Noradrenergic modulatoins of odor learning and odor representation in the rat

How experience alters neuronal ensemble dynamics and how locus coeruleus-mediated norepinephrine release facilitates memory formation in the brain are the topics of this thesis. Here we employed a visualization technique, cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH), to assess activation patterns of neuronal ensembles in the olfactory bulb (OB) and anterior piriform cortex (aPC) to repeated odor inputs. Two associative learning models were used, early odor preference learning in rat pups and adult rat go-no-go odor discrimination learning. With catFISH of an immediate early gene, Arc, we showed that odor representation in the OB and aPC was sparse (~5-10%) and widely distributed. Odor associative learning enhanced the stability of the rewarded odor representation in the OB and aPC. The stable component, indexed by the overlap between the two ensembles activated by the rewarded odor at two time points, increased from ~25% to ~50% (p = 0.004-1.43E⁻4; Chapter 3 and 4). Adult odor discrimination learning promoted pattern separation between rewarded and unrewarded odor representations in the aPC. The overlap between rewarded and unrewarded odor representations reduced from ~25% to ~14% (p = 2.28E⁻⁵). However, learning an odor mixture as a rewarded odor increased the overlap of the component odor representations in the aPC from ~23% to ~44% (p = 0.010; Chapter 4). Blocking both α- and β-adrenoreceptors in the aPC prevented highly similar odor discrimination learning in adult rats, and reduced OB mitral and granule ensemble stability to the rewarded odor. Similar treatment in the OB only slowed odor discrimination learning. However, OB adrenoceptor blockade disrupted pattern separation and ensemble stability in the aPC when the rats demonstrated deficiency in discrimination (Chapter 5). In another project, the role of α₂-adrenoreceptors in the OB during early odor preference learning was studied. OB α2-adrenoceptor activation was necessary for odor learning in rat pups. α₂-adrenoceptor activation was additive with β-adrenoceptor mediated signalling to promote learning (Chapter 2). Together, these experiments suggest that odor representations are highly adaptive at the early stages of odor processing. The OB and aPC work in concert to support odor learning and top-down adrenergic input exerts a powerful modulation on both learning and odor representation.

School and Community Screening Shows Malawi, Africa, to Have a High Prevalence of Latent Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the largest cardiac cause of morbidity and mortality in the world's youth. Early detection of RHD through echocardiographic screening in asymptomatic children may identify an early stage of disease, when secondary prophylaxis has the greatest chance of stopping disease progression. Latent RHD signifies echocardiographic evidence of RHD with no known history of acute rheumatic fever and no clinical symptoms.

OBJECTIVE: Determine the prevalence of latent RHD among children ages 5-16 in Lilongwe, Malawi.

DESIGN: This is a cross-sectional study in which children ages 5 through 16 were screened for RHD using echocardiography.

SETTING: Screening was conducted in 3 schools and surrounding communities in the Lilongwe district of Malawi between February and April 2014.

OUTCOME MEASURES: Children were diagnosed as having no, borderline, or definite RHD as defined by World Heart Federation criteria. The primary reader completed offline reads of all studies. A second reader reviewed all of the studies diagnosed as RHD, plus a selection of normal studies. A third reader served as tiebreaker for discordant diagnoses. The distribution of results was compared between gender, location, and age categories using Fisher's exact test.

RESULTS: The prevalence of latent RHD was 3.4% (95% CI = 2.45, 4.31), with 0.7% definite RHD and 2.7% borderline RHD. There was no significant differences in prevalence between gender (P = .44), site (P = .6), urban vs. peri-urban (P = .75), or age (P = .79). Of those with definite RHD, all were diagnosed because of pathologic mitral regurgitation (MR) and 2 morphologic features of the mitral valve. Of those with borderline RHD, most met the criteria by having pathological MR (92.3%).

CONCLUSION: Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

Outcome Measures in Polymyalgia Rheumatica. A Systematic Review

OBJECTIVE: To identify the instruments used to assess polymyalgia rheumatica (PMR) in published studies. METHODS: A systematic literature review of clinical trials and longitudinal observational studies related to PMR, published from 1970 to 2014, was carried out. All outcome and assessment instruments were extracted and categorized according to core areas and domains, as defined by the OMERACT (Outcome Measures in Rheumatology) Filter 2.0. RESULTS: Thirty-five articles (3221 patients) were included: 12 randomized controlled trials (RCT); 3 nonrandomized trials; and 20 observational studies. More than 20 domains were identified, measured by 29 different instruments. The most frequently used measures were pain, morning stiffness, patient global assessment and physician global assessment, erythrocyte sedimentation rate, and C-reactive protein. The definition of outcomes varied considerably between studies. CONCLUSION: The outcome measures and instruments used in PMR are numerous and diversely defined. The establishment of a core set of validated and standardized outcome measurements is needed.

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor.

Oclusão percutânea do apêndice auricular esquerdo e estrutura auricular: efeito na função mecânica e endócrina auricular

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular - Área de especialização: Intervenção Cardiovascular.

Agrandissement des feuillets mitraux en insuffisance aortique : un mécanisme actif pouvant prévenir l’insuffisance mitrale dans le ventricule dilaté

L’insuffisance mitrale (IM) fonctionnelle est une complication fréquente des cardiopathies, causée par la dilatation du ventricule gauche (VG) qui empêche la valve de se fermer. L’insuffisance aortique (IA) est une condition associée à des valves mitrales (VM) inhabituellement grandes, et relativement peu d’IM malgré des VG très dilatés. Cet élargissement de la VM a le potentiel de prévenir l’IM dans les VG dilatés. Les mécanismes sont cependant peu compris : il n’est pas clair s’il s’agit d’une croissance active ou d’un étirement passif des feuillets. Également, le timing de l’adaptation valvulaire n’est pas connu. Notre hypothèse est que l’agrandissement de la valve mitrale en IA est un phénomène actif avec réactivation des mécanismes de croissance embryonnaire. Cent-onze rats ont été divisés en deux groupes : IA (perforation aortique) et contrôle. Les animaux ont été sacrifiés à 48 h, 1 semaine et 3 mois après la création du modèle. Des échocardiographies ont évalué la sévérité de l’IA, la présence d’IM et les dimensions du VG. Les valves ont été prélevées pour analyses microscopiques et moléculaires. La création de l’insuffisance aortique a entrainé une dilatation et une hypertrophie du VG. Malgré cette dilatation rapide du VG, aucun animal n’a développé de l’IM fonctionnelle. À l’échographie, le feuillet antérieur mitral était significativement plus long dans les groupes IA. Par microscopie, les feuillets étaient plus épais dés la première semaine. L’IA était associée à une surexpression de collagène α-SMA (un marqueur de myofibroblastes), TGF-β1 et MMP-2 dans le tissu valvulaire dès la première semaine. Les valves exposées à l’IA étaient également positives pour ces différents facteurs dés les premiers jours. L’agrandissement de la VM est un phénomène actif qui survient rapidement après la création de l’IA, en parallèle de la dilatation du VG. La stimulation de cette croissance dans d’autres pathologies pourrait contribuer à prévenir l’IM fonctionnelle.

Two cases of right atrial myxoma in redo patients. A mere coincidence?

We describe two cases of right atrial myxoma in redo patients who had previously undergone to coronary artery by-pass grafting (CABGs) and mitral valve replacement respectively. Both of patients experienced effort dyspnea and were assessed by trans-thoracic echocardiography, revealing the right atrial masses. They were operated on for myxoma resection and postoperative course was uneventful. Our report deals with the interesting topic of the location of benign masses that are usually more common in the left atrium. Should we hypothesize that the right atrial manipulation during the previous surgery induces the onset of the right atrial mass? It is an interesting matter to debate.

Outcome Measures in Polymyalgia Rheumatica. A Systematic Review

OBJECTIVE: To identify the instruments used to assess polymyalgia rheumatica (PMR) in published studies. METHODS: A systematic literature review of clinical trials and longitudinal observational studies related to PMR, published from 1970 to 2014, was carried out. All outcome and assessment instruments were extracted and categorized according to core areas and domains, as defined by the OMERACT (Outcome Measures in Rheumatology) Filter 2.0. RESULTS: Thirty-five articles (3221 patients) were included: 12 randomized controlled trials (RCT); 3 nonrandomized trials; and 20 observational studies. More than 20 domains were identified, measured by 29 different instruments. The most frequently used measures were pain, morning stiffness, patient global assessment and physician global assessment, erythrocyte sedimentation rate, and C-reactive protein. The definition of outcomes varied considerably between studies. CONCLUSION: The outcome measures and instruments used in PMR are numerous and diversely defined. The establishment of a core set of validated and standardized outcome measurements is needed.

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor.

Behind Recurrent Thromboembolic Events

We describe the case of a 68-year-old man, who presented with an ischemic stroke due to cardiac embolization related to mitral valve endocarditis. Blood cultures were always negative and post-operative valve histology did not show microorganisms. The patient also presented further recurrent peripheral embolic events. These clinical aspects were the first sign of a pancreas adenocarcinoma, which was only diagnosed in the clinical autopsy. In conclusion, these clinical findings of recurrent thromboembolic events with no microorganisms isolated suggests the diagnostic of a marantic endocarditis.

Estudo funcional e fenotípico das células NK em esclerose sistémica

Introdução: A esclerose sistémica (ES) é uma doença reumática rara, onde se verifica uma reacção auto-imune, afectando o tecido conjuntivo. De etiologia desconhecida, esta patologia, dividide-se em dois subtipos: limitada e difusa, tendo como processos característicos e inter-relacionados: a lesão vascular, a reacção autoimune e a fibrose. As células NK modulam as doenças auto-imunes através das suas capacidades citotóxicas e de produção de citocinas. Deste modo procedeu-se ao estudo imunofenotípico e funcional de duas sub-populações de células Natural Killer (NK) (NK CD56dim e NK CD56bright). Métodos: Recorrendo à citometria de fluxo, caracterizamos fenotipicamente as células NK, com base na expressão de CD49e, CD29 e LAIR-1; funcionalmente, com base nas citocinas TNF-α e IFN-γ e citotoxicamente, com base na granzima B e na perforina. Resultados: Os nossos resultados sugerem uma diminuição da percentagem e valor absoluto de células NK totais e suas subpopulações, NK CD56dim e NK CD56bright, em doentes com ES, sobretudo na presença de úlceras digitais (UD) e fibrose pulmonar (FP). Observamos ainda uma diminuição da expressão de CD49e e um aumento da expressão de LAIR-1, nas células NK, em doentes com ES, principalmente nos que não apresentavam UD e FP. Num modo geral observou-se um aumento da frequência de células NK a expressar granzima B e perforina e um aumento da expressão destas duas proteínas. Conclusão: Concluímos que as células NK poderão ter um papel importante na fisiopatologia da ES, pelas alterações fenotípicas e funcionais, podendo, futuramente vir a ser utilizados na monitorização da severidade desta doença.

Importância do eletrocardiograma de doze derivações na localização da via acessória no padrão de Wolff-Parkinson-White

A ablação por cateter de radiofrequência tornou-se o tratamento de escolha para os pacientes com síndrome de Wolff-Parkinson-White, sintomáticos. A localização da via acessória a partir da morfologia do QRS no eletrocardiograma basal, torna-se útil para o planeamento do procedimento de ablação, por permitir um conjunto de informações que ajudam na escolha da melhor abordagem terapêutica, em particular no que respeita ao intervalo para a ablação, a necessidade de punção transeptal e o risco de bloqueio aurículo-ventricular, se a via acessória estiver próxima do nódulo aurículo-ventricular ou do feixe de His. Estão descritos vários algoritmos para prever a localização da via acessória a partir da análise da morfologia do QRS basal. Os seus autores relatam elevados índices de acerto, todavia, estudos subsequentes obtiveram resultados distintos, com índices de acerto menores. O presente estudo tem como objetivo principal a avaliação da capacidade diagnóstica do eletrocardiograma de doze derivações na localização da via acessória no padrão de Wolff- Parkinson-White. Os dados clínicos necessários a este estudo foram recolhidos no Serviço de Cardiologia do Centro Hospitalar S. João – EPE, através da consulta dos exames eletrocardiograma e estudo eletrofisiológico, nos indivíduos com diagnóstico prévio de síndrome de Wolff-Parkinson- White. Numa amostra formada por 111 indivíduos de ambos os géneros e com idade média de 36,54 (± 15,27) anos (idade mínima de 7 anos e idade máxima de 75 anos), procedeu-se à comparação da localização da via acessória no estudo eletrofisiológico, com a obtida pela aplicação dos algoritmos de Arruda et al., Boersma et al., Chiang et al., Ávila et al., Fitzpatrick et al., Iturralde et al. e Xie et al. (harmonizadas para todos os algoritmos, as localizações possíveis das vias acessórias). Em volta do anel mitral, encontravam-se distribuídas 59 vias acessórias (53,15%), sendo 52 as vias acessorias distribuídas em torno do anel tricúspide (46,85%). Nesta distribuição não se observaram diferenças estatisticamente significativas de acordo com o género. O acerto global em todos os algoritmos variou entre 27,00% a 47,00%, aumentando para 40,00% a 76,00%, incluindo as localizações adjacentes. A concordância entre os investigadores variou entre 40,00% a 80,00%, observando-se que em relação ao valor médio de concordância, os algoritmos com menores localizações possíveis para as vias acessórias, obtiveram melhor resultado (64,00%). O acerto para as vias acessórias septais (51 no total) variou entre 2,00% a 52,20% (aumentando para 5,90% a 90,20%, incluindo as localizações adjacentes). As vias acessórias direitas, 13 no total, obtiveram acerto entre 7,70% a 69,20% (aumentando para 42,90% a 100%, incluindo as vias acessórias adjacentes). Por último, as vias acessórios esquerdas, 47 no total, obtiveram acerto entre 21,70% a 54,50% (aumentando para 50,00% a 87,00%, incluindo as vias acessórias adjacentes). Para esta distribuição das vias acessórias (localização septal, direita e esquerda), não se observaram diferenças estatisticamente significativas, de acordo com o género. Os resultados obtidos revelam que todos os algoritmos obtiveram valores de acerto inferiores aos enunciados pelos seus autores, permitindo concluir que embora o eletrocardiograma constitua um método muito importante no diagnóstico da pré-excitação ventricular do tipo Wolff-Parkinson-White, este não é sensível, nem específico para a deteção da localização da via acessória.

La ateromatosis aórtica aumenta el riesgo de ataque cerebrovascular isquémico

Antecedentes: el ataque cerebrovascular isquémico (ACVi) es causa de mortalidad y discapacidad importante en adultos, siendo la cardioembolia, sobre todo por fibrilación auricular (FA), una etiología importante. Se conocen otras etiologías, cardíacas y no cardíacas, que no siempre pueden definirse, refiriéndose como probables o posibles de cardioaortoembolia. El rol de alguna de ellas, como la ateromatosis aórtica (AA), continúa siendo discutido. Objetivo: analizar fuentes posibles de cardioaortoembolia en pacientes con ACVi reciente. Material y método: estudio caso-control. Se analizaron 100 sujetos con ACVi de menos de 30 días de evolución estudiados prospectivamente con ecocardiograma transesofágico (ETE), entre febrero de 2012 y marzo de 2014. Se apareó cada caso según edad, sexo, presencia de flutter/FA y ausencia de prótesis valvular cardíaca, con un control que se buscó retrospectiva y aleatoriamente entre sujetos con ETE estudiados entre 2010 y 2015 sin ACVi. Se compararon variables binarias mediante test de McNemar y las cuantitativas por test de t pareado; se realizó regresión logística múltiple para ACVi con variables clínicas y hallazgos de ETE y p < 0,1 en el análisis univariado. Se consideró significativo p < 0,05. Variables cuantitativas se expresan en media y desvío estándar (DE) y nominales en valor absoluto y porcentaje, índice de probabilidad (OR) en su valor e intervalo de confianza (IC) 95%. Resultados: se formaron finalmente 76 pares caso-control. Edad casos: 64,3±1,4 y control 64,9±1,3 años (p=0,19); 39 mujeres (51,3%) y 15 sujetos (19,7%) con flutter/FA en cada grupo (p=1). No hubo diferencias significativas según factores de riesgo cardiovascular (FRCV) globales (p=0,06) ni alcoholismo (p=0,80); se encontraron diferencias significativas en la prevalencia de dislipemia (p=0,03) e hipertensión arterial (HTA) (p <0,05). Las indicaciones principales del ETE en los controles fueron: previo a cardioversión eléctrica de FA, sospecha de endocarditis, y valoración de valvulopatía mitral. La ateromatosis aórtica proximal y compleja (AAPC) (p=0,002, OR 5,5, IC95% 1,9-15,9) y la AA en forma global (p=0,001, OR 4,1, IC95% 1,8-9,3), además de la dislipemia (p=0,02, OR 2,8 IC95% 1,2-6,4), se asociaron significativamente con la presencia de ACVi en el análisis multivariado. Conclusión: la AA aumenta significativamente las chances de ACVi y las quintuplica cuando es proximal y compleja. La dislipemia se asoció a ACVi.

Estágio realizado no Programa Comunitário PLE²NO

A OA é a doença reumática mais comum no ser humano e uma doença crónica com impacto elevado na sociedade. Tem repercussões na saúde, ao nível da funcionalidade, comprometendo a realização das atividades da vida diária e a qualidade de vida dos indivíduos. Uma das articulações mais afetada pela OA é a articulação do joelho. O tratamento eficaz requer a combinação de tratamentos farmacológicos e não farmacológicos. Os tratamentos não farmacológicos, principalmente o exercício e a educação do doente têm vindo a ganhar importância, no que se refere ao controlo dos sintomas. A realização do estágio curricular surge no programa comunitário PLE²NO. O programa é considerado uma opção não farmacológica no tratamento e controlo dos sintomas da Osteoartrose (OA) no joelho. Os principais objetivos do estágio no PLE²NO consistiram: aquisição de conhecimentos teóricos relacionados com OA e práticos com vista ao aperfeiçoamento da prescrição do exercício; aquisição de competências essenciais à ótima liderança e comunicação com as pessoas e instituições envolvidas; prescrição de exercício a indivíduos com OA no joelho; cativar e motivar as pessoas para a prática de exercício; e determinar a eficácia de um programa de 3 meses de educação e exercício nos sintomas, aptidão física e qualidade de vida dos idosos com OA no joelho. Na aptidão física verificaram-se diferenças significativas na capacidade aeróbia, flexibilidade e velocidade da marcha. Nos indicadores de saúde houve melhoria em praticamente todos os parâmetros avaliados: mobilidade, cuidados pessoais, dor/mal-estar e sintomas de ansiedade/depressão. Assim, esta intervenção revelou-se ser uma mais-valia para o tratamento não farmacológico da osteoartrose do joelho a médio prazo.

Brachycephalic obstructive airway syndrome : a review with six clinical cases

Dissertação de Mestrado Integrado em Medicina Veterinária