Constrained self-organizing feature map to preserve feature extraction topology

In many classification problems, it is necessary to consider the specific location of an n-dimensional space from which features have been calculated. For example, considering the location of features extracted from specific areas of a two-dimensional space, as an image, could improve the understanding of a scene for a video surveillance system. In the same way, the same features extracted from different locations could mean different actions for a 3D HCI system. In this paper, we present a self-organizing feature map able to preserve the topology of locations of an n-dimensional space in which the vector of features have been extracted. The main contribution is to implicitly preserving the topology of the original space because considering the locations of the extracted features and their topology could ease the solution to certain problems. Specifically, the paper proposes the n-dimensional constrained self-organizing map preserving the input topology (nD-SOM-PINT). Features in adjacent areas of the n-dimensional space, used to extract the feature vectors, are explicitly in adjacent areas of the nD-SOM-PINT constraining the neural network structure and learning. As a study case, the neural network has been instantiate to represent and classify features as trajectories extracted from a sequence of images into a high level of semantic understanding. Experiments have been thoroughly carried out using the CAVIAR datasets (Corridor, Frontal and Inria) taken into account the global behaviour of an individual in order to validate the ability to preserve the topology of the two-dimensional space to obtain high-performance classification for trajectory classification in contrast of non-considering the location of features. Moreover, a brief example has been included to focus on validate the nD-SOM-PINT proposal in other domain than the individual trajectory. Results confirm the high accuracy of the nD-SOM-PINT outperforming previous methods aimed to classify the same datasets.

Papiloma invertido das fossas nasais e seios perinasais : revisão sistemática

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Manifestações endócrinas na anorexia nervosa

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

A doença de Parkinson no doente idoso

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Bases moléculaires et cellulaires d’un trouble neurodéveloppemental causé par l’haploinsuffisance de SYNGAP1

La déficience intellectuelle est la cause d’handicap la plus fréquente chez l’enfant. De nombreuses évidences convergent vers l’idée selon laquelle des altérations dans les gènes synaptiques puissent expliquer une fraction significative des affections neurodéveloppementales telles que la déficience intellectuelle ou encore l’autisme. Jusqu’à récemment, la majorité des mutations associées à la déficience intellectuelle a été liée au chromosome X ou à la transmission autosomique récessive. D’un autre côté, plusieurs études récentes suggèrent que des mutations de novo dans des gènes à transmission autosomique dominante, requis dans les processus de la plasticité synaptique peuvent être à la source d’une importante fraction des cas de déficience intellectuelle non syndromique. Par des techniques permettant la capture de l’exome et le séquençage de l’ADN génomique, notre laboratoire a précédemment reporté les premières mutations pathogéniques dans le gène à transmission autosomique dominante SYNGAP1. Ces dernières ont été associées à des troubles comportementaux tels que la déficience intellectuelle, l’inattention, des problèmes d’humeur, d’impulsivité et d’agressions physiques. D’autres patients sont diagnostiqués avec des troubles autistiques et/ou des formes particulières d’épilepsie généralisée. Chez la souris, le knock-out constitutif de Syngap1 (souris Syngap1+/-) résulte en des déficits comme l’hyperactivité locomotrice, une réduction du comportement associée à l’anxiété, une augmentation du réflexe de sursaut, une propension à l’isolation, des problèmes dans le conditionnement à la peur, des troubles dans les mémoires de travail, de référence et social. Ainsi, la souris Syngap1+/- représente un modèle approprié pour l’étude des effets délétères causés par l’haploinsuffisance de SYNGAP1 sur le développement de circuits neuronaux. D’autre part, il est de première importance de statuer si les mutations humaines aboutissent à l’haploinsuffisance de la protéine. SYNGAP1 encode pour une protéine à activité GTPase pour Ras. Son haploinsuffisance entraîne l’augmentation des niveaux d’activité de Ras, de phosphorylation de ERK, cause une morphogenèse anormale des épines dendritiques et un excès dans la concentration des récepteurs AMPA à la membrane postsynaptique des neurones excitateurs. Plusieurs études suggèrent que l’augmentation précoce de l’insertion des récepteurs AMPA au sein des synapses glutamatergiques contribue à certains phénotypes observés chez la souris Syngap1+/-. En revanche, les conséquences de l’haploinsuffisance de SYNGAP1 sur les circuits neuronaux GABAergiques restent inconnues. Les enjeux de mon projet de PhD sont: 1) d’identifier l’impact de mutations humaines dans la fonction de SYNGAP1; 2) de déterminer si SYNGAP1 contribue au développement et à la fonction des circuits GABAergiques; 3) de révéler comment l’haploinsuffisance de Syngap1 restreinte aux circuits GABAergiques affecte le comportement et la cognition. Nous avons publié les premières mutations humaines de type faux-sens dans le gène SYNGAP1 (c.1084T>C [p.W362R]; c.1685C>T [p.P562L]) ainsi que deux nouvelles mutations tronquantes (c.2212_2213del [p.S738X]; c.283dupC [p.H95PfsX5]). Ces dernières sont toutes de novo à l’exception de c.283dupC, héritée d’un père mosaïque pour la même mutation. Dans cette étude, nous avons confirmé que les patients pourvus de mutations dans SYNGAP1 présentent, entre autre, des phénotypes associés à des troubles comportementaux relatifs à la déficience intellectuelle. En culture organotypique, la transfection biolistique de l’ADNc de Syngap1 wild-type dans des cellules pyramidales corticales réduit significativement les niveaux de pERK, en fonction de l’activité neuronale. Au contraire les constructions plasmidiques exprimant les mutations W362R, P562L, ou celle précédemment répertoriée R579X, n’engendre aucun effet significatif sur les niveaux de pERK. Ces résultats suggèrent que ces mutations faux-sens et tronquante résultent en la perte de la fonction de SYNGAP1 ayant fort probablement pour conséquences d’affecter la régulation du développement cérébral. Plusieurs études publiées suggèrent que les déficits cognitifs associés à l’haploinsuffisance de SYNGAP1 peuvent émerger d’altérations dans le développement des neurones excitateurs glutamatergiques. Toutefois, si, et auquel cas, de quelle manière ces mutations affectent le développement des interneurones GABAergiques résultant en un déséquilibre entre l’excitation et l’inhibition et aux déficits cognitifs restent sujet de controverses. Par conséquent, nous avons examiné la contribution de Syngap1 dans le développement des circuits GABAergiques. A cette fin, nous avons généré une souris mutante knockout conditionnelle dans laquelle un allèle de Syngap1 est spécifiquement excisé dans les interneurones GABAergiques issus de l’éminence ganglionnaire médiale (souris Tg(Nkx2.1-Cre);Syngap1flox/+). En culture organotypique, nous avons démontré que la réduction de Syngap1 restreinte aux interneurones inhibiteurs résulte en des altérations au niveau de leur arborisation axonale et dans leur densité synaptique. De plus, réalisés sur des coupes de cerveau de souris Tg(Nkx2.1-Cre);Syngap1flox/+, les enregistrements des courants inhibiteurs postsynaptiques miniatures (mIPSC) ou encore de ceux évoqués au moyen de l’optogénétique (oIPSC) dévoilent une réduction significative de la neurotransmission inhibitrice corticale. Enfin, nous avons comparé les performances de souris jeunes adultes Syngap1+/-, Tg(Nkx2.1-Cre);Syngap1flox/+ à celles de leurs congénères contrôles dans une batterie de tests comportementaux. À l’inverse des souris Syngap1+/-, les souris Tg(Nkx2.1-Cre);Syngap1flox/+ ne présentent pas d’hyperactivité locomotrice, ni de comportement associé à l’anxiété. Cependant, elles démontrent des déficits similaires dans la mémoire de travail et de reconnaissance sociale, suggérant que l’haploinsuffisance de Syngap1 restreinte aux interneurones GABAergiques dérivés de l’éminence ganglionnaire médiale récapitule en partie certains des phénotypes cognitifs observés chez la souris Syngap1+/-. Mes travaux de PhD établissent pour la première fois que les mutations humaines dans le gène SYNGAP1 associés à la déficience intellectuelle causent la perte de fonction de la protéine. Mes études dévoilent, également pour la première fois, l’influence significative de ce gène dans la régulation du développement et de la fonction des interneurones. D’admettre l’atteinte des cellules GABAergiques illustre plus réalistement la complexité de la déficience intellectuelle non syndromique causée par l’haploinsuffisance de SYNGAP1. Ainsi, seule une compréhension raffinée de cette condition neurodéveloppementale pourra mener à une approche thérapeutique adéquate.

Tissue Doppler imaging for evaluation of myocardial function in patients with diabetes mellitus

Purpose of review Heart failure and diabetes mellitus are frequently associated, and diabetes appears to potentiate the clinical presentation of heart failure related to other causes. The purpose of this review is to examine recent advances in the application of tissue Doppler imaging for the assessment of diabetic heart disease. Recent findings Recent studies have documented that both myocardial systolic and diastolic abnormalities can be identified in apparently healthy patients with diabetes and no overt cardiac dysfunction. Interestingly, these are disturbances of longitudinal function, with compensatory increases of radial function-suggesting primary involvement of the subendocardium, which is a hallmark of myocardial ischemia. Despite this, there is limited evidence that diabetic microangiopathy is responsible-with reduced myocardial blood volume rather than reduced resting flow, and at least some evidence suggesting a normal increment of tissue velocity with stress. Finally, a few correlative studies have shown association of diabetic myocardial disease with poor glycemic control, while angiotensin converting enzyme inhibition may be protective. Summary Tissue Doppler imaging (and the related technique of strain rate imaging) appears to be extremely effective for the identification of subclinical LV dysfunction in diabetic patients It is hoped that the recognition of this condition will prompt specific therapy to prevent the development of overt LV dysfunction.

Gene expression in profiling in individual cases reveals consistent transcriptional changes in alcoholic human brain

Chronic alcohol exposure induces lasting behavioral changes, tolerance, and dependence. This results, at least partially, from neural adaptations at a cellular level. Previous genome-wide gene expression studies using pooled human brain samples showed that alcohol abuse causes widespread changes in the pattern of gene expression in the frontal and motor cortices of human brain. Because these studies used pooled samples, they could not determine variability between different individuals. In the present study, we profiled gene expression levels of 14 postmortem human brains (seven controls and seven alcoholic cases) using cDNA microarrays (46 448 clones per array). Both frontal cortex and motor cortex brain regions were studied. The list of genes differentially expressed confirms and extends previous studies of alcohol responsive genes. Genes identified as differentially expressed in two brain regions fell generally into similar functional groups, including metabolism, immune response, cell survival, cell communication, signal transduction and energy production. Importantly, hierarchical clustering of differentially expressed genes accurately distinguished between control and alcoholic cases, particularly in the frontal cortex.

GABAA receptor beta subunit mRNA expression in the human alcoholic brain

A competitive RT-PCR assay was used to quantify the expression of the GABA(A) receptor beta(1), beta(2) and beta(3) isoform mRNA transcripts in the superior frontal cortex and motor cortex of 21 control and 22 alcoholic cases. A single set of primers was designed that permitted amplification of all three transcripts and the internal standard simultaneously; differentiation of the individual transcripts was achieved by restriction enzyme digestion. Construction of a standard curve, using the internal standard and a concentration range of beta(2) cRNA-enabled quantitation of mRNA expression levels. No significant difference in mRNA expression was found between the control and alcoholic case groups in either the superior frontal or motor cortex for the beta(2) or beta(3) isoforms. A significant interaction was found between isoform and area, although, the two case groups did not partition on this measure. The interaction was due to a significant difference between superior frontal and motor cortex for the beta(3) isoform; this regional comparison was not significant for beta(2) mRNA. Age at death and post-mortem delay (PMD) had no significant effect on beta mRNA expression in either case group in either region. A beta(1) signal could not be detected in the RT-PCR assay. (C) 2004 Elsevier Ltd. All rights reserved.

Target tissue influences the peripheral trajectory of mouse primary sensory olfactory axons

Primary olfactory neurons situated in the nasal septum project axons within fascicles along a highly stereotypical trajectory en route to the olfactory bulb. The ventral fascicles make a distinct dorsovental turn at the rear of the septum so as to reach the olfactory bulb. In the present study we have used a brain and nasal septum coculture system to examine the role of target tissue on the peripheral trajectory of olfactory sensory axons. In cultures of isolated embryonic nasal septa, olfactory axons form numerous parallel fascicles that project caudally in the submucosa, as they do in vivo. The ventral axon fascicles in the septum, however, often fail to turn, and do not project dorsally towards the roof of the nasal cavity. The presence of olfactory bulb, cortical, or tectal tissue apposed to the caudal end of the septum rescued this phenotype, causing the ventral fascicles to follow a normal in vivo-like trajectory. Ectopic placements of the explants revealed that brain tissue is not tropic for olfactory axons but appears to maintain the peripheral trajectory of growing axons in the nasal septum. Although primary olfactory axons are able to penetrate into olfactory bulb in vitro, they only superficially enter cortical tissue, whereas they do not grow into tectal explants. The ability of axons to differentially grow into different brain regions was shown to be unrelated to the migratory behavior of olfactory ensheathing cells, indicating that olfactory axons are directly responsive to guidance cues in the brain. (C) 2004 Wiley Periodicals, Inc.

Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey

Objective: To determine the prevalence and predictors of left ventricular (LV) diastolic dysfunction in older adults. Design, setting and participants: A cross-sectional survey of 1275 randomly selected residents of Canberra, aged 60 to 86 years (mean age 69.4; 50% men), conducted between February 2002 and June 2003. Main outcome measures: Prevalence of LV diastolic dysfunction as characterised by comprehensive Doppler echocardiography. Results: The prevalence of any diastolic dysfunction was 34.7% (95% CI 32.1% to 37.4%) and that of moderate to severe diastolic dysfunction was 7.3% (95% CI 5.9% to 8.9%). Of subjects with moderate to severe diastolic dysfunction, 77.4% had an LV ejection fraction (EF) > 50% and 76.3% were in a preclinical stage of disease. Predictors of diastolic dysfunction were higher age (p < 0.0001), reduced EF (p < 0.0001), obesity (p < 0.0001) and a history of hypertension (p < 0.0001), diabetes (p = 0.02) and myocardial infarction (p = 0.003). Moderate to severe diastolic dysfunction with normal EF, although predominantly preclinical, was independently associated with increased LV mass (p < 0.0001), left atrial volume (p < 0.0001), and circulating amino-terminal pro-B-type natriuretic peptide concentrations (p < 0.0001), and with decreased quality of life (p < 0.005). Conclusion: Diastolic dysfunction is common in the community and often unaccompanied by overt congestive heart failure. Despite the lack of symptoms, advanced diastolic dysfunction with normal EF is associated with reduced quality of life and structural abnormalities that reflect increased cardiovascular risk.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis

Objectives: The antiinflammatory effect of macrolide antibiotics has been well-established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long-term, low-dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo-controlled study. Method: The authors conducted a double-blind, randomized, placebo-controlled clinical trial on 64 patients with chronic rhinosinusitis. Subjects received either 150 mg roxithromycin daily for 3 months or placebo. Outcome measures included the Sinonasal Outcome Test-20 (SNOT-20), measurements of peak nasal inspiratory flow, saccharine transit time, olfactory function, nasal endoscopic scoring, and nasal lavage assays for interleukin-8, fucose, and a2-macroglobulin. Results. There were statistically significant improvements in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P < .05) in the macrolide group. A correlation was noted between improved outcome measures and low IgE levels. No significant improvements were noted for olfactory function, peak nasal inspiratory flow, or lavage levels for fucose and a2-macroglobulin. No improvement in any outcome was noted in the placebo-treated patients. Conclusion: These findings suggest that macrolides may have a beneficial role in the treatment of chronic rhinosinusitis, particularly in patients with low levels of IgE, and supports the in vitro evidence of their antiinflammatory activity. Additional studies are required to assess their place in clinical practice.

Monitoring Infants By Automatic Video Processing

This work has, as its objective, the development of non-invasive and low-cost systems for monitoring and automatic diagnosing specific neonatal diseases by means of the analysis of suitable video signals. We focus on monitoring infants potentially at risk of diseases characterized by the presence or absence of rhythmic movements of one or more body parts. Seizures and respiratory diseases are specifically considered, but the approach is general. Seizures are defined as sudden neurological and behavioural alterations. They are age-dependent phenomena and the most common sign of central nervous system dysfunction. Neonatal seizures have onset within the 28th day of life in newborns at term and within the 44th week of conceptional age in preterm infants. Their main causes are hypoxic-ischaemic encephalopathy, intracranial haemorrhage, and sepsis. Studies indicate an incidence rate of neonatal seizures of 0.2% live births, 1.1% for preterm neonates, and 1.3% for infants weighing less than 2500 g at birth. Neonatal seizures can be classified into four main categories: clonic, tonic, myoclonic, and subtle. Seizures in newborns have to be promptly and accurately recognized in order to establish timely treatments that could avoid an increase of the underlying brain damage. Respiratory diseases related to the occurrence of apnoea episodes may be caused by cerebrovascular events. Among the wide range of causes of apnoea, besides seizures, a relevant one is Congenital Central Hypoventilation Syndrome (CCHS) \cite{Healy}. With a reported prevalence of 1 in 200,000 live births, CCHS, formerly known as Ondine's curse, is a rare life-threatening disorder characterized by a failure of the automatic control of breathing, caused by mutations in a gene classified as PHOX2B. CCHS manifests itself, in the neonatal period, with episodes of cyanosis or apnoea, especially during quiet sleep. The reported mortality rates range from 8% to 38% of newborn with genetically confirmed CCHS. Nowadays, CCHS is considered a disorder of autonomic regulation, with related risk of sudden infant death syndrome (SIDS). Currently, the standard method of diagnosis, for both diseases, is based on polysomnography, a set of sensors such as ElectroEncephaloGram (EEG) sensors, ElectroMyoGraphy (EMG) sensors, ElectroCardioGraphy (ECG) sensors, elastic belt sensors, pulse-oximeter and nasal flow-meters. This monitoring system is very expensive, time-consuming, moderately invasive and requires particularly skilled medical personnel, not always available in a Neonatal Intensive Care Unit (NICU). Therefore, automatic, real-time and non-invasive monitoring equipments able to reliably recognize these diseases would be of significant value in the NICU. A very appealing monitoring tool to automatically detect neonatal seizures or breathing disorders may be based on acquiring, through a network of sensors, e.g., a set of video cameras, the movements of the newborn's body (e.g., limbs, chest) and properly processing the relevant signals. An automatic multi-sensor system could be used to permanently monitor every patient in the NICU or specific patients at home. Furthermore, a wire-free technique may be more user-friendly and highly desirable when used with infants, in particular with newborns. This work has focused on a reliable method to estimate the periodicity in pathological movements based on the use of the Maximum Likelihood (ML) criterion. In particular, average differential luminance signals from multiple Red, Green and Blue (RGB) cameras or depth-sensor devices are extracted and the presence or absence of a significant periodicity is analysed in order to detect possible pathological conditions. The efficacy of this monitoring system has been measured on the basis of video recordings provided by the Department of Neurosciences of the University of Parma. Concerning clonic seizures, a kinematic analysis was performed to establish a relationship between neonatal seizures and human inborn pattern of quadrupedal locomotion. Moreover, we have decided to realize simulators able to replicate the symptomatic movements characteristic of the diseases under consideration. The reasons is, essentially, the opportunity to have, at any time, a 'subject' on which to test the continuously evolving detection algorithms. Finally, we have developed a smartphone App, called 'Smartphone based contactless epilepsy detector' (SmartCED), able to detect neonatal clonic seizures and warn the user about the occurrence in real-time.

ESTUDO DAS DIMENSÕES TRANSVERSAIS DOS ARCOS DENTAIS MANDIBULARES EM INDIVÍDUOS COM DIFERENTES PADRÕES FACIAIS

O presente estudo avaliou as dimensões transversais dos arcos dentais mandibulares em indivíduos com diferentes padrões faciais. A amostra foi constituída por telerradiografias em norma lateral direita e modelos em gesso de 33 indivíduos, leucodermas, em ambos os sexos, com idade entre 13 e 25 anos, na fase de dentição permanente. O Padrão Facial foi obtido pela análise facial subjetiva em fotografias frontal e de perfil de 1500 documentações ortodonticas, foi utilizada análise cefalométrica por meio do ângulo ANB para confirmar o padrão esquelético, o qual deveria coincidir com a classificação de maloclusão de Angle. A amostra foi dividida em três grupos: Grupo I Padrão I, Classe I de Angle e ANB 2,0 o ±0,5o; Grupo II Padrão II, Classe II divisão 1 de Angle e ANB ≥ 4,0, e Grupo III Padrão III, Classe III de Angle e ANB ≥ - 4,5o. As dimensões transversais do arco foram mensuradas após a digitalização dos modelos em gesso pelo Scanner Dental Wings (3D), a partir dos quais foram estabelecidas as distâncias transversais intercanino, inter 1º PM, inter 2º PM, inter 1º M (cúspide mesial e distal), inter 2º M (cúspide mesial e distal), com o auxílio do software Geomagic Studio® 12. As médias e desvio padrão das dimensões transversais foram obtidas, e, para comparação entre os três grupos foi utilizado a Análise de Variância e teste de Tukey. Em todos os testes estatísticos foi adotado nível de significância de 5% (p<0,05). Houve diferença estatística em duas dimensões transversais das 14 avaliadas no arco maxilar na região mesial do segundo molar (p=0,024) e no mandibular na região distal do primeiro molar (p=0,047). Os arcos dentais mandibulares foram semelhantes nos três grupos estudados.

ESTUDO COMPARATIVO ENTRE A ANÁLISE FACIAL SUBJETIVA E ANÁLISE CEFALOMÉTRICA DE TECIDOS MOLES NO DIAGNÓSTICO ORTODÔNTICO

O propósito deste estudo foi avaliar a concordância entre a Análise facial subjetiva, proposta por CAPELOZZA FILHO e a Análise Cefalométrica de Tecidos Moles, de ARNETT; McLAUGHLIN. Fotografias de frente e de perfil e telerradiografias em norma lateral padronizadas, de 50 indivíduos, com média de idade de 24 anos e 1 mês foram utilizadas para a avaliação. Verificou-se também nos indivíduos classificados como Padrão I, a correspondência dos valores médios e dos desvios-padrão das medidas obtidas, com os valores normativos da Análise Cefalométrica dos Tecidos Moles para os indivíd uos com harmonia facial. Constatou-se em indivíduos do Padrão I que os lábios sempre se encontram à frente da Linha Vertical Verdadeira, e que apesar de grandes variações do ponto pogônio, ainda é mantido o equilíbrio facial. Os resultados demonstraram que a Análise facial subjetiva eficiente na classificação do padrão facial.