Magnetic Resonance Imaging to Enhance the Diagnosis of Fetal Brain Abnormalities in utero

Purpose This thesis aims to determine the diagnostic performance of in utero MR (iuMR) imaging to diagnose fetal brain abnormalities and describes the development, application and processing of a 3D volume MR acquisition. Methods A systematic review and meta-analysis of existing evidence was conducted. A prospective multicentre study of pregnant women, with a fetal brain abnormality on ultrasound (USS), was undertaken – The MERIDIAN study. In addition, an investigation of fetuses with no brain abnormality on USS was undertaken. Diagnostic accuracy and confidence, as well as positive and negative predictive values, were calculated. A 3D image acquisition technique was introduced, its ability to aid diagnosis measured and computational post-processing applied. Fetal brain volumes were extracted from the 3D data using image segmentation and these were assessed for reproducibility and validity. Resultant data allowed 3D models of fetal brains to be printed. Normally developing fetal brain volumes were plotted graphically thereby allowing comparison with abnormal fetuses. Results A total of 570 complete datasets were available from 903 eligible participants. Diagnostic accuracy was 68% for USS and 93% for iuMR. 95% of diagnoses made by iuMR were reported with high confidence compared to 82% on USS. Changes in pregnancy management occurred in 33% of cases. Positive and negative predictive values of iuMR were 93% and 99.5% respectively. 3D image quality was diagnostic in 89.6%, of which 91.4% gave an accurate diagnosis. Intra- and inter-observer agreement of brain volume measurements was high. Agreement between computer based and brain model volume measurements was also high. Conclusions iuMR imaging improves diagnostic accuracy and confidence for fetal brain abnormalities, influencing pregnancy management in a high proportion of cases. 3D imaging enables versatile visualisation of fetal brain anatomy and reliable extraction of volumes. This additional quantitative information could improve diagnosis in relevant cases

Segmentation Automatique D'Images IRM 3D Anténatales

Desarrollo de un programa capaz de hacer una segmentación automática en imágenes de resonancia magnética 3D pertenecientes a niños recién nacidos. La segmentación consistirá en una clasificación de los diferentes tejidos cerebrales, es decir, clasificación de la materia gris, blanca y liquido encéfalo raquídeo. Además de una segmentación de el núcleo gris y de los ventrículos. Para ello, se ha realizado una interfaz para facilitar al médico la utilización de estas herramientas desarrolladas además de permitirle un seguimiento del niño, para comprobar su buen crecimiento y desarrollo. El algoritmo desarrollado esta basado en técnicas de procesamiento de imagen (morfología matemática, contornos activos, segmentación por watershed, técnicas de mejoramiento de imagen y K-medias).Automatic segmentation of antenatal 3D MRI images (analysis software development). The implemented software is a graphical interface that helps the doctor on his final diagnostic. The program which aims are to make an automatic segmentation of different brain tissues (gray matter, white matter and CSF) and different parts of the brain (ventricle and nucleus). The algorithm is based on image processing methods (mathematic morphology, actives contours, segmentation using watershed, techniques of image processing and K-means).Pacheco Lloret, MB.; Luzàrraga, E. (2014). Segmentation Automatique D'Images IRM 3D Anténatales. http://hdl.handle.net/10251/35155.Archivo delegad

Atrioventricular septal defect : advanced imaging from early development to long-term follow-up

The aim of this thesis is to review the current knowledge on atrioventricular septal defect (AVSD) (Part 1), to study the pathogenesis of AVSD (Part 2) and finally to analyze cardiac outcome long-term after AVSD correction (Part 3). Studies are performed with novel imaging techniques. In part 2 it is made plausible that AVSD is a sliding scale and that patients with Down syndrome without AVSD also have abnormalities of the membranous septum and atrioventricular valves. High frequency ultrasound in mouse embryos shows to be a promising technique to study cardiovascular flow in early stages of heart development. In a mouse model with disturbed VEGF signalling, the heart rate is reduced and the sinoatrial node develops abnormally. Finally, in part 3 of this thesis, 4DFlow MRI data reveals that patients with an abnormal left atrioventricular valve (LAVV) after AVSD correction have aberrant intra-cardiac flow patterns. During diastole the inflow into the left ventricle is directed more towards the lateral wall, more towards the apex and vortex formation is abnormal. During systole the dynamic and eccentric regurgitation of the LAVV disturbs the normal recirculating flow patterns in the left atrium.4DFlow MRI can be used to reliably quantify flow over the LAVV.UBL - phd migration 201

Hip deformities and femoroacetabular impingement

RESUMO: Conceptualmente, a conservação de uma estrutura anatómica é mais benéfica do que a sua substituição. No caso das articulações humanas, este conceito é particularmente importante face aos múltiplos problemas, ainda não resolvidos, relacionados com próteses e materiais usados na cirurgia ortopédica. Na articulação coxofemoral, o conceito de preservação, melhorando os parâmetros biomecânicos, assume uma complexidade técnica acrescida maioritariamente pelo facto de a circulação epifisária do fémur ser intra-articular e dada a proximidade de importantes estruturas neurovasculares. O conflito femoroacetabular (CFA) e a displasia acetabular no adulto jovem, são duas entidades patológicas comuns embora com múltiplas áreas ainda por investigar. A displasia infantil, não diagnosticada e não tratada, pode originar displasia acetabular residual na idade adulta e consequente sintomatologia e limitação funcional. O diagnóstico de CFA no adulto é baseado em critérios clínicos e radiográficos. Clinicamente apresenta-se igualmente com dor e limitação funcional. Radiologicamente, dois subtipos de CFA são habitualmente reconhecidos, o tipo Cam (mecanismo patológico decorrente de asfericidade femoral) e o tipo Pincer (por hipercobertura acetabular). Embora com padrões diferentes de envolvimento articular, os dois mecanismos de conflito condicionam dor, lesão estrutural do labrum e condropatia. Atualmente, a morfologia Cam é considerada como um dos principais fatores de risco morfológico que contribuem para o desenvolvimento de osteoartrose precoce da coxofemoral, eventualmente com necessidade de recurso a prótese total da anca. Apesar de a investigação inicial na área da cirurgia conservadora da anca ter documentado bons resultados cirúrgicos, atualmente a controvérsia é francamente superior ao consenso relativamente à melhor abordagem diagnóstica e terapêutica. Caracteristicamente, apesar de em muitos casos os achados clínicos e radiológicos serem inequívocos para o diagnóstico de CFA, um número substancial de doentes apresenta achados frustes ou equívocos. Por outro lado, múltiplos estudos descreveram uma alta prevalência de morfologia compatível com CFA na população adulta e em indivíduos saudáveis assintomáticos. Atualmente, não existe uma ferramenta de imagem ideal que facilite a alocação fidedigna de todos os doentes a um grupo patológico específico ou, por outro lado, exclua com confiança o diagnóstico de conflito. No entanto, os parâmetros de imagem podem ser utilizados para analisar e descrever as diferentes características morfológicas da anca e adicionalmente confirmar o diagnóstico de CFA. Esta tese enfoca, por um lado, a avaliação da morfologia coxofemoral em diferentes populações, investigando quais articulações estão mais predispostas ao desenvolvimento de sintomas e, por outro, os resultados do tratamento cirúrgico de uma coorte com o diagnóstico de CFA tipo Cam. Especificamente, a investigação efetuada: 1) examinou características morfológicas específicas da coxofemoral em diferentes populações (sintomáticas ou não sintomáticas); 2) desenhou um modelo estatístico baseado em preditores anatómicos no sentido de estabelecer as articulações em risco de desenvolvimento sintomático, incorporando geometrias articulares específicas e parâmetros espinhopélvicos; e 3) analisou os resultados de terapêutica cirúrgica numa coorte de doentes com o diagnóstico CFA tipo Cam. Durante a progressão clínica na área da imagiologia e nesta área patológica em particular, apercebemo-nos da existência de múltiplas lacunas de conhecimento que procurámos colmatar com a investigação agora publicada e descrita nesta tese. A sistematização por capítulos reflete precisamente a necessidade de abordar a questão em áreas de conhecimento, simultaneamente distintas e complementares. Os seis capítulos desta tese abrangem o espectro clínico desde o diagnóstico até ao tratamento da anca jovem. De modo a apresentar os objetivos desta tese numa sequência lógica, desde a anatomia geral até à morfologia e tratamento específicos do CFA, a análise da anca assintomática será descrita em primeiro lugar seguida pela análise da relação anatomoclínica entre morfologia articular e sintomas. Por último será abordada a terapêutica do doente sintomático. Na PARTE I, apresentamos os tópicos essenciais para compreender a abrangência do espectro da presente tese, designadamente a relevância e a contemporaneidade do tema “CFA” e adicionalmente o enquadramento anatómico, morfológico e vascular desta articulação. O Capítulo 1 é dedicado ao desenvolvimento e morfogénese da anca. No Capítulo 2, sublinhamos a importância e o papel da imagem através de uma revisão enfocada nas perspetivas atuais e futuras sobre este tópico (Artigo I). No Capítulo 3, realizamos uma revisão sistemática da literatura no sentido de descrever o estado da arte com foco na prevalência da morfologia de CFA em populações assintomáticas e sintomáticas. Este capítulo destaca as múltiplas lacunas de conhecimento relativas ao papel da morfologia da articulação coxofemoral na patogénese do CFA (Artigo II). Com base nesta parte introdutória, abordamos seguidamente os objetivos da presente tese, gerais e específicos, na PARTE II.Na PARTE III, descrevemos o corpo da investigação clínica original efetuada. O Capítulo 4 é dedicado à caracterização detalhada da morfologia da anca, designadamente óssea e vascular. A morfologia coxofemoral foi quantificada utilizando software com capacidade de semi-automatização analítica, permitindo estudar a prevalência e relação entre as diferentes morfologias articulares e o género, dominância e simetria articular (Artigo III). A morfologia Cam foi ainda alvo de caracterização mais aprofundada, através do desenvolvimento de um novo parâmetro quantitativo com potencialidade diagnóstica e de planeamento cirúrgico/ /prognóstico, primariamente testado numa coorte assintomática (Artigo IV) e seguidamente também em doentes com indicação cirúrgica (Artigo V). Na nossa atividade clínica diária apreciámos a necessidade urgente de melhor caracterizar a topografia da deformidade Cam e a respetiva relação com as artérias nutritivas da epífise femoral. A impressão clínica referida sugeria que a morfologia Cam frequentemente se estendia posteriormente ao quadrante póstero-superior, intersectando a região retinacular vascular. No entanto, por imagem a natureza arterial destas estruturas nunca havia sido confirmada. Por esta razão, a importância do parâmetro mencionado foi sublinhada e comprovada no estudo cadavérico com avaliação topográfica vascular do fémur proximal (Artigo VI). No Capítulo 5 testámos múltiplos parâmetros imagiológicos e respetivas variações/relações com diferentes morfologias coxofemorais, no sentido de identificar as articulações com risco clínico aumentado de desenvolvimento sintomático. Para este fim efetuámos estudos baseados em computação avançada com modelação estatística (Artigo VII) e também em ressonância magnética (RM) tridimensional (Artigo VIII). O Capítulo 6 descreve as opções de tratamento (Artigo IX) e os resultados clínicos num estudo clínico de uma coorte com follow-up mínimo de 2 anos, comparando a abordagem cirúrgica aberta e artroscópica (Artigo X). Os resultados dos diferentes capítulos estão sumarizados na PARTE IV, onde apresentamos a síntese geral, a discussão crítica dos resultados obtidos à luz da literatura atual e finalmente as conclusões relevantes. As oportunidades futuras de investigação são igualmente abordadas neste capítulo. Em resumo o trabalho constante da presente tese sugere: Primeiro, que a avaliação imagiológica detalhada da morfologia coxofemoral é essencial no sentido de compreender aprofundadamente não só a própria articulação como também a morfologia pélvica (Artigo I). Segundo, paradoxalmente, a definição clínica de um caso patológico e das diferentes entidades relacionadas, é ainda inexistente. Os parâmetros quantitativos e qualitativos que comummente estão associados com CFA tipo Pincer e Cam são francamente frequentes em diferentes populações (sintomáticas e assintomáticas) (Artigo II).Terceiro, em populações assintomáticas adultas, os intervalos de referência específicos para os parâmetros quantitativos associados a morfologia de CFA e displasia são mais latos e com limites superiores mais elevados do que os atualmente utilizados na prática clínica (Artigo III). A morfologia femoral bem como os epicentros/magnitudes das deformidades Cam são específicos de género, observando-se maiores valores de ângulo alfa e ómega em indivíduos do sexo masculino (Artigo IV). Quarto, é frequente a interseção entre a extensão póstero-superior da deformidade Cam e a convergência epifisária das estruturas vasculares retinaculares observadas em RM, aspetos que se revestem de primordial importância no planeamento cirúrgico. Adicionalmente a extensão radial da deformidade Cam (ângulo ómega) está significativamente mais relacionada com a sintomatologia clínica pré-cirúrgica do que o parâmetro mais comummente utilizado na prática clínica (ângulo alfa) (Artigo V). A origem das estruturas vasculares observadas por RM na prega retinacular é inequivocamente arterial, sendo que abrange uma extensão mais anterior do que classicamente assumido (Artigo VI). Quinto, as geometrias ovalares (em detrimento das morfologias esféricas e elipsoides) são melhor representativas de ambas as superfícies articulares da coxofemoral, designadamente do fémur e acetábulo, bem como das ancas sintomáticas que clinicamente exibem sinais de CFA (Pincer, Cam e misto) (Artigo VII). Indivíduos com maiores deformidades Cam, aspetos de hipocobertura acetabular e acentuação da anteflexão pélvica apresentam uma maior probabilidade de desenvolverem sintomas articulares (Artigo VIII). Esta observação é crítica, dado que fornece, na prática clínica, informação essencial acerca da potencial predisposição para fenómenos de exacerbação sintomática futura, permitindo desta forma instituição de medidas terapêuticas/preventivas adequadas. Na perspetiva do doente, um diagnóstico precoce e preciso, pode conceptualmente prevenir, numa primeira fase, alterações condropáticas articulares e, numa segunda instância, progressão para artrose estabelecida. Sexto, documentamos resultados clínicos e funcionais significativamente favoráveis quando comparamos a abordagem artroscópica e aberta no tratamento cirúrgico da deformidade Cam, sendo de observar que o género feminino está associado a menor score funcional na avaliação pré-operatória (Artigos IX e X). Futuramente, a imagiologia e a cirurgia conservadora da anca irão desenvolver-se conjuntamente e em paralelo com novos e maiores desafios. A descrição de novos parâmetros analíticos para avaliação da patoanatomia coxofemoral, associada à inovação tecnológica crescente e à implementação da inteligência artificial, impõem uma evolução clínica oposta à assunção de classificações patológicas demasiadamente simplistas. Nesse sentido a existência de guidelines de diagnóstico e terapêutica mais efetivas e baseadas na evidência, que nos levem além da pura diferenciação entre CFA e displasia, são urgentes. A história natural das deformidades Cam e Pincer, sintomáticas ou assintomáticas, é ainda grandemente desconhecida, assumindo-se como uma área determinante de investigação no que concerne ao diagnóstico, terapêutica e prognóstico.ABSTRACT: Conceptually, the preservation of a human anatomical structure makes more sense than its replacement. This concept is even more striking in the case of human joints due to the multitude of unsolved problems related to implants used in orthopaedic surgery. With respect to the hip, joint preservation assumes an increased technical complexity when compared to other joints; this is due to two main reasons: the intra-articular epiphyseal circulation of the femur and the proximity of large neurovascular structures. Femoroacetabular impingement (FAI) and acetabular dysplasia (DHD) in young adults are two common but poorly characterised pathological entities. If undiagnosed and untreated, dysplasia in childhood may lead to residual DHD in young adults, as diagnosed on radiographs, and may also give rise to symptoms such as hip pain and restricted range of motion. The diagnosis of FAI in adults is based on clinical and imaging criteria. The most frequently noticed symptoms of FAI include hip pain and restricted function. Radiologically, two main subtypes of FAI are recognised: The Cam-type, with the pathoanatomical mechanism located on the femoral side, and the Pincertype on the acetabular side. Although with different pathological patterns, both types cause pain and articular damage of the labrum and cartilage. While Cam-type FAI is believed to be a major contributing factor to the early onset of hip osteoarthritis (OA), which eventually requires a total hip replacement, the relationship of other shapes and morphologies with OA are still under debate. Despite the initial promising reports on outcomes following surgical management of these conditions, the best approach to diagnose and manage them still remains controversial. Although for some patients there are unambiguous clinical and imaging findings of FAI, for a substantial number of patients there are minimal or intermediate findings. Moreover, several studies have reported a high prevalence of FAI morphology among the “normal” population and in asymptomatic healthy individuals. At present, there is no adequate imaging tool to facilitate the reliable allocation of all patients into the correct diagnostic group or to confidently rule out diagnosis. However, imaging parameters can be used to describe different hip morphological characteristics and additionally confirm or preclude the diagnosis of FAI.This thesis focuses on assessing hip morphology in different populations by investigating which specific joints are more prone to developing symptoms and by evaluating treatment outcomes of a FAI cohort. Specifically, this research concentrates on the following: 1) examining population-specific (symptomatic and non-symptomatic) characteristics of hip morphology; 2) developing an anatomic-based model to establish “at-risk” hip joints, incorporating subject-specific hip geometries and spinopelvic parameters and 3) investigating treatment outcomes in a Cam-type FAI cohort. In our clinical progression in imaging and in this particular area of pathology, we became aware of the existence of several gaps that we sought to fill with the now published research hereby described. The systematisation by chapters precisely reflects the need to address the issue in simultaneously distinct and complementary areas of knowledge. This thesis consists of six chapters, which cover the entire spectrum from the diagnosis to treatment of the young hip. To present the aims of this thesis in a sequential manner from general morphology to more specific FAI-related topics, the analysis of the asymptomatic hip will be presented first, followed by how joint morphology is associated with symptoms and, finally, will conclude with treatment. In PART I, we introduce the topics that are relevant to understand the full scope of our thesis; we aim to accomplish this by addressing the relevance and contemporariness of the “FAI” theme and by describing the general and vascular anatomy of the hip. Chapter 1 is devoted to hip development and morphogenesis. In Chapter 2, we address the importance of imaging by conducting a thorough review of current and future perspectives on this topic (Paper I). In Chapter 3, we perform a systematic review of the literature to write a state-of-the-art overview, focussing on asymptomatic and symptomatic FAI morphology prevalence and highlighting the multiple gaps in knowledge regarding the role of hip morphology in the pathogenesis of FAI (Paper II). Building on the first part, we address the rationale and aims of this thesis in PART II. In PART III, we describe the original research that was performed and published. Chapter 4 focusses on the detailed characterisation of hip morphology, both osseous and vascular. Bony hip morphology was quantified using a semi-automated software, which allows to robustly study in detail shape variants in an asymptomatic population and their relationship with sex, side and limb dominance (Paper III). Cam morphology was further defined by developing a novel quantitative parameter, with diagnostic and treatment planning capabilities using a cohort of both asymptomatic individuals (Paper IV) and patients undergoing surgery (Paper V). Moreover, we felt the need to better characterise the topography of the deformity and its relationship with the nourishing arteries of the femoral head, as Cam morphology frequently has a posterior a bstr extension that overlaps the retinacular vascular structures. However, its arterial origin has never been described or confirmed in the literature. For this reason, the importance of the aforementioned parameter has been outlined by the cadaveric arterial topographic study of the proximal femur (Paper VI). In Chapter 5, we test multiple parameters and their associated shape variants to detect which ones allow identifying a risk-increased joint in various populations. To this end, we use both advanced computing for shape modelling (Paper VII) and three dimensional (3D) magnetic resonance imaging (MRI) (Paper VIII). Chapter 6 describes the various treatment options (Paper IX) and outcomes in a cohort clinical study, comparing open surgery with arthroscopic surgery in terms of treating Cam deformities (Paper X). The results of the aforementioned chapters are summarised in PART IV, presenting the general synthesis, discussing the results in the light of current literature and detailing the conclusions of this thesis. The scope of potential future research within this field is also presented in this chapter. In brief, this thesis suggests the following: First, detailed imaging assessment of hip morphology is paramount to better understanding both the hip joint and pelvic morphology (Paper I). Second, the case definitions of different morphologies and clinical entities are missing as far as FAI and related disorders are concerned. Qualitative and quantitative radiographic findings thought to be associated with Cam- and Pincer-type FAI, as well as the coexistence between them, are quite common among different populations (Paper II). Third, in adult asymptomatic populations, sex-specific reference intervals for hip measurements for DHD and FAI morphology are wider than currently accepted values (Paper III). Moreover, femoral morphology with distinct Cam magnitudes and epicentres is also sex-specific, with higher mean alpha angle (α°) and omega angle (Ω°) values seen in males (Paper IV). Forth, Cam deformity frequently overlaps with the retinacular vascular structures seen in an MRI; this finding has practical surgical relevance. Additionally, the radial extension of the Cam deformity (Ω°) is more significantly associated with the patients’ symptoms prior to surgery than the α° (paper V). The origin of the vascular structures seen in the retinacular fold is unequivocally arterial in nature, and these structures have a more anterior distribution than classically assumed (Paper VI). Fifth, ovoid geometries are more representative of both articular surfaces of the hip joint as well as of Cam, Pincer and mixed impinged hips when compared to spherical or ellipsoidal shapes (Paper VII). Individuals with larger Cam deformities, decreased acetabular coverage and increased pelvic anteflexion are more likely to experience hip symptoms (Paper VIII). This provides clinicians with indications of how the pathology exacerbates, allowing them to perform the correct clinical assessments and proceed with the correct form of care. From a patient’s perspective, an early and accurate diagnosis could prevent cartilage degradation and progression to OA. Sixth, similar outcomes and significant functional improvement are observed when comparing open and arthroscopic surgery in the treatment of Cam deformities (follow-up time of two years). It should be noted that the female gender was associated with poor hip function in the preoperative evaluation (papers IX and X). Looking ahead, imaging and hip preserving surgery (HPS) will evolve hand-in-hand in the face of new and greater challenges. The increasing number of analytic parameters describing hip joint pathomorphologies as well as new sophisticated 3D imaging-analysis together with emerging artificial intelligence-based technologies have transported us beyond simple classification systems. Moreover, more reliable diagnostic and treatment guidelines that go beyond differentiation into pure FAI and dysplasia are paramount. The largely unknown natural course of both hips with symptomatic FAI and asymptomatic individuals continues to present research opportunities as far as diagnosis, treatment and prognosis are concerned

Study of the neuropathology of HIV infection in an African Paediatric Cohort

BACKGROUND: In 1991-92 a large collaborative post-mortem study of adults and children was undertaken in the West African city of Abidjan, Cote d'lvoire, in order to document the impact of human immunodeficiency virus (HIV) infection on the already high mortality from infectious disease. As part of this original study, brain tissue preserved in paraffin wax blocks was retained from 78 HIV positive children (76 HIV-1 and 2 HIV-2) and 77 age-matched HIV-negative children. The baseline neuropathological findings were published and the material was stored as an archive at the Western General Hospital, Edinburgh. Further study of this unique collection of cases was clearly warranted.HYPOTHESES AND AIMS OF THE PRESENT STUDY: In the Initial Study, an attempt was made to quantify white matter cell numbers using a small sample of the whole cohort. The hypothesis was that it would be possible to obtain reproducible numbers for total cell counts in the white matter of HIV negative children and that the numbers were likely to be significantly higher in HIV positive children. The Main Study focussed on the extent of inflammatory change in HIV negative and positive cases, with the prediction that HIV positive children would show a higher level of inflammatory infiltrate than HIV negative children, despite the high level of background brain pathology in the latter group, and that this would be associated with evidence of greater white matter damage in the HIV positive cases. Lastly in the Apolipoprotein E (APOE) Study, it was predicted that the inflammatory response, particularly the degree of microglial activation would be influenced by the APOE genotype, being most evident in children possessing one or more APOE e4 alleles.MATERIALS AND METHODS: For the Initial Study, eight age-matched HIV negative and positive cases were selected from the African cohort, together with an additional HIV negative case at either end of the age spectrum. Four regions of the brain were selected from each of these 10 cases, including cerebral convexity, hippocampus, basal ganglia and the cerebellum. Sections were stained routinely with haematoxylin and eosin, Luxol fast blue and by immunohistochemistry. Total cell counts were performed in an area of one mm2, and subsequently for individual cell types identified using a combination of simple morphology and immunostaining for glial fibrillary acidic protein (GFAP). Although there is no immunostain that reliably identifies all of the members of a particular glial population, whether they be astrocytes, oligodendrocytes or microglia, separation of these cell types was attempted on the basis of GFAP positivity or on simple nuclear morphology. The results were tabulated in Excel.In the Main Study 40 further cases from the African cohort were examined. These included 20 HIV negative and 20 positive, chosen to represent three age groups, lower, middle and upper, up to the age of six years. The basal ganglia and the hippocampus were selected for examination in these cases. In about half of these cases, significant pathology other than HIV-associated changes was present and the spectrum of CNS disease included malaria, meningitis and non-HIV encephalitis. Sections were stained routinely with haematoxylin and eosin, Luxol fast blue and by immunohistochemistry for inflammatory cell markers (CD 14, CD 16 and CD68) or lymphocyte markers (CD8 and CD20). Sections were examined by routine microscopy, and by simple quantitation or image analysis.In the APOE study genotyping was undertaken first on the forty cases used in the main study. Twenty further cases were added subsequently, 10 HIV positive and 10 negative, and within the same age range as those in the main study. DNA was extracted from paraffin sections according to a standard protocol and amplified using polymerase chain reaction (PCR). The degree of inflammation, as detected by CD 16 and CD68 image analysis in these cases, was correlated with the different APOE genotypes. All cases used in this study were anonymised. Ethical permission was sought and obtained for this study (LREC/2003/6/6).RESULTS: The results of the Initial Study showed that the total cell numbers varied from case to case in the HIV negative group, and from one brain region to another, but that these differences were not statistically significant. The total cell counts also varied between individual HIV positive cases and these differences were not statistically significant either. However, comparison ofthe means for HIV negative cases with those of the HIV positive cases revealed significant increases in the latter group. Despite the obvious limitations of the morphological approach to individual cell typing, subset counts from the cerebral convexity, basal ganglia, hippocampus and cerebellum, putatively of astrocytes, oligodendrocytes, microglia and endothelial cells, showed significantly higher levels in the HIV positive cases.In the Main Study, changes in the white matter assessed by routine and Luxol fast blue staining, and by immunohistochemistry for myelin basic protein (MBP), P-amyloid precursor protein (BAPP) and GFAP, and graded according to a simple system, showed only limited differences between HIV positive and negative groups. A general increase in activation of macrophage/microglial cells and of lymphocyte numbers was found in both basal ganglia and hippocampus in the HIV positive group. This increase in the HIV positive group was detected despite a reasonable balance of background brain pathology between the HIV positive and negative subsets. In the case of CD68 immunostaining, the increase was statistically significant for the grey (p=0.002) and white (p=0.009) matter of the basal ganglia. For counts of CD8 positive perivascular cells, the increase was also significant in grey (p=0.001) and white matter (p=0.000) of the basal ganglia, and in grey (p=0.002) and white (p=0.000) matter of the hippocampus.In the APOE study, DNA extraction was successful in 47 cases in total. The distribution of APOE s3 and s4 alleles in this group proved in accordance with the known West African distributions where the s4 allele approaches a frequency of up to 29%. In this study, though the case numbers are small, the frequency of the e4 allele was 41% in HIV negative children and 23% in HIV positive children (p=0.01). These rates were significantly higher than in most Caucasian populations (p=0.001). Satisfactory immunostaining for inflammatory markers was achieved in 44 of the genotyped cases. Correlations with the degree of neuroinflammation in grey and white matter of the basal ganglia were confined to APOE s3/e3 and APOE e3/e4 cases because of the small numbers of cases with rarer APOE allelic patterns. For HIV negative children, there was little difference for CD 16 or CD68 staining between APOE e3/e3 and APOE e3/e4 cases, either in white or grey matter. For HIV positive children, subjects with e3/e4 genotypes did show a trend for higher levels of CD68 activation than those with 3/3 genotypes, particularly in the basal ganglia white matter, but failed to reach significance (p=0.07 for white matter and p=0.1 for grey matter).CONCLUSIONS: 1. Although the results of the initial study are limited in their possible application to any studies other than in this cohort, the increases in total and individual cell counts in the HIV positive group are intriguing. The limitations of a study based on morphological assessment are recognised. 2. In the main study the failure to demonstrate significant white matter change in either HIV negative or positive groups may mean that there is none, but wider sampling in each case and examination of a larger number of cases would increase confidence in this result. It is noted that incomplete myelination in these young subjects is a possible confounding factor in this study. Inflammatory changes, both innate and acquired, proved to be significantly greater in both grey and white matter of HIV positive compared with negative cases, there being a relative balance of co-existing disease in the two groups. This study shows, as predicted, that HIV infection is accompanied by significant microglial activation in these West African children, and that this occurs even in the absence of productive viral infection in the brain. This finding is in keeping with what is known in Western paediatric populations infected with HIV. 3. APOE genotyping revealed a distinctive allele distribution especially in respect of the s4 allele, which was found to be twice as common in this African cohort as in the Scottish population. Although there was trend for greater microglial activation in APOE c4 HIV positive children, the differences between these and APOE e3 HIV positive children did not reach significance

Patterns of injury and violence in Yaoundé Cameroon: an analysis of hospital data.

BackgroundInjuries are quickly becoming a leading cause of death globally, disproportionately affecting sub-Saharan Africa, where reports on the epidemiology of injuries are extremely limited. Reports on the patterns and frequency of injuries are available from Cameroon are also scarce. This study explores the patterns of trauma seen at the emergency ward of the busiest trauma center in Cameroon's capital city.Materials and methodsAdministrative records from January 1, 2007, through December 31, 2007, were retrospectively reviewed; information on age, gender, mechanism of injury, and outcome was abstracted for all trauma patients presenting to the emergency ward. Univariate analysis was performed to assess patterns of injuries in terms of mechanism, date, age, and gender. Bivariate analysis was used to explore potential relationships between demographic variables and mechanism of injury.ResultsA total of 6,234 injured people were seen at the Central Hospital of Yaoundé's emergency ward during the year 2007. Males comprised 71% of those injured, and the mean age of injured patients was 29 years (SD = 14.9). Nearly 60% of the injuries were due to road traffic accidents, 46% of which involved a pedestrian. Intentional injuries were the second most common mechanism of injury (22.5%), 55% of which involved unarmed assault. Patients injured in falls were more likely to be admitted to the hospital (p < 0.001), whereas patients suffering intentional injuries and bites were less likely to be hospitalized (p < 0.001). Males were significantly more likely to be admitted than females (p < 0.001)DiscussionPatterns in terms of age, gender, and mechanism of injury are similar to reports from other countries from the same geographic region, but the magnitude of cases reported is high for a single institution in an African city the size of Yaoundé. As the burden of disease is predicted to increase dramatically in sub-Saharan Africa, immediate efforts in prevention and treatment in Cameroon are strongly warranted

Representations of native and foreign talkers in brain and behaviour

Human listeners possess good speaker recognition abilities, and are capable of discriminating and identifying speakers from a range of spoken utterances. However, voice recognition can be enhanced when a listener is capable of understanding the speech produced by a talker. A well-established demonstration of this is known as the “Language-Familiarity” Effect (LFE) for voice recognition. This effect manifests as an impairment for voice recognition in foreign language speech conditions, as contrasted with recognition of talkers who are speaking in a listener’s mother tongue, and has been repeatedly demonstrated across a range of different tasks and languages. The LFE has previously been conceptualized as an analogue to the even better-known “Other-Race” Effect (ORE) for face recognition, where own-race faces are better remembered than other-race faces. An influential theoretical model of the ORE posits that faces are represented in a multidimensional “face-space”, whose dimensions are shaped by perceptual experience and code for features which are diagnostic for face individuation (Valentine, 1991). Over the course of an individual’s perceptual experience, these dimensions might become attuned for own-race face recognition; as a consequence, the dimensions will be sub-optimal for other-race recognition, leading to the illusion of increased similarity among different other-race faces, relative to own-race faces – what has been termed the “they-all-look-alike” effect. The idea of a complementary “voice-space” has already been posited in the auditory domain, and might serve as a useful model for the LFE. Speakers might be individuated on the basis of diagnostic dimensions which might code for important voice-acoustical attributes. However, these dimensions might also be shaped according to linguistic experience, and voice individuation (and recognition) might be optimised when listeners can take advantage of both general voice acoustics and stored representations of their native language to tell speakers apart. The face-space hypothesis represents a plausible model for the ORE, and evidence for it has accrued through computational modelling and neuroimaging work. Conversely, however, at present it merely serves as a descriptive model for the LFE. In this thesis, I combine behavioural testing, and neuroimaging studies using functional Magnetic Resonance Imaging (fMRI) to probe the nature of the representations of native and foreign speakers. Chapter 1 provides a general overview of voice processing with an emphasis on voice recognition. Subsequently, I provide a review of relevant literature pertaining to the LFE, and introduce a brief comparison to the ORE for faces in the context of the Valentine (1991) similarity model, ending with a description of the aims of the thesis. In Chapter 2, I present the results of a behavioural experiment where native English and Mandarin speaking listeners rated all pairwise combinations of a series of English- and Mandarin-speaking voices. Crucially, the LFE does not appear to be dependent on full comprehension of the linguistic message, as young infants can better tell apart speakers in their native language than in a foreign language before their speech comprehension abilities are fully mature. This suggests that exposure to the sound-structure characteristic of infants’ nascent mother tongue might be sufficient to enhance native language speaker discrimination, in the absence of full comprehension. Therefore, to examine a counterpart in adults, speech stimuli were subjected to time-reversal, a process which precludes lexical and semantic access but which leaves intact certain phonemic properties of the original speech signal. Both the English and Mandarin listeners rated pairs of native-language voices as sounding more dissimilar than foreign voices, suggesting that the language-specific sound-structure elements remaining in the reversed speech enabled an enhanced individuation of native voices. Next, in Chapter 3, I aimed to probe the neural basis of this enhanced individuation in an fMRI experiment which was intended to capture dissimilarities among paired cerebral responses to unintelligible native and foreign speakers. Here, I did not find a direct correlate of the behavioural effect, but did find that local patterns of response estimates in the bilateral superior temporal cortex (STC) appear to “discriminate” the different language categories in both English and Mandarin listeners. Specifically, when the pairwise dissimilarity in brain responses to different speakers was collected, relatively high dissimilarity was observed for pairs consisting of a response to an English speaker and a Mandarin speaker, whereas relatively low dissimilarity was observed for pairs consisting of two English or two Mandarin speakers. In Chapter 4, I report what is, to my knowledge, the first explicit examination of the neural basis for the LFE in intelligible speech. A monolingual sample of English speakers participated in an fMRI experiment where they listened to the voices of English and Mandarin speakers. Importantly, speech stimuli in both language conditions were matched in inter-speaker acoustical variability. Combined response patterns from bilateral voice-sensitive temporal lobe regions enabled a learning algorithm to decode the identities of the voices who elicited the responses, but, crucially, only in the native speech (English) condition. Interestingly, native-language speaker decoding was also achieved from a left-hemisphere voice-sensitive region alone, but not a right-hemisphere region. This putative leftward bias might reflect a higher discriminability of native-language talkers in the brain, via an enhanced ability to individuate voices on the basis of indexical variation around stored speech-sound representations. Finally, in Chapter 5, I conclude with a general discussion of the foregoing results, their implications for an analogous conception of the LFE and ORE, and some strands of thought for future investigation

Filtrage anisotrope robuste et segmentation par B-spline snake : application aux images échographiques

Le contexte de ce travail est le traitement d'images échographiques. Plus précisément, on s'est intéressé au filtrage et à la segmentation automatique d'images dégradées par du speckle. La première partie concerne les travaux effectués sur le filtrage du speckle. Ils ont abouti à la conception d'une méthode de diffusion anisotrope robuste, nommée -diffusion. Elle se fonde sur un coefficient de diffusion original qui exploite lui-mˆeme la statistique du coefficient de variation et une adaptation de la fonction de Tukey. Un estimateur robuste du paramètre d'échelle de ce filtre est présenté. L'évolution de la diffusion est modélisée par une équation aux dérivées partielles s'appliquant sur l'enveloppe du signal brut, non compressée logarithmiquement. Cette approche permet de réduire le bruit des images échographiques, tout en préservant les structures importantes pour leur interprétation. Dans la deuxieme partie, nous présentons un contour actif paramétrique de type B-spline snake. L'étude de la continuité géométrique des B-splines nous permet de justifier le choix de l'énergie interne. Nous proposons deux nouvelles énergies externes qui exploitent notamment un champ de flux de vecteurs gradients, nommé s-GVF, calculé sur une carte de coefficients de variation locaux. Une fonction d'inhibition contrôle l'influence respective de ces deux énergies externe lors de l'évolution du snake. Enfin, nous proposons une nouvelle méthode d'initialisation automatique pour contour actif paramétrique. Une application au cas du filtrage des images echographiques et de la segmentation des cavités cardiaques est présentée. Les résultats démontrent une robustesse et une précision accrue par les modèles proposés par rapport aux techniques classiques de filtrage et segmentation par contours actifs. ABSTRACT : This thesis presents a robust model for speckle anisotropic filtering, and a parametric active contour model (B-spline snake) for the segmentation of images affected by speckle. First an original diffusion tensor is developed. It is based on the Tukey's error norm and on a local estimation of the coefficient of variation. The diffusion evolution is modelled by a partial derivative equation for raw images with no log-compression. This model reduces speckle while preserving important image features that are used by doctors to perform a diagnosis. Then we present a B-spline snake model with an external energy term that uses the amplitude and direction of the coefficient of variation gradient. The geometric continuity is guaranted by a uniform parametrisation and an internal energy term which penalizes the curve for irregular nodes spacing. An application to ultrasound image filtering and heart cavities detection is presented