Abstract Reactive oxygen species such as superoxide are implicated in cardiac hypertrophy, but their contribution to the cardiac complications of insulin resistance is unresolved. We tested the ...hypothesis that the antioxidant tempol attenuates cardiac hypertrophy in insulin-resistant mice. Mice with cardiac GLUT4 deletion (GLUT4-knockout), superimposed on global GLUT4 suppression (GLUT4-knockdown) were administered tempol for 4 weeks. Age-matched GLUT4-knockdown littermates were used as controls (14 mice/group). GLUT4-knockout mice exhibited marked cardiac hypertrophy: heart to body weight ratio was increased 61 ± 7% and expression of the hypertrophic genes β-myosin heavy chain and B-type natriuretic peptide (BNP) were elevated 5.5 ± 0.7- and 6.2 ± 1.5-fold relative to control, respectively. Pro-fibrotic pro-collagen III expression was also higher (3.8 ± 0.7-fold) in the GLUT4-knockout myocardium (all p < 0.001). Both gp91phox and Nox1 subunits of NADPH oxidase were also upregulated, 4.9 ± 1.2- and 9.3 ± 2.8-fold (both p < 0.01). Tempol treatment significantly attenuated all of these abnormalities in GLUT4-knockout mice. Heart to body weight ratio was decreased, as was fold expression of β-myosin heavy chain (to 3.8 ± 0.8), BNP (to 2.5 ± 0.5), pro-collagen III (to 1.9 ± 0.4), gp91phox (to 0.9 ± 0.3) and Nox1 (to 2.3 ± 0.1, all p < 0.05 versus untreated GLUT4-knockout mice). In addition, tempol upregulated ventricular expression of both thioredoxin-2 (confirming an antioxidant action) and glycogen synthase kinase-3β (GSK-3β). Tempol did not elicit any other significant changes in control mice. Cardiac superoxide generation, however, was not altered by GLUT4-knockout or tempol. In conclusion, tempol treatment reduced morphological and molecular evidence of cardiac hypertrophy in the GLUT4-knockout insulin-resistant mouse in vivo , even at doses insufficient to lower cardiac superoxide. Parallel reductions in pro-collagen III and NADPH oxidase have important implications for our understanding of the molecular basis of cardiac hypertrophy in the setting of insulin resistance. Antioxidants may offer new alternatives in this disorder.
Quality issues in laboratory haemostasis PRESTON, F. E.; LIPPI, G.; FAVALORO, E. J. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
07/2010, Letnik:
16, Številka:
s5
Journal Article
Genetic diversity of Trypanosoma cruzi may play a role in pathogenesis of Chagas disease forms. Natural populations are classified into 6 Discrete Typing Units (DTUs) Tc I-VI with taxonomical status. ...This study aimed to identify T. cruzi DTUs in bloodstream and tissue samples of Argentinean patients with Chagas disease. PCR-based strategies allowed DTU identification in 256 clinical samples from 239 Argentinean patients. Tc V prevailed in blood from both asymptomatic and symptomatic cases and Tc I was more frequent in bloodstream, cardiac tissues and chagoma samples from immunosuppressed patients. Tc II and VI were identified in a minority of cases, while Tc III and Tc IV were not detected in the studied population. Interestingly, Tc I and Tc II/VI sequences were amplified from the same skin biopsy slice from a kidney transplant patient suffering Chagas disease reactivation. Further data also revealed the occurrence of mixed DTU populations in the human chronic infection. In conclusion, our findings provide evidence of the complexity of the dynamics of T. cruzi diversity in the natural history of human Chagas disease and allege the pathogenic role of DTUs I, II, V and VI in the studied population.
After cardiac valve replacement patients were blindly randomized into two groups, both receiving aspirin (330 mg) and dipyridamole (75 mg) twice daily and the oral anticoagulant acenocoumarol ...(Sintrom). An international normalized ratio of 2.0 to 2.99 was assigned to group A and 3.0 to 4.5 to group B; both groups were subsequently analyzed for thromboembolic and hemorrhagic complications. Final evaluation included 51 and 48 patients, respectively. The follow-up was 626 months for group A (12.3 months/patient) and 486 months for group B (10.1 months/patient). The frequency of thromboembolism was equal in both groups: one transient ischemic attack in group A (a rate of 1.92/100 patient-years) and two transient ischemic attacks in group B (a rate of 4.94/100 patient-years). There was, however, a statistical difference in bleeding complications between the two groups (p less than 0.02). Two patients bled in group A, a rate of 3.9% (3.8/100 patient-years), which represents an incidence of one episode each 25.6 years of treatment; 10 patients bled in group B, a rate of 20.8% (24.7/100 patient-years) representing an incidence of one episode each 4 years of treatment. We conclude that an international normalized ratio of 2 to 3 is safer than a ratio of 3 to 4.5 and confers good protection from thromboembolism when oral anticoagulant therapy is used conjointly with platelet function-inhibiting drugs in patients with mechanical substitute heart valves.
Heart transplantation (HTx) is a useful therapy for end‐stage Chagaś cardiomyopathy; however, Chagas reactivation remains a mayor complication. Parasitological methods offer poor diagnostic ...sensitivity, and use of more sensitive tools such as the Polymerase chain reaction (PCR) is usually necessary. In the present study, reactivation incidence and PCR usefulness for early reactivation diagnosis, as well as for treatment response evaluation during follow‐up, were analyzed using Strout parasite detection test, in 10 of 222 consecutive HTx patients suffering Chagas cardiomyopathy. PCR strategies targeted to minicircle sequences (kDNA, detection limit 1 parasite/ 10 mL blood) and miniexon genes (SL‐DNA, 200 parasite/10 mL) were performed to compare parasite burdens between samples. No patients received prophylactic antiprotozoal therapy (benznidazole). Five patients (50%) exhibited clinical reactivation within a mean period of 71.6 days; positive Strout results were observed in most cases presenting clinical manifestations. kDNA‐PCR was positive 38–85 days before reactivation, whereas SLDNA‐PCR became positive only 7–21 days later, revealing post‐HTx parasitic load enhancement present prior to clinical reactivation development. Reactivations were successfully treated with benznidazole and generated negative PCR results. Results observed in this study indicate the value of PCR testing for an early diagnosis of Chagas reactivation as well as for monitoring treatment efficacy.
PCR strategies to detect minicircle sequences and miniexon genes in parasites proved to be of value for early diagnosis of Chagas 'disease reactivation as well as monitoring treatment efficacy in patients at risk for Chagas 'disease reactivation post heart transplantation.
von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary ...categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.
The stochastic prepreg platelet molded composite (PPMC) occurs when the orientation and arrangement disorder of platelets are determined by the uncontrolled molding conditions. The understanding of ...composite structure-property relationship is essential for the engineering applications of PPMCs. Computational analysis of the structure-property relationship in a PPMC with stochastic meso-scale morphology is herein performed under uniaxial tension conditions. The virtual distributions of tensile properties are obtained from the in-silico tensile tests based on the progressive failure analysis in the full-sized stochastically generated PPMC coupons. The developed analysis allows investigation of how the PPMC meso-structure details, such as platelet geometry and system morphology, define the variability in PPMC effective tensile properties.
Prepreg platelet molded composite (PPMC) is derived from compression molded pieces of chopped unidirectional prepreg tape. The properties of a stochastic PPMC arise from the meso-structure that ...develops during processing. This paper describes an integrated methodology for analysis of stochastic PPMC to develop process-structure-property relationships. Flow-induced fiber orientation distributions were predicted using an anisotropic viscous constitutive model implemented in a nonlinear, explicit finite element (FE) solver. The predicted orientation state was validated by CT-based orientation measurements and optical microscopy. A computational framework for simulation of tensile property distributions of a stochastic PPMC by progressive failure analysis is presented. The probabilistic simulation results were statistically validated against experimental data. A FE analysis was developed with an explicitly modeled platelet meso-structure wherein the platelets are treated as a homogeneous orthotropic medium using continuum damage mechanics to model the intraplatelet failure and a cohesive zone model for interlaminar disbonding. Panels were molded using partial charge coverage to induce flow alignment of the fibers. Tensile coupons were excised from the molded panels both along (parallel) and transverse (perpendicular) to the preferential fiber direction to compare the composite effective properties with those reported in the literature for planar random orientation states. The composite tensile properties were found to be strongly dependent on the global orientation state.
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