Dissertations / Theses: 'Complex syndrome'

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Osborne, Scott. "Immunopathology of complex regional pain syndrome." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/14485/.

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Both increased mast cells numbers and raised immune mediator concentrations indicate immune activation in the affected skin of patients with early CRPS, but little is known about regional immune cell involvement in late stage CRPS. The aim of the current study was to determine skin immune cell populations in longstanding CRPS. Using 6mm skin punch biopsies from CRPS-affected and non-affected tissues, and a combination of chemical and immunofluorescence staining, we examined the density and function of key cell populations including mast cells, epidermal Langerhans cells (LCs), and tissue resident T-cells. We found no significant differences in either overall immune cell infiltrates, or mast cell density between CRPS-affected and non-affected sub-epidermal tissue sections, contrasting recent findings in early CRPS by other groups. However, CD1a+ LC densities in the epidermal layer were significantly decreased in affected compared to non-affected CRPS limbs (p = <0.01). T-cell clones isolated from CRPS- affected sub-epidermal tissues displayed a trend towards increased IL-13 production in ELIspot assays when compared to T-cells isolated from non-affected areas, suggesting a Th2 bias. Immune cell abnormalities are maintained in late stage CRPS disease as manifest by changes in epidermal LC density and tissue resident T-cell phenotype.

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2

Kohr, Danielle [Verfasser]. "Autoimmunity in complex regional pain syndrome / Danielle Kohr." Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1063177618/34.

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3

Lewis, Jenny. "Body perception disturbance in complex regional pain syndrome." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/65409/.

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Complex regional pain syndrome (CRPS) is a painful, debilitating condition that is poorly understood. The syndrome is characterised by pain, motor disturbances and abnormalities in trophic, sudomotor, vascular temperature and sensation. The underlying mechanisms are unknown. Clinical observations have identified a novel phenomenon whereby patients pay little attention to, and fail to care for, their painful affected limb. The literature describes this phenomenon in terms of neglect-like symptoms similar to neurological neglect as described in stroke literature. However, this does not seem to fully fit with or explain the nature of clinical observations. Therefore the aim of the qualitative first study was to more fully describe the phenomenon through an investigation of the patient experience and words used to describe those experiences. Six themes emerged from the data and were as follows: hostile feelings; spectrum of disassociation; disparity between what is apparent and what is felt; distorted mental image of affected parts; awareness of limb position and conscious attention. From these findings a theory emerged which serves to further our understanding of body perception disturbance in CRPS. Based on these findings, the second study aimed to quantify a feature of body perception disturbance by measuring limb position accuracy of those with CRPS compared to Healthy Controls (HC) and those with Rheumatological Pain (RP). The CRPS group were significantly less accurate in positioning of both the affected and unaffected upper limbs (median=9°, Interquartile rang e (IQR), 5.7°-13.3°) compared to both HC (6.5°, IQR, 4°-10.7°) and RP groups (7.7°, IQR, 5 °-11.7°). In the CRPS group position accuracy of the affected limb significantly improved with vision (8.3° in view, 10.7° not in view). Pain intensity was significantly greater in the CRPS (6.5, IQR, 5.4-7.7) than the RP group (4.6, IQR, 3.6-5.7). Based on the findings of this research programme, a definition of body perception disturbance in CRPS is presented. Furthermore, a disrupted body schema model is proposed as an explanation of the central mechanisms responsible for body perception disturbance in CRPS.

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Smedley, Richard. "Online social support for complex regional pain syndrome." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/32694/.

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Individuals living with Complex Regional Pain Syndrome (CRPS) often experience difficulties taking part in social and recreational activities, which can leave them with a greatly reduced social network and limited opportunities for obtaining social support. Online support communities may provide individuals with an alternative way of obtaining social support, but few studies have examined these communities in the context of CRPS. Furthermore, most online support community research has focussed on established communities, and little is known about how new communities become established. This thesis examines a bespoke CRPS online support community with two broad aims: to examine the development of online support processes in relation to the launch of a new online support community, and to investigate the provision of social support for CRPS within an online support community. The dataset comprised 221 messages posted by 23 participants. Study 1 used the full dataset to examine engagement with the online support community, focussing on the number of individuals who used the forum (membership growth), how they used it (header analysis) and how they introduced themselves (introductory messages). Study 2 used the full dataset to investigate how support processes became established, the support content of messages, and how this contributed to the CRPS ‘four pillars of intervention’. Study 3 used four longitudinal case studies from the dataset to conduct a linguistic analysis of messages, focussing on support providing behaviour and the number of replies received. The results indicate that support processes start almost immediately when a new online support community is launched, and membership growth is closely linked to promotional strategies. Online support may play an important role in CRPS self-management by contributing to the ‘four pillars of intervention’, and there is a possibility that diffusion of responsibility may occur in forums. The longitudinal case study approach may produce important new insights and suggests that the use of health words is unrelated to the number of replies received, the use of self and other-oriented messages may be linked to health status and support providing activities, and that the ratio of positive-to-negative words could potentially be used to identify individuals who might benefit from additional support.

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5

Forouzanfar, Tymour. "Complex Regional Pain Syndrome Type I measurements and treatment /." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 2004. http://arno.unimaas.nl/show.cgi?fid=7558.

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6

Niehof, Sjoerd Petrus. "Video thermography: complex regional pain syndrome in the picture." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10704.

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7

Maga, Tara Kristen. "Unraveling the complex genetics of atypical hemolytic uremic syndrome." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/2935.

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Atypical hemolytic uremic syndrome (aHUS) is characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. aHUS is far less common and more severe than typical HUS, which is caused by E. coli infection and manifests as diarrheal illness. The pathogenesis of the disease is linked to dysregulation of the alternative pathway of the complement cascade. Mutations in the complement regulators factor H (CFH), membrane cofactor protein (MCP), factor B (CFB), and factor I (CFI) have been implicated in aHUS. These loss or gain of function mutations lead to uncontrolled complement activity and immune-mediated host cell damage. Establishing a genetic etiology is important as it helps to direct treatment during the acute phase of disease and when transplantation is considered. It has been shown in previous studies that the age of onset as well the severity of the disease is correlated with the type of mutation a patient is found to carry. In forty percent of aHUS patients a mutation in CFH, MCP, CFB, CFI, C3 or THBD is not detected. These data strongly suggest that other genetic factors are involved in the pathogenesis of aHUS and that comprehensive mutation detection in aHUS patients is essential to provide diagnostic and prognostic information, and improve their clinical care. My thesis work has aimed to identify the other genetic contributors to this disease. To achieve this goal we began by screening the largest American cohort of aHUS patients for mutations in CFH, MCP, CFB, CFI, C3, THBD as well as CFHR5. This study identified over thirty novel mutations and suggests a more comprehensive genetic screening method that would better serve patients. To complement these studies multiplex ligation-dependent probe amplification was used to detect genetic rearrangements within the factor H related genes. A number of unique fusion proteins were seen in aHUS patients, all of which are predicted to affect the function of CFH. To discover mutations in novel genes that are causally related to aHUS, we have optimized a platform called CASCADE (Capture and Sequencing of Complement-Associated Disease Exons), which is based on targeted-genome capture and next-generation sequencing. This study revealed an unexpected role for ADAMTS13 and other genes in the coagulation pathway as modifiers of aHUS. Using functional assays we show two of the ADAMTS13 variants alter the behavior of this protein. This work has changed how we view this disease by identifying several novel candidate genes, for which we hope future analysis will lead to a better understanding of their role in aHUS. Using this knowledge we can provide better and more personalized treatments for patients.

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Graaff, Esther de. "The fragile X syndrome complex behavior of a simple repeat /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 1996. http://hdl.handle.net/1765/13736.

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Mitrani, Leila Mical. "Certain syndrome or complex conundrum? : the pollination of Erica lanuginosa." Bachelor's thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/26380.

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The flower of Erica lanuginosa has a tightly closed corolla, held in place by hinged sepals. with a dull reddish-pink colour which makes make it hard to determine a likely pollinator. Rodent trapping and pollen analysis of faecal matter showed it unlikely to be pollinated by a rodent. Flowers excluded from external pollination showed no seed set, hence it is not considered to be self-pollinated. Nectar analysis are inconclusive as an indicator of pollination syndrome. Entomophily by a robust insect with a medium length proboscis is considered unlikely due to phenology and morphology of the flower. Omothiphily is a possibility as stem thickness correlates with previous studies investigating the correlation between stem thickness and pollination syndromes. The pollination syndrome of Erica lanuginosa remains indeterminate by I hypothesize that, due to phenology, thick supportive, stem and large quantities of nectar and close-formed flower, which needs to be manoeuvred open, its pollinator is likely a short-billed generalist-feeding bird restricted by food choice during the winter months.

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10

Bu, Fengxiao. "Exploring the genetics of a complex disease - atypical hemolytic uremic syndrome." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3055.

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Atypical hemolytic uremic syndrome (aHUS) is a rare renal disorder characterized by thrombotic microangiopathy, thrombocytopenia, and acute kidney injury. Its pathogenesis has been attributed to a ‘triggering' event that leads to dysregulation of the complement cascade at the level of the endothelial cell surface. Consistent with this understanding of the disease, mutations in complement genes have been definitively implicated in aHUS. However, the existence of other genetic contributors is supported by two observations. First, in ~50% of cases, disease-causing variants are not identified in complement genes, and second, disease penetrance is typically incomplete and highly variable. To test this hypothesis, we identified pathways established to have crosstalk with the complement cascade, focusing initially on the coagulation pathway. Using targeted genomic enrichment and massively parallel sequencing we screened 36 European-American patients with sporadic aHUS patients for genetic variants in 85 complement and coagulation genes, identifying deleterious rare variants in several coagulation genes. The most frequently mutated coagulation gene in our study cohort was PLG, which encodes a zymogen of plasmin and plays key role in fibrinolysis. These results implicate the coagulation pathway in the pathogenesis of aHUS. Based on this outcome, we developed a clinical genetic testing panel to screen disease-related genes in a group of ultra-rare complement-mediated diseases that includes, in addition to aHUS, thrombotic thrombocytopenic purpura (TTP), C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) patients. Data from 193 patients validate the usage of this panel in clinical practice and also provide confirmatory insight into the pathogeneses of these diseases. Specifically, we found that in aHUS and TTP patients, variants were frequently identified in complement regulator genes, while in C3GN and DDD patients, variants were additionally found in C3 convertase genes. To understand variability in disease penetrance, we completed targeted genetic screening in two aHUS families grossly discordant for disease penetrance, identifying in one family a co-segregating Factor X-deficiency variant (F10 p.Glu142Lys) that abrogated the effect of the complement mutation. Functional studies of the F10 p.Glu142Lys variant show that it decreases Factor X activity predicting to a hypo-coagulable state and further illustrating the importance of complement-coagulation crosstalk in exacerbating, but also mitigating the aHUS phenotype. In our final studies, we have sought to complete a comprehensive analysis for other potentially related pathways by using bioinformatics to identify candidate pathways coupled with whole exome sequencing. Preliminary data from 43 aHUS patients and 300 controls suggest that pathways for dermatan and heparan sulfate synthesis, which are relevant to the formation of the extra-cellular matrix and cell surface adhesion, may be implicated in the aHUS.

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11

Fabre, Alexandre. "Bases moléculaires des diarrhées syndromiques(syndrome tricho-hépato-entérique)." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5066/document.

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Les diarrhées syndromiques ont été décrites pour la première fois en 1994. Il s'agit d'un syndrome associant une diarrhée grave rebelle néonatale nécessitant une nutrition parentérale, une dysmorphie faciale, un retard de croissance intra-utéro, des anomalies immunitaires et une atteinte hépatique. Au cours de la décennie suivante, de nouveaux cas ont été décrits avec des dénominations variées, la plus fréquente étant : « syndrome tricho-hépato-enterique ». Du fait de la variabilité clinique et de l'absence de signe spécifique à l'examen anatomopathologique le diagnostic des Diarrhées syndromiques/Syndrome Tricho-hépato-entérique (DS/THE) est difficile. Grâce à une collaboration multicentrique, nous avons pu constituer une cohorte homogène de 15 enfants atteints et de leurs apparentés. Par analyse de liaison et recherche de régions homozygotes dans ces familles, deux régions situées respectivement en 5q et en 6p ont été caractérisées. Dans la première région, le gène TTC37 a été incriminé par la mise en évidence de 12 mutations pathogènes chez 9 des15 patients. Bien que les connaissances sur TTC37 soient fragmentaires, nous avons remarqué qu'il était parfois décrit comme étant l'orthologue de SKI3 chez la levure. SKI3 constitue, avec SKI2 et SKI8, le complexe SKI qui, en tant que cofacteur de l'exosome, intervient dans un des systèmes de dégradation des ARN. L'exploration de SKIV2L, l'orthologue humain de SKI2, chez les 6 patients négatifs pour TTC37 a permis de mettre en évidence des mutations pathogènes pour tous. Nous avons voulu mieux caractériser l'expression des sous-unités du complexe SKI humain
The Syndromic Diarrhea has been described for the first time in 1994, as a probable congenital syndrome, associating intractable diarrhea of infancy with facial dysmorphism, intrauterine growth restriction, immunological defects and hepatic disease. Since then, several cases have been described, sometime using alternative names, the most common being the tricho-hepato-enteric syndrome. Because of the lack of pathological specific anomaly and the variation in severity of the clinical signs, the diagnosis of Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) remains difficult. Thanks to a multi-centric collaborative work, we have collected samples from 15 affected children and their families. Using linkage analysis and homozygosity mapping, we have isolated two regions in 5q and 6p, thus suggesting genetic heterogeneity. TTC37, a gene located in 5q, has been identified as responsible for SD/THE by the characterization of 12 non-ambiguous mutations in 9 children (out of the 15). At this time, TTC37 function was unknown but we noticed that it was reported as the putative ortholog of SKI3 (a yeast gene) which together with SKI2 and SKI8, constitutes the SKI complex. This complex is a cofactor of the exosome, a quality control RNA system. The analysis of the human ortholog of SKI2, SKIV2L, in the 6 patients negative for TTC37 mutations revealed deleterious mutations in all cases. In order to better characterize the expression of the human SKI complex sub-units, we have tested the expression of TTC37 transcript in a cDNA panel from normal tissues and found a ubiquitous expression excepted in the liver

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12

Vogel, Tobias. "Langzeitprognose des Complex Regional Pain Syndrome Type I (CRPS I - M. Sudeck)." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-76420.

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13

Schultz, Geoffrey Robert. "Complex visual hallucinations associated with deficits in vision : the Charles Bonnet Syndrome." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40243.

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The Charles Bonnet syndrome is characterized by complex visual hallucinations in people without psychopathology or disturbance of normal consciousness. This thesis highlights the association of visual deficits with the syndrome, and proposes that it is analogous to the perception of phantom limbs; both conditions arise when normal sensory input to the brain is severely reduced. The five studies that comprise this thesis systematically gather information on the syndrome to answer three basic questions: how can the hallucinations be classified, what are the clinical implications for individuals who experience them, and what might cause the hallucinations. Study 1 examines 64 cases described in the literature. Demographic information on the hallucinators, properties of the hallucinations, initiating factors, as well as etiological mechanisms are reviewed. Study 2 examines the properties of the hallucinations in a sample of 60 subjects and reveals, by statistical analysis, a dimension of the hallucinatory experience that ranges from discrete, singular perceptual experiences to multiple changing experiences. Studies 3 and 4 examine the mental status of hallucinators score within the normal range on tests of anxiety, depression, and psychological symptomology and exhibit no evidence of gross cognitive impairment. A detailed analysis of results show that a small proportion of hallucinators score within the normal range on tests of anxiety, depression, and psychological symptomology and exhibit no evidence of gross cognitive impairment. A detailed analysis of results show that a small proportion of hallucinators endorse comparatively more symptom-oriented items than the remainder of hallucinators, as well as more items non-hallucinators (in Study 4). Finally, Study 5 examines the performance of two hallucinating groups as well as a group of visually impaired non-hallucinating on threshold estimation and signal detection tasks. The results of the combined studies indicate

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14

Rakay, Chrisitine Alese. "Conquering the chimaera: an insight into the need to redefine the complex form of child abuse, Munchausen's Syndrome by Proxy." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12595.

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Thesis (M.S.)--Boston University
Munchausen Syndrome by Proxy (MSBP) is a term given to a situation which presents criteria for both Pediatric Condition Falsification (PCF) and factitious disorder by proxy (FDP). According to the Diagnostic and Statistical Manual of Mental Disorders-IV text revision (DSM-IV-TR), in child abuse cases where FDP is a result of PCF, then the nomenclature, MSBP, can be used interchangeably to describe such an event. Currently, in a situation that is diagnosed as Factitious Disorder by Proxy, the perpetrator of such an event is diagnosed as having Factitious Disorder Not Otherwise Specified (FD-NOS). An obvious issue stemming from this is the confusion over what should be diagnosed and remedied, i.e., the situation, the perpetrator, and/or the victim. Due to the convoluted and often controversial definition of such an event, as well as the criteria for diagnosis, it is proposed here that a new definition be adopted to explain this form of child abuse. With this novel definition, the symptoms of this psychological disorder of the perpetrator are observed in the victim. Under this new definition, the psychiatric term "Factitious Disorder by Proxy" would be used as a mental diagnosis of the caregiver, wherein the symptoms manifest in that of the victim. Additionally, an addendum to the type of symptoms exhibited in the child is proposed to include that of the exacerbation of symptoms in children with valid pre-existing conditions. An extensive literature review was performed to support the proposal for changing the criteria and diagnosis of FDP in the DSM. The implications of this change would greatly benefit not only the psychiatric, medical, and legal realm, but the forensic community as well.

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15

Gärtner, Andreas Richard. "Faktoren der Entzündungsreaktion beim „Complex Regional Pain Syndrome“ Typ I (CRPS Typ I)." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-24409.

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16

Scott, Jessica K. "Complex regional pain syndrome prevalence and perception of knowledge at Division 1 institutions /." Morgantown, W. Va. : [West Virginia University Libraries], 2008. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5683.

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17

Heutink, Peter. "Gene mapping of complex disorders Gilles de la Tourette syndrome and heriditary paragangliomas /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 1993. http://hdl.handle.net/1765/13745.

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18

Lohnberg, Jessica Ann. "An examination of the psychosocial profile of individuals with complex regional pain syndrome." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1244.

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This study sought to provide a description of the psychosocial profile of persons with complex regional pain syndrome (CRPS). CRPS is an excruciatingly painful and debilitating condition that is poorly understood by medical professionals. Its profound impact on an individual's quality of life prompts a closer examination of the psychosocial profile of individuals suffering from CRPS. The extant literature examining psychological variables associated with CRPS is inconclusive with regard to the role that these factors play in the course of the syndrome. It has been shown, however, that CRPS patients suffer tremendous physical discomfort and this is often reflected in increased emotional distress. The present study assesses level of pain, anxiety, depression, disability, intrusive thoughts, quality of life, and demographic variables utilizing a national sample obtained from an online survey distributed to members of an organization that provides resources to CRPS patients. Descriptive data are presented for all data gathered and specific correlates of quality of life were examined. Results of the study demonstrated that this sample endorsed high levels of anxiety and depression and reported low levels of both physical and mental quality of life. When compared to normative data, this sample endorsed more pain and anxiety than other pain populations and also endorsed lower mental and physical quality of life than other pain conditions. The psychosocial profile of individuals with CRPS type I did not vary significantly from individuals with type II. Intrusive thoughts were uniquely predictive of disability, physical quality of life, and mental quality of life after controlling for age, gender, and pain level. The role of intrusive thoughts in predicting disability and quality of life suggests a potential mechanism by which clinicians can target psychotherapeutic treatment. Understanding the psychosocial profile and psychological sequelae of this disorder will help both physicians and psychologists understand the impact of CRPS on patients and provide a pathway for improved comprehensive interdisciplinary treatments.

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Fowlie, Stephen McIntosh. "Irritable bowel syndrome : assessment of psychopathology and its impact on the symptom complex." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/28052.

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This thesis describes the assessment of depression and anxiety by questionnaire and visual analogue scale in patients with irritable bowel syndrome (IBS). It examines the relationship between such assessments and self-reported symptoms before and after a placebo controlled, double-blind trial of fibre supplementation in 49 IBS patients, and finds that a high depression score at outset may be a predictor of continuing symptoms regardless of treatment. The treatment itself was no better than placebo, though there was a substantial 'placebo' effect. I consider the use of putative biochemical markers of 'stress' in such patients, but find that neither salivary IgA nor urinary metanephrine correlate well with symptoms, symptom rsponse, or psychometric assessment scores. Platelet serotonin levels did not distinguish IBS subjects from those with other chronic gastrointestinal complaints. It seems unlikely that any of these parameters will be helpful in routine diagnosis or management of IBS. A second cohort of IBS subjects was studied five years after initial diagnosis, using similar psychometric assessments. The chronic nature of the disorder was confirmed. The results suggest that anxiety levels might be an important influence on the longer-term maintenance of the symptom complex. Finally the thesis examines aspects of the general practitioner consulting behaviour of a group of IBS patients. Such behaviour seems relatively stable over the longer term although there was a very high prevalence of diagnoses of depression or anxiety, both before the IBS diagnosis and during the five years to review. The studies are considered to support a holistic approach to IBS; its pathogenesis, management and natural history. The symptom complex is forged by the action of several factors, notably psychological, physical and circumstantial (life events). The behavioural and emotional elements of the symptom complex are best considered as one product, and the doctor-patient relationship plays an important modulating role. There is some evidence that depressed mood may be more important in determining short term responses, such as consulting behaviour, and anxiety in maintaining the perception of 'symptoms' in the longer term. Simple assessment of depression and anxiety, perhaps by 'user friendly' visual analogue scales, might usefully be incorporated in the routine assessment of IBS patients.

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Kruusvee, Valdeko. "The structural basis of MeCP2 interaction with NCoR/SMRT co-repressor complex." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/25703.

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Rett syndrome (RTT) is an X-linked neurological disorder primarily caused by mutations in the MECP2 gene. The majority of RTT mutations disrupt the interaction of MeCP2 with DNA or TBL1X/TBL1XR1, which forms the scaffold of NCoR/SMRT co-repressor complex. Patients with RTT show no signs of neuronal death, although they have abnormal neuronal morphology, indicating that it is a neurodevelopmental rather than a neurodegenerative disease. It has been shown that reactivation of silenced MeCP2 in mice rescues the RTT phenotype, which implies that the disease is treatable. The RTT mutations in MeCP2 cluster to two regions - the methyl-CpG-binding domain (MBD) and NCoR/SMRT Interaction Domain (NID). While the interaction between MBD and DNA has been biochemically and structurally characterised, there are no structural data about the interaction between MeCP2 NID and TBL1XR1. The aim of this work was to understand how mutations in the NID cause RTT by characterising the interaction between MeCP2 and TBL1XR1. I have solved the structure of MeCP2 NID bound to TBL1XR1 WD40 domain. I show that a small region of the MeCP2 NID makes extensive contacts with TBL1XR1, and that these contacts are mediated primarily by MeCP2 residues known to be mutated in RTT. I also measured the affinities between TBL1XR1 and MeCP2-derived peptides using fluorescence anisotropy and surface plasmon resonance assays. I determined the affinity between MeCP2 NID peptide and TBL1XR1 to be around 10- 20 μM, and show that mutations in either MeCP2 or TBL1XR1 can abolish this interaction. Taken together, these data strongly suggest that the abolition of the interaction between MeCP2 NID and TBL1XR1 WD40 domain is sufficient to cause RTT. This knowledge can help with the rational design of small drug-like molecules that might be able to mediate the interaction between mutated MeCP2 and TBL1XR1, potentially helping to treat the disease.

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Chen, Jingtao. "Analyse biomécanique de différents aspects de la réalité virtuelle : application." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAS002/document.

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Le Syndrome de la Douleur Régionale Complexe (SDRC) est une maladie se manifestant par des troubles moteurs et atteint généralement les membres supérieurs. Bien que l'effet positif de la thérapie de miroir sur SDRC ait été prouvé, la tête du patient fixée et orientée en direction du miroir et l'exigence d'ignorer le membre intact limite encore cette thérapie. Dans ce contexte, premièrement la pseudo-haptique est appliquée dans le cas de la thérapie physique pour la main des patients affectés par le SDRC. Ainsi, le premier travail que nous avons effectué était de comprendre comment l'effet pseudo-haptique influence le comportement moteur de la main de l'utilisateur. A cet effet, des tâches de discrimination de rigidité ont été conduites consistant à discriminer la raideur d'un ressort virtuel avec celle de trois ressorts réels de raideurs différentes. Il existe deux types de thérapie pour la réhabilitation des patients atteints de SDRC : kinésiologique et occupationnelle, qui visent à récupérer respectivement les fonctions motrices de base et de travail du membre affecté. Concernant la thérapie kinésiologique, une application fondée sur la technologie Leap Motion et Unity3D a été développée permettant de manipuler la relation entre le mouvement de la main physique de l'utilisateur et le mouvement rendu/virtuel de l’avatar. L’application a été validée par une étude pilote réalisée au CHU de Grenoble avec des patients, des sujets sains et une équipe médicale (docteurs et kinésithérapeutes. Durant les tests, le mouvement rendu de la main est présenté sur l’écran de l’ordinateur: identique, amplifié ou réduit. Le retour des sujets a montré qu’ils n’avaient pas des sensations d’inconfort en utilisant l’application développée. L’équipe médicale, quant à elle, a manifesté un vif intérêt concernant l’utilisation de l’application en thérapie kinésithérapique. A cause de la fonction motrice anormale et de la douleur chronique nous avons tenu compte de l'endurance à la fatigue des patients atteints de SDRC A cet effet, une nouvelle méthode pour l'évaluation de la fatigue de la tâche en démontage fondée sur la dépense d'énergie métabolique et l’estimation de la fatigue musculaire a été proposée. Elle permet d’estimer les niveaux de fatigue associés à des tâches de démontage différentes. La méthode proposée est validée par une série de tests expérimentaux de chargement effectués dans un environnement de RV. D’autre part, les niveaux de fatigue sont évalués en analysant des signaux EMG des muscles impliqués du bras de l’opérateur. Enfin, les résultats analytiques issus du modèle proposé et les résultats expérimentaux obtenus à partir de l'analyse des signaux EMG ont été comparés et montré une très bonne corrélation entre eux
Complex Regional Pain Syndrome (CRPS) is a disease which companies with motor disorder and is generally affecting the upper limbs. Although the positive effect of mirror therapy on CRPS has been proved, the patient’s fixed head oriented towards the mirror and the requirement of ignoring the intact limb still limits this therapy. In this context, firstly the pseudo-haptics is applied in the case of physical therapy for hand affected CRPS patients. Thus, our first work was to understand how the pseudo-haptic feedback affects the user’s motor behavior of hand. For this purpose, stiffness discrimination tasks were performed consisting in discriminating the stiffness of one virtual spring with three different compared real springs. For rehabilitation of CRPS patients, there are two types of therapy: a kinesiological and an occupational one, respectively aiming at recovering the basic and working motor functions of patient‘s affected limb. For the kinesiological therapy we developed a VR application, based on Leap Motion technology and Unity3D software, allowing to manipulate the relationship between the user’s physical hand motion and the rendered avatar virtual motion. The application was validated by a pilot study performed at University Hospital Center in Grenoble with patients, healthy subjects and medical staff (doctors and kinesitherapists). During the experiments the rendered hand motion on the computer screen, is shown identical, amplified or reduced compared to the users’ real hand motion. Users’ feedback shown that they had no uncomfortable feeling with using the developed application. Medical staff expressed a strongly interest in using the application in the kinesiological therapy. Due to the motor abnormal function and chronic pain, we also considered the fatigue in the muscles during rehabilitation. For this purpose, a new method for disassembly task fatigue evaluation based on metabolic energy expenditure and muscle fatigue estimation is proposed. It is validated by a set of experimental loading tests performed in a specially realized test bench and integrated in a VR environment. The analytical model for mechanical energy expenditure is also proposed allowing to evaluate different fatigue levels. On the other hand, the fatigue levels are evaluated by analyzing the recorded EMG signals on the involved muscles in operator’ arm. The analytical results, calculated based on the proposed model and the experimental results, obtained from the EMG signals analysis, were compared and showed a (very) good correlation between them

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Lienhardt, Stephanie Barbara. "Diagnostic criteria and follow-up parameters in Complex Regional Pain Syndrome type I : a Delphi survey /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000281140.

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23

Carr, Sarah. "Functional magnetic resonance imaging studies of the primary somatosensory cortex in relation to complex regional pain syndrome." Thesis, University of Exeter, 2009. http://hdl.handle.net/10036/90577.

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Functional MRI was used to detect brain activations in the primary somatosensory cortex (SI) in response to a vibrotactile stimulus applied to the thumb (D1) and little finger (D5) of the right (R) and left (L) hands. Four studies were carried out with healthy subjects in order to determine the scanning and stimulation protocols that resulted in consistent and robust SI activity. It was found that a strong stimulus, compared to a weak stimulus, led to the SI activity being detected more frequently and at a more statistically significant level. Also, extending the scanning duration per digit further increased the T-scores. The SI activations for each digit showed multiple foci and were distributed throughout the SI area. However, a clustering occurred in separate centres for stimulation to RD1 and RD5 near the Brodmann area 1/Brodmann area 3 boundary. The Euclidean separations of the cortical digit representations for LD1-D5 and RD1-D5 were calculated on the basis of the `centre of mass' of the multiple activations. Observed separations ranged between 1.2 mm to 22.8 mm. A further vibrotactile fMRI study was carried out involving patients with complex regional pain syndrome (CRPS). It has been suggested an altered central processing mechanism is involved in the disease, possibly due to cortical reorganisation in the sensory/motor cortices. The most efficient experimental protocols from the healthy subject studies were used to determine if these cortical differences were present in four patients. Data were acquired over two scanning sessions, approximately four months apart. The study revealed multiple SI foci and overlapping between the digits in both the healthy and CRPS hands, similar to those observed in the first studies. Larger SI activations were detected in one patient, smaller SI activations were detected in another patient and two patients demonstrated cluster sizes in the normal range. The cluster sizes and the changes in size between the two scans suggest a correlation with the amount of pain experienced by the patients. A general lack of consistency in the results from all the studies may be attributed to the difficulty of reliably detecting SI activity at a field strength of 1.5 T.

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Cohen, Helen. "Somaesthesia, autonomic dysfunction and the perception of pain in complex regional pain syndrome and chronic rheumatic disease." Thesis, University of Bath, 2012. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579161.

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The perception of pain is a complex process involving central integration of nociceptive sensory signals with autonomic, emotional, motor and behavioural cortical networks. The principal aim of this thesis was to explore how this process contributes to the presenting clinical phenotype in complex regional pain syndrome (CRPS), and whether this extends to other chronic pain conditions in rheumatic disease such as osteoarthritis (OA) and rheumatoid arthrits (RA). The first study established baseline quantitative sensory testing parameters and autonomic function. It found that allodynia was absent in controls, present in some OA and RA patients and most marked in CRPS patients. Autonomic function was normal in controls, with some impairment in OA and RA and most dysfunction in CRPS. The second study used an optokinetic visuo-motor challenge induced by a mirror-whiteboard device. The presence or absence of sensory disturbances and/or new/worsening pain was used to generate a vulnerability scale. Controls were the least vulnerable followed by RA, then OA with CRPS the most vulnerable. Autonomic responses, sensory disturbances and new/worsening pain to a pure visual conflict in the form of ambiguous visual stimuli (AVS) were used for the third study. Sensory disturbances, pain enhancement and abnormal asymmetric autonomic responses occurred only in the CRPS cohort. The final study investigated parietal lobe function in CRPS patients. It showed clinical evidence of parietal lobe dysfunction present in a substantial number of CRPS patients, and that this was reflected both in symptoms and impact upon activities of daily living. Overall, the thesis findings support the concept that perterbation of central somaesthetic integration may induce cortical network dysfunction, reflected in different patterns of autonomic and pain responses. This might contribute to the differing clinical presentations seen in CRPS. Similar processes may also occur in OA and RA. This work provides an approach to the clinical phenotyping of CRPS and other chronic painful rheumatic diseases. Appreciation of the potential mechanisms described may allow better targeting of therapy.

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Cartwright, Edward. "The molecular basis of von Hippel-Lindau (VHL) syndrome : an NMR-based description of the VCB complex." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608925.

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Geffroy, Guillaume. "Etude de la dysfonction cellulaire et moléculaire du syndrome mitochondrial MELAS." Thesis, Angers, 2017. http://www.theses.fr/2017ANGE0072.

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Chaque mitochondrie contient son propre génome en de multiples copies d’ADN. Les mutations de l'ADN mitochondriales (ADNmt) sont responsables de sévères dysfonctions de la chaîne respiratoire. Le ratio entre la proportion de copies sauvages et mutantes, qualifiée d'hétéroplasmie, détermine la sévérité de la pathologie. Une des mutations les plus répandues de l'ADNmt est la mutation m.3243A>G, affectant l'ARN de transfert de la leucine. Ce variant est à l'origine du syndrome mitochondrial MELAS. Il n’existe à l’heure actuelle aucun traitement curatif pour ce syndrome. Nous avons développé une série de cybrides neuronaux porteurs de la mutation m.3243A>G a différents taux d’hétéroplasmie. Nous avons mis en évidence que de fort taux de mutations sont responsables de sévères dysfonctions de la chaîne respiratoire, d’un défaut d’assemblage précoce du complexe I ainsi qu’une réduction du renouvellement mitochondrial. Différentes stratégies métaboliques ont été employées pour compenser ces déficits. L’exposition des cellules a une restriction glucidique ou à la diète cétogène associant réduction glucidique et ajout de corps cétoniques, améliore significativement les fonctions mitochondriales après 4 semaines. Ces effets passent notamment par une restauration de l’assemblage et de l’activité du complexe I médiée ces interventions métaboliques. Par ailleurs, l’administration de la diète cétogène à un patient atteint du syndrome MELAS a déjà montré des résultats encourageants. De telles approches pourraient alors, constituées des stratégies thérapeutiques futures dans le traitement du syndrome MELAS et des maladies mitochondriales
Each mitochondrion contains its own genome in multiple copies. Mitochondrial DNA (mtDNA) mutations are responsible for respiratory chain defects. The ratio of mutant to normal mtDNA, a condition known as heteroplasmy, may determine the disease severity. The m.3243A>G mutation, which affects the leucine tRNA, is one of the most common mtDNA mutation. This variant is responsible for the MELAS syndrome, a neurodegenerative disease, characterized by pseudostrokes. Unfortunately there are no curative treatments for MELAS syndrome. We have developed series of cybrid neuronal cells lines carrying the m.3243A>G mutation with different mutant loads, within the same nuclear background. High mutation load is associated to severe respiratory chain dysfunction, an early complex I assembly defect and a mitochondrial turn-over deficit. Different strategies were used to compensate the defects in the mutant cells. Cell exposure to low glucose or ketogenic diet, combining glucose reduction and the addition of ketone bodies, greatly improves mitochondrial functions after 4 weeks. Those effects are linked to a significant increase of complex I assembly and activity mediated by those metabolic interventions. In addition, a MELAS patient treated with ketogenic diet showed significant clinical improvement. Thus, metabolic approaches may constitute promising therapeutic strategies against MELAS syndrome and mitochondrial disorders

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Antunes, Marcelo. "Avaliação do efeito antinociceptivo da ablação neuropática e autonômica por radiofrequência em pacientes portadores de dor crônica Síndrome Dolorosa Complexa Regional do Tipo-I." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17142/tde-23042018-172407/.

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Introdução- Pacientes portadores de Síndrome Dolorosa Complexa Regional- I (SDCRI) lombar apresentam componente autonômico simpático associado à dor lombar facetaria, são submetidos de forma rotineira à sequência de 4 bloqueios autonômicos associado ao bloqueio do ramo mediano facetário, implicando em 4 procedimentos ambulatoriais por paciente, por semestre. Este estudo visou avaliar a eficácia da realização de ablação por radiofrequência após a realização do bloqueio teste. Métodos- Após aprovação do Comitê de Ética em Pesquisa e consentimento, 25 pacientes portadores de SDCR-I em membros inferiores e dor articular facetária lombar associada foram de forma prospectiva, submetidos a: 1) 4 sessões com intervalos semanais de bloqueio do ramo mediano facetário lombar de L2 a L5 bilateral, associado ao bloqueio do gânglio simpático autonômico L3. Quando a dor atingisse graduação VAS= 4 cm, foi considerado necessário repetição dos procedimentos realizados, e este tempo correspondeu ao tempo de analgesia, sendo calculado o custo anual e efeitos adversos por paciente. Os mesmos pacientes foram submetidos posteriormente a: 1) Bloqueios testes simpático e facetário, seguido de: 2) ablação por radiofrequência (RF) do ramo mediano facetário lombar de L2 a L5 bilateral, com 45 V, 80 segundos, 80 oC, + ablação por RF do gânglio simpático lombar de L3-L4 do lado acometido, 45V, 80 oC, 80 segundos em cada nível acometido, sob sedação consciente, com midazolam e alfentanil por via venosa. Cada paciente atuou como seu próprio controle. Resultados- 21 pacientes participaram da avaliação final. Cada paciente foi submetido a uma sequência semestral de bloqueios, sendo o tempo de analgesia após término do quarto procedimento 5±1 meses, e o custo anual de R$ 15.000,00. Quando os mesmos pacientes foram submetidos à RF, o tempo de analgesia foi em média 15±2 meses (p<0,001), havendo economia no primeiro ano de realização de RF de 23% no custo final e de 32% a 36% nos anos subsequentes, calculado por extrapolação. Durante o período de analgesia, a capacidade para realização de atividades rotineiras e a qualidade de sono melhoraram. Não foram observados efeitos adversos. Discussão- A realização de RF resultou menor número de internações anuais, menor custo anual e maior comodidade para o paciente, com mesma eficácia durante período de analgesia.
Introduction- Patients with Complex Regional Pain Syndrome type-I (CRPS-I) in lower members, often also present lumbar articular facetary pain, and are submitted as part of routine to a sequence of 4 weekly sympathetic blocks combined to facetary block, which sequence is usually repeated after six months for pain control. The study was designed to evaluate the efficacy of a test block followed by radiofrequency efficacy. Methods- After ethical approval and consent, 25 patients with CRPS-I in lower members were submitted to a 4-weekly sympathetic block at L3, combined to bilateral lumbar facetary block fromL2-L5. The sequence was repeated when pain VAS reached 4 cm, and this period was defined as time of analgesia. Thereafter, the same patients were submitted to a test block followed by radiofrequency (RF ablation of sympathetic ganglion L3 and L4 and bilateral ablation of facetary lumbar median branch from L2-L5), 45 V, 80 sec, 80 oC, under conscious sedation. Patients acted as their own control related to analgesia, routine activities, sleep and costs. Results: 21 patients completed the study. The analgesia time after the 4-block sequence was 5±1 months and the annual cost R$ 15.000,00 (USA$5000). The analgesia time after RF was 15±2 months (p<0.001) and the costs were reduced by 23% in the first year and 32%-36% in the following years extrapolation. Routine capacity and sleep at night were equally improved during analgesia for both treatments. There were no adverse effects. Discussion- Test block followed by RF resulted in 15 months of analgesia compared to 5 months for the routine technique of 4-blocks, in improved capacity and sleep comfort at night. Besides that, RF was costly effective, and reduced costs by 23% during the first year evaluation, followed by 32% to 36% cost reduction in following years, by extrapolation.

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Modi, Bhavi P. "GENETIC AND EPIGENETIC MECHANISMS OF COMPLEX REPRODUCTIVE DISORDERS." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4574.

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Common, complex disorders are polygenic and multifactorial traits representing interactions between environmental, genetic and epigenetic risk factors. More often than not, contributions of these risk factors have been studied individually and this is especially true for complex reproductive traits where application of genomic technologies has been challenging and slow to progress. This thesis explores the potential of genetic and epigenetic components contributing to a better understanding of the biological pathways underlying disease risk in two specific female complex reproductive traits - polycystic ovary syndrome (PCOS) and preterm premature rupture of membranes (PPROM). The PCOS projects focus on characterization of a gene, DENND1A, whose association to PCOS has been established by Genome Wide Association Studies (GWAS) and is known to contribute to PCOS steroidogenic phenotype. In addition, differential microRNAs expression contributing to DENND1A expression regulation in PCOS theca cells was identified. The studies on PPROM utilize a Whole Exome Sequencing approach to identify rare variants in fetal genes contributing to extracellular matrix composition and synthesis contributing to PPROM risk. The results suggest that fetal contribution to PPROM is polygenic and is driven by a significant genetic burden of potentially damaging rare variants in genes contributing to fetal membrane strength and integrity. Tissue and location specific expression patterns of the Chromosome 21 miRNA cluster (miR-99a, miR-125b, let-7c) in fetal membranes from term pregnancies with spontaneous rupture were investigated. The results suggest that these miRNAs play potential roles in fetal membrane rupture and fetal membrane defects associated with T21.

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Wizgall, Ingrid. "Wertigkeit der Kernspintomographie in der Frühdiagnostik des Complex Regional Pain Syndrome Typ I (CRPS Typ I) nach distaler Radiusfraktur." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-37700.

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Thompson, Nicolyn. "Complex immunophenotyping stratifies patients with primary and secondary Sjögren's syndrome into distinct clinically relevant groups with potential therapeutic implications." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10056217/.

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Sjögren’s syndrome (SS) and systemic lupus erythematosus (SLE) are distinct autoimmune rheumatic diseases (ARD) characterised by shared clinical features and immune abnormalities. A proportion of 15-20% of patients with SLE also have features of SS, manifesting as an overlap ARD called secondary SS associated with SLE (SS/SLE). Both SLE and SS are B cell driven diseases, with a recognised female predominance. SS is characterised by distinctive chronic inflammatory process leading to destruction of the exocrine glands orchestrated by T and B lymphocytes, dendritic cells (DCs), macrophages and other mononuclear cells. These cells have been demonstrated to also play a role in SLE and SS pathogenesis, while the immune phenotype of SS/SLE patients has not been investigated before. The results of my research demonstrated that the clinical, serological and histological parameters used by clinicians in routine practice have not been able to distinguish between patients with different diagnoses when stratified using unsupervised hierarchical clustering. However, in-depth immune phenotype have found that these patients also had both unique and shared defects in their CD19+ B cells, CD4+ and CD8+ T cells peripheral blood profiles, as well as defects in lipid raft expressions in these cell subsets, as assessed by flow-cytometry and ImageStream analyses. Overall, in-depth immune phenotyping was able to stratify pSS, SLE and SS/SLE with common underlying B and T cell abnormalities based on their immune signatures rather than diagnosis, which can have significant therapeutic implications in the selection of treatment strategies.

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McBride, Andrew Richard Thomson. "The efficacy of ascorbic acid in the prevention of complex regional pain syndrome (type 1) following distal radial fracture." Thesis, University of Bristol, 2011. http://hdl.handle.net/1983/bf33cf11-4800-4da2-8f0a-46c148a04ee1.

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Complex regional pain syndrome (CRPS) is a common problem presenting to orthopaedic surgeons or pain therapists, most frequently encountered following trauma. The cardinal features are of pain, hypersensitivity, vasomotor instability and joint stiffness. The exact cause remains unproven, however an exaggerated inflammatory response and free radical induced cellular damage has been proposed. A small number of previous studies have highlighted a potential role for antioxidants in the prevention of the condition. Over the last three decades pain researchers have developed and agreed on a set of modified International Association of the Study of Pain (IASP) diagnostic criteria. Orthopaedic researchers have developed their own criteria that have been subject to much debate as to their validity. The diagnosis of CRPS in two hundred and sixty-two patients from a previous study have been reanalysed using the Atkins and modified IASP diagnostic criteria of Bruehl. The incidence of CRPS was similar using either criteria (Bruehl 20.61% vs. Atkins 22.52%). Using the Bruehl criteria as a gold standard, there was strong diagnostic agreement (K = 0.79, sensitivity = 0.87, specificity = 0.94). Two hundred and eleven patients who had sustained an isolated distal radial fracture were recruited for a prospective double-blinded randomised control trial to assess the efficacy of five hundred milligrams of ascorbic acid in order to prevent CRPS. Using an intention to treat analysis one hundred and ninety-six were reviewed at a minimum of nine weeks. There was no significant difference in the incidence of CRPS (chi-squared=1.196, p=0.305) or the incidence or severity of the individual features of the condition between the two treatment groups. The results of this study suggest that prophylaxis with ascorbic acid does not prevent the occurrence of CRPS when diagnosed with validated criteria following a distal radial fracture.

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Salmaggi, Andrea, Lucia Zirilli, Chiara Pantaleoni, Joanna Gabriella De, Sorbo Francesca Del, Katrin Köhler, Manuela Krumbholz, Angela Hübner, and Vincenzo Rochira. "Late-Onset Triple A Syndrome: A Risk of Overlooked or Delayed Diagnosis and Management." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-134502.

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Background/Aims: A 33-year-old man was referred for the first time to the Division of Neurology because of the presence and progression of neurological symptoms. Dysphagia, weakness, reduced tear production, and nasal speech were present. In order to point the attention of late-onset triple A syndrome we describe this case and review the literature. Methods: Hormonal and biochemical evaluation, Schirmer test, tilt test and genetic testing for AAAS gene mutations. Results: Late-onset triple A syndrome caused by a novel homozygous missense mutation in the AAAS gene (A167V in exon 6) was diagnosed at least 17 years after symptom onset. Conclusions: The association between typical signs and symptoms of triple A syndrome should suggest the diagnosis even if they manifest in adulthood. The diagnosis should be confirmed by Schirmer test, endocrine testing (both basal and dynamic), genetic analysis, and detailed gastroenterological and neurological evaluations. Awareness of the possible late onset of the disease and of diagnosis in adulthood is still poor among clinicians, the acquaintance with the disease is more common among pediatricians. The importance of an adequate multidisciplinary clinical approach, dynamic testing for early diagnosis of adrenal insufficiency and periodical reassessment of adrenal function are emphasized
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

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Sahin, Hatice Bahar. "Drosophila fragile X mental retardation protein and WAVE/SCAR complex interaction, its role in synapse growth and actin modifying pathways." Strasbourg, 2009. http://www.theses.fr/2009STRA6260.

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Le syndrome de l’X Fragile est la cause héréditaire la plus commune des retards mentaux qui touche environ 1 sur 4000 garçons et 1 sur 8000 femmes. Les patients ont en moyenne un IQ inférieur à 75, en raison de défauts de transmission et de plasticité neuronale. Ce syndrome est causé par la perte de fonction de la protéine « Fragile X Mental Retardation Protein » (FMRP) via des mécanismes mal connus. Comprendre le rôle de FMRP dans la plasticité neuronale est très important pour traiter cette maladies. Cependant, étant donnée la difficulté d’étudier la protéine chez les humains pour des raisons éthiques, la maladie a été explorée en plusieurs aspects sur des modèles animaux simples, tels que Drosophila melanogaster. Ceci permet d’utiliser des approches génétiques, de biologie cellulaire et moléculaire et électrophysiologiques. La jonction neuromusculaire de la drosophile (JNM) représente une structure très accessible et un modèle classique de plasticité neuronale. Les animaux mutants pour la protéine FMRP, connue comme régulatrice de la traduction, ont des JNM très ramifiées par rapport aux animaux sauvages. Ce phénotype ressemble beaucoup aux longues et immatures épines dendritiques des patients atteints du syndrome de l'X fragile. Ainsi, le phénotype basique de la carence en FMRP peut être modélisé avec la JNM de la drosophile. Plusieurs études soulignent le rôle du remodelage du cytosquelette d'actine dans le développement des axones et dans la formation des synapses. Le complexe WAVE est connu pour réguler le complexe actin nucleator Arp2/3 et favorise ainsi le remodelage du cytosquelette. Deux événements cruciaux sont donc nécessaires pour le développement et la modulation de la fonction de JNM: remodelage du cytosquelette d'actine et la synthèse des protéines locales. De plus, les données acquises au laboratoire suggèrent une interférence entre ces deux processus. L’orthologue de FMRP chez la drosophile (dFMR1) representerait donc un pont, en interagissant directement avec le complexe WAVE/SCAR, qui induit le remodelage du cytosquelette d'actine, et avec des ARNm, qui contrôle la traduction locale. A l'intérieur du complexe, la protéine WAVE interagit directement avec HSPC300. Dans ma première année de thèse, j'ai participé à la caractérisation de HSPC300, la plus petite sous-unité du complexe. Nous avons déterminé le rôle de HSPC300 in vivo, caractérisé HSPC300 chez la drosophile et définir son rôle dans la connectivité neuronale. HSPC300 est une protéine de 8 KD hautement enrichie dans le système nerveux, comme observé par un anticorps produit dans la maison. En générant des mutants HSPC300 perte et gain de fonction, nous avons observé que cette petite protéine est essentielle pour la stabilité du complexe WAVE et pour la morphogenèse de JNM. La perte de HSPC300 entraîne des graves défauts des axones et des JNM. Ces défauts sont sauvés en exprimant spécifiquement HSPC300 dans le tissu neural. Ces données impliquent HSPC300 comme un élément indispensable du complexe WAVE, et une protéine cruciale pour le développement du système nerveux (Qurashi et al. 2007). Nous avons précédemment montré que dFMR1 interagit biochimiquement avec CYFIP, un autre membre du complexe WAVE, et on a constaté que les deux protéines affectent la croissance JNM dans des sens opposés. DFMR1 supprime la croissance synaptique alors que CYFIP est nécessaire pour la croissance des synapses. La perte de dFMR1 induit une exagération de la ramification et de la croissance, tandis que la perte de CYFIP donne lieu à des synapses courtes mais extrêmement greffés. En outre, des expériences de dosage ont prouvé que dFMR1 et CYFIP agissent ensemble pour le contrôle de la croissance de JNM et travaillent de façon antagoniste. Durant ma deuxième année, j'ai réalisé un projet en collaboration avec les Pr. Zhang (Chine) et Hassan (VIB, Belgique) et visant à cartographier les régions d’interaction. Nous avons généré des mouches portant une mutation ponctuelle intragénique de dFMR1 obtenu par mutagenèse à l’EMS. Un crible par double hybride montre que des mutations intragéniques spécifiques empêchent FMRP d'interagir avec CYFIP. Nous avons ainsi montré que l’extrémité N-terminale de FMRP est essentielle pour l'interaction avec CYFIP. J'ai analysé le phénotype de JNM en utilisant dix mutants intragéniques dFMR1 et j’ai défini in vivo le domaine requis pour l’interaction FMRP-CYFIP. J'ai montré que les mutants dFMR1 qui maintiennent l'interaction biochimique avec CYFIP, maintiennent aussi l'interaction génétique; par conséquent, la surexpression de CYFIP sauve la surexpression de ces formes de dFMR1 mutantes. Chez les mouches porteuses d'une mutation qui abolit l’interaction biochimique dFMR1-CYFIP, la surexpression de CYFIP ne réprime plus le phénotype de gain de la fonction dFMR1. La co-surexpression crée un phénotype d’une croissance exagérée de JNM, qui n'est pas obtenu par un simple CYFIP ou dFMR1 surexpression. Toutes ces données prouvent in vivo que dFMR1 interagit avec CYFIP par l'intermédiaire de l’extrémité N-terminale de la protéine dFMR1. Leur interaction a un rôle important pour un contrôle précis de la croissance synaptique et pour le remodelage du cytosquelette d'actine. Cette étude est publiée dans le Journal of Neuroscience en Mars 2008 (Reeve et al. 2008). Durant ma troisième année de doctorat, j'ai étudié le rôle de CYFIP dans le remodelage du cytosquelette d'actine chez les photorécepteurs de la drosophile. En utilisant le système binaire UAS/Gal4 nous avons obtenu des mutants conditionnels CYFIP, temps et tissu spécifiques. Nous avons révélé le rôle de CYFIP dans des cellules précises: les cellules photoréceptrices et les cellules pigmentaires. Nous avons également révélé la conséquence directe du défaut de nucléation de l'actine qui est observée dans les jonctions cellule-cellule (Galy et al, in prep). Plusieurs groupes ont suggéré que FMRP a une activité comme répresseur traductionnel. Même si le mode de cette activité est encore un mystère, certains chercheurs ont fourni des preuves montrant que FMRP interagit avec plusieurs composants du complexe RISC. Au cours de ma quatrième année de thèse, j'ai étudié l'interaction FMRP avec RISC en collaboration avec le Pr Bozzetti, en Italie (Specchia et al, in prep). Dans tous les projets auxquels j'ai participé jusqu'à présent, je vise à faire la lumière sur les voies FMRP et WAVE. Nous avions l'intention de déchiffrer les voies contrôlant le remodelage du cytosquelette d'actine et la synthèse des protéines locales dans JNMs chez la mouche. Dans la présente thèse, tous les résultats sont discutés en détail
Fragile X syndrome is the most common inherited cause of mental retardation affecting approximately 1 in 4000 males and 1 in 7000 females. Average IQ score of the patients is under 75 as a result of neural wiring and synaptic plasticity defects due to loss of functional Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA binding protein and a translational regulator highly abundant in the nervous system. We intend to explore underlying mechanisms of these defects using Drosophila (fruit fly) model organism. Several studies point out the role of actin cytoskeleton remodeling in synapse architecture and function. WAVE (/SCAR) complex stimulates the Arp2/3 complex actin nucleator and thereby promote cytoskeleton remodeling. Current data suggest that the crosstalk between actin cytoskeleton remodeling and local protein synthesis is essential for development and modulation of synapses. During my thesis, I have focused onto this topic and have the tackled three aspects of it: Characterization of the A) WAVE complex and its role in synaptic plasticity, B) the interaction between FMRP and WAVE complex, C) the actin cytoskeleton remodeling during morphogenesis. WAVE protein directly interacts with HSPC300, the smallest subunit of WAVE complex. Using targeted expression we characterize Drosophila HSPC300 and define its role in neural wiring. HSPC300 is highly enriched in the nervous system. Its mutation causes severe axonal/synaptic defects that are rescued by specific HSPC300 expression in the neural tissue. We conclude HSPC300 is an indispensable component of WAVE complex and an essential protein for nervous system development. We have previously shown that FMRP biochemically and genetically interacts with CYFIP, another member of the WAVE complex. To further characterize these interactions FMRP point mutations were generated in collaboration with two different labs. Particular mutants lose CYFIP binding. Using the intragenic mutants we point crucial FMRP residues for CYFIP interaction in vivo. FMRP is a negative regulator of neural growth. Here we describe nature of the FMRP-CYFIP genetic interaction in the context of neuromuscular synapses. We further assess CYFIP role on actin cytoskeleton in neatly organized fly eye and mostly actin-based photoreceptors. Making use of Drosophila genetics we define the spatiotemporal requirement of CYFIP for nervous system development. In all the projects I have been involved so far; I aimed at shedding light on FMRP and WAVE complex interaction. We intend to decipher these proteins and how their interactions regulate actin cytoskeleton remodeling, local protein synthesis and consequently neural connectivity using fly nervous system. I discuss these issues in the presented thesis

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Klöting, Nora. "Phenotypic and genetic analysis in animal models and humans with type 1 diabetes or metabolic syndrome: unraveling complex mammalian diseases." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974087254.

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Belitski, Maya Sophia. "Literature Review and Integration of Biomedical and Psychodynamic Conceptualizations of ADHD| Toward a Theoretical Synthesis of a Complex Multifactorial Syndrome." Thesis, California Institute of Integral Studies, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10618509.

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Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental syndrome associated with pervasive impairment in social, emotional, and cognitive functioning and development. The skyrocketing prevalence, controversial pharmaceutical treatment, and mounting public cost associated with ADHD has stimulated an explosion of research in increasingly specialized scientific domains, establishing a multifactorial etiology based in the dynamic transaction of genetic, neuromolecular, neurocognitive, and socioenvironmental mechanisms. Most contemporary biomedical research on ADHD has remained siloed in competing etiological models that independently account for this syndrome, yet fail to translate and integrate field-specific advances in knowledge across disciplines and persist in the outmoded tradition attempting to establish a putative single, or core, underlying cause. As a consequence, the current available treatment offered for ADHD has remained almost exclusively limited to the controversial and often contraindicated reliance on potentially dangerous psychostimulant drugs. The dearth of interdisciplinary collaboration and translational knowledge has significantly inhibited the development of a unifying diagnostic conceptualization of ADHD that is necessary to guide the study and implementation of more efficacious developmentally informed psychosocial interventions for ADHD.

This integrated literature review was undertaken to achieve greater consilience between the preeminent scientific clinical models proposed to account for the pathophysiology underlying ADHD. A detailed review of biomedical empirical investigation and psychoanalytic clinical theory revealed two distinct, yet highly complementary etiological models of ADHD. In particular, this literature review elucidates how adverse experiences encountered in early childhood, such as insecure attachment with primary caregivers, may pose a disproportionate risk to children with a biogenetic susceptibility to ADHD. Based on this review, it is proposed that a multifactorial analysis of the contemporary biopsychosocial perspectives on ADHD have relevance to improving clinical efforts to more holistically conceptualize, prevent, and treat this complex and pernicious syndrome. If patients and clinicians can share a more multidimensional understanding of what developmental factors are implicated in the risks associated with the causal etiology and maintenance of ADHD, they may be able to act as more agentic collaborators in addressing and treating problematic symptoms associated with this condition.

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Rendu, John. "Thérapie génique par saut d'exon : application à une Myopathie à Core et à un cas de syndrome OculoCérébroRénale de Lowe." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV014/document.

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Après la transcription, le pré ARNm subit des étapes de maturation avant de sortir du noyau pour être traduit. Une des étapes de maturation est l'épissage. Il permet de souder les séquences codantes de l'ARNm entre elles (les exons) et d'exclure les régions non codantes (les introns).Des mutations génétiques sont à l'origine de défaut d'épissage. Elles peuvent conduire à des rétentions d'intron, des sauts d'exon et des inclusions de séquences introniques appelées pseudo exons.Ma thèse a porté sur l'utilisation du saut d'exon pour corriger ces inclusions. Je me suis intéressé à deux pathologies : la myopathie à cores et le syndrome de LowePour le premier cas, je me suis intéressé à une mutation dans l'intron 101 du gène RyR1. Cette mutation est à l'origine de la création d'un site donneur d'épissage qui active un site accepteur provoquant l'inclusion d'un pseudo exon de 99 nucléotides. Cette inclusion induit une baisse de la quantité du canal calcique RyR1 dans les cellules du patient. Ce canal permet le couplage entre l'excitation et la contraction musculaire. Ses défauts conduisent à diverses myopathies dont la myopathie à cores. Le patient présentait une hypotonie néonatale, une scoliose et des défauts respiratoires, et n'a jamais acquis la marche. J'ai dessiné des oligonucléotides, je les ai transfectés dans les cellules du patient en culture et ainsi montré par RT PCR que le saut du pseudo exon était possible. Afin d'optimiser l'efficacité pour pouvoir évaluer la restauration au niveau protéique et fonctionnel, j'ai développé un lentivirus exprimant une cassette U7 SmOPT avec les AON choisis. Après transduction des cellules, j'ai pu montrer que le saut du pseudo exon permettait le retour de la protéine et de sa fonctionnalité, cette approche pourrait donc permettre une correction chez le patient.Pour le deuxième cas, j'ai tenté de corriger une mutation du gène OCRL. Cette mutation crée un site donneur d'épissage dans l'intron 4 du gène OCRL et active un site accepteur d'épissage 66 nucléotides en amont. L'inclusion du pseudo exon induit la chute du taux de transcrit OCRL par un mécanisme de "Non sense mediated mRNA Decay". OCRL est une phosphatidyl inositol 5 Phosphatase permettant de réguler la quantité de Ptd Ins(4,5)P2 dans la cellule. Les défauts dans OCRL sont responsables d'une pathologie multisystémique, le syndrome de Lowe. J'ai pu obtenir des fibroblastes cutanés du patient. J'ai transfecté ces cellules avec des AONs choisis pour permettre un saut de l'exon pathogène. J'ai ensuite intégré la séquence des AONs efficaces dans un lentivirus U7. J'ai transduit les cellules du patient en culture et observé un retour de la protéine et un retour de l'activité enzymatique, cette approche pourrait donc théoriquement permettre une correction chez le patient.Ces deux travaux sont les premières preuves de principes de thérapie par modulation de l'épissage pour les myopathies congénitales et pour le syndrome de Lowe. Ils ouvrent la voie à des perspectives de traitement pour ces maladies génétiques
After transcription, the pre mRNA will undergo different maturation step before getting out of the nucleus for translation. One of these step of maturation is the splicing. It allows to concatenate the coding sequences of the mRNA (the exons) and induces the exclusion of the non coding sequences (the introns).Genetics mutations can lead to splicing defects. These defects could be intron retention, exon skipping and exonisation of intronic sequences called pseudo exons.My thesis work was to evaluate the exon skipping therapy to correct these exonisation. I focuses on two diseases: core myopathy and Lowe syndrome.For the first one, my interest was on a mutation in the 101 th intron of RYR1 gene. This mutation creates a splicing donor site wich unveils a cryptic acceptor site. This leads to the inclusion of a 99 nucleotides pseudo exon. This inclusion induces a decrease of the quantity of the calcium channel RyR1 in the patient cells. This channel allows the excitation-contraction coupling, and therefore the muscular contraction. Defects in this channel lead to different myopathies (eg. core myopathy). The patient present at birth a major neonatal hypotonia, scoliosis and respiratory defects. He has never walked. I designed oligonucleotides (AON), transfected them in the cultured patient cells and showed by RT PCR that exon skipping was possible. In order to optimise the efficiency and to evaluate the rescue at a protein level and at a fonctionnal level, I devellopped a lentivirus which express a U7 Sm OPT cassette with the choosen AONs. After cell transduction, I have shown that exon skipping allowed the rescue of the protein and of its functionnality. This approach could permit a genetic correction for the patientFor the second case, I have tried to correct an OCRL mutation. This upstream creates a splicing donor site and unveils an acceptor site 66 nucleotides before. This leads to the inclusion of a pseudo exon which induces a severe decrease of OCRL transcripts level due to a "non sense mediated mRNA Decay". OCRL is a phosphatidyl inositol 5 Phosphatase, which regulates the Ptd Ins(4,5)P2 pool in the cell. OCRL defects induces a multi systemic disease the Lowe syndrome. I obtained patient cutaneous fibroblasts. I transfected these cells with choosen AONs to correct the splicing defect. I integrated the AONs sequence into a U7 lentiviral cassette. I transduced the cultured patient cells and observed a rescue of the protein with a rescue of its activity. This approach could, theoritically permit a correction in the patient.These two studies are the first proof of concept of splicing modulation therapy for congenital myopathy and for Lowe syndrome. This work offers a lot of perspective for the tratment of these genetic illness

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Grabarz, Anastazja. "Réparation des cassures double brin de l'adn chez les mammifères : rôle des protéines MRE11 et BLM dans l’initiation de la ligature d’extrémités non homologues (NHEJ )." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112172.

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Les cassures double brin de l’ADN (CDB) sont des lésions qui peuvent conduire à des réarrangements génétiques. Deux voies sont impliquées dans la réparation de ces dommages: la recombinaison homologue (HR) et la ligature d’extrémités nonhomologues (NHEJ).Au laboratoire un substrat intrachromosomique permettant de mesurer l’efficacité et la fidélité du NHEJ à été mis en place (Guirouilh-Barbat 2004). Cette approche a permis de démontrer l’existence d’une voie alternative à KU qui utilise des microhomologies présentes de part et d’autre de la cassure - le NHEJ alternatif (Guirouilh-Barbat 2004, Guirouilh-Barbat et Rass 2007). Les travaux de ma thèse consistent à caractériser les principaux acteurs de cette voie. En absence de KU, cette voie alternative du NHEJ, s'initierait tout d’abord parla résection d'extrémités d’ADN non protégées. Nous avons montré que l’activité nucléasique de MRE11 est nécessaire à ce mécanisme. La surexpression de MRE11 conduit à une stimulation du NHEJ, contrairement à l’extinction de la protéine par siRNA, résultant en une baisse de son efficacité de deux fois. Nos résultats montrent également que les protéines RAD50 et CtIP agissent dans la même voie que MRE11. De plus, dans les cellules déficientes pour XRCC4, la MIRIN – un inhibiteur du complexe MRN - conduit à une chute de l'efficacité de la réparation, démontrant le rôle de MRE11 dans la voie alternative du NHEJ. Nous avons aussi montré que MRE11 peut agir de manière dépendante et indépendante de la kinase ATM (Rass et Grabarz, Nat Struct Mol Biol 2009). L'initiation de la résection de la cassure doit être ensuite poursuivie par une dégradation plus importante de l'ADN qui est assuré par les protéines Exo1 et Sgs1/Dna2 chez la levure. Chez les mammifères, des études in vitro suggèrent un modèle similaire à deux étapes. Nous avons choisi de nous intéresser au rôle de la protéine BLM, qui est l’un des homologues humains de la RecQ hélicase Sgs1, dans la résection. Nos expériences montrent que l’absence de BLM diminue l’efficacité du NHEJ. De plus, l’extinction de BLM conduit à une augmentation d’évènements infidèles lors de la réparation par NHEJ et l’apparition d’évènements de résection de grande taille (>200nt). Ceci suggère que BLM protège contre de longues résections lors de la mise en place du NHEJ alternatif. De manière cohérente, BLM est impliquée dans la protection contre la résection dépendante de CtIP lors des étapes précoces de la recombinaison homologue. En conclusion, nos résultats montrent un rôle prédominant de BLM dans la protection contre un excès de résection médiée par CtIP. BLM interagit avec 53BP1 aux sites de dommages de manière dépendante d’ATM afin de réguler le processus de résection, en contrecarrant l’action de BRCA1. Ceci souligne à nouveau le rôle essentiel de BLM dans la protection contre la résection et la favorisation de la conversion génique sans crossing-over, ce qui est primordial pour le maintien de la stabilité du génome
DNA double strand breaks (DSBs) are highly cytotoxic lesions, which can lead to genetic rearrangements. Two pathways are responsible for repairing these lesions : homologous recombination (HR) and non homologous end joining (NHEJ). In our laboratory, an intrachromosomal substrate has been established in order to measure the efficiency and the fidelity of NHEJ in living cells (Guirouilh-Barbat 2004). This approach led us to identify a KU-independent alternative pathway, which uses microhomologies in the proximity of the junction to accomplish repair – the alternative NHEJ (Guirouilh-Barbat 2004, Guirouilh-Barbat et Rass 2007). The goal of my thesis consisted in identifying and characterising major actors of this pathway. In the absence of KU, alternative NHEJ would be initiated by ssDNA resection of damaged ends. We showed that the nuclease activity of MRE11 is necessary for this mechanism. MRE11 overexpression leads to a two fold stimulation of NHEJ efficiency, while the extinction of MRE11 by siRNA results in a two fold decrease. Our results demonstrate that the proteins RAD50 and CtIP act in the same pathway as MRE11. Moreover, in cells deficient for XRCC4, MIRIN – an inhibitor of the MRN complex – leads to a decrease in repair efficiency, implicating MRE11 in alternative NHEJ. We also showed that MRE11 can act in an ATM-dependent and independent manner (Rass et Grabarz Nat Struct Mol Biol 2009). The initiation of break resection needs to be pursued by a more extensive degradation of DNA, which is accomplished in yeast by the proteins Exo1 and Sgs1/Dna2. In human cells, in vitro studies have recently proposed a similar model of a two-step break resection. We chose to elucidate the role of one of the human homologs of Sgs1 – the RecQ helicase BLM – in the resection process. Our experiments show, that he absence of BLM decreases the efficiency of end joining by NHEJ, accompanied by an increase in error-prone events, especially long-range deletions (>200nt). This suggests that BLM protects against extensive resection during alternative NHEJ. Furthermore, BLM is implicated in the protection against CtIP-dependent resection at the initiation of HR. In conclusion, our results show a major role of BLM in protecting against an excess of resection, mediated by the MRN cofactor – CtIP. BLM interacts with 53BP1 at sites of damage, in an ATM-dependent manner, in order to regulate the resection process and counteract BRCA1 activity. This underlines the novel role of BLM in the protection against resection and favouring gene conversion events without crossing-over, which is substantial for maintaining genomic integrity

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Alberts, Terri Lynn. "Chronic fatigue and immune dysfunction syndrome: its relationship to underlying emotional and psychological issues." CSUSB ScholarWorks, 1997. https://scholarworks.lib.csusb.edu/etd-project/1181.

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This post-positivist research study explored the possible relationship between Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) and the presence of underlying psychological and emotional issues. An exploratory design with naturalistic methods of inquiry was utilized to investigate whether the presence, or absence, of these issues had any impact on the overall disease process.

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Karns, Rebekah A. B. S. "Integrative and Multivariate Statistical Approaches to Assessing Phenotypic and Genotypic Determinants of Complex Disease." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1335554184.

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Xanthos, Dimitris. "Role of the sympathetic nervous system in chronic post ischemia pain, a rodent model of complex regional pain syndrome type 1." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=21952.

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Complex regional pain syndrome (CRPS) is a severe neuropathic-like chronic pain disorder that is characterized by spontaneous and stimulus-evoked pain, vascular abnormalities, sudomotor changes, and muscle and bone abnormalities. Growing evidence suggests that ischemic processes may be particularly important pain mechanisms in CRPS, particularly for CRPS-type I, for which a major nerve injury is not indicated. Chronic ischemia in limbs of CRPS patients may underlie the analgesic effectiveness of anti-sympathetic treatments and vascular abnormalities. Since most animal models of neuropathic pain involve injury of a major nerve, development and characterization of an animal model that mimicks signs and symptoms of CRPS by an ischemic injury would increase our understanding of the mechanisms underlying CRPS-I. After a 3-hour tourniquet-induced ischemia and reperfusion of the rat hind paw (chronic post-ischemia pain; CPIP), a majority of animals develop chronic pathology that mimicks CRPS-I, with long-lasting sensory symptoms of mechanical allodynia, mechanical hyperalgesia, and cold allodynia following short-lasting signs of hyperemia and oedema. Chemical sympathectomy and phentolamine reduce signs of mechanical allodynia, suggesting this animal model exhibits what has been clinically defined as sympathetically-maintained pain (SMP). Further, the systemic administration of an α1-adrenergic antagonist, an α2-adrenergic agonist, a nitric oxide (NO) donor, but not an α2-adrenergic antagonist, also reduce mechanical allodynia, suggesting that vasodilation may be a way to relieve allodynia in this animal model. The relationship between mechanical allodynia and painful reactions to intracutaneous norepinephrine (NE) injection was also measured behaviourally, and was compared with changes in NE-induced reductions in hind paw blood flow in CPIP rats. As in CRPS patients with SMP, intradermal injection of NE into the affected hind paw induced dose-dependent nociceptive
Le syndrome douloureux régional complexe (SDRC) est une douleur chronique sévère semblable à la douleur neuropathique, et se caractérise par la présence de douleur spontanée et évoquée par stimulation, des anomalies vasculaires, des changements sudomoteurs et des anomalies ossseuses et musculaires. Les recherches récentes suggèrent que les processus d'ischémie sont impliqués dans les mécanismes de la douleur du syndrome SDRC et particulièrement pour le syndrome SDRC de type I, dans lequel il n´y a pas de lésion de nerf majeure identifiable. On pense que l'ischémie chronique dans les membres des patients SDRC est reliée à l'efficacité des traitements anti-sympathetiques analgésique et aux anormalités vasculaires présentes. Puisque la majorité des modèles animaux de la douleur neuropathique se caractérisent par une lésion de nerf majeur, on suggère que pour mieux comprendre les mécanismes pathologiques du SDRC-type I, il est necessaire de déveloper et de caractériser un nouveau modèle animal de la douleur chronique induie par une bléssure ischémique et qui reproduit les signes et les symptomes du SDRC de type-I. Un épisode d´ischémie suivi de réperfusion de la patte du rat par tourniquet pendant 3 heures cause chez une majorité d´animaux une pathologie chronique qui resemble au syndrome SDRC-type I (douleur chronique post-ischémique; DCPI), avec des symptomes sensoriels de longue durée comme l'allodynie tactile, l'hyperalgésie tactile, l'allodynie au froid, et aussi de l'hyperhémie et de l'oedème de courte durée. La sympathéctomie chimique et la phéntolamine diminuent les signes d'allodynie, ce qui demontre de la douleur en composant sympathique (SMP) dans ce modèle animal. En plus, l'administration systémique d'un antagoniste α1-adrénergique, d'un agoniste α2-adrénergique, d'un doneur de l'oxyde nitrique, mais pas d'un antagoniste α2-adrenergique diminue l'allodynie tactile, ce qui suggère que la vasodilata

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Liman, Suryamin, and 陳明正. "Ketamine on chronic post-ischemia pain (CPIP) model of complex regional pain syndrome (CRPS) type I in Sprague-Dawley (SD) rats." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45989448.

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Christo, George. "Post substance dependence stress syndrome : a complex post-traumatic stress disorder (PTSD) conceptualisation of residual psychopathology during abstinence after substance dependence." Thesis, University of Surrey, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362327.

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Salmaggi, Andrea, Lucia Zirilli, Chiara Pantaleoni, Joanna Gabriella De, Sorbo Francesca Del, Katrin Köhler, Manuela Krumbholz, Angela Hübner, and Vincenzo Rochira. "Late-Onset Triple A Syndrome: A Risk of Overlooked or Delayed Diagnosis and Management." Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27573.

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Background/Aims: A 33-year-old man was referred for the first time to the Division of Neurology because of the presence and progression of neurological symptoms. Dysphagia, weakness, reduced tear production, and nasal speech were present. In order to point the attention of late-onset triple A syndrome we describe this case and review the literature. Methods: Hormonal and biochemical evaluation, Schirmer test, tilt test and genetic testing for AAAS gene mutations. Results: Late-onset triple A syndrome caused by a novel homozygous missense mutation in the AAAS gene (A167V in exon 6) was diagnosed at least 17 years after symptom onset. Conclusions: The association between typical signs and symptoms of triple A syndrome should suggest the diagnosis even if they manifest in adulthood. The diagnosis should be confirmed by Schirmer test, endocrine testing (both basal and dynamic), genetic analysis, and detailed gastroenterological and neurological evaluations. Awareness of the possible late onset of the disease and of diagnosis in adulthood is still poor among clinicians, the acquaintance with the disease is more common among pediatricians. The importance of an adequate multidisciplinary clinical approach, dynamic testing for early diagnosis of adrenal insufficiency and periodical reassessment of adrenal function are emphasized.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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Cottrell, Catherine E. "Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829.

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Jühlen, Ramona. "Role of ALADIN for Oxidative Stress Response and Microsomal Steroidogenesis in Human Adrenocortical Cells." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-188752.

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Autosomal recessive triple A syndrome is caused by mutations in the AAAS gene encoding the protein ALADIN. The disorder manifests with the triad of adrenocorticotropin-resistant adrenal insufficiency, achalasia of the stomach cardia and impaired tear production (alacrima) in combination with progressive neurological impairment of the central, peripheral and autonomic nervous systems. ALADIN is part of the nuclear pore complex acting as a scaffold nucleoporin. In this work the role of ALADIN in the human adrenocortical tumour cell line NCI-H295R1 was investigated. These cells were engineered to either over-express or down-regulate AAAS by inducible stable transfection. Alterations in steroidogenic gene expression and functional consequences were determined. In addition, the role of ALADIN on cell viability and oxidative stress response was analysed. Using both the human adrenal NCI-H295R1-TR AAAS knock-down and over-expression models the potential impairment of the nuclear import of aprataxin, DNA ligase 1 and ferritin heavy chain 1 was investigated. For this YFP-specific vectors transiently transfected into the cell lines were employed. The findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore I demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, I show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. I conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting the knock-down cell model as an important in vitro tool for studying the adrenal phenotype in triple A syndrome. In an approach to identify new interaction partners of ALADIN, co-immunoprecipitation followed by proteome analyses using mass spectrometry was conducted in a GFP-ALADIN over-expression model using the human adrenocortical tumor cell line NCI-H295R. These results were verified in co-immunoprecipitation assays of endogenous ALADIN using NCI-H295R wild-type cells. The results suggest a possible interaction between ALADIN and microsomal flavoprotein cytochrome P450 oxidoreductase and progesterone receptor membrane compartment 2. Co-localisation analyses of these findings were done using immunofluorescence. The data are suggestive for an involvement of ALADIN in the export of nuclear-encoded mitochondrial proteins. Regulation of adrenocortical steroidogenesis is complex and there is increasing evidence that oxidative stress due to ROS accumulation and mitochondria are significantly involved. Furthermore, there may be an important cross-talk between functional organelles comprising nucleus, ER and mitochondria which presumably involves lipid metabolism. The goal of this work was to elucidate the function of ALADIN for the cellular oxidative stress response and its possible consequences for adrenocortical steroidogenesis in triple A syndrome patients
Mutationen im AAAS Gen verursachen die autosomal rezessive Krankheit Triple-A-Syndrom. AAAS kodiert das Nukleoporin ALADIN, welches Bestandteil des nukleären Porenkomplexes ist. Phänotypische Charakteristika des Triple-A-Syndroms sind Nebennierenrinden-Insuffizienz, Achalasie des unteren Speiseröhrenschließmuskels und eine fehlende Tränenproduktion (Alakrimie). Diese Symptome sind kombiniert mit progredienten neurologischen Störungen des zentralen, peripheren und autonomen Nervensystems. In dieser Arbeit wurde die Rolle von ALADIN in der humanen Karzinom-Zelllinie NCI-H295R1 untersucht. Diese Nebennierenrinden-Zellen wurden stabil transfiziert und mit einem induzierbaren Expressionssystem modifiziert, so dass sie AAAS entweder überexprimierten oder herunterregulierten. In NCI-H295R1-Zellen wurden Veränderungen der Genexpression von Enzymen der Steroidogenese und funktionelle Konsequenzen der Überexpression oder Herunterregulation von ALADIN gemessen. Des Weiteren wurde die Rolle von ALADIN auf die Zellviabilität und die Redox-Homöostase analysiert. ALADIN überexprimierende und herunterregulierte Zellen wurden verwendet, um die potentielle Behinderung des nukleären Imports von Proteinen zu untersuchen, welche den Zellkern gegen oxidativen Stress schützen (z.B. Aprataxin, DNA-Ligase 1 und Ferritin Heavy Chain 1). Dazu wurden YFP-spezifische Vektoren transient in diese Zellen gebracht. Mit den Ergebnissen dieser Arbeit wurde gezeigt, dass die Herunterregulation von AAAS eine Verminderung der Genexpression von CYP17A1 und CYP21A2 und deren Elektronendonor Cytochrom P450 Oxidoreduktase bewirken. Die Biosynthese der Vorläufermetabolite von Kortisol und Aldosteron ist in diesen Zellen ebenfalls vermindert. Des Weiteren zeigen die ALADIN-defizienten NCIH295R1-Zellen eine erhöhte Sensitivität gegenüber oxidativem Stress und eine veränderte Redox-Homöostase nach der Behandlung mit Paraquat. Darüber hinaus konnte in dieser Studie auch gezeigt werden, dass herunterregulierte ALADIN NCI-H295R1-Zellen einen verminderten Zellkernimport von Aprataxin, DNA-Ligase 1 und Ferritin heavy chain 1 besitzen. Aus diesen Ergebnissen kann geschlussfolgert werden, dass ALADIN-defiziente Nebennierenzellen eine verminderte Stressantwort auf oxidativen Stress besitzen; dies führt schlussendlich zu einer veränderten Steroidogenese. Das beschriebene ALADIN knock-down Modell in NCI-H295R1-Zellen ist ein wichtiges in vitro Werkzeug, um die Pathogenese der Nebennierenveränderungen im Triple-A-Syndrom zu erforschen. Neue Interaktionspartner von ALADIN wurden mit Hilfe von Co-Immunpräzipitation gefolgt von Proteom-Analysen durch Massenspektrometrie in einem GFP-ALADIN Überexpressionsmodell in NCI-H295R charakterisiert. Die Ergebnisse wurden durch Experimente auf endogenem Niveau in NCI-H295R-Wildtypzellen verifiziert. Mit diesen Daten wird in dieser Arbeit erstmals eine Interaktion zwischen ALADIN und dem Flavoprotein Cytochrom P450 Oxidoreduktase und Progesterone Receptor Membrane Compartment 2 nachgewiesen. Diese Ergebnisse wurden mit Co-Lokalisierungsanalysen durch Immunfluoreszenzfärbung von ALADIN und Cytochrome P450 Oxidoreduktase ergänzt. Außerdem gibt die Arbeit Hinweise darauf, dass ALADIN als Nukleoporin an dem nuklearen Export mitochondrialer Vorläuferproteine beteiligt ist. Die Regulation der Steroidogenese in der Nebennierenrinde ist komplex und es existieren zahlreiche Hinweise darauf, dass oxidativer Stress aufgrund der Ansammlung reaktiver Sauerstoffradikale und. dass die Mitochondrien involviert sind. Außerdem ist ein funktionelles Zusammenspiel verschiedener Organellen, darunter Nukleus, ER und Mitochondrien, von großer Bedeutung. Das Ziel dieser Arbeit war die Identifizierung der Funktion von ALADIN in der zellulären oxidativen Stressantwort und die möglichen Konsequenzen für die Steroidogenese in der Nebennierenrinden in Triple-A-Syndrom-Patienten

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46

Goldthorpe, Joanna. "Developing and evaluating a complex intervention to treat chronic orofacial pain." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/developing-and-evaluating-a-complex-intervention-to-treat-chronic-orofacial-pain(29158f44-c916-41c4-a84f-c6481437dc9e).html.

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Introduction: Chronic orofacial pain (COFP) is distressing and disabling to sufferers and can be costly to patients, health services and society. Frequently, no underlying medical pathology can be found to account for the condition. Despite this, patients are treated according to a biomedical model, often by mechanistic and invasive procedures, which tend to be unsuccessful and not evidence based. Evidence suggests that cognitive behavioural therapy (CBT) based management may produce improved outcomes for patients. However, published studies can tell us little about which intervention components are effective, or recommend an optimum way for these components to be applied. Aim: To develop an evidence based intervention for the management of COFP that is feasible and acceptable to patients and practitioners. Method: The Medical Research Council’s guidelines for developing complex interventions were used as a framework for the research. Evidence from multiple sources was synthesised to produce the draft components of an intervention to manage COFP. An exploratory trial investigated preliminary outcomes, acceptability, feasibility and explored parameters for a full scale randomised control trial. Results: The intervention was acceptable to participants and could be feasibly implemented. No conclusions could be drawn relating to the effectiveness of the intervention. Participants were not affected at baseline for a number of outcomes, which implies that cut off points should be introduced into the inclusion and exclusion criteria of any future studies. Conclusion: The study produced an intervention which is acceptable and feasible to participants, however it is not known if it is effective. A number of recommendations are made for progression to a larger, definitive trial.

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Flatt, Kimberlee Kay. "Complex-Restricted Repetitive Patterns of Vocal Behavior of Individuals with High Functioning Autism: An Innovative Intervention." Thesis, University of North Texas, 2019. https://digital.library.unt.edu/ark:/67531/metadc1505190/.

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Repetitive verbal patterns of speech are a trait associated with high-functioning autism (HFA). For some, this higher-order restricted, repetitive behavior impedes learning, social opportunities, and access to work environments. Despite emerging motivation for establishing social relationships, some individuals with HFA lack the behavioral prerequisites to establish meaningful relationships. The purpose of this study is to demonstrate the effectiveness of teaching interaction to decrease higher-order verbal restricted and repetitive behaviors (RRBs) for four adults with HFA. Through a multiple baseline design across participants, individuals were exposed to a function-based intervention (i.e., teaching interaction) that systematically taught and reinforced alternative communicative behaviors while interrupting repetitive speech with specific feedback. Teaching interaction effectively reduced RRBs and increased alternative conversation for all four participants. Three of the four participants elected to participate in post-intervention maintenance sessions that occurred in individualized naturalistic settings. Their conversation behaviors maintained with one participant receiving one booster session.

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Zhang, Chi. "The X-linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10763.

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Intellectual disability is a prevalent developmental disorder for which no effective treatments are available. Mutations of the X-linked protein PHF6 cause the Börjeson-Forssman-Lehmann syndrome (BFLS) that is characterized by intellectual disability and epilepsy. However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. Here, I present my dissertation research demonstrating that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo, leading to the formation of white matter heterotopias that harbor aberrant patterns of neuronal activity. Importantly, BFLS patient specific mutation of PHF6 blocks its ability to promote neuronal migration. I also elucidate the mechanism by which PHF6 drives neuronal migration in the cerebral cortex. PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. I further identify Neuroglycan C (NGC), a susceptibility gene for schizophrenia, as a critical downstream target of PHF6 and the PAF1 complex, and I demonstrate that NGC mediates PHF6-dependent neuronal migration. These findings define PHF6, the PAF1 transcription elongation complex, and NGC as components of a novel cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of intellectual disability and potentially other neuropsychiatric disorders.

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Kozel, Carrie L. "Early Feeding In Lake Trout Fry (salvelinus Namaycush) As A Mechanism For Ameliorating Thiamine Deficiency Complex." ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/685.

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Recruitment failure of lake trout (Salvelinus namaycush) in the Great Lakes has been attributed in part to the consumption of alewife (Alosa pseudoharengus) by adult lake trout, leading to Thiamine Deficiency Complex (TDC) and early mortality in fry. The current understanding of thiamine deficiency in lake trout fry is based on information from culture and hatchery settings, which do not represent conditions fry experience in the wild and may influence the occurrence of TDC. In the wild, lake trout fry have access to zooplankton immediately following hatching; previous studies found that wild fry begin feeding before complete yolk-sac absorption. However, hatchery-raised fry are not provided with food until after yolk-sac absorption, long after the development of TDC. Zooplankton are a potential source of dietary thiamine for wild fry in the early life stages that has not previously been considered in the occurrence of thiamine deficiency. We postulated that wild-hatched fry could mitigate thiamine deficiency through early feeding on natural prey. Specifically, we hypothesized 1) feeding should increase thiamine concentrations relative to unfed fry and 2) feeding should increase survival relative to unfed fry. Feeding experiments were conducted on lake trout fry reared from eggs collected from Lake Champlain in 2014 and Cayuga Lake in 2015. A fully crossed experimental design was used to determine the effect of early feeding by lake trout fry in thiamine replete and thiamine deplete treatments before and after feeding. Overall, thiamine concentrations and survival did not significantly differ between fed and unfed fry. Thiamine concentrations increased from egg stage to hatching in both years, suggesting a potential source of thiamine, which had not previously been considered, was available to the lake trout eggs during development.

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Dharmalingam, Backialakshmi [Verfasser]. "Immune mediated disturbances of bone, connective tissue and vascular metabolism in Complex Regional Pain Syndrome (CRPS) : a new pathogenic mechanism of therapeutic relevance / Backialakshmi Dharmalingam." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1076980287/34.

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Dissertations / Theses on the topic 'Complex syndrome'

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