24 research outputs found
Specific features of cognitive and socio-emotional development in young children with dual diagnosis of Downâ syndrome and Autism Spectrum Disorder
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Characteristics and Prognosis of Patients With Hypertensive Encephalopathy: A French Nationwide Cohort Study
International audienceBACKGROUND: Hypertensive encephalopathy (HE) constitutes a serious condition, usually observed in patients with long-lasting hypertension. Hypertension-associated HE is sometimes differentiated from the stroke-associated hypertensive emergency. Whether prognosis of hypertension-associated and stroke-associated HE is different is unclear. METHODS: Characteristics and prognosis of HE were assessed in this nationwide retrospective cohort study in all patients with an administrative code of HE compared with age-, sex- and year of inclusion-matched controls admitted to French hospitals during the 2014 to 2022 period. RESULTS: HE was identified in 7769 patients. Chronic kidney disease (19.3%), coronary artery disease (13.8%), diabetes (22.1%), and ischemic stroke (5.2%) were frequent but thrombotic microangiopathy, hemolytic-uremic syndrome, systemic sclerosis or renal infarction were <1%. HE prognosis was poor (death: 10.4%/y, heart failure: 8.6%/y, end-stage kidney disease: 9.0%/y, ischemic stroke: 3.6%/y, hemorrhagic stroke: 1.6%/y, dementia: 4.1%/y). The risk of death was increased to a similar extent in patients with HE, regardless of the presence of known hypertension or concomitant stroke (versus patients without HE). Among patients with HE, known hypertension was significantly associated with increased risks of ischemic stroke, hemorrhagic stroke, heart failure, vascular dementia, and all-cause dementia and to a lesser extent with chronic dialysis in multivariable analyses including adjustment on concomitant stroke. CONCLUSIONS: HE remains a considerable health burden and is associated with a poor prognosis. The distinction between hypertension- versus stroke-associated HE is relevant as these 2 situations convey different risks of stroke, heart failure, vascular dementia, and end-stage kidney disease
Long-term impact of cardiorenal syndromes on major outcomes based on their chronology: a comprehensive French nationwide cohort study
International audienceABSTRACT Background Cardiorenal syndromes (CRS) are reputed to result in worse prognosis than isolated heart failure (HF) and chronic kidney disease (CKD). Whether it is true for all major outcomes over the long-term regardless of CRS chronology (simultaneous, cardiorenal and renocardiac CRS) is unknown. Methods The 5-year adjusted risk of major outcomes was assessed in this nationwide retrospective cohort study in all 385 687 with either CKD or HF (out of 5123 193 patients who were admitted in a French hospital in 2012). Results Overall, 84.0% patients had HF and 8.9% had CKD (they had similar age, sex ratio, diabetes and hypertension prevalence) while 7.1% had CRS (cardiorenal: 44.6%, renocardiac: 14.5%, simultaneous CRS: 40.8%). The incidence of major outcomes was 57.3%; 53.0%; 79.2% for death, 18.8%; 10.9%; 27.5% cardiovascular death, 52.6%; 34.7%; 64.3% for HF, 6.2%; 5.5%; 5.6% for myocardial infarction (MI), 6.1%; 5.8%; 5.3% for ischemic stroke, and 23.1%; 4.8%; 16.1% for end-stage kidney disease (ESKD) for isolated CKD, isolated HF and CRS, respectively. As compared to isolated CKD or HF, the risk of death, cardiovascular death and HF was markedly increased in CRS, the worse phenotype being cardiorenal CRS, while the increased risk of MI and ischemic stroke associated with CRS subtypes was statistically but not clinically significant. As compared to isolated CKD, the risk of ESKD was similar for cardiorenal syndrome only and marginally increased for renocardiac and simultaneous CRS. We could not find a synergy between HF and CKD on major clinical outcomes in the whole population (n = 5123 193 patients). Conclusions The additional impact of CRS vs isolated HF or CKD on long-term kidney and cardiovascular risk is highly heterogenous, depending of the event considered and CRS chronology. No synergy between HF and CKD could be demonstrated
Molecular signatures of cardiac defects in down syndrome lymphoblastoid cell lines suggest altered ciliome and hedgehog pathways
Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD) and less frequently a ventricular septal defect (VSD) or atrial septal defect (ASD). Lymphoblastoid cell lines (LCLs) were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD-; n = 22) were compared with those of LCLs from patients with cardiac malformations (CHD+; n = 21). After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD) carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD- and AVSD and CHD- and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset). Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21. © 2012 Ripoll et al
Transcriptome signature of heart defects.
<p>Comparison of ratios for DE genes up- or down-regulated in the AVSD or ASD+VSD group between (1) array ratio in the Ts21 CHD<sup>â</sup> vs 2N, (2) array ratio in CHD<sup>+</sup> vs CHD<sup>â</sup>, (3) q-PCR ratio from different experiments in CHD<sup>+</sup> vs CHD<sup>â</sup> using additional samples (total number in parentheses). Gene nomenclature, <i>AUTS2</i>: autism susceptibility candidate 2; <i>CNN2</i>: calponin 2; <i>DSCR3</i>: Down syndrome critical region gene 3; <i>DYNLT3</i>: dynein, light chain, Tctex-type 3; <i>NQO1</i>: NAD(P)H dehydrogenase, quinone 1; <i>OFD1</i>: oral-facial-digital syndrome 1; <i>PDIA4</i>: protein disulfide isomerase family A, member 4; <i>PIGP</i>: phosphatidylinositol glycan anchor biosynthesis, class P; <i>TTC3</i>: tetratricopeptide repeat domain 3; <i>TUBB2B</i>: tubulin, beta 2B; <i>ACTG1</i>: actin, gamma 1; <i>ALDOC</i>: aldolase C, fructose-bisphosphate; <i>CACYBP</i>: calcyclin binding protein; <i>DTYMK</i>: deoxythymidylate kinase (thymidylate kinase); <i>ENO2</i>: enolase 2 (gamma, neuronal); <i>GART</i>: phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase; <i>IFNAR1</i>: interferon (alpha, beta, and omega) receptor 1; <i>PLTP</i>: phospholipid transfer protein; <i>RPL10A</i>: ribosomal protein L10a; <i>TNFAIP2</i>: tumor necrosis factor, alpha-induced protein 2.</p
Principal component analysis of gene expression profiles of LCLs from individuals with DS and with CHD: red- AVSD (nâ=â7); green- ASD (nâ=â8); blue- VSD (nâ=â6).
<p>Red circle indicates AVSD, blue circle indicates ASD and VSD.</p
A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients
International audienceBackgroundIntellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Downâs syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials.ObjectiveWe developed a novel visual analogical reasoning paradigm, inspired by the Progressive Ravenâs Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients.MethodsWe performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2).ResultsDown syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups.ConclusionWe suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations
Classification of heart defects (CHD+) according to the distribution frequency of their p-values.
<p>Empirical cumulative distributions of p-values for the 2-by-2 Student tests A: AVSD/ASD; B: AVSD/VSD; C: ASD/VSD. Comparisons were obtained for 11 224 tests. The comparison to the uniform distribution shows that there is no overall differential expression between ASD and VSD (less small p-values than for an uniform distribution). Cdf: cumulative distribution function.</p
GO categories in the CDH<sup>+</sup> DE genes.
<p>Analysis of the enrichment of GO categories for the genes DE in the comparison between AVSD or ASD+VSD set of genes and CHD<sup>â</sup> set of genes compared to the genes expressed in LCLs. Analysis used GOrilla software with a p-value threshold at 10<sup>â3</sup>. N - is the total number of genes, B - is the total number of genes associated with a specific null, n - is the number of genes in the group with heart defect, b - is the number of genes in the intersection.</p
The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.
International audienceBACKGROUND: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. METHODS: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. RESULTS: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. CONCLUSION: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia