary prophylaxis is superior with respect to joint outcome in children with severe HA.
Increased thrombin generation and fibrinogen level after therapeutic plasma transfusion: Relation to bleeding
Authors: Meijden Paola E. J. van der , Oerle René van , Curvers Joyce , Pampus Elisabeth C. M. van , Schols Saskia E. M , Heemskerk Johan W. M
Published: December 2007

In a clinical setting, fresh frozen plasma (FFP) is transfused to diluted patients with complicated surgery or trauma, as guided by prolonged conventional coagulation times or low fibrinogen levels. However, the limited sensitivity of these coagulation tests may restrict their use in measuring the effect of transfusion and hence predicting the risk of perioperative bleeding. We used the more sensitive, calibrated automated thrombogram (CAT) method to evaluate the result of therapeutic FFP transfusion to 51 patients with dilutional coagulopathy. Thrombin generation was measured in pre- and post-transfusion plasma samples in the presence of either platelets or phospholipids. For all patients, the transfusion led to higher plasma coagulation factor levels, a shortened activated partial thromboplastin time, and a significant increase in thrombin generation (peak height and endogenous thrombin potential). Interestingly, thrombin generation parameters and fibrinogen levels were higher in posttransfusion plasmas from patients who stopped bleeding (n=32) than for patients with ongoing bleeding (n=19). Plasmas from 15 of the 19 patients with ongoing bleeding were markedly low in either thrombin generation or fibrinogen level. We conclude that the thrombin generation method detects improved haemostatic activity after plasma transfusion. Furthermore, the data suggest that thrombin generation and fibrinogen are independent determinants of the risk of perioperative bleeding in this patient group.
Efficacy and safety of enoxaparin in unselected patients with ST-segment elevation myocardial infarction
Authors: Gitt Anselm , Jünger Claus , Bauer Timm , Heer Tobias , Koeth Oliver , Wienbergen Harm , Zahn Ralf , Senges Jochen , Zeymer Uwe
Published: December 2007

In randomized clinical trials the low-molecular-weight heparin enoxaparin has been shown to reduce ischemic complications in patients with acute ST elevation myocardial infarction (STEMI) treated with fibrinolysis. Little is known about the use and efficacy of enoxaparin in unselected patients with STEMI in clinical practice. In a retrospective analysis of the prospective ACOS registry we compared the outcomes of patients with STEMI treated with enoxaparin or unfractionated heparin. A total of 6,299 patients with STEMI < 12 hours were included in this analysis, 609 (10%) were treated with enoxaparin and 5,690 (90%) with unfractionated heparin. In the multivariable propensity score analysis enoxaparin was associated with a reduction in the combined endpoint of death and non-fatal reinfarction in the entire group (odds ratio 0.59; 95% CI 0.43–0.80) and the subgroups of patients treated without early reperfusion (odds ratio 0.65, 95% CI 0.43–0.97), fibrinolysis (odds ratio 0.64; 95% CI 0.33–1.26) and primary percutaneous coronary intervention (odds ratio 0.33;95% CI 0.15–0.72).There was no significant increase in severe bleeding complications with enoxaparin (6.5% versus 5.5%, p=0.4). In clinical practice in unselected patients with STEMI treated with or without early reperfusion therapy early treatment with enoxaparin compared to unfractionated heparin is associated with a significant reduction of the combined endpoint of inhospital death and reinfarction without a significant increase in severe bleeding complications.
Alcohol consumption is associated with a decreased risk of venous thrombosis
Authors: Rosendaal Frits R , Doggen Carine J. M , Pomp Elisabeth R
Published: December 2007

Moderate alcohol consumption is associated with lower levels of several coagulation factors. It is an established protective factor for cardiovascular disease; however, the effect on venous thrombosis is unknown. In a large population-based case-control study, we evaluated the association between alcohol consumption and the risk of venous thrombosis. The MEGA study included consecutive patients with a first venous thrombosis between March 1999 and September 2004 from six anticoagulation clinics in the Netherlands. Partners of patients were asked to participate, and additional controls were recruited using a random digit dialling method. All participants completed a standardized questionnaire, and blood samples were collected. A total of 4,423 patients and 5,235 controls were included in the analyses. Alcohol consumption was associated with a reduced risk of venous thrombosis, with 2–4 glasses per day resulting in the largest beneficial effect (odds ratio [OR] 0.67, 95% confidence interval [CI95] 0.58–0.77) compared to abstainers. The effect was more pronounced in women (OR 0.66, CI95 0.53–0.84) than men (OR 0.82, CI95 0.63–1.07) and also more striking for pulmonary embolism (OR 0.56, CI95 0.46–0.70) than for deep venous thrombosis of the leg (OR 0.74, CI95 0.63–0.88). Compared to abstainers, fibrinogen levels were decreased in individuals who consumed alcohol (maximum decrease: 0.30 g/l). FactorVII and vonWillebrand levels were mildly decreased in these individuals but not consistently over the categories of alcohol consumption. In conclusion, alcohol consumption is associated with a reduced risk of venous thrombosis, which may be in part mediated by decreased fibrinogen levels. Thromb
Persistent hyperfibrinogenemia in acute ischemic stroke / transient ischemic attack (TIA)
Authors: Assayag Einor Ben , Bova Irena , Shopin Ludmila , Cohen Michael , Berliner Shlomo , Shapira Itzhak , Shenhar-Tsarfaty Shani , Bornstein Natan M
Published: December 2007

Increased fibrinogen concentration is a well known phenomenon following acute ischemic stroke. However, the natural course of this hyperfibrinogenemia is uncertain. We aimed to clarify whether it is of a transient or more persistent nature in patients who harbor an underlying morbid biology of atherothrombo-inflammation. Venous blood for fibrinogen measurements was obtained from the control group participants and from stroke patients within 24 hours of admission, as well as 12 months following the acute event. In order to perform a time course analysis, we divided our cohort into tiles of time from symptoms' onset and compared the fibrinogen concentrations usingANOVA. Elevated fibrinogen concentrations were found in stroke patients on admission compared with matched controls (p<0.001).Analysis of variance in the different tertiles of time from symptoms' onset identified that fibrinogen concentrations were already relatively high during the initial phase of the event and did not differ significantly between the tiles (p=0.268). Moreover, when we calculated the absolute differences between the patients' fibrinogen concentrations and that of the matched controls there was clearly a minor increment during the time course from symptoms' onset in the stroke patients group. In conclusion, persistent hyperfibrinogenemia is present in patients with acute ischemic cerebral events and it might be present during the earlier stages of the disease as presently shown. Prompt and longterm, rather than short term, interventions to reduce the concentrations of this protein might therefore be of relevance.
Simulation of platelet adhesion and aggregation regulated by fibrinogen and von Willebrand factor
Authors: Yano Koichiro , Tsubota Ken-ichi , Ishikawa Takuji , Wada Shigeo , Yamaguchi Takami , Mori Daisuke
Published: December 2007

We propose a method to analyze platelet adhesion and aggregation computationally, taking into account the distinct properties of two plasma proteins, vonWillebrand factor (vWF) and fibrinogen (Fbg). In this method, the hydrodynamic interactions between platelet particles under simple shear flow were simulated using Stokesian dynamics based on the additivity of velocities. The binding force between particles mediated by vWF and Fbg was modeled using the Voigt model. Two Voigt models with different properties were introduced to consider the distinct behaviors of vWF and Fbg. Our results qualitatively agreed with the general observation of a previous in-vitro experiment, thus demonstrating that the significant development of thrombus formation in height requires not only vWF, but also Fbg. This agreement of simulation and experimental results qualitatively validates our model and suggests that consideration of the distinct roles of vWF and Fbg is essential to investigate the physiological and pathophysiological mechanisms of thrombus formation using a computational approach.
Factor XIa and tissue factor activity in patients with coronary artery disease
Authors: Undas Anetta , Gissel Matthew T , Szuldrzynski Konstanty , Zmudka Krzysztof , Mann Kenneth G , Butenas Saulius
Published: December 2007

It has been established that inflammation and enhanced procoagulant activity are associated with the pathogenesis of atherosclerotic vascular disease. We evaluated and compared the contributions of the factor (F)XIa and tissue factor (TF) activity in plasma of patients with coronary artery disease (CAD). Citrate plasma was obtained prior to therapy from 53 patients with stable angina (29 with a history of previous myocardial infarction; CAD-MI) and 30 with acute coronary syndrome (ACS) within 12 hours from pain onset. Four ACS patients treated with heparin were excluded. FXIa andTF activity were determined in clotting assays based upon the prolongation of clotting time by inhibitory monoclonal antibodies. Twenty-five of 26ACS patients (96%) and 22 of 29 CAD-MI patients (76%) had quantifiable FXIa (50 ± 33 and 42 ± 45pM, respectively).Ten of 26 (38%) ACS patients and only three of 53 (6%) stable CAD patients showedTF activity (<0.4pM). No FXIa or TF activity was observed in agematched healthy controls (n=12).For both CAD-MI andACS patients, there were correlations (p<0.05) between FXIa and interleukin-6 (R2= 0.59 and 0.39, respectively) and between FXIa and TAT (R2= 0.64 and 0.63, respectively). In conclusion, the majority of ACS and CAD-MI patients have circulating FXIa that correlates with markers of coagulation and inflammation.
Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement
Authors: Hochholzer Willibald , Frundi Devine , Stratz Christian , Valina Christian M , Bestehorn Hans-Peter , Büttner Heinz Joachim , Neumann Franz-Josef , Trenk Dietmar
Published: December 2007

Early studies suggested interactions between statins and clopidogrel. Based on the outcome and platelet data, there is now huge evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with 600-mg loading are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P4503A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63 and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 μM was similar irrespective of statin treatment at baseline (p=0.968). RPA at CA was 46.2 ± 16.8% in patients without statin (n=682), 45.5 ± 17.0% in patients with atorvastatin (n=255), 45.8 ± 16.3% with simvastatin (n=335), 47.3 ± 14.9% with fluvastatin (n=42) and 45.9 ± 16.2% with pravastatin (n=81; p=0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n=553), the one-year incidence of death, myocardial infarction and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p=0.645).Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.
Idiopathic thrombocytopenic purpura: Current concepts in pathophysiology and management
Authors: Evangelista Maria Laura , Stipa Elisa , Buccisano Francesco , Venditti Adriano , Amadori Sergio , Stasi Roberto
Published: December 2007

Idiopathic thrombocytopenic purpura (ITP) is characterized by a low platelet count, which is the result of both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP, several abnormalities involving the cellular mechanisms of immune modulation have been identified. Conventional treatments for ITP aim at reducing platelet destruction, either by immunosuppression or splenectomy. Two new thrombopoietic agents, AMG 531 and eltrombopag, have been used in clinical trials to stimulate platelet production in ITP patients not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin, but still bind and activate the thrombopoietin receptor. This review will focus on the pathophysiology and treatment of ITP in adults, highlighting recent advances in both fields.
Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden
Authors: Duchemin Jèrôme , Leroyer Christophe , Delahousse Bènèdicte , Abgrall Jean François , Mottier Dominique , Couturaud Francis ,   for the Groupe d’Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O)
Published: December 2007

The thrombin generation test appears to be a highly sensitive and specific test in the detection of thrombophilia in patients with venous thromboembolism. We aimed to determine the accuracy of the thrombin generation test to detect factorV Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden. Sixty-two first-degree relatives of 21 index cases were tested for factor V Leiden, the G20210A prothrombin gene mutation and thrombin generation. Information about oestrogen therapy and previousVTE was also collected. The normalized Thrombomodulin sensitivity ratio (n-TMsr) was defined as the ratio of endogenous thrombin potential determined in the presence and absence of thrombomodulin which was normalized against the same ratio determined in normal control plasma. The mean n-TMsr was 1.37 (± 0.33) in the 45 relatives with one or more prothrombotic state (factor V Leiden, G20210A prothrombin mutation, oestrogen therapy or hormonal therapy) and 1.02 (± 0.34) in the 17 relatives without prothrombotic state (p = 0.001). The positive predictive value was 90.3 (95%CI, 73.1 – 97.4). In relatives with an abnormal n-TMsr, the adjusted odds ratio for having a prothrombotic state was 8.3 (95%CI, 1.9 – 36.9) and the adjusted odds ratio for having the factor V Leiden was 14.3 (95%CI, 2.9 – 71.2).An abnormal thrombin generation test appears highly predictive for having factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden.
A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry
Authors: Payne Christopher D , Li Ying G , Farid Nagy A , Brandt John T , Small David S , Salazar Daniel E , Winters Kenneth J , Jakubowski Joseph A
Published: December 2007

Platelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared theVASP assay and LTA at the levels of P2Y12 blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg).The aim was to compare theVASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y12 receptor blockade was estimated using theVASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 μM ADP).Twenty-four hoursafter prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from ∼80% to 8.9%, 54.7%, and 39.0 %, and maximal platelet aggregation (MPA) decreased from ∼79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p<0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0–93%; 600 mg: 0–80%) than prasugrel (0–13%); MPA responses followed a similar trend. Pearson’s correlation suggested a strong agreement between VASP and LTA (20 μM ADP) for MPA (r=0.86, p<0.0001).VASP and LTA demonstrated concordance across the response range of P2Y12 receptor blockade following thienopyridine LDs.
Clopidogrel in addition to aspirin reduces in-hospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial
Authors: Gitt Anselm K , Jünger Claus , Bauer Timm , Koeth Oliver , Heer Tobias , Mark Bernd , Zahn Ralf , Gottwik Martin , Senges Jochen , Zeymer Uwe
Published: December 2007

We sought to assess the effect of clopidogrel on in-hospital events in unselected patients with acute ST elevation myocardial infarction (STEMI). In a retrospective analysis of consecutive patients enrolled in the Acute Coronary Syndromes (ACOS) registry with acute STEMI we compared outcomes of either adjunctive therapy with aspirin alone or aspirin plus clopidogrel within 24 hours after admission. A total of 7,559 patients were included in this analysis, of whom 3,541 were treated with aspirin alone, and 4,018 with dual antiplatelet therapy. The multivariable analysis with adjustment for baseline characteristics and treatments showed that the rate of in-hospital MACCE (death, non-fatal reinfarction, non-fatal stroke) was significantly lower in the aspirin plus clopidogrel group, compared to the aspirin alone group in the entire cohort and all three reperfusion strategy groups (entire group odds ratio 0.60, 95% CI 0.49–0.72, no reperfusion OR 0.69,95% CI 0.51–0.94,fibrinolysis OR 0.62,95% CI 0.44–0.88, primary PCI OR 0.54, 95% CI 0.39–0.74).There was a significant increase in major bleeding complications with clopidogrel (7.1% vs. 3.4%, p<0.001). In clinical practice early adjunctive therapy with clopidogrel in addition to aspirin in patients with STEMI is associated with a significant reduction of in-hospital MACCE regardless of the initial reperfusion strategy. This advantage was associated with an increase in major bleeding complications.
Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions
Authors: Bernardo Esther , Palazuelos Jorge , Desai Bhaloo , Weisberg Ian , Alfonso Fernando , Guzman Luis A , Hernández-Antolin Rosana , Zenni Martin Z , Macaya Carlos , Fernandez-Ortiz Antonio , Bass Theodore A , Angiolillo Dominick J
Published: December 2007

The currently recommended maintenance dose of clopidogrel is often associated with inadequate platelet inhibition, suggesting the need for a higher dose. The aim of this pilot study was to assess the functional impact of a high (150 mg/day) maintenance dose of clopidogrel in patients undergoing elective percutaneous coronary intervention (PCI).This is a prospective, randomized, platelet function study which was performed in elective PCI patients assigned to treatment with either a 75 mg (n=20) or 150 mg (n=20) daily maintenance dose of clopidogrel for 30 days;afterwards, all patients resumed standard dosing. Platelet aggregation was performed using light transmittance aggregometry following 20 μM and 5 μM adenosine diphosphate (ADP) stimuli 30 days after randomization and 30 days after resuming standard dosing. Patients treated with 150 mg/day clopidogrel had lower 20 μMADP-induced platelet aggregation compared to patients on 75 mg/day (52.1±9% vs. 64.0±8%; p<0.001; primary endpoint).The dose-dependent effect was confirmed by the absolute and relative increase in platelet aggregation after resuming standard dosing (p<0.001). No changes were observed in patients randomized to standard dosing. Parallel findings were observed following 5 μM ADP stimuli for all assessments. A broad variability in clopidogrel-induced antiplatelet effects was observed irrespective of dosing. In conclusion, a 150 mg/day maintenance dose regimen of clopidogrel is associated with reduced platelet reactivity and enhanced platelet inhibition compared to that achieved with the currently recommended 75 mg/day in patients undergoing elective PCI.
Magnitude and time course of platelet inhibition with extended release dipyridamole with or without aspirin in healthy Japanese volunteers
Authors: Malinin Alex I , Hanley Dan F , Serebruany Victor L
Published: December 2007

Randomized trials showed greater stroke prevention with extended release dipyridamole in combination with low dose aspirin than with either aspirin or dipyridamole alone. However, most studies with this formulation (AggrenoxⓇ) were carried out in Europe and North America. Considering potential inter-racial differences in drug response, we conducted a small randomized study in healthy Japanese volunteers to compare antiplatelet regimens with regard to the changes in the platelet biomarkers. Thirty healthy volunteers (18–40 years old, 15 male and 15 female) of Japanese descent were randomized to Aggrenox (n=17) or aspirin 81 mg (n=13 volunteers) for 30 days. Platelet function was assessed at baseline, and on days 15, and 30 by conventional aggregometry, whole blood flow cytometry, and cartridge-based analyzer. Both Aggrenox and aspirin provided sustained platelet inhibition at Day 15 and Day 30.Therapy withAggrenox, however, was associated with more prominent and significant inhibition of collagen-induced aggregation (p=0.08, Day 15), as well as prolongation of the closure time (p=0.001, Day 30); diminished expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) (p=0.02, Day 30), glycoprotein IIb (GPIIb) antigen (p=0.001 and 0.024 for Day 15 and Day 30), and GPIIb/IIIa activity by PAC-1 antibody (p = 0.014 and 0.03), CD62 (P-selectin) (p = 0.03 for Day 15 and Day 30), as well as inhibition of protease activated receptors (PAR-1) associated with intact WEDE-15 (p = 0.002 and 0.003) and SPAN-12 (p = 0.002 and 0.04) thrombin receptors when compared with aspirin. The magnitude and durability of platelet response after Aggrenox in healthy Japanese is similar to those effects observed in Caucasians and African- Americans. A larger study to assess drug efficacy and safety in the Japanese post-stroke patients is warranted.
No effect of C-reactive protein on early atherosclerosis in LDLR-/- / human C-reactive protein transgenic mice
Authors: Cheng Fei , Wiese Elena , Küpper Ines , Crain Jeanine , Lackner Karl J , Bhakdi Sucharit , Torzewski Michael , Reifenberg Kurt
Published: December 2007

summary

The association between increased concentrations of C-reactive protein (CRP) and future cardiovascular events is well established. However, it is currently unclear whether this clinical observation represents an epiphenomenon or whether the pentraxin may actively promote the development of atherosclerosis. Experimental studies with knockout mice with a defect in apolipoprotein E (ApoE-/-) have been used to investigate the role of CRP in atherogenesis, but the results obtained have been contradictory so far. Since knockout mice with a defect in low density lipoprotein receptor (LDLR-/-) may represent a better model of atherogenesis compared to ApoE-/- animals, we undertook experiments to investigate the atherogenic potential of CRP using LDLR-/- knockout mice. We crossbred CRP transgenic animals expressing the human CRP pentraxin (huCRP) to LDLR-/- mice, fed the resulting double mutants a pro-atherogenic Western type diet (WTD) for four, eight or 12 weeks, respectively, and quantitated atherosclerotic lesion development. Significant differences of lesion size or lesion composition could not be detected between the huCRP-positive LDLR-/- mice and the huCRP–negative LDLR-/- controls corroborating the contention that CRP does not play a pathogenetic role in early murine atherogenesis.
Mutation of the HEXIM1 Gene Results in Defects During Heart and Vascular Development Partly Through Downregulation of Vascular Endothelial Growth Factor
Authors: Montano Monica M. , Doughman Yong Qui , Deng Huayun , Chaplin Laura , Yang Jianqi , Wang Nancy , Zhou Qiang , Ward Nicole L. , Watanabe Michiko
Published: December 2007

Our previous studies and those of others indicated that the transcription factor Hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) is a tumor suppressor and cyclin-dependent kinase inhibitor, and that these HEXIM1 functions are mainly dependent on its C-terminal region. We provide evidence here that the HEXIM1 C-terminal region is critical for cardiovascular development. HEXIM1 protein was detected in the heart during critical time periods in cardiac growth and chamber maturation. We created mice carrying an insertional mutation in the HEXIM1 gene that disrupted its C-terminal region and found that this resulted in prenatal lethality. Heart defects in HEXIM1
1 to 312
mice included abnormal coronary patterning and thin ventricular walls. The thin myocardium can be partly attributed to increased apoptosis. Platelet endothelial cell adhesion molecular precursor-1 staining of HEXIM1
1 to 312
heart sections revealed decreased vascularization of the myocardium despite the presence of coronary vasculature in the epicardium. The expression of vascular endothelial growth factor (VEGF), known to affect angioblast invasion and myocardial proliferation and survival, was decreased in HEXIM1
1 to 312
mice compared with control littermates. We also observed decreased fibroblast growth factor 9 (FGF9) expression, suggesting that effects of HEXIM1 in the myocardium are partly mediated through epicardial FGF9 signaling. Together our results suggest that HEXIM1 plays critical roles in coronary vessel development and myocardial growth. The basis for this role of HEXIM1 is that VEGF is a direct transcriptional target of HEXIM1, and involves attenuation a repressive effects of C/EBPα on VEGF gene transcription.
Protein Carbonylation as a Novel Mechanism in Redox Signaling
Authors: Wong Chi Ming , Cheema Amrita K. , Zhang Lihua , Suzuki Yuichiro J.
Published: December 2007

Reactive oxygen species serve as second messengers for signal transduction; however, molecular targets of oxidant signaling have not been defined. Here, we show that ligand–receptor–mediated signaling promotes reactive oxygen species–dependent protein carbonylation. Treatment of pulmonary artery smooth muscle cells with endothelin-1 increased protein carbonyls. Carbonylation of the majority of proteins occurred transiently, suggesting that there is also a mechanism for decarbonylation induced by endothelin-1. Decarbonylation was suppressed by inhibition of thioredoxin reductase, and cellular thioredoxin was upregulated during the decarbonylation phase. These results indicate that endothelin-1 promotes oxidant signaling as well as thioredoxin-mediated reductive signaling to regulate carbonylation and decarbonylation mechanisms. In cells treated with endothelin receptor antagonists, hydrogen peroxide scavengers, or an iron chelator, we identified, via mass spectrometry, proteins that are carbonylated in a receptor- and Fenton reaction–dependent manner, including annexin A1, which promotes apoptosis and suppresses cell growth. Carbonylation of annexin A1 by endothelin-1 was followed by proteasome-dependent degradation of this protein. We propose that carbonylation and subsequent degradation of annexin A1 may play a role in endothelin-mediated cell growth and survival, important events in pulmonary vascular remodeling. Protein carbonylation in response to ligand–receptor interactions represents a novel mechanism in redox signaling.
Remodeling of T-Tubules and Reduced Synchrony of Ca
2+
Release in Myocytes From Chronically Ischemic Myocardium
Authors: Heinzel Frank R. , Bito Virginie , Biesmans Liesbeth , Wu Ming , Detre Elke , von Wegner Frederik , Claus Piet , Dymarkowski Steven , Maes Frederik , Bogaert Jan , Rademakers Frank , D’hooge Jan , Sipido Karin
Published: December 2007

In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca
2+
release and could be involved in the reduced SR Ca
2+
release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca
2+
release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91±3%, N=13) with myocardial infarction (8.8±2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27±7% (
P
<0.05). Synchrony of SR Ca
2+
release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, half-maximal [Ca
2+
]
i
occurring later than 20 ms) occurred at 35.5±6.4% of the scan line in myocardial infarction versus 22.7±2.5% in control pigs (
P
<0.05), prolonging the time to peak of the line-averaged [Ca
2+
]
i
transient (121±9 versus 102±5 ms in control pigs,
P
<0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca
2+
]
i
transient amplitude was reduced, whereas L-type Ca
2+
current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca
2+
-induced Ca
2+
release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca
2+
release and reduced efficiency of coupling Ca
2+
influx to Ca
2+
release.
Osteopontin Expression Is Required for Myofibroblast Differentiation
Authors: Lenga Yair , Koh Adeline , Perera Aruni Shamalee , McCulloch Christopher A. , Sodek Jaro , Zohar Ron
Published: December 2007

Osteopontin (OPN) is a multifunctional cytokine that is strongly expressed in healing wounds and fibrotic lesions, both of which are characterized by the formation of myofibroblasts. We examined the role of OPN in myofibroblast differentiation induced by the profibrotic cytokine transforming growth factor-β1. In cultured cardiac or dermal fibroblasts treated with transforming growth factor-β1, there was a 2- to 5-fold increase in the expression of the myofibroblast markers α-smooth muscle actin and extradomain A fibronectin but no significant increase of these proteins in OPN-null fibroblasts. Phalloidin staining for actin filaments and immunostaining for α-smooth muscle actin and focal adhesion proteins showed reduced stress fibers, focal adhesions, and lamellipodia in OPN-null fibroblasts compared with wild-type cells. OPN-null fibroblasts exhibited 40% to 60% less spreading, 50% less resistance to detachment by shear force, and a ≈3-fold reduction in collagen gel contraction. These defects were partially rescued by ectopic expression of OPN. Mass spectrometric analysis of proteins in focal adhesions formed on collagen type I beads revealed an enrichment of HMGB1 protein in wild-type cells, whereas HMGB1 was not detected in OPN-null cells. Treatment of wild-type cells with small interfering RNA to knock down OPN reduced transforming growth factor-β1–induced α-smooth muscle actin and HMGB1 to levels observed in OPN-null cells. These studies demonstrate that OPN is required for the differentiation and activity of myofibroblasts formed in response to the profibrotic cytokine transforming growth factor-β1.
Smooth Muscle Protein 22α–Mediated Patchy Deletion of
Bmpr1a
Impairs Cardiac Contractility but Protects Against Pulmonary Vascular Remodeling
Authors: El-Bizri Nesrine , Wang Lingli , Merklinger Sandra L. , Guignabert Christophe , Desai Tushar , Urashima Takashi , Sheikh Ahmad Y. , Knutsen Russell H. , Mecham Robert P. , Mishina Yuji , Rabinovitch Marlene
Published: December 2007

Vascular expression of bone morphogenetic type IA receptor (
Bmpr1a
) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of
Bmpr1a
in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted
Bmpr1a
in vascular smooth muscle cells and in cardiac myocytes in mice using the
SM22α;TRE-Cre/LoxP;R26R
system. The LacZ distribution reflected patchy deletion of
Bmpr1a
in the lung vessels, aorta, and heart of
SM22α;TRE-Cre;R26R;Bmpr1a

flox
/+

and
flox/flox
mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the
flox/flox
group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O
2
) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both
SM22α;TRE-Cre;R26R;Bmpr1a

flox
/+

and
flox/flox
mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When
Bmpr1a
expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When
Bmpr1a
was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the
flox/flox
mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.
Faculty Members' Provision of Instructional Accommodations to Students with LD
Authors: Bourke Andrew B. , Strehorn K.C. , Silver Patricia
Published: December 2007

The existing research on the instructional accommodation process of college students with learning disabilities focuses on attitudes and theoretical models without delineating actual practices. To date, the discussion of facilitating factors and barriers to this process has been broad and lacking specificity. Surveys were mailed to 485 faculty members at the University of Massachusetts, Amherst, who received an instructional accommodation form from the office of Learning Disabilities Support Services in the fall of 1995. The survey focused on faculty members' reported degree of ease or difficulty in implementing instructional accommodations, their perceptions regarding adequacy of support, and their own beliefs and understandings concerning the need for and benefit of providing instructional accommodations. The results indicate that beliefs about the helpfulness of and need for instructional accommodations were associated with the provision of the accommodations. Also, a perception of support from the University influenced the ease of providing instructional accommodations. A significant difference was found between the behavior of tenure-track faculty and non-tenure-track faculty.
Adolescents With and Without LD Make the Transition to Middle School
Authors: Forgan James W. , Vaughn Sharon
Published: December 2007

The purpose of this 2-year study was to describe how Hispanic students with and without learning disabilities fared academically and socially during the transition from elementary school to middle school. Participants were 14 Hispanic students who were instructed in a sixth-grade consultation / collaboration, inclusive elementary classroom before making the transition to middle school. Examination of social, academic, and student perception data revealed that, on the whole, the students with learning disabilities and those without experienced the transition similarly and fared well during the elementary-to-middle-school transition.
Profiles of Asian American Students with LD at Initial Referral, Assessment, and Placement in Special Education
Authors: Poon-McBrayer Kim Fong , García Shernaz B.
Published: December 2007

Alhough Asian American students are underrepresented in special education, recent studies have highlighted concerns about the cultural and linguistic appropriateness of the identification and placement process. This study examined the characteristics of Asian American elementary students with learning disabilities (LD) in a school district in the Southwest that was selected because it served the largest number of Asian American students with LD in the state. Due to the small numbers of students served, the sample included all Asian American students with LD in Grades K to 5 (N = 26). Variables of interest included students' demographic characteristics, factors associated with referral, assessment practices and student profiles, and instructional recommendations for special education services. The results suggest that the experiences of Asian American students with LD are similar to those of Mexican American students with LD reported in earlier studies. These findings also reflect the challenges faced by educators in providing appropriate educational services for language minority students.
Reciprocal Teaching of Social Studies in Inclusive Elementary Classrooms
Authors: Lederer Jeffrey M.
Published: December 2007

Reading comprehension relies on the use of metacognitive strategies. Reciprocal teaching has been found to be an effective comprehension technique to use with students with learning disabilities. This study examined the effectiveness of reciprocal teaching during social studies instruction with several students with learning disabilities in fourth-, fifth-, and sixth-grade inclusive classrooms.

One hundred and twenty-eight students in Grades 4, 5, and 6 participated. Four comprehension assessments were administered, as well as an external measure and 30-day maintenance assessment. A mixed-design MANOVA was used to determine interaction on three reading comprehension measures.

Results indicated that all students improved their performance on comprehension measures compared with students in the control groups. Improvement continued to be displayed after 30 days in both the sixth and the fourth grades. Students with learning disabilities significantly improved their ability to compose summaries compared to the control students.
A Meta-Analysis of Single-Subject-Design Intervention Research for Students with LD
Authors: Lee Swanson H. , Sachse-Lee Carole
Published: December 2007

This article summarizes single-subject-design intervention studies that include students with learning disabilities. Effect sizes of 85 studies were analyzed across instructional domains (e.g., reading, mathematics); sample characteristics (e.g., age, intelligence); intervention parameters (e.g., number of instructional sessions, instructional components); and methodological procedures (e.g., internal validity, treatment integrity, sample representation). The major findings were as follows: (a) All domain areas except handwriting yielded effect sizes at or above Cohen's .80 threshold for a substantial finding; (b) instructional components related to drill-repetition-practice-review, segmentation, small interactive groups, and the implementation of cues to use strategies contributed significant variance (15%) to estimates of effect size; (c) strategy instruction (SI) models better predicted effect size estimates than direct instruction (DI) models when the results were qualified by the reported intellectual and reading levels of the participants; (d) high-IQ discrepancy groups yielded lower effect sizes compared to low-IQ discrepancy groups in the domain of reading, whereas the reverse effect occurred when treatment outcomes were not reading measures; and (e) the low-IQ discrepancy groups yielded higher effect sizes for a Combined DI and SI Model when compared to competing models. The results are supportive of the pervasive influence of cognitive strategy and direct instruction models across treatment domains and of the notion that variations in sample definition moderate treatment outcomes.
Characteristic Behaviors of Students with LD Who Have Teacher-Identified Math Weaknesses
Authors: Bryant Diane Pedrotty , Bryant Brian R. , Hammill Donald D.
Published: December 2007

Mathematics learning disabilities (LD) have gained increased attention over the last decade from both researchers and practitioners. A large percentage of students receiving learning disability services experience difficulties with mathematics, but little research has examined the specific mathematics behaviors of students with LD who have teacher-identified math weaknesses. This study examines the literature on mathematics LD and identifies specific behaviors from that body of research for the purpose of determining the extent to which those behaviors are observed in students with LD. Data are presented from observations of 391 special education professionals on 1724 students with LD, 870 of whom had identified math weaknesses and 854 of whom did not. Our results validate the existing literature and provide implications for teachers, researchers, and others interested in studying mathematics LD.
Differential Genetic Etiology of Reading Disability as a Function of IQ
Authors: Wadsworth Sally J. , Olson Richard K. , Pennington Bruce F. , DeFries John C.
Published: December 2007

To test the hypothesis that the genetic etiology of reading disability differs as a function of IQ, composite reading performance data from 223 pairs of identical twins and 169 pairs of same-gender fraternal twins in which at least one member of each pair was classified with reading disability were subjected to multiple regression analysis (DeFries & Fulker, 1985, 1988). In the total sample, heritability of the group deficit in reading performance ( h2g) was .58 (± .08). However, when the basic regression model was fitted separately to data from twin pairs with average Wechsler (1974, 1981) full scale IQ scores below 100 or 100 and above, resulting estimates of h2 g were .43 and .72, respectively, a significant difference ( p ≤ .03, one-tailed). The results of fitting extended regression models to reading performance and continuous IQ data provide evidence that the genetic etiology of reading disability differs as a linear function of IQ ( p ≤ .007, one-tailed). These results suggest that IQ is relevant for the diagnosis of reading disability and that environmental influences may be more salient as a cause of reading difficulties in children with lower IQ scores.