The illness experience of persons with Parkinson's Disease

Background. Parkinson's disease is a chronic, progressive, age-related, neurodegenerative disorder with no known cause or promising cure. While substantial information is known about the pathophysiology of Parkinson's disease, little is known about the illness experience of persons living with the disease. The purpose of this study was to understand how persons with Parkinson's disease construct their illness experience and manage living with their illness on a daily basis. ^ Method. A qualitative study with an ethnographic approach employed the strategies of participant observations and fieldwork. Field data were generated from a two year exposure to two Parkinson's disease support groups in east Texas. Open-ended semi-structured interviews with seven men and seven women with Parkinson's disease were also conducted. These data were combined and analyzed using thematic analysis. ^ Findings. The illness experience is described through the metaphor "Sailing the Sea in The Eye of the Storm." This metaphor served as the overarching theme that covered the two interacting content themes of the voyage of Daily Negotiations in the Midst of Uncertainty and Reconstruction of the Self with Parkinson's Disease. Daily negotiations incorporated navigating daily activities with the uncertainty of both the progression and daily vicissitudes of the disease. Participants described their symptoms as progressive imprisonment that interfered with daily activities. The progressive nature of the disease required the participants to reconstruct their perceptions of themselves. Reconstructing the self involved the paradoxical balancing of preserving the self while simultaneously releasing aspects of the former self to reconstruct the self with Parkinson's disease. This process was reflected in four exemplars: I Know Me." "It's Still Me," "See Me." and "Remember Me." ^ Conclusions. This qualitative study illuminated the struggle of persons in dealing with the uncertainties and fluctuations of Parkinson's disease and the process of reconstructing their perceptions of themselves. The meaning and reconstruction of the illness experience expressed by participants will inform understanding beyond the disease itself to the illness experience that these participants must deal with on a daily basis. ^

Toxina botulínica para la secreción descontrolada de saliva : presentación de un caso

La neurotoxina botulínica es producida por la bacteria anaerobia Clostridium botulinum (NTBo). Bloquea la transmisión neuromuscular por lo cual es utilizada para el tratamiento de enfermedades con hiperactividad muscular, bloqueando la liberación de acetilcolina y así la transmisión sináptica en la unión neuromuscular, lo que lleva al debilitamiento y atrofia de los músculos. Este mecanismo de acción motivó el uso de la toxina botulínica en las enfermedades con elevado tono muscular, como la distonía y la espasticidad, por lo cual también ha revolucionado la opción de tratamiento de los trastornos autónomos de hipersecreción. La sialorrea es un síntoma común en diversas enfermedades neurológicas. Las inyecciones de toxina botulínica, guiadas por ultrasonidos en las glándulas salivales, produce una disminución de la salivación excesiva en niños con deficiencias neurológicas como parálisis cerebral. La utilización de la toxina botulínica tipo A ha sido sugerida como tratamiento de la sialorrea en pacientes con parálisis cerebral (PC). Esta recomendación ha sido hecha por el efecto anticolinérgico de esta sustancia, principalmente por su capacidad para bloquear la liberación de acetilcolina a nivel de las membranas pre-sinápticas Aunque la respuesta al tratamrento es distinta en cada niño, en general se ha observado que cuanto más a menudo se utiliza la toxlna botulínica y más alta es la dosis utilizada, los resultados son mejores. Los expertos consideran conveniente el procedimiento porque muchos de estos pacientes están utilizando la toxina botulínica para sus problemas musculares y las distrntas condiciones pueden ser tratadas al mismo tiempo Se reporta la descripción de la aplicación de toxina botulínica en una paciente niña que concurre al Instituto de Rehabilitación Infantil TELETON de la ciudad de Valparaíso, Chile, con un trastorno motor severo y con salivación incontrolada persistente que provoca enfermedades respiratorias a repetición

Oxygen extended sooting index of FAME blends with aviation kerosene

The use of biofuels in the aviation sector has economic and environmental benefits. Among the options for the production of renewable jet fuels, hydroprocessed esters and fatty acids (HEFA) have received predominant attention in comparison with fatty acid methyl esters (FAME), which are not approved as additives for jet fuels. However, the presence of oxygen in methyl esters tends to reduce soot emissions and therefore particulate matter emissions. This sooting tendency is quantified in this work with an oxygen-extended sooting index, based on smoke point measurements. Results have shown considerable reduction in the sooting tendency for all biokerosenes (produced by transesterification and eventually distillation) with respect to fossil kerosenes. Among the tested biokerosenes, that made from palm kernel oil was the most effective one, and nondistilled methyl esters (from camelina and linseed oils) showed lower effectiveness than distilled biokerosenes to reduce the sooting tendency. These results may constitute an additional argument for the use of FAME’s as blend components of jet fuels. Other arguments were pointed out in previous publications, but some controversy has aroused over the use of these components. Some of the criticism was based on the fact that the methods used in our previous work are not approved for jet fuels in the standard methods and concluded that the use of FAME in any amount is, thus, inappropriate. However, some of the standard methods are not updated for considering oxygenated components (like the method for obtaining the lower heating value), and others are not precise enough (like the methods for measuring the freezing point), whereas some alternative methods may provide better reproducibility for oxygenated fuels.

Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with the most severe pathology in the T lymphocytes and platelets. The disease arises from mutations in the gene encoding the WAS protein. T lymphocytes of affected males with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that the WAS protein could regulate its organization. We show here that WAS protein interacts with a member of the Rho family of GTPases, Cdc42. This interaction, which is guanosine 5'-triphosphate (GTP)-dependent, was detected in cell lysates, in transient transfections and with purified recombinant proteins. A weaker interaction was also detected with Rac1 using WAS protein from cell lysates. It was also found that different mutant WAS proteins from three affected males retained their ability to interact with Cdc42 and that the level of expression of the WAS protein in these mutants was only 2-5% of normal. Taken together these data suggest that the WAS protein might function as a signal transduction adaptor downstream of Cdc42, and in affected males, the cytoskeletal abnormalities may result from a defect in Cdc42 signaling.

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R-avg) and then weighted for sample size (rootN[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P-AvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P-ord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (P-AvgRnk

The outcome in Australian children with hyperinsulinism of infancy: early extensive surgery in severe cases lowers risk of diabetes

AIMS Hyperinsulinism of infancy (HI) is characterized by unregulated insulin secretion in the presence of hypoglycaemia, often resulting in brain damage. Pancreatic resection for control of hypoglycaemia is frequently resisted because of the risk of diabetes mellitus (DM). We investigated retrospectively 62 children with HI from nine Australian treatment centres born between 1972 and 1998, comparing endocrine and neurological outcome in 28 patients receiving medical therapy alone with 34 who required pancreatic resection to control their hypoglycaemia. METHODS History, treatment and clinical course were ascertained from file audit and interview. Risk of DM (hazard ratio) attributable to age at surgery (< vs. greater than or equal to 100 days at last pancreatectomy) and extent of resection (< vs. greater than or equal to 95%) were calculated using Cox proportional hazards regression and categorical variables compared by the chi(2) -test. Neurological outcome (normal, mild deficit or severe deficit) was derived from the most authoritative source. RESULTS Surgically treated patients had a greater birthweight, earlier presentation and higher plasma insulin levels. Of 18 infants < 100 days and 16 greater than or equal to 100 days of age at surgery, four (all greater than or equal to 100 days) became diabetic as an immediate consequence of surgery and five (two < 100 days and three greater than or equal to 100 days) became diabetic 7-18 years later. Surgery greater than or equal to 100 days and pancreatectomy greater than or equal to 95% were associated with development of diabetes (HR = 12.61, CI 1.53-104.07 and HR = 7.03, CI 1.43-34.58, respectively). Neurodevelopmental outcome was no different between the surgical and medical groups with 44% overall with neurological deficits. Patients euglycaemic within 35 days of the first symptom of hypoglycaemia (Group A) had a better neurodevelopmental outcome than those still hypoglycaemic > 35 days from first presentation (Group B) (P = 0.007). Prolonged hypoglycaemia in Group B was due either to delayed diagnosis or to need for repeat surgery because of continued hypoglycaemia. Within Group A, medically treated patients (who presented later with apparently milder disease) had a higher incidence of neurodevelopmental deficit (n = 15, four mild, three severe deficit) compared with surgically treated patients (n = 18, two mild, none severe deficit) (P < 0.025). CONCLUSIONS Poor neurodevelopmental outcome remains a major problem in hyperinsulinism of infancy. Risk of diabetes mellitus with pancreatectomy varies according to age at surgery and extent of resection. Patients presenting early with severe disease have a better neurodevelopmental outcome and lower risk of diabetes if they are treated with early extensive surgery.

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8x10(-6)) and genotype distributions (P=4x10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.

Follicular dendritic cell sarcoma associated with Castelmans disease presenting in the oral cavity

Follicular dendritic cell sarcoma (FDCS) is a rare intermediate grade malignant neoplasm of reticular dendritic origin. Castleman’s disease (CD) represents a non-neoplastic lymphoproliferative disorder with various clinical and morphological features. FDCS has been reported to be associated with CD. In this article, we describe the first case of follicular dendritic cell sarcoma associated with Castleman’s disease presenting in the oral cavity. Copyright © 2005 Elsevier Ltd All rights reserved.

Frontoparietal control of spatial attention and motor intention in human EEG

Relations between spatial attention and motor intention were investigated by means of an EEG potential elicited by shifting attention to a location in space as well as by the selection of a hand for responding. High-density recordings traced this potential to a common frontoparietal network activated by attentional orienting and by response selection. Within this network, parietal and frontal cortex were activated sequentially, followed by an anterior-to-posterior migration of activity culminating in the lateral occipital cortex. Based on temporal and polarity information provided by EEG, we hypothesize that the frontoparietal activation, evoked by directional information, updates a task-defined preparatory state by deselecting or inhibiting the behavioral option competing with the cued response side or the cued direction of attention. These results from human EEG demonstrate a direct EEG manifestation of the frontoparietal attention network previously identified in functional imaging. EEG reveals the time course of activation within this network and elucidates the generation and function of associated directing-attention EEG potentials. The results emphasize transient activation and a decision-related function of the frontoparietal attention network, contrasting with the sustained preparatory activation that is commonly inferred from neuroimaging.

Behavioural and neuroimaging investigations of the relationship between visual attention, affordance and action

In this thesis the relationship between visual attention, affordance and action was investigated using a combination of neuroimaging and behavioural studies. Neuronal activity and movement construction were assessed when individuals passively viewed or produced action towards stimuli varying in their affordance and/or attentional attributes. The main findings were: (i) the passive perception of both object and abstract visual patterns was associated with decreased alpha and/or beta activity in sensori-motor cortex, occipito-temporal cortex and cerebellum. These are brain regions associated with the planning and production of visually guided action; (ii) for object patterns, decreased alpha and beta activity was also observed in regions of superior parietal and premotor cortex. These regions contain neurons argued to be essential for matching hand kinematics with manipulate objects; and (iii) in both control participants and a deafferented individual, studies of planned and unplanned pointing manoeuvres revealed that the attentional bias of a stimulus was critical for fast, efficient action production whereas the affordance bias was critical in determining end-point accuracy. Taken together, these findings demonstrate that affordance is not a necessary prerequisite for the potential of motor codes. Rather, affordance enables the construction of motor responses that reflect object functionality and/or manipulability. They further demonstrate that visual attention is associated with the potentiation of motor codes. Indeed, directed visual attention would appear critical for speeded responses. These findings provide new insights into the roles of directed visual attention and affordance upon action.

The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

Modulation of long-range neural synchrony reflects temporal limitations of visual attention in humans

Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little is known about how these areas interact to form a dynamic attentional network. We hypothesized that the network communicates by means of neural phase synchronization, and we used magnetoencephalography to study transient long-range interarea phase coupling in a well studied attentionally taxing dual-target task (attentional blink). Our results reveal that communication within the fronto-parieto-temporal attentional network proceeds via transient long-range phase synchronization in the beta band. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioral performance. Thus, we show how attentional limitations arise from the way in which the subsystems of the attentional network interact. The human brain faces an inestimable task of reducing a potentially overloading amount of input into a manageable flow of information that reflects both the current needs of the organism and the external demands placed on it. This task is accomplished via a ubiquitous construct known as “attention,” whose mechanism, although well characterized behaviorally, is far from understood at the neurophysiological level. Whereas attempts to identify particular neural structures involved in the operation of attention have met with considerable success (1-5) and have resulted in the identification of frontal, parietal, and temporal regions, far less is known about the interaction among these structures in a way that can account for the task-dependent successes and failures of attention. The goal of the present research was, thus, to unravel the means by which the subsystems making up the human attentional network communicate and to relate the temporal dynamics of their communication to observed attentional limitations in humans. A prime candidate for communication among distributed systems in the human brain is neural synchronization (for review, see ref. 6). Indeed, a number of studies provide converging evidence that long-range interarea communication is related to synchronized oscillatory activity (refs. 7-14; for review, see ref. 15). To determine whether neural synchronization plays a role in attentional control, we placed humans in an attentionally demanding task and used magnetoencephalography (MEG) to track interarea communication by means of neural synchronization. In particular, we presented 10 healthy subjects with two visual target letters embedded in streams of 13 distractor letters, appearing at a rate of seven per second. The targets were separated in time by a single distractor. This condition leads to the “attentional blink” (AB), a well studied dual-task phenomenon showing the reduced ability to report the second of two targets when an interval <500 ms separates them (16-18). Importantly, the AB does not prevent perceptual processing of missed target stimuli but only their conscious report (19), demonstrating the attentional nature of this effect and making it a good candidate for the purpose of our investigation. Although numerous studies have investigated factors, e.g., stimulus and timing parameters, that manipulate the magnitude of a particular AB outcome, few have sought to characterize the neural state under which “standard” AB parameters produce an inability to report the second target on some trials but not others. We hypothesized that the different attentional states leading to different behavioral outcomes (second target reported correctly or not) are characterized by specific patterns of transient long-range synchronization between brain areas involved in target processing. Showing the hypothesized correspondence between states of neural synchronization and human behavior in an attentional task entails two demonstrations. First, it needs to be demonstrated that cortical areas that are suspected to be involved in visual-attention tasks, and the AB in particular, interact by means of neural synchronization. This demonstration is particularly important because previous brain-imaging studies (e.g., ref. 5) only showed that the respective areas are active within a rather large time window in the same task and not that they are concurrently active and actually create an interactive network. Second, it needs to be demonstrated that the pattern of neural synchronization is sensitive to the behavioral outcome; specifically, the ability to correctly identify the second of two rapidly succeeding visual targets

To which extent can attention and/or modulation explains deficits in dyslexia?

This thesis investigates the visual deficits associated with developmental dyslexia, particularly that of visual attention. Visual attention has previously been investigated in a wide array of behavioural and psychophysical (amongst others) studies but not many have produced consistent findings. Attention processes are believed to play an integral part in depicting the overall "extent" of reading deficits in dyslexia, so it was of paramount importance to aim at such attention mechanisms in this research. The experiments in this thesis focused on signal enhancement and noise (distractor) exclusion. Given the flexibility of the visual search paradigms employed in this research, factors such as visual crowding and attention distribution was also investigated. The experiments systematically manipulated noise (by increasing distractor count, i.e. set-size), crowding (varying the spacing between distractors), attention allocation (use of peripheral cues to direct attention), and attention distribution (influence of one visual field over the other), all of which were tied to a critical factor, the "location/spatial/decisional uncertainty". Adults with dyslexia were: (i) able to modulate attention appropriately using peripheral pre-cues, (ii) severely affected by crowding, and (iii) unable to counteract increased set-sizes when post or un-cued, the latter signifying poor distractor (noise) suppression. By controlling for location uncertainty, the findings confirmed that adults with dyslexia were yet again affected by crowding and set-size, in addition to an asymmetric attention distribution. Confounding effects of ADHD symptoms did not explain a significant independent variance in performance, suggesting that the difficulty shown by adult dyslexics were not accounted for by co-morbid ADHD. Furthermore, the effects of crowding, set-size and asymmetric attention correlated significantly with literacy, but not ADHD measures. It is believed that a more diffuse and an asymmetric attention system (in dyslexia) to be the limiting factor concerning noise exclusion and attention distribution. The findings from this thesis add to the current understanding of the potential role of deficits in visual attention in dyslexia and in the literacy difficulties experienced by this population.

The ecocultural context and child behavior problems: A qualitative analysis in rural Nepal.

Commonly used paradigms for studying child psychopathology emphasize individual-level factors and often neglect the role of context in shaping risk and protective factors among children, families, and communities. To address this gap, we evaluated influences of ecocultural contextual factors on definitions, development of, and responses to child behavior problems and examined how contextual knowledge can inform culturally responsive interventions. We drew on Super and Harkness' "developmental niche" framework to evaluate the influences of physical and social settings, childcare customs and practices, and parental ethnotheories on the definitions, development of, and responses to child behavior problems in a community in rural Nepal. Data were collected between February and October 2014 through in-depth interviews with a purposive sampling strategy targeting parents (N = 10), teachers (N = 6), and community leaders (N = 8) familiar with child-rearing. Results were supplemented by focus group discussions with children (N = 9) and teachers (N = 8), pile-sort interviews with mothers (N = 8) of school-aged children, and direct observations in homes, schools, and community spaces. Behavior problems were largely defined in light of parents' socialization goals and role expectations for children. Certain physical settings and times were seen to carry greater risk for problematic behavior when children were unsupervised. Parents and other adults attempted to mitigate behavior problems by supervising them and their social interactions, providing for their physical needs, educating them, and through a shared verbal reminding strategy (samjhaune). The findings of our study illustrate the transactional nature of behavior problem development that involves context-specific goals, roles, and concerns that are likely to affect adults' interpretations and responses to children's behavior. Ultimately, employing a developmental niche framework will elucidate setting-specific risk and protective factors for culturally compelling intervention strategies.

Exploration génétique de l'hypothyroïdie congénitale par dysgénésie thyroïdienne

L'hypothyroïdie congénitale par dysgénésie thyroïdienne (HCDT, ectopie dans plus de 80 %) a une prévalence de 1 cas sur 4000 naissances vivantes. L’HCDT est la conséquence d'une défaillance de la thyroïde embryonnaire à se différencier, à se maintenir ou à migrer vers sa localisation anatomique (partie antérieure du cou), qui aboutit à une absence totale de la thyroïde (athyréose) ou à une ectopie thyroïdienne (linguale ou sublinguale). Les HCDT sont principalement non-syndromiques (soit 98% des cas sont non-familiale), ont un taux de discordance de 92% chez les jumeaux monozygotes, et ont une prédominance féminine et ethnique (i.e., Caucasienne). La majorité des cas d’HCDT n’a pas de cause connue, mais est associée à un déficit sévère en hormones thyroïdiennes (hypothyroïdie). Des mutations germinales dans les facteurs de transcription liés à la thyroïde (NKX2.1, FOXE1, PAX8, NKX2.5) ont été identifiées dans seulement 3% des patients atteints d’HCDT sporadiques et l’analyse de liaisons exclue ces gènes dans les rares familles multiplex avec HCDT. Nous supposons que le manque de transmission familiale claire d’HCDT peut résulter de la nécessité d’au moins deux « hits » génétiques différents dans des gènes importants pour le développement thyroïdien. Pour répondre au mieux nos questions de recherche, nous avons utilisé deux approches différentes: 1) une approche gène candidat, FOXE1, seul gène impliqué dans l’ectopie dans le modèle murin et 2) une approche en utilisant les techniques de séquençage de nouvelle génération (NGS) afin de trouver des variants génétiques pouvant expliquer cette pathologie au sein d’une cohorte de patients avec HCDT. Pour la première approche, une étude cas-contrôles a été réalisée sur le promoteur de FOXE1. Il a récemment été découvert qu’une région du promoteur de FOXE1 est différentiellement méthylée au niveau de deux dinucléotides CpG consécutifs, définissant une zone cruciale de contrôle de l’expression de FOXE1. L’analyse d’association basée sur les haplotypes a révélé qu’un haplotype (Hap1: ACCCCCCdel1C) est associé avec le HCDT chez les Caucasiens (p = 5x10-03). Une réduction significative de l’activité luciférase est observée pour Hap1 (réduction de 68%, p<0.001) comparé au promoteur WT de FOXE1. Une réduction de 50% de l’expression de FOXE1 dans une lignée de cellules thyroïdienne humaine est suffisante pour réduire significativement la migration cellulaire (réduction de 55%, p<0.05). Un autre haplotype (Hap2: ACCCCCCC) est observé moins fréquemment chez les Afro-Américain comparés aux Caucasiens (p = 1.7x10-03) et Hap2 diminue l’activité luciférase (réduction de 26%, p<0.001). Deux haplotypes distincts sont trouvés fréquemment dans les contrôles Africains (Black-African descents). Le premier haplotype (Hap3: GTCCCAAC) est fréquent (30.2%) chez les contrôles Afro-Américains comparés aux contrôles Caucasiens (6.3%; p = 2.59 x 10-9) tandis que le second haplotype (Hap4: GTCCGCAC) est trouvé exclusivement chez les contrôles Afro-Américains (9.4%) et est absent chez les contrôles Caucasiens (P = 2.59 x 10-6). Pour la deuxième approche, le séquençage de l’exome de l’ADN leucocytaire entre les jumeaux MZ discordants n’a révélé aucune différence. D'où l'intérêt du projet de séquençage de l’ADN et l’ARN de thyroïdes ectopiques et orthotopiques dans lesquelles de l'expression monoallélique aléatoire dans a été observée, ce qui pourrait expliquer comment une mutation monoallélique peut avoir des conséquences pathogéniques. Finalement, le séquençage de l’exome d’une cohorte de 36 cas atteints d’HCDT a permis d’identifier de nouveaux variants probablement pathogéniques dans les gènes récurrents RYR3, SSPO, IKBKE et TNXB. Ces quatre gènes sont impliqués dans l’adhésion focale (jouant un rôle dans la migration cellulaire), suggérant un rôle direct dans les défauts de migration de la thyroïde. Les essais de migration montrent une forte diminution (au moins 60% à 5h) de la migration des cellules thyroïdiennes infectées par shRNA comparés au shCtrl dans 2 de ces gènes. Des zebrafish KO (-/- et +/-) pour ces nouveaux gènes seront réalisés afin d’évaluer leur impact sur l’embryologie de la thyroïde.