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1. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

Author

Géraldine Sicot, Laurent Servais, Diana M. Dinca, Axelle Leroy, Cynthia Prigogine, Fadia Medja, Sandra O. Braz, Aline Huguet-Lachon, Cerina Chhuon, Annie Nicole, Noëmy Gueriba, Ruan Oliveira, Bernard Dan, Denis Furling, Maurice S. Swanson, Ida Chiara Guerrera, Guy Cheron, Geneviève Gourdon, and Mário Gomes-Pereira

Subjects
myotonic dystrophy, unstable microsatellite repeats, brain, cerebellum, neurons, astrocytes, Bergmann glia, GLT1, glutamate, transgenic mice, ceftriaxone, Biology (General), QH301-705.5
Abstract

Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.

Published
2017
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2. Prognostic Value of TIMI Score versus GRACE Score in ST-segment Elevation Myocardial Infarction

Author

Luis C. L. Correia, Guilherme Garcia, Felipe Kalil, Felipe Ferreira, Manuela Carvalhal, Ruan Oliveira, André Silva, Isis Vasconcelos, Caio Henri, and Márcia Noya-Rabelo

Subjects
Infarto do Miocárdio, Pontuação de Propensão, Fatores de Risco, Estudo Comparativo, Síndrome Coronariana Aguda / diagnóstico, Prognóstico, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The TIMI Score for ST-segment elevation myocardial infarction (STEMI) was created and validated specifically for this clinical scenario, while the GRACE score is generic to any type of acute coronary syndrome. Objective: Between TIMI and GRACE scores, identify the one of better prognostic performance in patients with STEMI. Methods: We included 152 individuals consecutively admitted for STEMI. The TIMI and GRACE scores were tested for their discriminatory ability (C-statistics) and calibration (Hosmer-Lemeshow) in relation to hospital death. Results: The TIMI score showed equal distribution of patients in the ranges of low, intermediate and high risk (39 %, 27 % and 34 %, respectively), as opposed to the GRACE Score that showed predominant distribution at low risk (80 %, 13 % and 7%, respectively). Case-fatality was 11%. The C-statistics of the TIMI score was 0.87 (95%CI = 0.76 to 0.98), similar to GRACE (0.87, 95%CI = 0.75 to 0.99) - p = 0.71. The TIMI score showed satisfactory calibration represented by χ2 = 1.4 (p = 0.92), well above the calibration of the GRACE score, which showed χ2 = 14 (p = 0.08). This calibration is reflected in the expected incidence ranges for low, intermediate and high risk, according to the TIMI score (0 %, 4.9 % and 25 %, respectively), differently to GRACE (2.4%, 25% and 73%), which featured middle range incidence inappropriately. Conclusion: Although the scores show similar discriminatory capacity for hospital death, the TIMI score had better calibration than GRACE. These findings need to be validated populations of different risk profiles.

Published
2014
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3. Proteína C-Reativa Incrementa o Valor Prognóstico do Escore GRACE em Síndromes Coronarianas Agudas?

Author

Luis Cláudio Lemos Correia, Isis Vasconcelos, Guilherme Garcia, Felipe Kalil, Felipe Ferreira, André Silva, Ruan Oliveira, Manuela Carvalhal, Caio Freitas, and Márcia Maria Noya-Rabelo

Subjects
Proteína C-reativa, Síndrome coronariana aguda, Prognóstico, Probabilidade, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Fundamento: O valor prognóstico incremental da dosagem plasmática de Proteína C-reativa (PCR) em relação ao Escore GRACE não está estabelecido em pacientes com síndromes coronarianas agudas sem supradesnivelamento do segmento ST (SCA). Objetivo: Testar a hipótese de que a medida de PCR na admissão incrementa o valor prognóstico do escore GRACE em pacientes com SCA. Métodos: Foram estudados 290 indivíduos, internados consecutivamente por SCA, os quais tiveram material plasmático colhido na admissão para dosagem de PCR por método de alta sensibilidade (nefelometria). Desfechos cardiovasculares durante hospitalização foram definidos pela combinação de óbito, infarto não fatal ou angina refratária não fatal. Resultados: A incidência de eventos cardiovasculares durante hospitalização foi 15% (18 óbitos, 11 infartos, 13 anginas), tendo a PCR apresentado estatística-C de 0,60 (95% IC = 0,51 - 0,70; p = 0,034) na predição desses desfechos. Após ajuste para o Escore GRACE, PCR elevada (definida pelo melhor ponto de corte) apresentou tendência a associação com eventos hospitalares (OR = 1,89; 95% IC = 0,92 - 3,88; p = 0,08). No entanto, a adição da variável PCR elevada no modelo GRACE não promoveu incremento significativo na estatística-C, a qual variou de 0,705 para 0,718 (p = 0,46). Da mesma forma, não houve reclassificação de risco significativa com a adição da PCR no modelo preditor (reclassificação líquida = 5,7%; p = 0,15). Conclusão Embora PCR possua associação com desfechos hospitalares, esse marcador inflamatório não incrementa o valor prognóstico do Escore GRACE.

Published
2014
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4. Does C-reactive Protein Add Prognostic Value to GRACE Score in Acute Coronary Syndromes?

Author

Felipe Ferreira, Luis C. L. Correia, Ruan Oliveira, Isis Vasconcelos, André Silva, Márcia Noya-Rabelo, Guilherme Garcia, Felipe Kalil, Caio Freitas, and Manuela Carvalhal

Subjects
Male, medicine.medical_specialty, Acute coronary syndrome, Risk Assessment, Sensitivity and Specificity, Angina, Reference Values, Risk Factors, Internal medicine, Medicine, Humans, Myocardial infarction, Prospective Studies, Prospective cohort study, Probability, Aged, Aged, 80 and over, biology, business.industry, Incidence (epidemiology), C-reactive protein, Reproducibility of Results, Original Articles, C-Reactive protein, Middle Aged, medicine.disease, Prognosis, Surgery, Hospitalization, Logistic Models, Hospital outcomes, Cardiology, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Risk assessment, Biomarkers
Abstract

Background: The incremental prognostic value of plasma levels of C-reactive protein (CRP) in relation to GRACE score has not been established in patients with acute coronary syndrome (ACS) with non-ST segment elevation. Objective: To test the hypothesis that CRP measurements at admission increases the prognostic value of GRACE score in patients with ACS. Methods: A total of 290 subjects, consecutively admitted for ACS, with plasma material obtained upon admission CRP measurement using a high-sensitivity method (nephelometry) were studied. Cardiovascular outcomes during hospitalization were defined by the combination of death, nonfatal myocardial infarction or nonfatal refractory angina. Results: The incidence of cardiovascular events during hospitalization was 15% (18 deaths, 11 myocardial infarctions, 13 angina episodes) with CRP showing C-statistics of 0.60 (95% CI = 0.51-0.70, p = 0.034) in predicting these outcomes. After adjustment for the GRACE score, elevated CRP (defined as the best cutoff point) tended to be associated with hospital events (OR = 1.89, 95% CI = 0.92 to 3.88, p = 0.08). However, the addition of the variable elevated CRP in the GRACE model did not result in significant increase in C-statistics, which ranged from 0.705 to 0.718 (p = 0.46). Similarly, there was no significant reclassification of risk with the addition of CRP in the predictor model (net reclassification = 5.7 %, p = 0.15). Conclusion: Although CRP is associated with hospital outcomes, this inflammatory marker does not increase the prognostic value of the GRACE score.

Published
2014

5. Valor Prognóstico do Escore TIMI versus Escore GRACE no Infarto com Supradesnível do Segmento ST

Author

Isis Vasconcelos, Felipe Ferreira, Manuela Carvalhal, Felipe Kalil, Guilherme Garcia, Luis C. L. Correia, Caio Henri, Ruan Oliveira, Márcia Noya-Rabelo, and André Silva

Subjects
Fatores de Risco, Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Acute coronary syndrome, medicine.medical_specialty, Acute Coronary Syndrome / diagnosis, Time Factors, Prognóstico, Myocardial Infarction, Síndrome Coronariana Aguda / diagnóstico, Risk Assessment, Sensitivity and Specificity, Risk Factors, Reference Values, Internal medicine, medicine, ST segment, Humans, Comparative Study, Infarto do Miocárdio, Myocardial infarction, cardiovascular diseases, Hospital Mortality, Acute Coronary Syndrome, Propensity Score, Aged, Pontuação de Propensão, business.industry, Incidence (epidemiology), Reproducibility of Results, Middle Aged, medicine.disease, Prognosis, Surgery, surgical procedures, operative, lcsh:RC666-701, Propensity score matching, Cardiology, Original Article, Female, Myocardial infarction diagnosis, Estudo Comparativo, Cardiology and Cardiovascular Medicine, Risk assessment, business, TIMI
Abstract

Background: The TIMI Score for ST-segment elevation myocardial infarction (STEMI) was created and validated specifically for this clinical scenario, while the GRACE score is generic to any type of acute coronary syndrome. Objective: Between TIMI and GRACE scores, identify the one of better prognostic performance in patients with STEMI. Methods: We included 152 individuals consecutively admitted for STEMI. The TIMI and GRACE scores were tested for their discriminatory ability (C-statistics) and calibration (Hosmer-Lemeshow) in relation to hospital death. Results: The TIMI score showed equal distribution of patients in the ranges of low, intermediate and high risk (39 %, 27 % and 34 %, respectively), as opposed to the GRACE Score that showed predominant distribution at low risk (80 %, 13 % and 7%, respectively). Case-fatality was 11%. The C-statistics of the TIMI score was 0.87 (95%CI = 0.76 to 0.98), similar to GRACE (0.87, 95%CI = 0.75 to 0.99) - p = 0.71. The TIMI score showed satisfactory calibration represented by χ2 = 1.4 (p = 0.92), well above the calibration of the GRACE score, which showed χ2 = 14 (p = 0.08). This calibration is reflected in the expected incidence ranges for low, intermediate and high risk, according to the TIMI score (0 %, 4.9 % and 25 %, respectively), differently to GRACE (2.4%, 25% and 73%), which featured middle range incidence inappropriately. Conclusion: Although the scores show similar discriminatory capacity for hospital death, the TIMI score had better calibration than GRACE. These findings need to be validated populations of different risk profiles. Fundamento: O Escore TIMI para infarto com supradesnível do segmento ST (IAMcSST) foi criado e validado especificamente para este cenário clínico, enquanto o Escore GRACE é genérico para qualquer tipo de síndrome coronariana aguda. Objetivo: Identificar qual dos escores, TIMI ou GRACE, apresenta melhor desempenho prognóstico em pacientes com IAMcSST. Métodos: Foram incluídos 152 indivíduos consecutivamente internados por IAMcSST. Os escores TIMI e GRACE foram testados quanto a sua capacidade discriminatória (estatística-C) e calibração (teste Hosmer-Lemeshow), em relação ao desfecho óbito hospitalar. Resultados: O Escore TIMI apresentou distribuição equitativa de pacientes nas faixas de baixo, intermediário e alto risco (39%, 27% e 34%, respectivamente), diferente do Escore GRACE que apresentou distribuição predominante em baixo risco (80%, 13% e 7%, respectivamente). A letalidade da amostra foi de 11%. A estatística-C do Escore TIMI foi de 0,87 (95% IC = 0,76 - 0,98), semelhante ao GRACE (0,87; 95% IC = 0,75-0,99) - p = 0,71. O Escore TIMI apresentou calibração satisfatória, representada por χ2 de 1,4 (p = 0,92), nitidamente superior à calibração do Escore GRACE, que apresentou χ2 de 14 (p = 0,08). Esta calibração se reflete em incidências esperadas para as faixas de baixo, intermediário e alto risco de acordo com o Escore TIMI (0%, 4,9% e 25%, respectivamente), diferente do GRACE (2,4%, 25% e 73%) que caracterizou inadequadamente a faixa intermediária. Conclusão: Os escores TIMI e GRACE apresentam semelhante capacidade discriminatória em relação a óbito hospitalar, porém o Escore TIMI possui calibração superior ao GRACE. Para populações de risco diferente da nossa amostra, esta conclusão deve ser validada por futuros trabalhos.

Published
2014

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