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1.
Eur Heart J ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

2.
J Phys Chem Lett ; 10(6): 1374-1381, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30829040

RESUMO

We employed bias-assisted charge extraction techniques to investigate the transient and steady-state recombination of photogenerated charge carriers in complete devices of a disordered polymer-fullerene blend. Charge recombination is shown to be dispersive, with a significant slowdown of the recombination rate over time, consistent with the results from kinetic Monte Carlo simulations. Surprisingly, our experiments reveal little to no contributions from early time recombination of nonequilibrated charge carriers to the steady-state recombination properties. We conclude that energetic relaxation of photogenerated carriers outpaces any significant nongeminate recombination under application-relevant illumination conditions. With equilibrated charges dominating the steady-state recombination, quasi-equilibrium concepts appear suited for describing the open-circuit voltage of organic solar cells despite pronounced energetic disorder.

3.
J Phys Chem C Nanomater Interfaces ; 122(31): 17660-17667, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30116464

RESUMO

Because of its thermal stability, lead-free composition, and nearly ideal optical and electronic properties, the orthorhombic CsSnI3 perovskite is considered promising as a light absorber for lead-free all-inorganic perovskite solar cells. However, the susceptibility of this three-dimensional perovskite toward oxidation in air has limited the development of solar cells based on this material. Here, we report the findings of a computational study which identifies promising Rb y Cs1-y Sn(Br x I1-x )3 perovskites for solar cell applications, prepared by substituting cations (Rb for Cs) and anions (Br for I) in CsSnI3. We show the evolution of the material electronic structure as well as its thermal and structural stabilities upon gradual substitution. Importantly, we demonstrate how the unwanted yellow phase can be suppressed by substituting Br for I in CsSn(Br x I1-x )3 with x ≥ 1/3. We predict that substitution of Rb for Cs results in a highly homogeneous solid solution and therefore an improved film quality and applicability in solar cell devices.

4.
Adv Mater ; 30(26): e1707350, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29736912

RESUMO

Recent success in achieving highly stable Rb-containing organolead halide perovskites has indicated the possibility of incorporating small monovalent cations, which cannot fit in the lead-halide cage with an appropriate tolerance factor, into the perovskite lattice while maintaining a pure stable "black" phase. In this study, through a combined experimental and theoretical investigation by density functional theory (DFT) calculations on the incorporation of extrinsic alkali cations (Rb+ , K+ , Na+ , and Li+ ) in perovskite materials, the size-dependent interstitial occupancy of these cations in the perovskite lattice is unambiguously revealed. Interestingly, DFT calculations predict the increased ion migration barriers in the lattice after the interstitial occupancy. To verify this prediction, ion migration behavior is characterized through hysteresis analysis of solar cells, electrical poling, temperature-dependent conductivity, and time-dependent photoluminescence measurements. The results collectively point to the suppression of ion migration after lattice interstitial occupancy by extrinsic alkali cations. The findings of this study provide new material design principles to manipulate the structural and ionic properties of multication perovskite materials.

5.
Sci Rep ; 7(1): 14386, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29084980

RESUMO

The outstanding optoelectronics and photovoltaic properties of metal halide perovskites, including high carrier motilities, low carrier recombination rates, and the tunable spectral absorption range are attributed to the unique electronic properties of these materials. While DFT provides reliable structures and stabilities of perovskites, it performs poorly in electronic structure prediction. The relativistic GW approximation has been demonstrated to be able to capture electronic structure accurately, but at an extremely high computational cost. Here we report efficient and accurate band gap calculations of halide metal perovskites by using the approximate quasiparticle DFT-1/2 method. Using AMX3 (A = CH3NH3, CH2NHCH2, Cs; M = Pb, Sn, X = I, Br, Cl) as demonstration, the influence of the crystal structure (cubic, tetragonal or orthorhombic), variation of ions (different A, M and X) and relativistic effects on the electronic structure are systematically studied and compared with experimental results. Our results show that the DFT-1/2 method yields accurate band gaps with the precision of the GW method with no more computational cost than standard DFT. This opens the possibility of accurate electronic structure prediction of sophisticated halide perovskite structures and new materials design for lead-free materials.

6.
Sci Rep ; 7: 41171, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28117371

RESUMO

We report charge transport measurements in nanoscale vertical pillar structures incorporating ultrathin layers of the organic semiconductor poly(3-hexylthiophene) (P3HT). P3HT layers with thickness down to 5 nm are gently top-contacted using wedging transfer, yielding highly reproducible, robust nanoscale junctions carrying high current densities (up to 106 A/m2). Current-voltage data modeling demonstrates excellent hole injection. This work opens up the pathway towards nanoscale, ultrashort-channel organic transistors for high-frequency and high-current-density operation.

7.
Cardiovasc Revasc Med ; 17(3): 169-75, 2016 Apr-May.
Artigo em Inglês | MEDLINE | ID: mdl-27157293

RESUMO

BACKGROUND: The reactivity of platelets is increased in patients with peripheral artery disease (PAD). RANTES and sCD40L are chemokines which are stored in the alpha-granules of platelets. Clopidogrel inhibits and thus reduces platelet reactivity. Whether a treatment with clopidogrel is associated with an inhibition of systemic inflammation in patients with PAD has not been thoroughly explored. This study examined the effect of clopidogrel on platelet reactivation and the release of inflammatory chemokines in patients with PAD. METHODS: 40 patients with PAD were randomized into two groups. In the first group A the patients were treated with 100mg acetylsalicylic acid (ASA) and additional placebo for 4weeks. The patients in group B received 75mg/d clopidogrel in addition to ASA 100mg for 4weeks. After obtaining blood at days 0, 7 and 28 the platelet activation was determined by measuring the surface protein expression of CD63, CD62p and thrombospondin (TSP) after stimulation with TRAP and ADP. The release of the chemokines RANTES and sCD40L from platelets was analyzed by ELISA. RESULTS: Platelet activation markers (CD62p and CD63) and chemokine RANTES were significantly reduced in patients with PAD after 7 and 28days after treatment with clopidogrel. No alterations were found in TSP expression and sCD40L during the treatment. CONCLUSION: The treatment with clopidogrel leads to a reduction of platelet reactivity and release of RANTES from the platelets of patients with PAD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Plaquetas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Anti-Inflamatórios/efeitos adversos , Aspirina/uso terapêutico , Biomarcadores/sangue , Plaquetas/metabolismo , Ligante de CD40/sangue , Quimiocina CCL5/sangue , Clopidogrel , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Alemanha , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Mediadores da Inflamação/sangue , Selectina-P/sangue , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Tetraspanina 30/sangue , Trombospondinas/sangue , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
8.
Phys Rev Lett ; 117(27): 276803, 2016 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-28084749

RESUMO

Charge transport in disordered organic semiconductors is generally described as a result of incoherent hopping between localized states. In this work, we focus on multicomponent emissive host-guest layers as used in organic light-emitting diodes (OLEDs), and show using multiscale ab initio based modeling that charge transport can be significantly enhanced by the coherent process of molecular superexchange. Superexchange increases the rate of emitter-to-emitter hopping, in particular if the emitter molecules act as relatively deep trap states, and allows for percolation path formation in charge transport at low guest concentrations.

9.
Cardiovasc Diabetol ; 14: 15, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25645908

RESUMO

BACKGROUND: Although antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters. METHODS: A total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test). RESULTS: Patients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose. Moreover, we observed that ADP-PGE-induced platelet inhibition was positively correlated with fasting blood glucose and HbA1c (p < 0.01). CONCLUSIONS: Patients with type-2 diabetes exhibited increased platelet reactivity compared to patients without diabetes despite combined treatment with clopidogrel and ASA. Using a loading dose of clopidogrel rather than small daily doses was not sufficient for adequately overcoming increased platelet reactivity in patients with type-2 diabetes, highlighting the need for more effective anti-platelet drugs for such patients.


Assuntos
Plaquetas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Plaquetas/metabolismo , Clopidogrel , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/fisiologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico , Resultado do Tratamento
10.
J Card Fail ; 21(4): 330-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25498756

RESUMO

BACKGROUND: Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme involved in nicotinamide adenine dinucleotide biosynthesis. Nampt functions as gatekeeper of energy status and survival in cardiac myocytes in animal models of ischemia-reperfusion and might regulate inflammatory processes. Therefore, we performed for the 1st time a clinical study to determine the effects of Nampt on cardiac function in patients with nonischemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy. METHODS AND RESULTS: A total of 113 patients were enrolled in the study and classified into control (n = 25), DCM (n = 38), and DCMi (n = 50) groups. Cardiac functional and inflammatory parameters as well as plasma Nampt and cardiac mRNA and protein Nampt expression were determined at baseline and follow-up after 6 months. Patients with DCM (1.04 ± 0.8 ng/mL; P < .001) and DCMi (1.07 ± 0.7 ng/mL; P < .001) showed significantly increased Nampt plasma concentrations at baseline compared with the control group (0.57 ± 0.5 ng/mL). Patients with higher Nampt concentrations in both heart failure groups showed significant better improvement of cardiac functional parameters (correlation between Nampt plasma levels and the change of left ventricular ejection fraction after 6 months: DCM: r = 0.698, P < .001; DCMi: r = 0.503, P < .001). Moreover, cardiac inflammation did not influence Nampt expression, and Nampt concentrations did not modulate cardiac inflammation in DCMi. A multivariate linear regression model revealed high plasma Nampt expression to contribute to better improvement of cardiac function in patients of both heart failure groups. Moreover, heart failure patients with high plasma Nampt levels showed suppressed cardiac TNF-α and IL-6 mRNA expression after 6 months' follow-up as well as lower B-type natriuretic peptide levels compared with heart failure patients with low Nampt plasma concentrations. CONCLUSIONS: High Nampt expression in patients with nonischemic DCM and DCMi is associated with a favorable outcome and improvement in functional status.


Assuntos
Cardiomiopatia Dilatada/sangue , Citocinas/genética , Regulação da Expressão Gênica , Miocárdio/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Células Precursoras de Linfócitos B/metabolismo , RNA Mensageiro/genética , Função Ventricular Esquerda/fisiologia , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Citocinas/biossíntese , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Nicotinamida Fosforribosiltransferase/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
11.
Science ; 345(6203): 1450-1, 2014 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-25237087
12.
J Cardiol ; 63(5): 379-84, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24230464

RESUMO

BACKGROUND: Patients with cardiomyopathy show a significantly increased risk for thromboembolic events due to a hypercoagulable state and platelet dysfunction. The pathophysiologic mechanism underlying the increasing platelet activity in patients with cardiomyopathy remains unclear. We performed a clinical study to elucidate the link between myocardial tissue alterations and platelet activation in patients with cardiomyopathy. METHODS: A total of 30 patients with suspected cardiomyopathy and 10 healthy control patients were included in our study. Hemodynamic parameters were measured by catheterization and echocardiography. Endomyocardial biopsies were taken to determine myocardial inflammation. Flow cytometry was performed to examine the platelet activation by quantification of p-selectin and thrombospondin expression on platelets. RESULTS: The p-selectin (8.46 ± 3.67 AU) and thrombospondin (26.56 ± 23.21 AU) expression was significantly correlated with the amount of CD3+ T cells (p-selectin: r=0.573, p<0.05; thrombospondin: r=0.488, p<0.05) and the endothelial/interstitial activation (p-selectin: r=0.521, p<0.05; thrombospondin: r=0.39, p<0.05). This was found to be independent of hemodynamic parameters, age, and gender. The platelet activation of patients (n=3) with echocardiographically documented ventricular thrombi was significantly increased (p-selectin: 12.57 ± 5.5 AU vs. 8.1 ± 3.2 AU, p<0.05) and this was associated with elevated myocardial inflammation scores. CONCLUSION: Myocardial inflammation is associated with a significant increase in platelet activation and ventricular thrombus formation independently of the hemodynamic conditions.


Assuntos
Miocardite/sangue , Miocardite/complicações , Ativação Plaquetária , Tromboembolia/etiologia , Adulto , Biomarcadores/sangue , Plaquetas/metabolismo , Feminino , Ventrículos do Coração , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/patologia , Miocardite/fisiopatologia , Miocárdio/patologia , Selectina-P/sangue , Risco , Trombospondinas/sangue
13.
Eur J Emerg Med ; 21(2): 105-11, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23751288

RESUMO

OBJECTIVE: The use of emergency medical services increases with the age of patients. Some care providers hold on to the prejudice that these alarms are unnecessary or of a lower importance. We assessed the relation of age and age-dependent emergency characteristics, taking into consideration the ratings of emergency physicians on whether or not emergency cases were considered truly in need of emergency physician attendance. METHODS: Emergency physicians dispatched by the Berlin Fire Department evaluated for each case the necessity of emergency physician attendance. Case characteristics such as the day of the week and location of the emergency as well as patient characteristics such as age, sex, prior status, and care dependency were recorded. In addition, whether or not the physician accompanied the patient to the hospital was recorded as a parameter for emergency severity. Analysis was performed using multiple logistic regression modeling. RESULTS: During the 6-month prospective study period, 2702 cases were evaluated. Emergency medical services are used more frequently by older individuals, especially octogenarians. Emergency cases in older individuals were significantly more often rated as in need of emergency physician attendance; however, the rate of patients accompanied by the emergency physician to the hospital did not differ between the age groups. The age of patients, the primary diagnosis, the day and location of the emergency, and the presence of pre-existing dementia showed a significant impact on the necessity of physician-attended emergency missions. CONCLUSION: Despite common prejudices, emergency cases in elder patients are rated more often as in need of emergency physician attendance compared with those involving younger patients.


Assuntos
Doença Crônica/terapia , Serviços Médicos de Emergência/organização & administração , Serviços de Saúde para Idosos/organização & administração , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Emergências , Serviços Médicos de Emergência/normas , Alemanha , Serviços de Saúde para Idosos/normas , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade da Assistência à Saúde , Inquéritos e Questionários , Adulto Jovem
14.
Nat Nanotechnol ; 8(12): 887, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24302020
15.
J Am Coll Cardiol ; 62(19): 1737-45, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-23871888

RESUMO

OBJECTIVES: This study sought to evaluate the role of protease-activated receptor-2 (PAR2) in coxsackievirus B3 (CVB3)-induced myocarditis. BACKGROUND: An infection with CVB3 leads to myocarditis. PAR2 modulates the innate immune response. Toll-like receptor-3 (TLR3) is crucial for the innate immune response by inducing the expression of the antiviral cytokine interferon-beta (IFNß). METHODS: To induce myocarditis, wild-type (wt) and PAR2 knockout (ko) mice were infected with 10(5) plaque-forming units CVB3. Mice underwent hemodynamic measurements with a 1.2-F microconductance catheter. Wt and PAR2ko hearts and cardiac cells were analyzed for viral replication and immune response with plaque assay, quantitative polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: Compared with wt mice, PAR2ko mice and cardiomyocytes exhibited a reduced viral load and developed no myocarditis after infection with CVB3. Hearts and cardiac fibroblasts from PAR2ko mice expressed higher basal levels of IFNß than wt mice did. Treatment with CVB3 and polyinosinic:polycytidylic acid led to higher IFNß expression in PAR2ko than in wt fibroblasts and reduced virus replication in PAR2ko fibroblasts was abrogated by neutralizing IFNß antibody. Overexpression of PAR2 reduced the basal IFNß expression. Moreover, a direct interaction between PAR2 and Toll-like receptor 3 was observed. PAR2 expression in endomyocardial biopsies of patients with nonischemic cardiomyopathy was positively correlated with myocardial inflammation and negatively with IFNß expression and left ventricular ejection fraction. CONCLUSIONS: PAR2 negatively regulates the innate immune response to CVB3 infection and contributes to myocardial dysfunction. The antagonism of PAR2 is of therapeutic interest to strengthen the antiviral response after an infection with a cardiotropic virus.


Assuntos
Enterovirus Humano B/imunologia , Infecções por Enterovirus/imunologia , Imunidade Inata , Miocardite/imunologia , Miocárdio/enzimologia , Receptor PAR-2/biossíntese , Animais , Anticorpos Antivirais/análise , Biópsia , Western Blotting , Modelos Animais de Doenças , Infecções por Enterovirus/virologia , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/patologia , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor PAR-2/genética , Receptor 3 Toll-Like/biossíntese , Receptor 3 Toll-Like/genética
16.
Nat Mater ; 12(7): 652-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23584141

RESUMO

In multilayer white organic light-emitting diodes the electronic processes in the various layers--injection and motion of charges as well as generation, diffusion and radiative decay of excitons--should be concerted such that efficient, stable and colour-balanced electroluminescence can occur. Here we show that it is feasible to carry out Monte Carlo simulations including all of these molecular-scale processes for a hybrid multilayer organic light-emitting diode combining red and green phosphorescent layers with a blue fluorescent layer. The simulated current density and emission profile are shown to agree well with experiment. The experimental emission profile was obtained with nanometre resolution from the measured angle- and polarization-dependent emission spectra. The simulations elucidate the crucial role of exciton transfer from green to red and the efficiency loss due to excitons generated in the interlayer between the green and blue layers. The perpendicular and lateral confinement of the exciton generation to regions of molecular-scale dimensions revealed by this study demonstrate the necessity of molecular-scale instead of conventional continuum simulation.

17.
Cardiovasc Ther ; 31(2): 115-23, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22212466

RESUMO

AIM: A major concern of stent implantation after percutaneous coronary intervention (PCI) is acute stent thrombosis. Effective inhibition of periprocedural platelet function in patients with coronary artery disease (CAD) leads to an improved outcome. In this study, we examined the periprocedural platelet reactivity after administrating bivalirudin during PCI compared to unfractionated heparin (UFH) administration. Further, the effect of bivalirudin on induced tissue factor (TF) expression in smooth muscle cells (SMC) was determined. METHODS: Patients with CAD (n = 58) and double antithrombotic medication were treated intraprocedural with UFH (n = 30) or bivalirudin (n = 28). Platelet activation markers were flow cytometrically measured before and after stenting. The expression of TF in SMC was determined by real-time PCR and Western blotting. The thrombogenicity of platelet-derived microparticles and SMC was assessed via a TF activity assay. RESULTS: Bivalirudin significantly diminished the agonist-induced platelet reactivity post-PCI. Compared to UFH treatment, the adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP)-induced thrombospondin expression post-PCI was reduced when bivalirudin was administrated during intervention. In contrast to UFH, bivalirudin reduced the P-selectin expression of unstimulated and ADP-induced platelets post-PCI. Moreover, bivalirudin inhibited the thrombin-, but not FVIIa- or FVIIa/FX-induced TF expression and pro-coagulant TF activity of SMC. Moreover, bivalirudin reduced the TF activity of platelet-derived microparticles postinduction with TRAP or ADP. CONCLUSIONS: Bivalirudin is better than UFH in reducing periprocedural platelet activation. Moreover, thrombin-induced TF expression is inhibited by bivalirudin. Thus, bivalirudin seems to be a better anticoagulant during PCI than UFH.


Assuntos
Antitrombinas/uso terapêutico , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/terapia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Ativação Plaquetária/efeitos dos fármacos , Tromboplastina/metabolismo , Idoso , Anticoagulantes/uso terapêutico , Biomarcadores/sangue , Plaquetas/metabolismo , Western Blotting , Células Cultivadas , Doença da Artéria Coronariana/sangue , Fator VIIa/metabolismo , Fator X/metabolismo , Feminino , Citometria de Fluxo , Alemanha , Heparina/uso terapêutico , Hirudinas , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Selectina-P/sangue , Intervenção Coronária Percutânea/instrumentação , Testes de Função Plaquetária , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Stents , Tetraspanina 30/sangue , Tromboplastina/genética , Trombospondinas/sangue , Resultado do Tratamento
18.
Blood Coagul Fibrinolysis ; 23(8): 723-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23135379

RESUMO

Dual antiplatelet medication with acetylsalicylic acid (ASA) and clopidogrel is the main therapy for patients with stable coronary vessel disease (CVD) after percutaneous coronary intervention (PCI). Despite platelet inhibition subgroups of patients have been shown to exhibit an increase of risk for adverse cardiovascular events. The aim of our study was to elucidate the influence of sex on platelet reactivity in patients with CVD under medication with ASA and clopidogrel. Two hundred and thirty patients with CVD on combined therapy with ASA (100 mg/day) and clopidogrel (75 mg/day) were included into our study. These patients were divided into a male (n = 128) and female (n = 102) group. Platelet reactivity was assessed by impedance aggregometry. Women demonstrated a significantly higher thrombin receptor-activating peptide (TRAP)-induced platelet reactivity than men (male 79.43 ± 28.55 U vs. female 89.3 ± 30.69 U; P < 0.05). The ADP-induced (male 19.81 ± 15.51 U vs. female 23.73 ± 17.68 U; P > 0.05) or arachidonic acid-induced (male 10.3 ± 12.87 U vs. female 12.76 ± 14.44 U; P > 0.05) platelet aggregation did not differ significantly between women and men. A multivariate linear regression model revealed female sex to be a significant prognostic marker for an increased TRAP-induced platelet reactivity, independent of the ASA and clopidogrel-associated platelet function inhibition. Sex differences did not influence the effectiveness of ASA or clopidogrel-mediated platelet function inhibition. Nevertheless, women had a significantly increased maximal platelet reactivity compared to men despite antiplatelet therapy.


Assuntos
Plaquetas/efeitos dos fármacos , Doença das Coronárias/sangue , Intervenção Coronária Percutânea , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Idoso , Ácido Araquidônico/farmacologia , Aspirina/farmacologia , Aspirina/uso terapêutico , Clopidogrel , Doença das Coronárias/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Pós-Menopausa/sangue , Estudos Prospectivos , Fatores Sexuais , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
19.
Eur J Heart Fail ; 14(11): 1265-75, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22764185

RESUMO

AIM: The expression of leptin and resistin is known to be positively correlated with the incidence of chronic heart failure (CHF). Both adipokines have been implicated in immunomodulation and cardiac remodelling. Therefore, we performed for the first time a clinical study to elucidate the effects of leptin and resistin on progression of CHF in patients with non-ischaemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy. METHODS AND RESULTS: For the clinical study 120 patients were divided into a control (n = 16), DCM (n = 52), and DCMi (n = 52) group to determine the effect of leptin and resistin on CHF progression. Nuclear factor-κB (NF-κB) activation, reactive oxygen species generation, and tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression following adipokine exposition were determined in vitro in cardiomyocytes. Leptin and resistin systemic plasma levels and not cardiac expression were significantly elevated in patients with DCM (leptin, 13.12 ± 17.2 ng/mL, P < 0.05; resistin, 6.87 ± 2.25 ng/mL, P < 0.05) and DCMi (leptin, 13.63 ± 16 ng/mL, P < 0.05; resistin, 7.27 ± 2.2 ng/mL, P < 0.05) compared with the control group (leptin, 7.34 ± 5.7 ng/mL; resistin, 4.4 ± 1.18 ng/mL). A multivariate linear regression model revealed low leptin and resistin plasma levels as contributors for favourable cardiac functional parameters at 6-month follow-up independent of inflammatory conditions. Cell culture experiments in vitro showed leptin and resistin to be potent regulators of TNF-α and IL-6 expression in cardiomyocytes, leading to significantly increased redox stress in cardiac cells. CONCLUSIONS: High leptin and resistin expression in patients with DCM and DCMi is associated with CHF progression, i.e. severe cardiac dysfunction, independent of immune responses.


Assuntos
Cardiomiopatias/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Inflamação/sangue , Leptina/biossíntese , Resistina/biossíntese , Adulto , Biomarcadores , Cardiomiopatias/epidemiologia , Progressão da Doença , Feminino , Indicadores Básicos de Saúde , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/patologia , Hemodinâmica , Humanos , Inflamação/patologia , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Curva ROC , Resistina/sangue , Estatística como Assunto , Volume Sistólico , Resultado do Tratamento , Disfunção Ventricular Esquerda
20.
Adv Mater ; 24(9): 1146-58, 2012 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-22298508

RESUMO

Organic field-effect transistors (OFETs) are considered in technological applications for which low cost or mechanical flexibility are crucial factors. The environmental stability of the organic semiconductors used in OFETs has improved to a level that is now sufficient for commercialization. However, serious problems remain with the stability of OFETs under operation. The causes for this have remained elusive for many years. Surface potentiometry together with theoretical modeling provide new insights into the mechanisms limiting the operational stability. These indicate that redox reactions involving water are involved in an exchange of mobile charges in the semiconductor with protons in the gate dielectric. This mechanism elucidates the established key role of water and leads in a natural way to a universal "stress function", describing the stretched exponential-like time dependence ubiquitously observed. Further study is needed to determine the generality of the mechanism and the role of other mechanisms.


Assuntos
Transistores Eletrônicos , Oxirredução , Potenciometria , Prótons , Dióxido de Silício/química , Propriedades de Superfície , Transistores Eletrônicos/economia
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