A hermeneutical model of doing research is adopted to investigate the process of coping and self-management in the experience of recovering from Chronic Fatigue Syndrome (CFS). Three research participants who consider themselves as recovering or recovered from CFS were interviewed to obtain data for analysis. The findings are that once the participants cope with the uncertainty about the meaning of the onset of symptoms by defining themselves as ill in somatic terms, the participants use external social and treatment resources to cope with the onset of symptoms and being chronically ill with CFS. As a consequence of feeling stigmatised in relation to social and professional scepticism about initially being ill and subsequently, being chronically ill with CFS, the participants become uncertain about the meaning of having CFS. Coping shifts to using internal resources by adopting self-management practises. In this process, firstly, existing self-management shifts in such a way that the participants view themselves as recovering or recovered from CFS, and secondly, the participants come to the understanding that difficulties with self-management cause and maintain CFS. The findings are discussed to conclude that CFS may be a misdiagnosis of difficulties with self-management. CFS itself may not be an 'objective' disorder, but a constituent of social processes. Becoming diagnosed with CFS arises as a consequence of the search for meaning in relation to the lay and professional assumption that psychological illness does not constitute 'real' illness, operating at both the levels of popular society and the doctor-patient relationship. Difficulties with self-management rather than the diagnosis of CFS provide a more adequate understariding of the participants' illnesses. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

Abstract The Prader-Willi (PWS) and Angelman (AS) syndromes are clinically distinct developmental disorders which are caused by genetic defects in the imprinted domain at chromosome 15q11-q13, resulting in the loss of paternal (PWS) or maternal (AS) gene function. In this study, the genetic changes of 15q11-q13 and their possible inheritance in Finnish PWS (n=76) and AS (n=47) patients are described. The diagnosis could be confirmed by laboratory methods in all PWS and in 43 (91%) AS patients. A deletion of 15q11-q13 accounted for 76% of the PWS and 67% of the AS patients in whom a specific genetic defect had been established. The origin of deletion was always paternal in PWS and maternal in AS. In PWS, deletions of four different sizes were detected, while in AS only type I or II deletions were found. The smallest overlap of deletions/critical region detected was from locus D15S13 to locus D15S10 in PWS and from locus D15S128 to locus D15S12 in AS. A rare recurrence of del(15)(q11q13) due to maternal germ line mosaicism is described. Maternal uniparental disomy of chromosome 15 accounted for 21% of PWS patients and paternal UPD for 2% of AS patients. In PWS, most UPD cases were due to errors in maternal meiosis (87%), most commonly leading to maternal heterodisomy (MI error). In AS, a rare error in the second segregation of paternal meiosis was found. UPD was associated with advanced maternal age, the mean being 34.6 years. Imprinting defects were found in 3% of PWS (two non-IC-deletions) and 11% of AS (IC deletion in one sib pair and three non-IC-deletions) patients. In the case with IC deletion, the mutation was seen in several generations. The non-deletion cases were thought to be due to a de novo prezygotic or postzygotic error. In the non-deletion PWS cases, the maternally imprinted paternal chromosome region was shown to have been inherited from the paternal grandmother, while in AS the paternally imprinted maternal chromosome region had been inherited from either the maternal grandfather or the maternal grandmother. The region of IC involved in AS was defined to be 1.15 kb. Five (11%) AS patients with normal DNA methylation test results had a UBE3A mutation. One of the two novel missense mutations (902A→C) had been inherited from the mosaic mother, while the mutation 975T→C was a new one. De novo deletions 1930delAG and 3093delAAGA have also been described previously, suggesting that these sites may be mutation hotspots in UBE3A. Identification of different genetic aetiologies with different recurrence risks is essential for genetic counselling, and close co-operation between clinicians and the laboratory is required both for diagnosis and for the detection of possible inheritance.

Congenital microcephaly (conMiC) is a manifestation of severely disrupted prenatal brain development, caused by genetic defects, toxins, severe maternal malnutrition, or infection. The Zika virus outbreak and the devastating impact of Zika infection on the fetal brain have focused much attention on the cellular and molecular pathophysiology of conMiC. Mendelian conMiC disorders offer a unique opportunity for understanding gene and protein networks that direct cellular processes essential for prenatal brain development. Using OMIM and literature searches, I analyzed 68 conMiC disorders and their 65 corresponding genes. ConMiC-disorder phenotypes were characterized by analyzing the co-occurrence of ID, retinal abnormalities, seizures, and short stature. Short stature co-occurred with 70% of conMiC disorders, while seizures and retinopathy co-occurred with 68% and 37%, respectively. In 53% of conMiC disorders, seizures and short stature overlapped, while all features overlapped in 22% of conMiC disorders; only 7% of conMiC disorders lacked one of these co-occurring features. This shows conMiC genes are rarely specialized for brain growth, with generalized functions in overall body growth, retinal development, and/or regulation of neural activity. ConMiC-gene transcript accumulation in the brain is typically greatest during the prenatal period, and then declines postnatally, suggesting active transcriptional repression. Nonetheless, in neurons and glia of the adult brain, 44 conMiC genes had confirmed persistent protein accumulation. Experimental evidence indicates transcription in neural progenitor cells (NPCs) for at least 82% of conMiC genes. The spatiotemporal expression patterns of conMiC genes tend to align well with their biological functions and corresponding mutant phenotypes. Nearly 60% of conMiC gene products have functions in the cell cycle and/or DNA repair. Most conMiC disorders are caused by recessive, loss-of-function mutations. There are direct binding and regulatory interactions amongst many conMiC genes, which interact in larger networks and shared pathways. Depletion of single conMiC gene products can affect the transcript and/or protein levels of other conMiC gene products, which could have a “domino effect”, and disrupt entire networks important for brain development. Further evidence for this model is that 22 conMiC genes are consistently dysregulated in Zika-infected developing human brain tissue. Due to the complexity of conMiC genes and their interactions, there are many unique challenges to developing treatments for conMiC, particularly conMiC caused by maternal Zika-virus infection. However, insights to treatment strategies could be gained by using human genetics to find potential modifiers, screening for drugs that can normalize disrupted cell cycle and DNA-repair processes, or can stabilize protein complexes that are disrupted due to a conMiC gene mutation.

Le Syndrome WHIM (SW) est un déficit immuno-hématologique rare qui se caractérise notamment par une profonde leucopénie circulante. Le SW résulte principalement de mutations hétérozygotes autosomiques dans CXCR4 qui tronquent partiellement le domaine C-terminal de la protéine et entraînent un défaut de désensibilisation de CXCR4 en réponse à CXCL12. L’impact in vivo d’un gain de fonction de CXCR4 sur le développement et la différenciation lymphocytaires restant à définir, nous avons généré un modèle murin hétérozygote pour la mutation ponctuelle identifiée chez certains patients. L’objectif de ma thèse a été de déterminer si un défaut de différenciation des cellules souches et des progéniteurs hématopoïétiques (CSPH) était à l’origine de ces anomalies de lymphopoïèse. Nous avons observé que le nombre et la clonogénicité des CSH sont préservés dans la moelle osseuse des souris mutantes. Toutefois, les CSH porteuses de la mutation gain de fonction de Cxcr4 ont une quiescence accrue alors que leur multipotence et leur auto-renouvellement sont réduits. Ces dérégulations du compartiment des CSH entraînent, in vivo et in vitro, une altération de la production et de la spécification lymphoïde des progéniteurs multipotents (MPP). En périphérie, nous avons mis en évidence une diminution des CSPH dans le sang des souris mutantes, anomalie également retrouvée à partir de prélèvements sanguins de quatre patients atteints du SW et porteurs d’une mutation hétérozygote dans CXCR4. Ces résultats indiquent une anomalie de circulation des CSPH, hypothèse confortée par le développement d’une hématopoïèse extra-médullaire intra-splénique chez les souris mutantes. Ces données suggèrent que la désensibilisation de Cxcr4 régule la quiescence, la multipotence et l’auto-renouvellement des CSH et serait requise pour la spécification lymphoïde des MPP. Ainsi, l’absence de ce processus pourrait être à l’origine de la lymphopénie observée dans notre modèle murin et, par extrapolation, chez les patients. / The Warts, Hypogammaglobulinemia, Infections and Myelokathexis Syndrome (WS) is a rare immuno-hematological disorder characterized notably by a pan-leukopenia. It is mostly caused by heterozygous autosomal dominant gain-of-function mutations in CXCR4, which engender a distal truncation in the carboxyl-terminal tail domain and lead to a desensitization-resistant receptor. The in vivo impact of a gain-of-CXCR4 function on lymphocyte development and differentiation remain to be established. Then we recently produced major breakthroughs in the pathophysiology of the WS by generating a mouse strain harbouring a WS-linked heterozygous Cxcr4 mutation. The aim of my PhD was to determine if a HSPC differentiation defect would account for the lymphopenia. We showed that the total number and the clonogenicity of HSC were not altered in the BM of mutant mice. However, HSC carrying the gain-of-function mutation in Cxcr4 have an increased quiescence but a decreased multipotency and self-renewal. These HSC compartment deregulations lead to a in vivo and in vitro decline of multipotent progenitors (MPP) production and lymphoid specification. Furthermore, we reported a decrease in the total number of HSPC in the blood of mutant mice, an anomaly also found in four WS patients carrying a heterozygous CXCR4 mutation. This suggested an abnormal HSPC circulation that was strengthened by an enhanced extramedullary haematopoiesis observed in the spleen of mutant mice. These results suggest that Cxcr4 desensitization regulates HSC quiescence, multipotency and self-renewal and is required for MPP lymphoid specification. In this respect, the absence of such process could account for the lymphopenia in this model and likely in patients.

Histiocytoid Sweet syndrome (HSS) is a rare histologic variation of Sweet syndrome (SS) predominantly exhibiting mononuclear histiocytoid cells instead of neutrophils. We report a 22-year-old woman with HSS, who, after minimal improvement with colchicine and dapsone, had significant improvement of her cutaneous eruption and systemic symptoms following empiric treatment with azathioprine. Since azathioprine has historically been known to cause SS, this case highlights a previously unreported treatment response for the histiocytoid variant.

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BACKGROUND: The ability to recognize and respond appropriately to threat is critical to survival, and the neural substrates subserving attention to threat may be probed using depictions of media violence. Whether neural responses to potential threat differ in Down syndrome is not known. METHODS: We performed functional MRI scans of 15 adolescent and adult Down syndrome and 14 typically developing individuals, group matched by age and gender, during 50 min of passive cartoon viewing. Brain activation to auditory and visual features, violence, and presence of the protagonist and antagonist were compared across cartoon segments. fMRI signal from the brain's dorsal attention network was compared to thematic and violent events within the cartoons between Down syndrome and control samples. RESULTS: We found that in typical development, the brain's dorsal attention network was most active during violent scenes in the cartoons and that this was significantly and specifically reduced in Down syndrome. When the antagonist was on screen, there was significantly less activation in the left medial temporal lobe of individuals with Down syndrome. As scenes represented greater relative threat, the disparity between attentional brain activation in Down syndrome and control individuals increased. There was a reduction in the temporal autocorrelation of the dorsal attention network, consistent with a shortened attention span in Down syndrome. Individuals with Down syndrome exhibited significantly reduced activation in primary sensory cortices, and such perceptual impairments may constrain their ability to respond to more complex social cues such as violence. CONCLUSIONS: These findings may indicate a relative deficit in emotive perception of violence in Down syndrome, possibly mediated by impaired sensory perception and hypoactivation of medial temporal structures in response to threats, with relative preservation of activity in pro-social brain regions. These findings indicate that specific genetic differences associated with Down syndrome can modulate the brain's response to violence and other complex emotive ideas.

No description available.