Parasite neuropeptide biology:Seeding rational drug target selection?

The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components - putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths.

Self correction of refractive error among young people in rural China: results of cross sectional investigation.

OBJECTIVE: To compare outcomes between adjustable spectacles and conventional methods for refraction in young people. DESIGN: Cross sectional study. SETTING: Rural southern China. PARTICIPANTS: 648 young people aged 12-18 (mean 14.9 (SD 0.98)), with uncorrected visual acuity ≤ 6/12 in either eye. INTERVENTIONS: All participants underwent self refraction without cycloplegia (paralysis of near focusing ability with topical eye drops), automated refraction without cycloplegia, and subjective refraction by an ophthalmologist with cycloplegia. MAIN OUTCOME MEASURES: Uncorrected and corrected vision, improvement of vision (lines on a chart), and refractive error. RESULTS: Among the participants, 59% (384) were girls, 44% (288) wore spectacles, and 61% (393/648) had 2.00 dioptres or more of myopia in the right eye. All completed self refraction. The proportion with visual acuity ≥ 6/7.5 in the better eye was 5.2% (95% confidence interval 3.6% to 6.9%) for uncorrected vision, 30.2% (25.7% to 34.8%) for currently worn spectacles, 96.9% (95.5% to 98.3%) for self refraction, 98.4% (97.4% to 99.5%) for automated refraction, and 99.1% (98.3% to 99.9%) for subjective refraction (P = 0.033 for self refraction v automated refraction, P = 0.001 for self refraction v subjective refraction). Improvements over uncorrected vision in the better eye with self refraction and subjective refraction were within one line on the eye chart in 98% of participants. In logistic regression models, failure to achieve maximum recorded visual acuity of 6/7.5 in right eyes with self refraction was associated with greater absolute value of myopia/hyperopia (P<0.001), greater astigmatism (P = 0.001), and not having previously worn spectacles (P = 0.002), but not age or sex. Significant inaccuracies in power (≥ 1.00 dioptre) were less common in right eyes with self refraction than with automated refraction (5% v 11%, P<0.001). CONCLUSIONS: Though visual acuity was slightly worse with self refraction than automated or subjective refraction, acuity was excellent in nearly all these young people with inadequately corrected refractive error at baseline. Inaccurate power was less common with self refraction than automated refraction. Self refraction could decrease the requirement for scarce trained personnel, expensive devices, and cycloplegia in children's vision programmes in rural China.

‘To me, it's like a little box of tricks’: Breaking the depressive interlock as a programme participant in mindfulness-based cognitive therapy

Objectives. Mindfulness meditation practices have become increasingly popular in clinical therapies, changing patterns of depressogenic thinking for individuals who experience consecutive episodes of depression. We were interested in finding out how Mindfulness Based Cognitive Therapy (MBCT) worked for programme participants by focussing on how meditative practices changed their relationships to their thoughts. Design. Data for the study came from six semi-structured research interviews carried out with individuals who had taken part in an 8 week MBCT programme Methods. We used Interpretative Phenomenological Analysis (IPA) to analyse the experiential accounts. Results. We report on two superordinate themes – Engaging the Neutral Mind (with subordinate themes ‘breaking the paralysis of worry’ and ‘choosing to think differently’) and Experiencing the Neutral Mind (with subordinate themes of ‘reflection on previous thinking styles’ and ‘becoming psychologically self-reliant’). Conclusions. Themes from the present study offer support to the assertion that mindfulness meditation helps facilitate a different mode of meta-cognitive processing with which to handle depression-related cognitions. Practitioner Points Participants reported that they experienced an enhanced capacity to differentiate between their thought processes, experiencing an ability to tolerate some more uncomfortable thoughts and experiencing a/more choice in how to respond to thoughts Participants recognised that ruminating over negative thoughts was related to depressive states and experienced a shift in meta-cognitive processes that actively challenged depressogenic cognitions Participants became more psychologically self-reliant and therapeutically independent following MBCT Integrating mindfulness based practices in therapy may be a mediating factor in sustaining psychological wellbeing and may help clients develop self-compassion Future research looks to examining exit cases to understand elements of MBCT which are experienced as less successful by clients

Caractérisation de nouveaux aspects de l’ataxie spastique autosomale récessive de Charlevoix-Saguenay à l’aide d’un procédé d’imagerie: la tomographie par cohérence optique (OCT)

L’Ataxie spastique autosomale récessive de Charlevoix-Saguenay (ARSACS) est un syndrome héréditaire précoce caractérisé par un tableau clinique particulier incluant des anomalies oculaires. Quatorze ARSACS et 36 témoins sains ont été suivis prospectivement durant 20 mois et ont subi différents tests neuro-ophtalmologiques et des mesures par tomographie par cohérence optique. Des augmentations de l’épaisseur moyenne de la couche de fibres nerveuses (mRNFL), de l’épaisseur fovéolaire centrale et de l’épaisseur moyenne du cube maculaire (CAT) ont été mises en évidence chez les ARSACS en comparaison avec les témoins (p<0,0001 à toutes les séances). Une différence cliniquement significative a été observée dans l’évolution au cours du suivi des épaisseurs de la mRNFL et la CAT des ARSACS par rapport aux contrôles (p=0,030, p=0,026 respectivement), et ces paramètres étaient inversement corrélés avec le degré de sévérité de la maladie, suggérant une diminution d’épaisseur de la mRNFL et de la CAT à mesure que progresse la maladie.

Descrição de uma população narcoléptica portuguesa

Tese de mestrado, Ciências do Sono, Faculdade de Medicina, Universidade de Lisboa, 2015

Análise comparativa entre a promoção para arrendamento e venda de imóveis de habitação

Dissertação para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização de Edificações

A inclusão de uma criança com nee – papel do adulto e dos pares na sua participação ativa no jardim de infância

Relatório da Prática Profissional Supervisionada Mestrado em Educação Pré-Escolar

Comportamento da tibiotársica na sequência de movimento de sentar para de pé em crianças prematuras

Introdução: A prematuridade constitui um fator de risco para a ocorrência de lesões ao nível do sistema nervoso central, sendo que uma idade gestacional inferior a 36 semanas potencia esse mesmo risco, nomeadamente para a paralisia cerebral (PC) do tipo diplegia espástica. A sequência de movimento de sentado para de pé (SPP), sendo uma das aprendizagens motoras que exige um controlo postural (CP) ao nível da tibiotársica, parece ser uma tarefa funcional frequentemente comprometida em crianças prematuras com e sem PC. Objetivo(s): Descrever o comportamento dos músculos da tibiotársica, tibial anterior (TA) e solear (SOL), no que diz respeito ao timing de ativação, magnitude e co-ativação muscular durante a fase I e início da fase II na sequência de movimento de SPP realizada por cinco crianças prematuras com PC do tipo diplegia espástica e cinco crianças prematuras sem diagnóstico de alteração neuromotoras, sendo as primeiras sujeitas a um programa de intervenção baseado nos princípios do conceito de Bobath – Tratamento do Neurodesenvolvimento (TND). Métodos: Foram avaliadas 10 crianças prematuras, cinco com PC e cinco sem diagnóstico de alterações neuromotoras, tendo-se recorrido à eletromiografia de superfície para registar parâmetros musculares, nomeadamente timings, magnitudes e valores de co-ativação dos músculos TA e SOL, associados à fase I e inico da fase II da sequência de movimento de SPP. Procedeu-se ao registo de imagem de modo a facilitar a avaliação dos componentes de movimento associados a esta tarefa. Estes procedimentos foram realizados num único momento, no caso das crianças sem diagnóstico de alterações neuromotoras e em dois momentos, antes e após a aplicação de um programa de intervenção segundo o Conceito de Bobath – TND no caso das crianças com PC. A estas foi ainda aplicado o Teste da Medida das Funções Motoras (TMFM–88) e a Classificação Internacional da Funcionalidade Incapacidade e Saúde – crianças e jovens (CIF-CJ). Resultados: Através da eletromiografia constatou-se que ambos os grupos apresentaram timings de ativação afastados da janela temporal considerada como ajustes posturais antecipatórios (APAs), níveis elevados de co-ativação, em alguns casos com inversão na ordem de recrutamento muscular o que foi possível modificar nas crianças com PC após o período de intervenção. Nestas, verificou-se ainda que, a sequência de movimento de SPP foi realizada com menor número de compensações e com melhor relação entre estruturas proximais e distais compatível com o aumento do score final do TMFM-88 e modificação positiva nos itens de atividade e participação da CIF-CJ. Conclusão: As crianças prematuras com e sem PC apresentaram alterações no CP da tibiotársica e níveis elevados de co-ativação muscular. Após o período de intervenção as crianças com PC apresentaram modificações positivas no timing e co-ativação muscular, com impacto funcional evidenciado no aumento do score final da TMFM-88 e modificações positivas na CIF-CJ.

Influência do alinhamento do pé nos Ajustes Posturais Antecipatórios em crianças com Paralisia Cerebral

Introdução: A dificuldade na organização dos ajustes posturais antecipatórios (APAs) é frequentemente associada ao défice de controlo postural (CP) em crianças/jovens com um quadro motor de hemiplegia espástica, resultante de paralisia cerebral. As alterações biomecânicas da tibiotársica e do pé são características comummente observadas nestas crianças/jovens e influenciam o CP na sua globalidade. Objectivo(s): descrever o comportamento dos APAs associados ao início da marcha, face à modificação do alinhamento do pé em crianças/jovens com hemiplegia espástica, após 12 semanas de intervenção, segundo o Conceito Bobath-TND e aplicação de uma Ligadura Funcional (LF). Métodos: Foram avaliadas quatro crianças/jovens num momento inicial (M0) e após 12 semanas de intervenção e de aplicação de uma LF (M1). Recorrendo à eletromiografia de superfície, registaram-se os timings de activação dos músculos tibial anterior, solear, recto abdominal e erector da espinha (bilateralmente). O início do movimento foi calculado a partir da alteração do sinal obtido através da plataforma de pressões. Recorreu-se à aplicação da TMFM-88 para avaliar a função motora global e à aplicação da CIF-CJ para classificar a funcionalidade mediante as actividades e a participação. Procedeu-se ao registo de imagem para facilitar a observação/avaliação das componentes de movimento das crianças/jovens em estudo. Resultados: Após o período de intervenção, verificou-se uma modificação nos valores dos timings de ativação dos músculos em análise, que se aproximaram da janela temporal definida como APAs, bem como na distribuição de carga na base de suporte, nos scores da TMFM-88 e nos qualificadores das “Actividades e Participação”, sugestivos de uma melhor organização dos mecanismos de controlo postural. Conclusão: As crianças/jovens em estudo evidenciaram, após uma intervenção de fisioterapia baseada no Conceito Bobath- TND e aplicação de uma LF, uma evolução favorável tanto ao nível do CP da tibiotársica e do pé, apresentando timings de ativação muscular temporalmente mais ajustados à tarefa, com repercussões positivas nas actividades e participação.

Activity-Dependent Neurorehabilitation Beyond Physical Trainings: "Mental Exercise" Through Mirror Neuron Activation

The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot make such efforts. Here the authors proposed the employment of mirror neurons system in promoting brain rehabilitation by "observation based stimulation". Mirror neuron system has been considered as an important basis for action understanding and learning by mimicking others. During the action observation, mirror neuron system mediated the direct activation of the same group of motor neurons that are responsible for the observed action. The effect is clear, direct, specific and evolutionarily conserved. Moreover, recent evidences hinted for the beneficial effects on stroke patients after mirror neuron system activation therapy. Finally some music-relevant therapies were proposed to be related with mirror neuron system.

Partial Rhombencephalosynapsis.

Clinical history - A 4-year-old boy, born prematurely at 29 weeks (twin pregnancy), with periventricular leukomalacia and epilepsy underwent brain MRI. Neurological examination showed severe developmental retardation with axial hypotonia, spastic tetraparesis and convergent strabismus. Imaging findings - Cranial MRI revealed typical aspects of partial rhombencephalosynapsis with vermian hypoplasia, midline fusion of the cerebellar hemispheres and transversely oriented folia and fissures. There was also mild dilatation and dysmorphism of the ventricular system, the septum pellucidum was absent, the hippocampi were malrotated and had vertical orientation and additional finding of associated periventricular cystic leukomalacia. Discussion - Rhombencephalosynapsis (RS) is a rare congenital defect of the cerebellum classically characterised by vermian agenesis or hypogenesis, fusion of the hemispheres, and closely apposed or fused dentate nuclei. It is now considered to result from an absence of division of the cerebellar hemispheres, following an insult between the 28th and 44th day of gestation (i.e., before the formation of the vermis). Other features have also been described such as fusion of the thalami and cerebral peduncles, malrotated hippocampi, corpus callosum agenesis, hypoplastic chiasm, absence of the septum pellucidum, ventriculomegaly, agenesis of the posterior lobe of the pituitary and cortical malformations. Musculoskeletal, cardiovascular, urinary tract, and respiratory abnormalities have been reported. Typical symptoms consist of swallowing difficulties, delayed motor acquisitions, muscular hypotonia, spastic quadriparesis, cerebellar signs including dysarthria, gait ataxia, abnormal eye movements, and seizures and hydrocephalus. The major MRI signs consist of fused cerebellar hemispheres, with absent or hypoplastic vermis, narrow diamond-shaped fourth ventricle and fused dentate nuclei. In a minority of cases, partial RS has been identified by MRI, demonstrating the presence of the nodulus and the anterior vermis and absence of part of the posterior vermis with only partial fusion of the hemispheres in the inferior part. Other cerebellar malformations involving vermian agenesis or hypoplasia include the Dandy–Walker continuum, Joubert syndrome, tectocerebellar dysraphy or pontocerebellar hypoplasias, and are now easily distinguished from RS by both brain MRI and morphology.

Artificial muscle: the human chimera is the future.

Severe heart failure and cerebral stroke are broadly associated with the impairment of muscular function that conventional treatments struggle to restore. New technologies enable the construction of "smart" materials that could be of great help in treating diseases where the main problem is muscle weakness. These materials "behave" similarly to biological systems, because the material directly converts energy, for example electrical energy into movement. The extension and contraction occur silently like in natural muscles. The real challenge is to transfer this amazing technology into devices that restore or replace the mechanical function of failing muscle. Cardiac assist devices based on artificial muscle technology could envelope a weak heart and temporarily improve its systolic function, or, if placed on top of the atrium, restore the atrial kick in chronic atrial fibrillation. Artificial sphincters could be used to treat urinary incontinence after prostatectomy or faecal incontinence associated with stomas. Artificial muscles can restore the ability of patients with facial paralysis due to stroke or nerve injury to blink. Smart materials could be used to construct an artificial oesophagus including peristaltic movement and lower oesophageal sphincter function to replace the diseased oesophagus thereby avoiding the need for laparotomy to mobilise stomach or intestine. In conclusion, in the near future, smart devices will integrate with the human body to fill functional gaps due to organ failure, and so create a human chimera.

Imaging findings in fetal diaphragmatic abnormalities.

Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome.

Anatomo-functional magnetic resonance imaging of the spinal cord and its application to the characterization of spinal lesions in cats

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique.

Caractérisation clinique et génétique d’une nouvelle forme d’ataxie autosomique récessive dans la population québécoise

Les ataxies autosomiques récessives sont un groupe de troubles neurologiques hétérogènes caractérisés par une incoordination brute des mouvements musculaires impliquant le dysfonctionnement nerveux du cervelet qui coordonne le mouvement. Plusieurs formes héréditaires ont été décrites dont la plus connue : l’ataxie de Friedriech. Dans cette thèse nous rapportons l'identification et la caractérisation d’une nouvelle forme dans la population québécoise. L’ataxie récessive spastique avec leucoencéphalopathie (ARSAL; aussi connue comme l’ataxie autosomique récessive spastique de type 3 (SPAX3); OMIM 611390) est la deuxième ataxie spastique décrite dans la population canadienne française. En effet, près de 50 % de nos cas sont originaires de la région de Portneuf. En 2006, nous avons décrit les caractéristiques cliniques de cette nouvelle forme d’ataxie. Un premier criblage du génome entier, constitué de plus de 500 marqueurs microsatellites, a permis la localisation du locus sur le chromosome 2q33-34. Suite au séquençage de plus de 37 gènes candidats et afin de rétrécir cet intervalle candidat, nous avons utilisé une micro-puce d’ADN constituée de marqueurs SNP «single nucleotide polymorphism» et nous avons identifié un deuxième intervalle candidat de 0.658Mb au locus 2q33 dans lequel se trouvent moins de 9 gènes. L’identification et la caractérisation de ces mutations a nécessité l’utilisation de diverses technologies de pointe. Trois mutations (une délétion et deux réarrangements complexes) dans le gène mitochondrial tRNA-synthetase (MARS2) ont été identifiées dans notre cohorte. Nous émettons l’hypothèse que la nature des mutations complexes est responsable d’un dérèglement de la transcription du gène, ce qui a un impact néfaste sur la fonction mitochondriale et le tissu neuronal.