Descending pain modulation in a Kaolin-induced hydrocephalus rat model

Pain transmission at the spinal cord is modulated by descending actions that arise from supraspinal areas which collectively form the endogenous pain control system. Two key areas involved of the endogenous pain control system have a circunventricular location, namely the periaqueductal grey (PAG) and the locus coeruleus (LC). The PAG plays a crucial role in descending pain modulation as it conveys the input from higher brain centers to the spinal cord. As to the LC, it is involved in descending pain inhibition by direct noradrenergic projections to the spinal cord. In the context of neurological defects, several diseases may affect the structure and function of the brain. Hydrocephalus is a congenital or acquired disease characterized by an enlargement of the ventricles which leads to a distortion of the adjacent tissues, including the PAG and LC. Usually, patients suffering from hydrocephalus present dysfunctions in learning and memory and also motor deficits. It remains to be evaluated if lesions of the periventricular brain areas involved in pain control during hydrocephalus may affect descending pain control and, herein, affect pain responses. The studies included in the present thesis used an experimental model of hydrocephalus (the rat injected in the cisterna magna with kaolin) to study descending modulation of pain, focusing on the two circumventricular regions referred above (the PAG and the LC). In order to evaluate the effects of kaolin injection into the cisterna magna, we measured the degree of ventricular dilatation in sections encompassing the PAG by standard cytoarquitectonic stanings (thionin staining). For the LC, immunodetection of the noradrenaline-synthetizing enzyme tyrosine hydroxylase (TH) was performed, due to the noradrenergic nature of the LC neurons. In general, rats with kaolin-induced hydrocephalus presented a higher dilatation of the 4th ventricle, along with a tendency to a higher area of the PAG. Due to the validated role of detection the c-fos protooncogene as a marker of neuronal activation, we also studied neuronal activation in the several subnuclei which compose the PAG, namely the dorsomedial, dorsolateral, lateral and ventrolateral (VLPAG) parts. A decrease in the numbers of neurons immunoreactive for Fos protein (the product of activation of the c-fos protooncogene) was detected in rats injected with kaolin, whereas the remaining PAG subnuclei did not present changes in Fos-immunoreactive nuclei. Increases in the levels of TH in the LC, namely at the rostral parts of the nucleus, were detected in hydrocephalic animals. The following pain-related parameters were measured, namely 1) pain behavioural responses in a validated pain inflammatory test (the formalin test) and 2) the nociceptive activation of spinal cord neurons. A decrease in behavioral responses was detected in rats with kaolin-induced hydrocephalus was detected, namely in the second phase of the test (inflammatory phase). This is the phase of the formalin test in which the motor behaviour is less important, which is important since a semi-quantitative analysis of the motor performance of rats injected with kaolin indicates that these animals may present some motor impairments. Collectively, the results of the behavioral studies indicate that rats with kaolin-induced hydrocephalus exhibit hypoalgesia. A decrease in Fos expression was detected at the superficial dorsal layers of the spinal cord in rats with kaolin-induced hydrocephalus, further indicating that hydrocephalus decreases nociceptive responses. It remains to be ascertained if this is due to alterations in the PAG and LC in the rats with kaolin-induced hydrocephalus, which may affect descending pain modulation. It remains to be evaluated what are the mechanisms underlying the increased pain inhibition at the spinal dorsal horn in the hydrocephalus rats. Regarding the VLPAG, the decrease in neuronal activity may impair descending modulation. Since the LC has higher levels of TH in rats with kaolininduced hydrocephalus, which also appears to increase the noradrenergic innervation in the spinal dorsal horn, it is possible that an increase in the release of noradrenaline at the spinal cord accounts for pain inhibition. Our studies also determine the need to study in detail patients with hydrocephalus namely in what concerns their thresholds to pain and to perform imaging studies focused on the structure and function of pain control areas in the brain.

Cavin 1 and cavin 2 roles on adipocyte cell function

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina

Microglial clearance function: dependence on phenotypes

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina

On the numerical computation of the Mittag-Leffler function

Recently simple limiting functions establishing upper and lower bounds on the Mittag-Leffler function were found. This paper follows those expressions to design an efficient algorithm for the approximate calculation of expressions usual in fractional-order control systems. The numerical experiments demonstrate the superior efficiency of the proposed method.

Molecular modulation of brain development and function: lessons from “old” and “new”

Dissertation presented to obtain the Ph.D degree in Biology

Utilidade do Doppler Tecidular na Predição de Eventos Arrítmicos em Adultos com Tetralogia de Fallot Corrigida

INTRODUCTION: Adults with repaired tetralogy of Fallot (TOF) may be at risk for progressive right ventricular (RV) dilatation and dysfunction, which is commonly associated with arrhythmic events. In frequently volume-overloaded patients with congenital heart disease, tissue Doppler imaging (TDI) is particularly useful for assessing RV function. However, it is not known whether RV TDI can predict outcome in this population. OBJECTIVE: To evaluate whether RV TDI parameters are associated with supraventricular arrhythmic events in adults with repaired TOF. METHODS: We studied 40 consecutive patients with repaired TOF (mean age 35 +/- 11 years, 62% male) referred for routine echocardiographic exam between 2007 and 2008. The following echocardiographic measurements were obtained: left ventricular (LV) ejection fraction, LV end-systolic volume, LV end-diastolic volume, RV fractional area change, RV end-systolic area, RV end-diastolic area, left and right atrial volumes, mitral E and A velocities, RV myocardial performance index (Tei index), tricuspid annular plane systolic excursion (TAPSE), myocardial isovolumic acceleration (IVA), pulmonary regurgitation color flow area, TDI basal lateral, septal and RV lateral peak diastolic and systolic annular velocities (E' 1, A' 1, S' 1, E' s, A' s, S' s, E' rv, A' rv, S' rv), strain, strain rate and tissue tracking of the same segments. QRS duration on resting ECG, total duration of Bruce treadmill exercise stress test and presence of exercise-induced arrhythmias were also analyzed. The patients were subsequently divided into two groups: Group 1--12 patients with previous documented supraventricular arrhythmias (atrial tachycardia, fibrillation or flutter) and Group 2 (control group)--28 patients with no previous arrhythmic events. Univariate and multivariate analysis was used to assess the statistical association between the studied parameters and arrhythmic events. RESULTS: Patients with previous events were older (41 +/- 14 vs. 31 +/- 6 years, p = 0.005), had wider QRS (173 +/- 20 vs. 140 +/- 32 ms, p = 0.01) and lower maximum heart rate on treadmill stress testing (69 +/- 35 vs. 92 +/- 9%, p = 0.03). All patients were in NYHA class I or II. Clinical characteristics including age at corrective surgery, previous palliative surgery and residual defects did not differ significantly between the two groups. Left and right cardiac chamber dimensions and ventricular and valvular function as evaluated by conventional Doppler parameters were also not significantly different. Right ventricular strain and strain rate were similar between the groups. However, right ventricular myocardial TDI systolic (Sa: 5.4+2 vs. 8.5 +/- 3, p = 0.004) and diastolic indices and velocities (Ea, Aa, septal E/Ea, and RV free wall tissue tracking) were significantly reduced in patients with arrhythmias compared to the control group. Multivariate linear regression analysis identified RV early diastolic velocity as the sole variable independently associated with arrhythmic history (RV Ea: 4.5 +/- 1 vs. 6.7 +/- 2 cm/s, p = 0.01). A cut-off for RV Ea of < 6.1 cm/s identified patients in the arrhythmic group with 86% sensitivity and 59% specificity (AUC = 0.8). CONCLUSIONS: Our results suggest that TDI may detect RV dysfunction in patients with apparently normal function as assessed by conventional echocardiographic parameters. Reduction in RV early diastolic velocity appears to be an early abnormality and is associated with occurrence of arrhythmic events. TDI may be useful in risk stratification of patients with repaired tetralogy of Fallot.

Analysis of Systems with Backlash and Impacts through the Describing Function

This paper analyses the dynamical properties of systems with backlash and impact phenomena based on the describing function method. The dynamics is illustrated using the Nyquist and Bode plots and the results are compared with those of standard models.

Avaliação Preoperatória do Doente Vascular

Periferal vascular disease usually results from a systemic entity in which atherothrombosis develops in different vascular territories, having common risk factors. It is hence usual to find coexistent, often subclinical, coronary artery disease, which is responsible for most of perioperatory morbidity and mortality in patients submitted to vascular surgery. An adequate preoperatory risk stratification must be accomplished, having in mind the clinical manifestations, risk factors, comorbidities, functional capacity and global left ventricular systolic function of the patient. He should be included in one of three different subgroups: low, high or intermediate risk, which might reinforce the need for further testing, most often aiming at the detection of coronary artery disease and foresee the short, medium and long term outcome. This strategy is very important and it is in part due to it and to better medical/surgical and anesthetic care that the surgical results have markedly improved in recent years. In this paper a state of the art is done of the guidelines to follow and the results of several studies performed on this subject. The role of methods to detect coronary ischemia is remarked, using either nuclear or echocardiographic techniques for this purpose.

Tratamento Cirúrgico dos Defeitos do Septo Auriculo-Ventricular. Experiência Uni-Institucional

OBJECTIVES: Atrio-ventricular septal (AVSD) defects include a variable spectrum of congenital malformations with different forms of clinical presentation. We report the surgical results, from a single institution, with this type of congenital cardiac malformation. Patients with hypoplasia of one of the ventricles were excluded from this analysis. POPULATION: Between November of 1998 and June of 2005, 49 patients with AVSD were operated on by the same team and in the same department. The average age was 37.3 months (medium 6 months) and 31 patients were female. In 38 patients (78%) an inter-ventricular communication was present (AVSD-complete) and of these, 26 were of the type A of Rastelli, being 13 of type B or C. The age for defect correction of the complete form was of 5.5 months, palliative surgery was not carried out on any of the patients. Associated lesions included: Down's syndrome in 22 patients (45%), patent arterial duct in 17 patients (35%), severe AV regurgitation in 4 patients (8%), tetralogy of Fallot in two (4%) and sub-aortic stenosis in one patient (2%). Pre-operatively 10 patients presented severe congestive heart failure and two were mechanically ventilated. RESULTS: Complete biventricular correction was carried out in all patients. The average time on bypass (ECC) was 74.1+/-17.5 min. and time of aortic clamping was 52.0+/-12.9 min. The complete defects were corrected by the double patch technique, and in all patients the mitral cleft was closed, except in two with single papillary muscle. There was no intra-operative mortality, but hospital mortality was 8%(4 patients), due to pulmonary hypertension crises, in the first 15 post-operative days. The mean ventilation time was of 36.5+/-93 hours (medium 7 h) and the average ICU stay was of 4.3+/-4.8 days (medium 3 days). The minimum follow-up period is 1 month and the maximum is 84 months (medium 29.5 months), during which time 4 re-operations (8%) took place: two for residual VSD's and two for mitral regurgitation. There was no mortality at re-do surgery. At follow up there was residual mitral regurgitation, mild in 17 patients and moderate in two. Four other patients presented with minor residual defects. CONCLUSIONS: The complete correction of AVSD can be carried out with acceptable results, in a varied spectrum of anatomic forms and of clinical severity. Despite the age of correction, for the complete forms, predominantly below 12 months, pulmonary hypertension was the constant cause for post operative mortality. Earlier timing of surgery and stricter peri-operative control might still improve results.

Assistência Ventricular em Crianças

Descreve-se a utilização de um sistema de assistência mecânica bi-ventricular, para-corpórea (Berlin Heart), como ponte para transplante, numa criança de dois anos, sofrendo de miocardiopatia dilatada. O período de assistência durou três meses e meio e o transplante foi bem sucedido. Descreve-se o caso clínico, os protocolos usados e revêem-se as indicações, as técnicas e os problemas com a assistência ventricular mecânica em crianças.

Adrenal function in 23 children with paracoccidioidomycosis

Adrenal involvement by Paracoccidioides brasiliensis was described at necropsies and in many clinical studies, but only in adults. Therefore, the aim of this study was to evaluate adrenal function in children with paracoccidioidomycosis. Twenty-three children with the systemic form of paracoccidioidomycosis were evaluated and divided in two Groups: Group A (n = 8) included children before treatment and Group B (n = 15) children after the end of treatment. Plasma cortisol (basal and after ACTH test), ACTH, renin activity, aldosterone, sodium and potassium were measured. They were within normal range in all cases, except for renin activity and aldosterone, which were elevated in some cases. Group A patients showed basal and post-ACTH cortisol levels significantly greater than Group B patients. The results showed that adrenal function was not compromised in these children with paracoccidioidomycosis.

Inducibility of Atrial Fibrillation During Electrophysiologic Evaluation is Associated with Increased Dispersion of Atrial Refractoriness

The impact of atrial dispersion of refractoriness (Disp_A) in the inducibility and maintenance of atrial fibrillation (AF) has not been fully resolved. AIM: To study the Disp_A and the vulnerability (A_Vuln) for the induction of self-limited (<60 s) and sustained episodes of AF. METHODS AND RESULTS: Forty-seven patients with paroxysmal AF (PAF): 29 patients without structural heart disease and 18 with hypertensive heart disease. Atrial effective refractory period (ERP) was assessed at five sites--right atrial appendage and low lateral right atrium, high interatrial septum, proximal and distal coronary sinus. We compared three groups: group A - AF not inducible (n=13); group B - AF inducible, self-limited (n=18); group C - AF inducible, sustained (n=16). Age, lone AF, hypertension, left atrial and left ventricular (LV) dimensions, LV systolic function, duration of AF history, atrial flutter/tachycardia, previous antiarrhythmics, and Disp_A were analysed with logistic regression to determine association with A_Vuln for AF inducibility. The ERP at different sites showed no differences among the groups. Group A had a lower Disp_A compared to group B (47+/-20 ms vs 82+/-65 ms; p=0.002), and when compared to group C (47+/-20 ms vs 80+/-55 ms; p=0.008). There was no significant difference in Disp_A between groups B and C. By means of multivariate regression analysis, the only predictor of A_Vuln was Disp_A (p=0.04). Conclusion: In patients with PAF, increased Disp_A represents an electrophysiological marker of A_Vuln. Inducibility of both self-limited and sustained episodes of AF is associated with similar values of Disp_A. These findings suggest that the maintenance of AF is influenced by additional factors.

Incidência de Arritmias Ventriculares em Doentes com Disfunção Sistólica Ventricular Esquerda Grave: Existe Benefício Após Terapêutica de Ressincronização Cardíaca

Introdução: A terapêutica de ressincronização cardíaca (TRC) tem benefícios significativos em doentes seleccionados. O impacto desta modalidade na incidência de taquidisritmias ventriculares permanece controverso. Analisámos a ocorrência de terapêuticas apropriadas em doentes submetidos a TRC combinada com cardioversor-desfibrilhador (CDI). Métodos: Estudo de 123 doentes com fracção de ejecção ventricular esquerda (FEVE) < 35%, submetidos a implantação com sucesso de TRC-CDI ou CDI isoladamente (prevenção primária). Resultados: Idade média foi 63±12 anos, FEVE de 25±6%, seguimento mediano de 372 dias. Implantou-se TRC-CDI em 63 doentes (grupo A) e CDI isoladamente em 60 doentes (grupo B). No grupo A tivemos 86% de respondedores clínicos, menor prevalência de miocardiopatia isquémica(30% versus 72%), e mais doentes em classe III da NYHA antes da implantação do dispositivo(90% versus 7%) comparativamente com o grupo com CDI isoladamente. Não se identificaram diferenças relativamente à incidência de terapêuticas apropriadas (19% versus 12%) ou no tempo para a primeira terapêutica (305 dias versus 293 dias). A mortalidade total foi de 11% no grupo A e de 12% no grupo B. As curvas de Kaplan-Meier para eventos arrítmicos em doentes com TRC, não mostraram diferenças significativas (HR 3,02, IC 95% 0,82-11,09, p = NS) comparativamente com doentes sem TRC. Conclusões: Em doentes submetidos a TRC-CDI por prevenção primária, apesar da elevada taxa de respondedores, a incidência de terapêuticas apropriadas não foi diferente do obtido em doentes com CDI isoladamente.