Browsing by Author "Alves, S"
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- Anatomical Basis, Histological Findings and Hemodinamics in the Modern Perfusion Model for Human CorpsesPublication . Júnior, E; Bettencourt-Pires, M; Alves, S; Casal, D; Pais, D; Goyri O’neill, J; Vassilenko, VsSeveral modern human cadaveric fixation methods are subject to permanent evaluation. Formaldehyde is the oldest and still the most widely used method of embalming. However, the International Agency for Research on Cancer has proven its high carcinogenic potential and its use was banned, with the recommendation of research for better alternatives in the conservation of corpses. The embalming method of excellence, which preserves all features, while keeping the disinfectant properties against cadaveric decomposition was proposed by João Goyri O’Neill. Their method was considered “the most modern and efficient technique in cadaveric preservation”. The aim of this present study was to analyze the quality of this original perfusion technique, at the organic level, based on central and peripheral hemodynamics. The cadaveric material was embalmed through a pulsed arterial perfusion system, connected to an automatic intermittent pump, that permits stability of the microvascular network, as well as the computerized measurement of the main perfusion parameters, such as flow and pressure. This procedure ensures good preservation of color, elasticity, texture, flexibility and fresh appearance, for several years. The morphological characteristics of the organs exhibited astonishing similarity to the living organic tissues, even several years after embalming and high freezing. Microscopic analysis demonstrated preservation of the structure of vessels, such as the aorta. Further studies on the integrity of the endocardial layer of the heart will enable to adapt the intermittent perfusion pump system to best simulate cardiac rhythm and arterial pulse, during cadaveric surgical training.
- Angioplastia Coronária no Enfarte Agudo do Miocárdio: Impacto do Timing da Revascularização na Alternância da Onda TaPublication . Pelicano, NJ; Oliveira, MM; Nogueira da Silva, M; Anão, A; Feliciano, J; Fiarresga, A; Alves, S; Silva, S; Quininha, JEncontra-se bem estabelecido que, na abordagem terapêutica do enfarte agudo do miocárdio (EAM), a trombólise e a angioplastia coronária percutânea (ACTP) permitem diminuir a mortalidade e melhorar o prognóstico, sendo esse benefício tanto maior quanto menor o tempo decorrido entre o evento isquémico e o procedimento terapêutico. No entanto, não está ainda estabelecido qual o impacto que o atraso da implementação dessas terapêuticas tem no desenvolvimento de taquidisritmias ventriculares e por consequência no resultado da alternância da onda T(TWA), que representa um método reconhecido para avaliação da vulnerabilidade ventricular às referidas arritmias. Objectivo: Analisar os resultados da TWA por microvoltagem numa população submetida a ACTP na sequência de EAM e avaliar a influência do timing de revascularização miocárdica nos resultados da TWA. Métodos: Estudámos 79 doentes (67 do sexo masculino; 57 ± 11 anos) consecutivos, admitidos por EAM e sujeitos a revascularização miocárdica por ACTP durante o internamento. A TWA foi avaliada utilizando um aparelho da HeartTwave System (Cambridge Heart, Inc., Bedford, Massachusetts) nos 30 dias pós-EAM. Durante a realização de uma prova de esforço em tapete rolante com protocolo manual, com o objectivo de elevar a frequência cardíaca até aos 110 batimentos por minuto, realizou-se o registo electrocardiográfico através da aplicação de sete eléctrodos standard e outros sete eléctrodos sensores de alta-resolução, especialmente concebidos para redução do «ruído», dispostos segundo as derivações ortogonais de Frank(X,Y, Z). A TWA foi considerada positiva quando se verificou a presença de alternância da onda T de magnitude ³ 1,9 μV de forma consistente e mantida (> 1 minuto), com início para frequências cardíacas < 110 batimentos/minuto ou quando esta alternância se verificou em doentes em repouso. Foi considerada negativa quando se conseguiu obter dados sem artefactos durante pelo menos um minuto, com frequências > 105 batimentos/minuto, sem atingir critério de positividade e indeterminada se não podia ser classificada como positiva ou negativa. Foram excluídos doentes com EAM ou revascularização miocárdica (cirúrgica ou percutânea) prévios, os que apresentavam insuficiência cardíaca congestiva, com fibrilhação auricular, > 10 extrassístoles por minuto, pacemaker definitivo, bradicárdia < 40 bpm, complexos QRS com duração > 130 ms ou sob terapêutica anti-arrítmica. Considerámos como marcador de risco para a ocorrência de eventos arrítmicos ventriculares malignos a presença de TWA positiva ou indeterminada. (TWA «nãonegativa»). Os resultados da TWA foram comparados entre o grupo de doentes submetidos a ACTP nas primeiras 24 horas pós-EAM (Grupo A; n = 45) e o grupo de doentes submetidos a ACTP > 24 horas pós-EAM. (Grupo B; n = 34) Resultados: A TWA foi positiva em 16 doentes (20,2%) e negativa em 56 (70,9%). Em 7 casos (8,9%), o resultado do teste foi considerado indeterminado. A TWA foi «não-negativa» em 29,1% da população. No grupo A a TWA foi “não-negativa” em 9 doentes (20 %) (6 com TWA positiva e três com TWA indeterminada) e negativa em 36 doentes (80 %) e no grupo B foi «não-negativa» em 14 doentes (41%) (10 com TWA positiva e quatro com TWA indeterminada) e negativa em 20 (59 %) (p < 0,05). Não se encontraram diferenças entre os dois grupos no que respeita à fracção de ejecção ventricular esquerda. No seguimento até aos 60 dias após a alta hospitalar não foram documentados eventos arrítmicos ventriculares, síncopes ou óbito. Foram reinternados cinco doentes (7 %) por recorrênciade angor. Conclusões: Numa população de sobreviventes de EAM encontrámos uma prevalência de TWA não negativa de 29 %, apesar da revascularização miocárdica com ACTP. A ACTP, quando efectuada nas primeiras 24 horas após o início do EAM, reduz de forma significativa o número de doentes com TWA não negativa,sugerindo que esta intervenção precoce poderá baixar o risco arrítmico destes doentes e influenciar favoravelmente o prognóstico pós-EAM. O impacto da morte súbita na mortalidade pós-EAM justifica estudos prospectivos de maiores dimensões
- BD-2 and BD-3 Increase Skin Flap Survival in a Model of Ischemia and Pseudomonas Aeruginosa InfectionPublication . Casal, D; Iria, I; Ramalho, JS; Alves, S; Mota-Silva, E; Mascarenhas-Lemos, L; Pontinha, C; Guadalupe-Cabral, M; Ferreira-Silva, J; Ferraz-Oliveira, M; Vassilenko, V; Goyri-O'Neill, J; Pais, D; Videira, PThe main aim of this work was to study the usefulness of human β-defensins 2 (BD-2) and 3 (BD-3), which are part of the innate immune system, in the treatment of infected ischemic skin flaps. We investigated the effect of transducing rat ischemic skin flaps with lentiviral vectors encoding human BD-2, BD-3, or both BD-2 and BD-3, to increase flap survival in the context of a P. aeruginosa infection associated with a foreign body. The secondary endpoints assessed were: bacterial counts, and biofilm formation on the surface of the foreign body. A local ischemic environment was created by producing arterialized venous flaps in the left epigastric region of rats. Flaps were intentionally infected by placing underneath them two catheters with 105 CFU of P. aeruginosa before the surgical wounds were hermetically closed. Flap biopsies were performed 3 and 7 days post-operatively, and the specimens submitted to immunohistochemical analysis for BD-2 and BD-3, as well as to bacterial quantification. Subsequently, the catheter segments were analyzed with scanning electron microscopy (SEM). Flaps transduced with BD-2 and BD-3 showed expression of these defensins and presented increased flap survival. Rats transduced with BD-3 presented a net reduction in the number of P. aeruginosa on the surface of the foreign body and lesser biofilm formation.
- Blood Supply to the Integument of the Abdomen of the Rat: A Surgical PerspectivePublication . Casal, D; Pais, D; Iria, I; Videira, P; Mota-Silva, E; Alves, S; Mascarenhas-Lemos, L; Pen, C; Vassilenko, V; Goyri-O'Neill, JBACKGROUND: Many fundamental questions regarding the blood supply to the integument of the rat remain to be clarified, namely the degree of homology between rat and humans. The aim of this work was to characterize in detail the macro and microvascular blood supply to the integument covering the ventrolateral aspect of the abdominal wall of the rat. METHODS: Two hundred five Wistar male rats weighing 250-350 g were used. They were submitted to gross anatomical dissection after intravascular colored latex injection (n = 30); conversion in modified Spalteholz cleared specimens (n=10); intravascular injection of a Perspex solution, and then corroded, in order to produce vascular corrosion casts of the vessels in the region (n = 5); histological studies (n = 20); scanning electron microscopy of vascular corrosion casts (n = 10); surgical dissection of the superficial caudal epigastric vessels (n = 100); and to thermographic evaluation (n = 30). RESULTS: The ventrolateral abdominal wall presented a dominant superficial vascular system, which was composed mainly of branches from the superficial caudal epigastric artery and vein in the caudal half. The cranial half still received significant arterial contributions from the lateral thoracic artery in all cases and from large perforators coming from the intercostal arteries and from the deep cranial epigastric artery. CONCLUSIONS: These data show that rats and humans present a great deal of homology regarding the blood supply to the ventrolateral aspect of the abdominal integument. However, there are also significant differences that must be taken into consideration when performing and interpreting experimental procedures in rats.
- Cardiac Rehabilitation After Acute Coronary Syndrome: Do All Patients Derive the Same Benefit?Publication . Aguiar Rosa, S; Abreu, A; Marques Soares, R; Rio, P; Filipe, C; Rodrigues, I; Monteiro, A; Soares, C; Ferreira, V; Silva, S; Alves, S; Cruz Ferreira, RINTRODUCTION: Cardiac rehabilitation (CR) has been demonstrated to improve exercise capacity in acute coronary syndrome (ACS), but not all patients derive the same benefit. Careful patient selection is crucial to maximize resources. OBJECTIVE: To identify in a heterogeneous ACS population which patients would benefit the most with CR, in terms of functional capacity (FC), by using cardiopulmonary exercise testing (CPET). METHODS: A retrospective analysis of consecutive ACS patients who underwent CR and CPET was undertaken. CPET was performed at baseline and after 36 sessions of exercise. Peak oxygen uptake (pVO2), percentage of predicted pVO2, minute ventilation/CO2 production (VE/VCO2) slope, VE/VCO2 slope/pVO2 and peak circulatory power (PCP) (pVO2 times peak systolic blood pressure) were assessed in two moments. The differences in pVO2 (ΔpVO2), %pVO2, PCP and exercise test duration were calculated. Patients were classified according to baseline pVO2 (group 1, <20 ml/kg/min vs. group 2, ≥20 ml/kg/min) and left ventricular ejection fraction (group A, <50% vs. group B, ≥50%). RESULTS: We analyzed 129 patients, 86% male, mean age 56.3±9.8 years. Both group 1 (n=31) and group 2 (n=98) showed significant improvement in FC after CR, with a more significant increase in pVO2, in group 1 (ΔpVO2 4.4±7.3 vs. 1.6±5.4; p=0.018). Significant improvement was observed in CPET parameters in group A (n=34) and group B (n=95), particularly in pVO2 and test duration. CONCLUSION: Patients with lower baseline pVO2 (<20 ml/kg/min) presented more significant improvement in FC after CR. CPET which is not routinely used in assessement before CR in context of ACS, could be a valuable tool to identify patients who will benefit the most.
- Collagen Type IV-Related Nephropathies in Portugal: Pathogenic COL4A5 Mutations and Clinical Characterization of 22 FamiliesPublication . Nabais Sá, MJ; Sampaio, S; Oliveira, A; Alves, S; Moura, CP; Silva, SE; Castro, R; Araújo, JA; Rodrigues, M; Neves, F; Seabra, J; Soares, C; Gaspar, MA; Tavares, I; Freitas, L; Sousa, TC; Henriques, AC; Costa, FT; Morgado, E; Sousa, FT; Sousa, JP; da Costa, AG; Filipe, R; Garrido, J; Montalban, J; Ponce, P; Alves, R; Faria, B; Carvalho, MF; Pestana, M; Carvalho, F; Oliveira, JPAlport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.
- Congenital Heart Disease in Adults: Assessment of Functional Capacity Using Cardiopulmonary Exercise TestinPublication . Aguiar Rosa, S; Agapito, A; Soares, RM; Sousa, L; Oliveira, JA; Abreu, A; Silva, AS; Alves, S; Aidos, H; Pinto, MF; Cruz Ferreira, RAIM: The aim of the study was to compare functional capacity in different types of congenital heart disease (CHD), as assessed by cardiopulmonary exercise testing (CPET). METHODS: A retrospective analysis was performed of adult patients with CHD who had undergone CPET in a single tertiary center. Diagnoses were divided into repaired tetralogy of Fallot, transposition of the great arteries (TGA) after Senning or Mustard procedures or congenitally corrected TGA, complex defects, shunts, left heart valve disease and right ventricular outflow tract obstruction. RESULTS: We analyzed 154 CPET cases. There were significant differences between groups, with the lowest peak oxygen consumption (VO2) values seen in patients with cardiac shunts (39% with Eisenmenger physiology) (17.2±7.1ml/kg/min, compared to 26.2±7.0ml/kg/min in tetralogy of Fallot patients; p<0.001), the lowest percentage of predicted peak VO2 in complex heart defects (50.1±13.0%) and the highest minute ventilation/carbon dioxide production slope in cardiac shunts (38.4±13.4). Chronotropism was impaired in patients with complex defects. Eisenmenger syndrome (n=17) was associated with the lowest peak VO2 (16.9±4.8 vs. 23.6±7.8ml/kg/min; p=0.001) and the highest minute ventilation/carbon dioxide production slope (44.8±14.7 vs. 31.0± 8.5; p=0.002). Age, cyanosis, CPET duration, peak systolic blood pressure, time to anaerobic threshold and heart rate at anaerobic threshold were predictors of the combined outcome of all-cause mortality and hospitalization for cardiac cause. CONCLUSION: Across the spectrum of CHD, cardiac shunts (particularly in those with Eisenmenger syndrome) and complex defects were associated with lower functional capacity and attenuated chronotropic response to exercise.
- Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast CancerPublication . Silva, G; Sales-Dias, J; Casal, D; Alves, S; Domenici, G; Barreto, C; Matos, C; Lemos, A; Matias, A; Kucheryava, K; Ferreira, A; Moita, MR; Braga, S; Brito, C; Cabral, MG; Casalou, C; Barral, D; Sousa, P; Videira, P; Bandeiras, T; Barbas, AThe Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER+) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER+ BC; however, relapse is a major clinical issue, and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment, which was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibited DLL1 specificity and affinity in the low nanomolar range and significantly impaired DLL1-Notch signaling and expression of Notch target genes in ER+ BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. These findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER+ BC, warranting further preclinical investigation.
- Impacto da Terapia de Ressincronização Cardíaca na Qualidade de Vida em Doentes com Insuficiência Cardíaca Congestiva RefractáriaPublication . Nave Leal, E; Pais Ribeiro, JL; Oliveira, MM; Nogueira da Silva, M; Feliciano, J; Cunha, P; Soares, RM; Santos, S; Alves, S; Rebelo da Silva, N; Cruz Ferreira, RA terapêutica de ressincronização cardíaca (TRC), associada ou não a cardioversor-desfibrilhador, está recomendada no tratamento de doentes com insuficiência cardíaca congestiva (ICC) refractária e disfunção sistólica grave do ventrículo esquerdo, com evidência de dessíncronia. Objectivo: avaliar o impacto da TRC na qualidade de vida de doentes com ICC refractária ao tratamento farmacológico optimizado.
- Incidência de "Falsos-Positivos" em Idosos com Fibrilhação Auricular Paroxística Submetidos a Teste de InclinaçãoPublication . Oliveira, MM; Feliciano, J; Timóteo, AT; Nogueira da Silva, M; Antunes, E; Silva, S; Alves, S; Silva-Carvalho, L; Cruz Ferreira, RThe autonomic nervous system (ANS) plays a role as a modulator in the pathogenesis of paroxysmal atrial fibrillation (PAF). The clinical pattern of vagally mediated PAF has been observed mainly in young patients. Neurocardiogenic responses during orthostatic stress are related to autonomic reflexes in which the vagal influence predominates. AIM: To evaluate the susceptibility of elderly patients with PAF to activation of vasovagal syncope mechanisms. METHODS: We performed passive head-up tilt testing (HUT) in 34 patients (62% women, aged 72 +/- 7 years), with > or = 1 year of clinical history of PAF--19 without structural heart disease, 11 with hypertensive heart disease and 4 with coronary artery disease (who had no previous myocardial infarction, had undergone myocardial revascularization, and had no documented ischemia) (PAF group), and compared the results with those obtained in a group of 34 age-matched patients (53% women, aged 74 +/- 6 years), who underwent HUT due to recurrent syncope (Sc group). In this group, 21 had no documented heart disease and none had a clinical history of AF. There was no diabetes, congestive heart failure or syncope in the PAF group. After a supine resting period, the subjects were tilted at 70 degrees for 20 minutes while in sinus rhythm. No provocative agents were used to complement the HUT. ECG and blood pressure were continuously monitored (Task Force Monitor, CNSystems). The test was considered positive when syncope or presyncope occurred with bradycardia and/or arterial hypotension. Abnormal responses were classified as cardioinhibitory, vasodepressor or mixed. RESULTS: HUT was positive in seven patients of the PAF group--vasodepressor response in five and mixed in two (20.5% of the total; 26.3% of those without heart disease)--and in eight patients (vasodepressor in six and mixed in two) of the Sc group (p=NS). During HUT, three patients of the PAF group had short periods of self-limited PAF (in one, after vasodepressor syncope). There were no differences in gender distribution, age or heart disease. No cardioinhibitory responses or orthostatic hypotension were observed. CONCLUSION: In elderly patients with PAF, a significant number of false positive results during passive HUT may be expected, suggesting increased vasovagal reactions despite aging. This suggests that ANS imbalances may be observed in this population.
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