Pioneer of Cardiothoracic Surgery - Luiz Tavares da Silva

ABSTRACT Luis Tavares revolutionized cardiac surgery, always bringing the most modern instruments and equipment from his travels to England - surgical forceps, scissors, scalpels, etc. He always insisted that he was not just a thoracic surgeon, for his work extended over a wide field and created three important cardiac surgery centers which promoted a great development of cardiology. He carried out the first open heart surgery (atrial septal defect) employing extracorporeal circulation and closure of a ventricular septal defect with deep surface hypothermia of north and northeast Brazil. He promoted an intense scientific exchange program between Recife and England, resulting in significant advances in medicine, and participated directly in the creation of HEMOPE), leading to radical changes and improvements in blood therapy in the whole country. The PROCAPE, inaugurated in 2006, was the result of the cardiac center created by him in early 1970 at Hospital Oswaldo Cruz and can be considered the second largest public-university cardiology center in Brazil. He is thus widely regarded as an outstanding name in medicine in the 20th century and one of the fathers of modern cardiac surgery in Brazil.

Pioneer of Cardiothoracic Surgery - Luiz Tavares da Silva.

Luis Tavares revolutionized cardiac surgery, always bringing the most modern instruments and equipment from his travels to England - surgical forceps, scissors, scalpels, etc. He always insisted that he was not just a thoracic surgeon, for his work extended over a wide field and created three important cardiac surgery centers which promoted a great development of cardiology. He carried out the first open heart surgery (atrial septal defect) employing extracorporeal circulation and closure of a ventricular septal defect with deep surface hypothermia of north and northeast Brazil. He promoted an intense scientific exchange program between Recife and England, resulting in significant advances in medicine, and participated directly in the creation of HEMOPE), leading to radical changes and improvements in blood therapy in the whole country. The PROCAPE, inaugurated in 2006, was the result of the cardiac center created by him in early 1970 at Hospital Oswaldo Cruz and can be considered the second largest public-university cardiology center in Brazil. He is thus widely regarded as an outstanding name in medicine in the 20th century and one of the fathers of modern cardiac surgery in Brazil.

Transcranial Focal Electric Stimulation Avoids P-Glycoprotein Over-Expression during Electrical Amygdala Kindling and Delays Epileptogenesis in Rats.

Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.

Noninvasive transcranial focal stimulation affects the convulsive seizure-induced P-glycoprotein expression and function in rats.

Transcranial focal stimulation (TFS) is a noninvasive neuromodulation strategy that reduces seizure activity in different experimental models. Nevertheless, there is no information about the effects of TFS in the drug-resistant phenotype associated with P-glycoprotein (Pgp) overexpression. The present study focused on determining the effects of TFS on Pgp expression after an acute seizure induced by 3-mercaptopropionic acid (MPA). P-glycoprotein expression was analyzed by western blot in the cerebral cortex and hippocampus of rats receiving 5 min of TFS (300 Hz, 50 mA, 200 µs, biphasic charge-balanced squared pulses) using a tripolar concentric ring electrode (TCRE) prior to administration of a single dose of MPA. An acute administration of MPA induced Pgp overexpression in cortex (68 ±â€¯13.4%, p < 0.05 vs the control group) and hippocampus (48.5 ±â€¯14%, p < 0.05, vs the control group). This effect was avoided when TFS was applied prior to MPA. We also investigated if TFS augments the effects of phenytoin in an experimental model of drug-resistant seizures induced by repetitive MPA administration. Animals with MPA-induced drug-resistant seizures received TFS alone or associated with phenytoin (75 mg/kg, i.p.). TFS alone did not modify the expression of the drug-resistant seizures. However, TFS combined with phenytoin reduced seizure intensity, an effect associated with a lower prevalence of major seizures (50%, p = 0.03 vs phenytoin alone). Our experiments demonstrated that TFS avoids the Pgp overexpression induced after an acute convulsive seizure. In addition, TFS augments the phenytoin effects in an experimental model of drug-resistant seizures. According with these results, it is indicated that TFS may represent a new neuromodulatory strategy to revert the drug-resistant phenotype.

Iatrogenic Complications During the Diagnostic Work-Up of an Inflammatory Cardiomyopathy

Abstract A 72-year-old woman was admitted for acute heart failure. The echocardiography revealed moderate depression of the left ventricular ejection fraction. Coronary disease was excluded by coronarography. Cardiac magnetic resonance showed predominantly left ventricular septal hypertrophy and severe depression of the left ventricular systolic function. There was also a bright, multifocal and patchy late gadolinium enhancement with subendocardial, mesocardial and subepicardial involvement, suggestive of sarcoidosis. Biochemical study, thoracic computed tomography and positron emission tomography were inconclusive for extra-cardiac sarcoidosis. Therefore, an endomyocardial biopsy was performed. The procedure was complicated by the development of complete atrioventricular block, requiring implantation of a cardiac resynchronization pacing device. A few days after device implantation, the patient developed fever. The echocardiography revealed extensive vegetations, and thus the diagnosis of a device-associated infective endocarditis was made. Even though antibiotic therapy was promptly started, the patient ended up dying. Biopsy results revealed lymphocytic myocarditis. This case is paradigmatic because it shows how the etiologic diagnosis of dilated cardiomyopathy can be challenging. Non-invasive diagnostic exams may not provide a definite diagnosis, requiring an endomyocardial biopsy. However, the benefits versus risks of such procedure must always be carefully weighted.

Glutamate induced neonatal excitotoxicity modifies the expression level of EAAT1 (GLAST) and EAAT2 (GLT-1) proteins in various brain regions of the adult rat.

Glutamate-mediated excitatory synaptic signalling is primarily controlled by excitatory amino acid transporters (EAATs), such as EAAT1 and EAAT2, which are located mostly on astrocytes and, together, uptake more than 95 % of extracellular glutamate. Alterations in the functional expression levels of EAATs can lead to excessive extracellular glutamate accumulation, potentially triggering excitotoxicity and seizures, among other neurological disorders. Excitotoxicity induced in early developmental stages can lead to lasting changes in several neurotransmission systems, including the glutamatergic system, which could make the brain more susceptible to a second insult. In this study, the expression levels of EAAT1 (GLAST) and EAAT2 (GLT-1) proteins were assessed in the cerebral motor cortex (CMC), striatum, hippocampus and entorhinal cortex (EC) of male adult rats following the neonatal excitotoxic process triggered by monosodium glutamate (MSG)-treatment (4 g/kg of body weight at postnatal days 1,3,5 and 7, subcutaneously). Western blot analysis showed that neonatal MSG-treatment decreased EAAT1 expression levels in the CMC, striatum and hippocampus, while EAAT2 levels were increased in the striatum and EC and decreased in the CMC. Immunofluorescence staining confirmed the changes in EAAT1 and EAAT2 expression induced by neonatal MSG-treatment, which were accompanied by an increase in the glial fibrillary acidic protein (GFAP) immunofluorescence signalthat was particularly significant in the hippocampus. Our results show that a neonatal excitotoxic processes can induce lasting changes in the expression levels of EAAT1 and EAAT2 proteins and suggest that although astrogliosis occurs, glutamate uptake could be deficient, particularly in the CMC and hippocampus.

Endocannabinoid System and Cannabinoid 1 Receptors in Patients With Pharmacoresistant Temporal Lobe Epilepsy and Comorbid Mood Disorders.

Experimental evidence points out that the activation of the endocannabinoid system induces neuroprotective effects and reduces mood disorders. In the hippocampus of patients with mesial temporal lobe epilepsy (MTLE), studies indicated augmented cannabinoid 1 receptor (CB1R) binding, in spite of its low mRNA and protein expressions. Although this situation suggests an enhanced CB1R-induced neurotransmission in patients with MTLE, especially those with pharmacoresistant seizures, which present important neuronal damage and high comorbid mood disorders. The present study focused to investigate the status of CB1R and the endocannabinoid system by obtaining CB1R-induced G-protein signaling efficacy and measuring the tissue levels of endocannabinoids in the hippocampus and the temporal neocortex of patients with pharmacoresistant MTLE. Furthermore, the obtained results were correlated with comorbid anxiety and depression. The experiments revealed that patients with MTLE present increased CB1R-induced G-protein signaling efficacy (Emax) as well as an augmented tissue content of anandamide and oleoylethanolamine and low 2-arachidonoylglycerol. Some of these changes were more evident in patients with MTLE without mood disorders. The current findings indicate that pharmacoresistant MTLE is associated with increased CB1R-induced transductional mechanisms as well as augmented tissue content of specific endocannabinoids in the hippocampus and the temporal neocortex. The enhanced endocannabinoid neurotransmission may be involved in the absence of comorbid mood disorders in some patients with MTLE.

Neuroprotective and Neurorestorative Effects of Epo and VEGF: Perspectives for New Therapeutic Approaches to Neurological Diseases.

BACKGROUND: Erythropoietin (Epo) and vascular endothelial growth factor (VEGF) are two vasoactive molecules with essential trophic effects for brain development. The expression and secretion of both molecules increase in response to neuronal damage and they exert protective and restorative effects, which may also be accompanied by adverse side effects. OBJECTIVE: We review the most relevant evidence on the neuroprotective and neurorestorative effects of Epo and VEGF in three of the most frequent neurological disorders, namely, stroke, epilepsy and Alzheimer's disease, to develop new therapeutic approaches. METHODS: Several original scientific manuscripts and reviews that have discussed the evidence in critical way, considering both the beneficial and adverse effects of Epo and VEGF in the selected neurological disorders, were analysed. In addition, throughout this review, we propose several considerations to take into account in the design of therapeutic approaches based on Epo and VEGF signalling. RESULTS: Although the three selected disorders are triggered by different mechanisms, they evolve through similar processes: excitotoxicity, oxidative stress, neuroinflammation, neuronal death, glial reactivity and vascular remodelling. Epo and VEGF exert neuroprotective and neurorestorative effects by acting on these processes due to their pleiotropism. In general, the evidence shows that both Epo and VEGF reduce neuronal death but that at the vascular level, their effects are contradictory. CONCLUSION: Because the Epo and VEGF signalling pathways are connected in several ways, we conclude that more experimental studies, primarily studies designed to thoroughly assess the functional interactions between Epo and VEGF in the brain under both physiological and pathophysiological conditions, are needed.

Drug-Resistant Temporal Lobe Epilepsy Alters the Expression and Functional Coupling to Gαi/o Proteins of CB1 and CB2 Receptors in the Microvasculature of the Human Brain.

Cannabinoid receptors 1 and 2 (CB1 and CB2, respectively) play an important role in maintaining the integrity of the blood-brain barrier (BBB). On the other hand, BBB dysfunction is a common feature in drug-resistant epilepsy. The focus of the present study was to characterize protein expression levels and Gαi/o protein-induced activation by CB1 and CB2 receptors in the microvascular endothelial cells (MECs) isolated from the brain of patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). MECs were isolated from the hippocampus and temporal neocortex of 12 patients with DR-MTLE and 12 non-epileptic autopsies. Immunofluorescence experiments were carried out to determine the localization of CB1 and CB2 receptors in the different cell elements of MECs. Protein expression levels of CB1 and CB2 receptors were determined by Western blot experiments. [35S]-GTPγS binding assay was used to evaluate the Gαi/o protein activation induced by specific agonists. Immunofluorescent double-labeling showed that CB1 and CB2 receptors colocalize with tight junction proteins (claudin-5, occludin, and zonula occludens-1), glial fibrillary acidic protein and platelet-derived growth factor receptor-ß. These results support that CB1 and CB2 receptors are expressed in the human isolated microvessels fragments consisting of MECs, astrocyte end feet, and pericytes. The hippocampal microvasculature of patients with DR-MTLE presented lower protein expression of CB1 and CB2 receptors (66 and 43%, respectively; p < 0.001). However, its Gαi/o protein activation was with high efficiency (CB1, 251%, p < 0.0008; CB2, 255%, p < 0.0001). Microvasculature of temporal neocortex presented protein overexpression of CB1 and CB2 receptors (35 and 41%, respectively; p < 0.01). Their coupled Gαi/o protein activation was with higher efficiency for CB1 receptors (103%, p < 0.006), but lower potency (p < 0.004) for CB2 receptors. The present study revealed opposite changes in the protein expression of CB1 and CB2 receptors when hippocampus (diminished expression of CB1 and CB2) and temporal neocortex (increased expression of CB1 and CB2) were compared. However, the exposure to specific CB1 and CB2 agonists results in high efficiency for activation of coupled Gαi/o proteins in the brain microvasculature of patients with DR-MTLE. CB1 and CB2 receptors with high efficiency could represent a therapeutic target to maintain the integrity of the BBB in patients with DR-MTLE.

Application of Risks Scores in Acute Coronary Syndromes. How Does ProACS Hold Up Against Other Risks Scores?

BACKGROUND: Multiple risk scores (RS) are approved in the prediction of worse prognosis in acute coronary syndromes (ACS). Recently, the Portuguese Journal of Cardiology has proposed the ProACS RS. OBJECTIVE: Application of several validated RS, as well as ProACS in patients, admitted for ACS. Evaluation of each RS's performance in predicting in-hospital mortality and the occurrence of all-cause mortality or non-fatal ACS at one-year follow-up and compare them to the ProACS RS. METHODS: A retrospective study of ACS was performed. The following RS were applied: GRACE, ACTION Registry-GWTG, PURSUIT, TIMI, EMMACE, SRI, CHA2DS2-VASc-HS, C-ACS and ProACS. ROC Curves were created to determine the predictive power for each RS and then were directly compared to ProACS. RESULTS: The ProACS, ACTION Registry-GWTG and GRACE showed a c-statistics of 0.908, 0.904 and 0.890 for predicting in-hospital mortality, respectively, performing better in ST-segment elevation myocardial infarction patients. The other RS performed satisfactorily, with c-statistics over 0.750, apart from the CHA2DS2-VASc-HS and C-ACS which underperformed. All RS underperformed in predicting worse long-term prognosis revealing c-statistics under 0.700. CONCLUSION: ProACS is an easily obtained risk score for early stratification of in-hospital mortality. When evaluating all RS, the ProACS, ACTION Registry-GWTG and GRACE RS showed the best performance, demonstrating high capability of predicting a worse prognosis. ProACS was able to demonstrate statistically significant superiority when compared to almost all RS. Thus, the ProACS has showed that it is able to combine simplicity in the calculation of the score with good performance in predicting a worse prognosis.

Application of Risks Scores in Acute Coronary Syndromes. How Does ProACS Hold Up Against Other Risks Scores? / Aplicação de Escores de Risco em Síndromes Coronárias Agudas: Como o ProACS se Comporta Diante de Outros Escores de Risco?

Abstract Background: Multiple risk scores (RS) are approved in the prediction of worse prognosis in acute coronary syndromes (ACS). Recently, the Portuguese Journal of Cardiology has proposed the ProACS RS. Objective: Application of several validated RS, as well as ProACS in patients, admitted for ACS. Evaluation of each RS's performance in predicting in-hospital mortality and the occurrence of all-cause mortality or non-fatal ACS at one-year follow-up and compare them to the ProACS RS. Methods: A retrospective study of ACS was performed. The following RS were applied: GRACE, ACTION Registry-GWTG, PURSUIT, TIMI, EMMACE, SRI, CHA2DS2-VASc-HS, C-ACS and ProACS. ROC Curves were created to determine the predictive power for each RS and then were directly compared to ProACS. Results: The ProACS, ACTION Registry-GWTG and GRACE showed a c-statistics of 0.908, 0.904 and 0.890 for predicting in-hospital mortality, respectively, performing better in ST-segment elevation myocardial infarction patients. The other RS performed satisfactorily, with c-statistics over 0.750, apart from the CHA2DS2-VASc-HS and C-ACS which underperformed. All RS underperformed in predicting worse long-term prognosis revealing c-statistics under 0.700. Conclusion: ProACS is an easily obtained risk score for early stratification of in-hospital mortality. When evaluating all RS, the ProACS, ACTION Registry-GWTG and GRACE RS showed the best performance, demonstrating high capability of predicting a worse prognosis. ProACS was able to demonstrate statistically significant superiority when compared to almost all RS. Thus, the ProACS has showed that it is able to combine simplicity in the calculation of the score with good performance in predicting a worse prognosis.

Resumo Fundamento: Existem muitos escores de risco (ERs) aprovados na predição de um pior prognóstico em síndromes coronárias agudas (SCAs). Recentemente, a Revista Portuguesa de Cardiologia propôs o ER ProACS. Objetivo: Aplicar vários ERs validados, bem como o ProACS em pacientes internados por SCA. Avaliar o desempenho de cada ER em predizer mortalidade hospitalar e a ocorrência de mortalidade por todas as causas ou SCA não fatal em um ano de acompanhamento e compará-los com o ProACS. Métodos: Estudo retrospectivo de SCA. Os seguintes ERs foram aplicados: GRACE, ACTION Registry-GWTG, PURSUIT, TIMI, EMMACE, SRI, CHA2DS2-VASc-HS, C-ACS e ProACS. Curvas ROC foram criadas para determinar o poder preditivo de cada ER e diretamente comparadas com a do ProACS. Resultados: Os escores ProACS, ACTION Registry-GWTG e GRACE mostraram estatística-C de 0,908, 0,904 e 0,890, respectivamente, em predizer mortalidade hospitalar, mostrando melhor desempenho em pacientes com infarto do miocárdio com elevação do segmento ST. Os demais ERs mostraram desempenho satisfatório, com estatística-C acima de 0,750, com exceção de CHA2DS2-VASc-HS e C-ACS, que mostraram baixa performance. Todos os ERs apresentaram baixo desempenho em predizer um pior prognóstico em longo prazo, com estatística-C abaixo de 0,700. Conclusão: O ProACS é um escore de risco facilmente obtido para estratificação precoce de mortalidade intra-hospitalar. Ao avaliar todos os ERs, ProACS, ACTION Registry-GWTG e GRACE mostraram o melhor desempenho, com alta capacidade de predizer um pior prognóstico. O ProACS mostrou superioridade estatisticamente significativa em comparação aos outros ERs. Portanto, o ProACS mostrou-se capaz de combinar simplicidade no cálculo do escore com bom desempenho em predizer um pior prognóstico.

Increased protein expression of VEGF-A, VEGF-B, VEGF-C and their receptors in the temporal neocortex of pharmacoresistant temporal lobe epilepsy patients.

The vascular endothelial growth factor (VEGF) system has been shown to play a crucial role in several neuropathological processes. Temporal lobe epilepsy (TLE) is the most common focal epilepsy type in adult humans. We assessed the protein expression levels of VEGF-A, VEGF-B, and VEGF-C, their specific receptors VEGFR-2 and -3, their accessory receptors neuropilins 1 and 2, and PI3 and Akt kinases, in temporal neocortex from pharmacoresistant TLE (PR-TLE) patients and control subjects by western blotting. All proteins were found to be significantly overexpressed in samples of PR-TLE patients, indicating that the VEGF system contributes to PR-TLE pathogenesis and should be further studied.

Glutamate Neonatal Excitotoxicity Modifies VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 Protein Expression Profiles During Postnatal Development of the Cerebral Cortex and Hippocampus of Male Rats.

Vascular endothelial growth factor (VEGF) exerts both neuroprotective and proinflammatory effects in the brain, depending on the VEGF (A-E) and VEGF receptor (VEGFR1-3) types involved. Neonatal monosodium glutamate (MSG) treatment triggers an excitotoxic degenerative process associated with several neuropathological conditions, and VEGF messenger RNA (mRNA) expression is increased at postnatal day (PD) 14 in rat hippocampus (Hp) following the treatment. The aim of this work was to establish the changes in immunoreactivity to VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 proteins induced by neonatal MSG treatment (4 g/kg, subcutaneous, at PD1, 3, 5 and 7) in the cerebral motor cortex (CMC) and Hp. Samples collected from PD2 to PD60 from control and MSG-treated male Wistar rats were assessed by western blotting for each protein. Considering that immunoreactivity measured by western blotting is related to the protein expression level, we found that each protein in each cerebral region has a specific expression profile throughout the studied ages, and all profiles were differentially modified by MSG. Specifically, neonatal MSG treatment significantly increased the immunoreactivity to the following: (1) VEGF-A at PD8-PD10 in the CMC and at PD6-PD8 in the Hp; (2) VEGF-B at PD2, PD6 and PD10 in the CMC and at PD8-PD9 in the Hp; and (3) VEGFR-2 at PD6-PD8 in the CMC and at PD21-PD60 in the Hp. Also, MSG significantly reduced the immunoreactivity to the following: (1) VEGF-B at PD8-PD9 and PD45-PD60 in the CMC; and (2) VEGFR-1 at PD4-PD6 and PD14-PD21 in the CMC and at PD4, PD9-PD10 and PD60 in the Hp. Our results indicate that VEGF-mediated signalling is involved in the excitotoxic process triggered by neonatal MSG treatment and should be further characterized.