Factors associated with the continuum of care of HIV infected patients in Belgium

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Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials

Study of blood platelets in patients with neurological disorders

The process ofregulated granule secretion in platelets involves a complex molecular machinerythat for at least in some aspects is highly conserved in other specializedsecretory cells such as neurons. In addition, both platelets and neuronsexpress similar neurotransmitter pathway regulators. Based on these cellularsimilarities, my PhD project focused on the study of platelet function andmorphology in different neurological diseases in order to gain novel insightsin their underlying molecular and biological defects. In the first part of this thesis, thehomozygous AQP7-G264V defect wasidentified as cause for the hyperglyceroluria that was present in patients fromthree unrelated families with also a variable degree of mental disability. AQP7belongs to the aquaglyceroporin family transporting glycerol and water and withhigh expression in adipocytes and renal proximal tubule cells. AQP7 deficientmice develop obesity, insulin resistance and hyperglyceroluria. The AQP7-G264V mutation was previously shownto be associated with disturbed permeability of glycerol in Xenopus oocytes but it was not found tobe associated with obesity or type 2 diabetes in humans. This study shows thatindividuals homozygous for the AQP7-G264Vmutation have a subclinical platelet secretion defect with reduced ATPsecretion and an absent secondary aggregation wave after epinephrinestimulation. Electron microscopy revealed round platelets with centrallylocated granules and the presence of empty vacuoles. Immunostaining showed AQP7colocalisation with dense granules, which seems to be released upon strongplatelet activation. The association of urine glycerol loss and a plateletgranule secretion defect is novel and our findings imply for the first time a rolefor AQPs in platelet secretion. The functional significance of the AQP7-G264V variant in mental disabilitydeserves further studies. In the second and third part of this thesis, platelet studies enabled us to betterunderstand the biological defective pathways in two neurological disorders witha known genetic defect. The congenital variant of Rett syndrome is caused bymutations in the transcription factor FOXG1.It was recently suggested that this syndrome can also be due to the disruptionof FOXG1 long-range regulatory elements by 14q12 translocations or chromosomalmicrodeletions that do not harbor the FOXG1gene itself. This hypothesis was supported by our finding of reduced FOXG1mRNA and protein levels in platelets and skin fibroblasts from these cases. Electron microscopy of their plateletsshowed rounder platelets with often abnormal alpha and fewer dense granules.Functional platelet studies were possible in one 14q12 translocation patientwith a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 p.Tyr416X mutation. Both patients havea prolonged PFA100 occlusion time after activation with collagen andepinephrine, and aggregations with a low dose of ADP and epinephrine were alsoreduced while ATP secretion was normal. These functional platelet abnormalitiesdeserve further investigation regarding a non-transcriptional regulatory rolefor FOXG1 in these anucleated cells. In the third part of this thesis the biologicalrole of ATP1A3 and the mechanism for its dysfunction in AHC were investigated.Platelets from 9 AHC patients with ATP1A3mutations have structural and functional abnormalities related to granulespositive for the lysosomal marker CD63. Similar structural granuleabnormalities were detected in the patients fibroblasts. We found 93 proteinsthat were differentially expressed in AHC using a proteomic analysis ofplatelets and fibroblasts. These proteins are predicted to be mainly involvedin metabolism. Interestingly, 7 of them were detected in both cell types, includingthe lysosomal protein cathepsin. AHC fibroblasts have significantly increasedlevels of activated cathepsin B that was associated with increased intrinsicapoptosis. This is the first study that links ATP1A3 defects in AHC to a platelet and fibroblast lysosomal defectwith evidence of increased apoptosis. Further studies, however, are needed todefine how this lysosomal defect is related to decreased ATPase activity.nrpages: 154status: publishe

Screening and evaluation tools of dysphagia in adults with neuromuscular diseases: a systematic review.

BACKGROUND: The purpose of this systematic review was to summarize the different dysphagia screening and evaluation tools, and to identify their measurement properties in adults with neuromuscular diseases (NMDs). METHODS: A systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was conducted across three databases (PubMed, CINAHL and ScienceDirect). Measurement properties of each tools and the Quality Index, developed by Downs and Black, were considered for the different investigated studies. RESULTS: The search strategy produced 2221 articles. After removal of duplicates and full-text analysis, 19 studies were included. Most of the publications focused on amyotrophic lateral sclerosis (ALS; n = 10) and Duchenne muscular dystrophy (DMD; n = 4). A total of 12 tools, listed as instrumental and noninstrumental examinations, were retrieved. A total of five of them used videofluoroscopic swallow study (VFSS). Measurement properties of the tools are not completely described in detail in many studies. The neuromuscular disease swallowing status scale, a noninstrumental tool, is the only one that assessed all measurement properties in ALS patients. The median score reported for the Quality Index was 16. CONCLUSIONS: This systematic review identified 12 different tools for the screening and evaluation of dysphagia in adults with NMD. Majority of the studies presented VFSS as a valid and reliable examination to assess dysphagia in ALS and DMD. Other tools were mainly evaluated in ALS patients, but further studies are needed to complete their measurement properties. In other NMDs, no firm conclusion can be made because of insufficient data and heterogeneity of NMDs

Correlation Between Cardiopulmonary Exercise Test, Spirometry, and Congenital Heart Disease Severity in Pediatric Population.

Congenital heart disease (CHD) is a common chronic disease. This study aimed to verify the relationship between spirometry and exercise capacity in children, considering the CHD severity. All cardiopulmonary exercise testing (CPET) and Spirometry from CHD children (5-18 years) were retrospectively reviewed during three years. CPET and Spirometry were analyzed and correlated based on the CHD severity[modified Ross classification (mR)]. Patients (n = 321) were analyzed and subdivided for CHD severity (n = 49, n = 149, n = 80, n = 43, from mR1 to mR4, respectively). The maximal workload (Wmax) in mR1 and mR2 was higher than in patients from mR3 and mR4. Peak oxygen uptake (peak VO2) was reduced in mR3 and mR4 compared to mR1 and mR2. Carbon dioxide output was only significantly lower in mR4. Although spirometric parameters were globally in the normal range, forced expiratory volume and forced vital capacity were different between subgroups (p < 0.001 and p = 0.002, respectively). Wmax and peakVO2 were weakly or moderately but significantly correlated with spirometry. Respiratory exchange ratio and final blood oxygen saturation were only significantly and weakly correlated to obstruction in small airways. The most severe CHD patients had lower exercise capacity and lung function parameters. A weak to moderate correlation between CPET and spirometry was found. However, the lung function reported in our study was normal, but with a negative correlation with the age. It reinforces the benefits of precocious and regularly spirometry and CPET assessment in CHD children

Drug resistance in HIV-infected children living in rural South Africa: Implications of an antiretroviral therapy initiated during the first year of life

Introduction Management of antiretroviral-drug resistance in HIV-infected children is a global health concern. We compared the long-term virological outcomes of two cohorts of children living in a rural setting of South Africa. The first cohort initiated treatment before one year and the second after two years of age. The aim of this study was to describe the long-term consequences of early treatment initiation in terms of viral load and drug-resistance. Methods This retrospective study was conducted at the Edendale Hospital located in a peri-urban area of KwaZulu-Natal. Children were included during their planned appointment. Drug resistance was assessed genotypically on proviral DNA. Results From the 161 children included in this study, 93 samples were successfully genotyped. Both cohorts had comparable viral loads, but children treated early more often presented NRTI or NNRTI mutations, while there was no difference for PI mutations rates. Conclusions Treatment was highly effective when comparing virological outcomes in both early- and late-treated cohorts. The persistence of NNRTI mutations could lead to treatment failures in children older than 3 years initiating their therapy with a NNRTI, or for those switching from a PI to NNRTI based regimen. The accumulation of NRTI mutations may lead to a functional PI monotherapy and consequently to viral escape. To promote access to HIV genotyping in resource-limited settings is challenging but essential to avoid inappropriate therapy switches in case of virological failure, and to adapt national treatment guidelines in line with the epidemiology of resistance