Celia Strunz

Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes.

After injury to the adult central nervous system (CNS), numerous cytokines and growth factors are released that contribute to reactive gliosis and extracellular matrix production. In vitro examination of these cytokines revealed that the presence of transforming growth factor‐β1 (TGF‐β1) and epidermal growth factor (EGF) greatly increased the production of several chondroitin sulfate proteoglycans (CSPG) by astrocytes. Treatment of astrocytes with other EGF‐receptor (ErbB1) ligands, such as TGF‐α and HB‐EGF, produced increases in CSPG production similar to those observed with EGF. Treatment of astrocytes, however, with heregulin, which signals through other members of the EGF‐receptor family (ErbB2, ErbB3, ErbB4), did not induce CSPG upregulation. The specificity of activation through the ErbB1 receptor was further verified by using a selective antagonist (AG1478) to this tyrosine kinase receptor. Western blot analysis of astrocyte supernatant pre‐digested with chondroitinase ABC indicated the presence of multiple core proteins containing 4‐sulfated or 6‐sulfated chondroitin. To identify some of these CSPGs, Western blots were screened using antibodies to several known CSPG core proteins. These analyses showed that treatment of astrocytes with EGF increased phosphacan expression, whereas treatment with TGF‐β1 increased neurocan expression. Reverse transcription‐polymerase chain reaction (RT‐PCR) was used to examine the expression of these molecules in vivo, which result in increased expression of TGF‐β1, EGF‐receptor, neurocan, and phosphacan after injury to the brain. These data begin to elucidate some of the injury‐induced growth factors that regulate the expression of CSPGs which could be targeted in the future to modulate CSPG production after injury to the central nervous system.

Effects of home-based exercise training on neurovascular control in patients with heart failure

The effect of home‐based exercise training on neurovascular control in heart failure patients is unknown.

Effect of Hypoglycemic Agents on Ischemic Preconditioning in Patients With Type 2 Diabetes and Symptomatic Coronary Artery Disease

OBJECTIVE To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4). RESULTS In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069). CONCLUSIONS Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.

Glycosaminoglycan Distribution in Atherosclerotic Saphenous Vein Grafts

Glycosaminoglycan composition of normal saphenous veins and atherosclerotic saphenous vein grafts is reported. Dermatan sulfate is the main glycosaminoglycan present in both normal saphenous veins and saphenous vein grafts. These tissues also contain chondroitin sulfate and heparan sulfate. Although the total amount of glycosaminoglycans decreased in the grafts (compared with normal saphenous veins), the grafts showed an increase in the relative amounts of dermatan sulfate and chondroitin sulfate. Heparan sulfate was decreased, compared with normal controls. These findings suggest the involvement of blood vessel glycosaminoglycans (not only the arterial glycosaminoglycans) in the process of atherosclerosis.

Comparison of MB Fraction of Creatine Kinase Mass and Troponin I Serum Levels With Necropsy Findings in Acute Myocardial Infarction

Serum levels of troponin and heart-related fraction of creatine kinase (CK-MB) mass are used as diagnostic and prognostic criteria in myocardial infarction, but the relation between those levels and the necropsy-determined size of necrosis has not been tested in human beings. In this retrospective study, 1-cm-thick transverse sections of the ventricles were cut from the base to the apex in the necropsy hearts of 27 patients aged 47 to 86 years (mean 66, median 69; 19 men). Total and necrotic areas were measured using a computer-linked image analysis system. The weights of the necrotic areas were also calculated. The correlations of the areas and weights of necrotic myocardium with the highest serum values of CK-MB mass and troponin I, which had been quantified during life by chemiluminescence immunoassays, were verified by Pearsons test; results were considered significant at p<or=0.05. Significant correlations were detected between CK-MB mass peak and infarct size (r=0.63, p<0.01) and weight (r=0.69, p<0.01) and between CK-MB mass and highest troponin level (r=0.73, p<0.01); however, the correlations between highest troponin level and myocardial infarct size (r=0.31, p=0.11) and weight (r=0.35, p=0.07) were small and nonsignificant. In conclusion, despite the well-established role of serum levels of troponin as a diagnostic tool for myocardial infarction, their highest values showed poor correlations with the extent of infarct. In contrast, the highest serum level of CK-MB mass was well correlated with myocardial infarct size.

Perfil neuro-hormonal de pacientes reumáticos com insuficiência aórtica crônica importante

BACKGROUND Neurohormones are involved in the physiopathology of heart failure, but little is known about its behavior in significant chronic aortic regurgitation (AR). We aimed at analyzing the behavior of these mediators in AF. OBJECTIVE We aimed at analyzing the behavior of these mediators in AF. METHODS We analyzed 89 patients with AF, whose mean age was 33.6+/-11.5 years and of whom 84.6% were males, 60% asymptomatic, all with rheumatic etiology. After the clinical and echocardiographic assessment, plasma measurements of tumor necrosis factor (TNF), soluble TNF receptor types I and II (sTNFRI e sTNFRII), interleukin-6 (IL-6), its soluble receptor (sIL6R), endothelin-1 and B-type natriuretic peptide (BNP) were carried out; 12 healthy individuals were used as controls. RESULTS The mean values of the left ventricle diastolic diameter (LVDD) were 71.9+/-8.3mm, whereas the mean values of the LV systolic diameter (LVSD) were 50.4+/-9.3mm. The neurohormonal levels were elevated in patients with AF (TNF 92.65+/-110.24 pg/mL vs. 1.67+/-1.21 pg/ml in controls, p<0.001), (IL-6 7.17+/-7.78 pg/ml vs. 0.81+/-0.38 pg/mL in controls, p=0.0001) and TNFRI (894.75+/-348.87 pg/mL vs. 521.42+/-395.13 pg/ml, p=0.007). Except for the BNP levels, symptomatic and asymptomatic patients presented a similar neurohormonal profile. There was a correlation between TNFRII and LVDD (r=-0.329, p=0.038) and LVSD (r=-0.352, p=0.027). BNP levels were significantly higher in symptomatic patients and only in the latter it was possible to establish a correlation between BNP and ventricular diameters. CONCLUSION Patients with significant chronic AF present high neurohormonal levels, with no correlation with the symptomatic status. The TNFRII and BNP levels could be correlated with ventricular diameters, but only the latter could be correlated with symptoms.FUNDAMENTO: Os neuro-hormonios estao envolvidos na fisiopatologia da insuficiencia cardiaca, mas pouco se sabe sobre seu comportamento na insuficiencia aortica cronica importante (IAo). OBJETIVO: Analisar o comportamento desses mediadores na IAo. METODOS: Analisamos 89 pacientes com IAo, com media etaria de 33,6±11,5 anos, 84,6% do sexo masculino, 60% assintomaticos, todos de etiologia reumatica. Apos avaliacao clinica e ecocardiografica, realizaram-se dosagens plasmaticas de fator de necrose tumoral (TNF), seus antagonistas receptores soluveis tipos I e II (sTNFRI e sTNFRII), interleucina-6 (IL-6), seu receptor soluvel, endotelina-1 e peptideo natriuretico tipo B (BNP). Doze individuos saudaveis serviram como controle. RESULTADOS: O valor medio de diâmetro diastolico (DD) do ventriculo esquerdo (VE) foi de 71,9±8,3 mm, e o do diâmetro sistolico (DS) do VE, de 50,4±9,3 mm. Os niveis de neuro-hormonios estavam elevados nos pacientes com IAo: TNF 92,65±110,24 pg/ml vs. 1,67±1,21 pg/ml nos controles, p<0,001; IL-6 7,17±7,78 pg/ml vs. 0,81±0,38 pg/ml nos controles, p = 0,0001; e TNFRI 894,75±348,87 pg/ml vs. 521,42±395,13 pg/ml, p = 0,007. Com excecao dos niveis de BNP, os pacientes sintomaticos e assintomaticos apresentaram perfil neuro-hormonal semelhante. Houve correlacao entre TNFRII e diâmetro diastolico do ventriculo esquerdo (DDVE) (r = -0,329, p = 0,038) e diâmetro sistolico do ventriculo esquerdo (DSVE) (r = -0,352, p = 0,027). Os niveis de BNP estavam significativamente mais altos em pacientes sintomaticos, e apenas nestes foi possivel correlacao entre BNP e diâmetros ventriculares. CONCLUSAO: Pacientes com insuficiencia aortica cronica importante apresentam altos niveis neuro-hormonios, sem correlacao com o status sintomatico. Os niveis de TNFRII e BNP puderam ser correlacionados com diâmetros ventriculares, mas apenas este ultimo com sintomas.

Polimorfismo S447X da lipase lipoprotéica: influência sobre a incidência de doença arterial coronariana prematura e sobre os lípides plasmáticos

OBJETIVO: O objetivo deste estudo foi avaliar o efeito do polimorfismo S447X sobre os lipides plasmaticos em pacientes com doenca arterial coronariana (DAC) prematura. METODOS: Os lipides plasmaticos e a genotipagem foram determinados em 2 grupos: 313 pacientes com DAC prematura (<55 anos) e 150 controles sem DAC. RESULTADOS: A frequencia do polimorfismo S447X foi de 18% nos pacientes com DAC e de 23% no grupo controle. O polimorfismo S447X da lipase lipoproteica esta relacionado com diminuicao das concentracoes plasmatica de triglicerides nos pacientes do sexo masculino com DAC, nao havendo essa relacao no sexo feminino. CONCLUSAO: A presenca do polimorfismo S447X da lipase lipoproteica nao foi associada a incidencia de DAC.OBJECTIVE The objective of this study was to evaluate the effect of polymorphism S447X on plasma lipids of patients with premature coronary artery disease (CAD). METHODS Plasma lipids and genotypes were determined in 2 groups: 313 patients with premature CAD (<55 years of age) and 150 controls without CAD. RESULTS Frequency of the S447X polymorphism was 18% in patients with CAD and 23% in the control group. The S447X polymorphism of lipoprotein lipase is related to a decrease in plasma triglyceride concentrations in male patients with CAD, but this correlation is not observed in female patients. CONCLUSION The presence of the S447X lipoprotein lipase polymorphism was not associated with the incidence of CAD.

Acute and Chronic Pleural Changes after the Intrapleural Instillation of Mitoxantrone in Rabbits

Abstract. A previous study demonstrated that the intrapleural injection of 2 mg/kg mitoxantrone in rabbits resulted in a degree of pleurodesis which is comparable to that seen after 35 mg/kg tetracycline but that the animals had a high mortality rate after this dose of mitoxantrone. The objective of the present study was to assess the acute pleural fluid findings, the acute gross and microscopic pleural findings, and the chronic gross and microscopic findings in rabbits that received mitoxantrone. Mitoxantrone, 1.5 mg/kg, was instilled intrapleurally in 70 lightly anesthetized male rabbits. Groups of rabbits were sacrificed 1, 2, 4, 7, 15, 28, and 60 days after the injection. The intrapleural injection of mitoxantrone resulted in an exudative effusion on day 1. The pleural fluid contained predominantly neutrophils and had a mean lactate dehydrogenase (LDH) level that exceeded 4,000 IU/liter. Over the following week the volume of fluid diminished, the predominant cell became the macrophage, and the LDH levels decreased to less than 400 IU/liter. Macroscopic examination of the pleural space revealed that the mean degree of pleurodesis increased progressively over the 60-day observation period. With microscopy, the mean degree of pleural fibrosis also increased progressively. There were also substantial fibrosis and inflammation of the underlying lung and the contralateral lung. The mortality rates were low in the first 28 days (3/70) but subsequently increased and exceeded 80% in the period between 60 and 120 days. This experimental model of pleurodesis should be useful in future studies directed toward uncovering the mechanisms of pleurodesis.

Development of a pharmacogenetic-based warfarin dosing algorithm and its performance in Brazilian patients: highlighting the importance of population-specific calibration

BACKGROUND The main aims of the present study were to develop a pharmacogenetic-based warfarin dosing algorithm and to validate it in a highly admixed population. MATERIALS & METHODS We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). RESULTS Our algorithm achieved a determination coefficient of 40% including the variables age, gender, weight, height, self-declared race, amiodarone use, enzyme inducers use, VKORC1 genotypes and predicted phenotypes according to CYP2C9 polymorphisms. CONCLUSION Data suggest that our developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Population-specific derivation and/or calibration of warfarin dosing algorithms may lead to improved performance compared with general use dosing algorithms currently available. Original submitted 26 November 2014; Revision submitted 9 April 2015.

Long-Term Prospective Study of the Influence of Estrone Levels on Events in Postmenopausal Women with or at High Risk for Coronary Artery Disease

Background. The link between endogenous estrogen, coronary artery disease (CAD), and death in postmenopausal women is uncertain. We analyzed the association between death and blood levels of estrone in postmenopausal women with known coronary artery disease (CAD) or with a high-risk factor score for CAD. Methods. 251 postmenopausal women age 50–90 years not on estrogen therapy. Fasting blood for estrone and heart disease risk factors were collected at baseline. Women were grouped according to their estrone levels (<15 and ≥15 pg/mL). Fatal events were recorded after 5.8 ± 1.4 years of followup. Results. The Kaplan-Meier survival curve showed a significant trend (P = 0.039) of greater all-cause mortality in women with low estrone levels (<15 pg/mL). Cox multivariate regression analysis model adjusted for body mass index, diabetes, dyslipidemia, family history, and estrone showed estrone (OR = 0.45; P = 0.038) as the only independent variable for all-cause mortality. Multivariate regression model adjusted for age, body mass index, hypertension, diabetes, dyslipidemia, family history, and estrone showed that only age (OR = 1.06; P = 0.017) was an independent predictor of all-cause mortality. Conclusions. Postmenopausal women with known CAD or with a high-risk factor score for CAD and low estrone levels (<15 pg/mL) had increased all-cause mortality.