33 results on '"Benarroch L"'
Search Results
2. P422 A robust and practical myogenic system to explore cellular and genomic features of muscle differentiation
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Benarroch, L., primary, Madsen-Østerbye, J., additional, Abdelhalim, M., additional, Mamchaoui, K., additional, Ohana, J., additional, Bigot, A., additional, Mouly, V., additional, Bertrand, A., additional, Collas, P., additional, and Bonne, G., additional
- Published
- 2023
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3. P.145 Identification of potential genetic modifiers underlying phenotypic variability in a French family with striated muscle laminopathies
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Benarroch, L., primary, Bertrand, A., additional, Beuvin, M., additional, Nelson, I., additional, Naouar, N., additional, Simonet, F., additional, Dina, C., additional, Pionneau, C., additional, Schott, J., additional, Yaou, R. Ben, additional, and Bonne, G., additional
- Published
- 2022
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4. 480P Comparative analysis of CRISPR/Cas9-targeted Nanopore long-read sequencing approaches in repeat expansion disorders.
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Bonne, G., Benarroch, L., Boëlle, P., Labrèche, K., Madry, H., Mohand-Oumoussa, B., Eura, N., Nishino, I., Gourdon, G., and Tomé, S.
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MICROSATELLITE repeats , *TRINUCLEOTIDE repeats , *NEUROMUSCULAR diseases , *CRISPRS , *NUCLEOTIDE sequencing , *SPINOCEREBELLAR ataxia - Abstract
Over the past 30 years, more than 50 repeat expansion disorders have been identified, thanks to the exponential development of genetic tools and next-generation sequencing technologies. Long-read sequencing has emerged as a new milestone in the diagnosis of these disorders. Despite these major achievements, the comprehensive characterization of short tandem repeats in a pathological context remains challenging, primarily due to their inherent characteristics such as motif complexity, high GC content, and variable length. In this study, we implemented CRISPR/Cas9-based enrichment strategy combined to Oxford Nanopore (ONT) long-read sequencing. Our aim was to thoroughly characterize trinucleotide repeat expansion in two neuromuscular diseases: oculopharyngodistal myopathy (OPDM) and myotonic dystrophy type 1 (DM1). We conducted precise analyses of the OPDM and DM1 loci, determining repeat size, repeat length distribution, and DNA methylation. We achieved this by distinguishing normal and expanded alleles, using three different basecallers (Guppy, Bonito and Dorado). Our observations revealed miscalling of CGG and CTG repeats, with errors highly dependent on library preparation protocols (ONT R.9.4 vs R10.4 chemistries) and the chosen basecalling strategy. Our findings highlight the importance of the choice of basecalling strategies for the true characterization of repeated regions. Given our results, we propose guidelines for the CRISPR/Cas9-enrichment long-read sequencing strategy for repeat expansion diseases, which could be readily applicable in research but also in diagnostic settings. [ABSTRACT FROM AUTHOR]
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- 2024
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5. A mutation in theLMOD1actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections
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Wan, Y.B.A., primary, Simpson, M.A., additional, Aragon-Martin, J.A., additional, Osborn, D.P.S., additional, Regalado, E., additional, Guo, D.C., additional, Boileau, C., additional, Jondeau, G., additional, Benarroch, L., additional, Isekame, Y., additional, Bharj, J., additional, Sneddon, J., additional, Fisher, E., additional, Dean, J., additional, Tome Esteban, M.T., additional, Saggar, A., additional, Milewicz, D., additional, Jahangiri, M., additional, Behr, E. R., additional, Smith, A., additional, and Child, A. H., additional
- Published
- 2017
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6. IMMUNOPATHOLOGY OF HUMAN SCHISTOSOMIASIS MANSONI. II. NK ACTIVITY AND STIMULATION BY SPECIFIC ANTIGEN.
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BENARROCH, L. K., NOYA, O., NOYA, B., BIANCO, N. E., and BLANCA, I.
- Published
- 1988
7. The 2024 version of the gene table of neuromuscular disorders (nuclear genome).
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Benarroch L, Bonne G, Rivier F, and Hamroun D
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- Humans, Neuromuscular Diseases genetics
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- 2024
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8. [CRIPSR-Cas9: A therapeutic strategy for laminopathies?]
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Benarroch L
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- Humans, Gene Editing, Lamin Type A genetics, CRISPR-Cas Systems, Laminopathies
- Published
- 2023
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9. Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts.
- Author
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Benarroch L, Madsen-Østerbye J, Abdelhalim M, Mamchaoui K, Ohana J, Bigot A, Mouly V, Bonne G, Bertrand AT, and Collas P
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- Humans, Adolescent, Cell Differentiation genetics, Myoblasts metabolism, Genomics, Muscle Fibers, Skeletal, Fibroblasts
- Abstract
The ability to recapitulate muscle differentiation in vitro enables the exploration of mechanisms underlying myogenesis and muscle diseases. However, obtaining myoblasts from patients with neuromuscular diseases or from healthy subjects poses ethical and procedural challenges that limit such investigations. An alternative consists in converting skin fibroblasts into myogenic cells by forcing the expression of the myogenic regulator MYOD. Here, we directly compared cellular phenotype, transcriptome, and nuclear lamina-associated domains (LADs) in myo-converted human fibroblasts and myotubes differentiated from myoblasts. We used isogenic cells from a 16-year-old donor, ruling out, for the first time to our knowledge, genetic factors as a source of variations between the two myogenic models. We show that myo-conversion of fibroblasts upregulates genes controlling myogenic pathways leading to multinucleated cells expressing muscle cell markers. However, myotubes are more advanced in myogenesis than myo-converted fibroblasts at the phenotypic and transcriptomic levels. While most LADs are shared between the two cell types, each also displays unique domains of lamin A/C interactions. Furthermore, myotube-specific LADs are more gene-rich and less heterochromatic than shared LADs or LADs unique to myo-converted fibroblasts, and they uniquely sequester developmental genes. Thus, myo-converted fibroblasts and myotubes retain cell type-specific features of radial and functional genome organization. Our results favor a view of myo-converted fibroblasts as a practical model to investigate the phenotypic and genomic properties of muscle cell differentiation in normal and pathological contexts, but also highlight current limitations in using fibroblasts as a source of myogenic cells.
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- 2023
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10. The 2023 version of the gene table of neuromuscular disorders (nuclear genome).
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Benarroch L, Bonne G, Rivier F, and Hamroun D
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- Humans, Chromosome Mapping, Cell Nucleus, Genome, Neuromuscular Diseases genetics
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- 2023
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11. [Looking for genetic modifying factors in cardiomyopathies].
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Benarroch L
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- Cardiac Myosins, Genetic Testing, Humans, Lamin Type A, Myosin Heavy Chains, Cardiomyopathies genetics
- Published
- 2021
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12. Preclinical Advances of Therapies for Laminopathies.
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Benarroch L, Cohen E, Atalaia A, Ben Yaou R, Bonne G, and Bertrand AT
- Abstract
Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.
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- 2021
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13. Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.
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Elbitar S, Renard M, Arnaud P, Hanna N, Jacob MP, Guo DC, Tsutsui K, Gross MS, Kessler K, Tosolini L, Dattilo V, Dupont S, Jonquet J, Langeois M, Benarroch L, Aubart M, Ghaleb Y, Abou Khalil Y, Varret M, El Khoury P, Ho-Tin-Noé B, Alembik Y, Gaertner S, Isidor B, Gouya L, Milleron O, Sekiguchi K, Milewicz D, De Backer J, Le Goff C, Michel JB, Jondeau G, Sakai LY, Boileau C, and Abifadel M
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- ADAM Proteins, Animals, Exome genetics, Fibrillin-1 genetics, Humans, Mice, Aortic Dissection genetics, Aortic Aneurysm, Thoracic genetics
- Abstract
Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD., Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models., Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4
+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix., Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.- Published
- 2021
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14. The 2021 version of the gene table of neuromuscular disorders (nuclear genome).
- Author
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Benarroch L, Bonne G, Rivier F, and Hamroun D
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- Chromosome Mapping, Genome, Humans, Neuromuscular Diseases classification, Neuromuscular Diseases genetics
- Published
- 2020
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15. Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability.
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Grange T, Aubart M, Langeois M, Benarroch L, Arnaud P, Milleron O, Eliahou L, Gross MS, Hanna N, Boileau C, Gouya L, and Jondeau G
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- Adolescent, Adult, Aged, Aged, 80 and over, Aorta metabolism, Aorta pathology, Ectopia Lentis physiopathology, Female, Genotype, Humans, Male, Marfan Syndrome physiopathology, Microfilament Proteins genetics, Middle Aged, Mutation genetics, Phenotype, Young Adult, Ectopia Lentis genetics, Fibrillin-1 genetics, Fibrillins genetics, Marfan Syndrome genetics
- Abstract
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the "Carter effect" in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.
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- 2020
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16. Lamin A/C Assembly Defects in LMNA -Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy.
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Bertrand AT, Brull A, Azibani F, Benarroch L, Chikhaoui K, Stewart CL, Medalia O, Ben Yaou R, and Bonne G
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- Animals, Cells, Cultured, Computer Simulation, Databases, Genetic, Disease Models, Animal, Humans, Lamin Type A genetics, Mice, Muscle Fibers, Skeletal metabolism, Muscular Dystrophies genetics, Muscular Dystrophy, Emery-Dreifuss genetics, Mutation genetics, Myoblasts metabolism, Phenotype, Lamin Type A deficiency, Lamin Type A metabolism, Muscular Dystrophies pathology, Muscular Dystrophy, Emery-Dreifuss pathology, Severity of Illness Index
- Abstract
LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery-Dreifuss (EDMD) and LMNA -related congenital muscular dystrophies (L-CMD) without clear genotype-phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD- LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.
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- 2020
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17. The 2020 version of the gene table of neuromuscular disorders (nuclear genome).
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Benarroch L, Bonne G, Rivier F, and Hamroun D
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- Humans, Mutation, Neuromuscular Diseases classification, Neuromuscular Diseases genetics
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- 2019
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18. Core-Shell Polymer-Based Nanoparticles Deliver miR-155-5p to Endothelial Cells.
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Antunes JC, Benarroch L, Moraes FC, Juenet M, Gross MS, Aubart M, Boileau C, Caligiuri G, Nicoletti A, Ollivier V, Chaubet F, Letourneur D, and Chauvierre C
- Abstract
Heart failure occurs in over 30% of the worldwide population and most commonly originates from cardiovascular diseases such as myocardial infarction. microRNAs (miRNAs) target and silence specific mRNAs, thereby regulating gene expression. Because the endogenous miR-155-5p has been ascribed to vasculoprotection, loading it onto positively charged, core-shell poly(isobutylcyanoacrylate) (PIBCA)-polysaccharide nanoparticles (NPs) was attempted. NPs showed a decrease (p < 0.0001) in surface electrical charge (ζ potential), with negligible changes in size or shape when loaded with the anionic miR-155-5p. Presence of miR-155-5p in loaded NPs was further quantified. Cytocompatibility up to 100 μg/mL of NPs for 2 days with human coronary artery endothelial cells (hCAECs) was documented. NPs were able to enter hCAECs and were localized in the endoplasmic reticulum (ER). Expression of miR-155-5p was increased within the cells by 75-fold after 4 hours of incubation (p < 0.05) and was still noticeable at day 2. Differences between loaded NP-cultured cells and free miRNA, at days 1 (p < 0.05) and 2 (p < 0.001) suggest the ability of prolonged load release in physiological conditions. Expression of miR-155-5p downstream target BACH1 was decreased in the cells by 4-fold after 1 day of incubation (p < 0.05). This study is a first proof of concept that miR-155-5p can be loaded onto NPs and remain intact and biologically active in endothelial cells (ECs). These nanosystems could potentially increase an endogenous cytoprotective response and decrease damage within infarcted hearts., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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19. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD).
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Arnaud P, Hanna N, Benarroch L, Aubart M, Bal L, Bouvagnet P, Busa T, Dulac Y, Dupuis-Girod S, Edouard T, Faivre L, Gouya L, Lacombe D, Langeois M, Leheup B, Milleron O, Naudion S, Odent S, Tchitchinadze M, Ropers J, Jondeau G, and Boileau C
- Subjects
- Adolescent, Adult, Aged, Aortic Dissection diagnosis, Aortic Dissection physiopathology, Aortic Aneurysm, Thoracic diagnosis, Child, Codon, Nonsense genetics, Female, Genetic Predisposition to Disease, Genetic Testing methods, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Pathology, Molecular methods, Pedigree, Young Adult, Aortic Dissection genetics, Aortic Aneurysm, Thoracic genetics, Fibrillin-1 genetics, Smad3 Protein genetics
- Abstract
Purpose: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD., Methods: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed., Results: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant., Conclusion: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.
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- 2019
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20. Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome.
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Benarroch L, Aubart M, Gross MS, Arnaud P, Hanna N, Jondeau G, and Boileau C
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- Cells, Cultured, Fibrillin-1 metabolism, Fibroblasts metabolism, Humans, Marfan Syndrome metabolism, Marfan Syndrome pathology, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Alternative Splicing, Fibrillin-1 genetics, Marfan Syndrome genetics, Phenotype
- Abstract
Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001 , FBN1_004 , and FBN1_009 . The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
- Published
- 2019
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21. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability.
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Aubart M, Gazal S, Arnaud P, Benarroch L, Gross MS, Buratti J, Boland A, Meyer V, Zouali H, Hanna N, Milleron O, Stheneur C, Bourgeron T, Desguerre I, Jacob MP, Gouya L, Génin E, Deleuze JF, Jondeau G, and Boileau C
- Subjects
- Adolescent, Adult, Aged, Cells, Cultured, Collagen Type IV genetics, Female, Fibrillin-1 genetics, Fibroblasts metabolism, Genetic Linkage, Humans, Male, Marfan Syndrome pathology, Middle Aged, Mutation, Quantitative Trait Loci, Genes, Modifier, Marfan Syndrome genetics, Multifactorial Inheritance, Phenotype
- Abstract
Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.
- Published
- 2018
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22. Effects of acute olanzapine exposure on central insulin-mediated regulation of whole body fuel selection and feeding.
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Castellani LN, Wilkin J, Abela AR, Benarroch L, Ahasan Z, Teo C, Wilson V, Kowalchuk C, Giacca A, Remington GJ, and Hahn MK
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- Animals, Antipsychotic Agents pharmacology, Exhalation drug effects, Glucose metabolism, Hypothalamus drug effects, Insulin, Insulin Resistance physiology, Male, Olanzapine metabolism, Rats, Rats, Sprague-Dawley, Eating drug effects, Lipid Metabolism drug effects, Olanzapine pharmacology
- Abstract
The use of antipsychotics is associated with severe disruptions in whole body glucose and lipid metabolism which may in part occur through the central nervous system and impaired insulin action at the brain. Here we investigated whether olanzapine treatment might also affect the ability of central insulin treatment to regulate food intake and fuel preference in the light and dark cycle. Male Sprague-Dawley rats were treated with olanzapine (or vehicle solution; 3 mg/kg, subcutaneous) and a simultaneous acute intracerebral ventricular (ICV) infusion of insulin (or vehicle; 3 μL at 10mU; ICV) at the beginning of the 12-h light and dark cycles. Olanzapine treatment reduced RER in the dark and light phases (most consistently in the 4-hours post-treatment), while ICV insulin reduced average RER predominantly in the dark phase, but also at the end of the light cycle. The RER lowering effect of ICV-insulin during the light cycle was absent in the group co-administered olanzapine. The reduction in RER during the dark phase was mirrored by decreased food intake with ICV insulin, but not olanzapine treated rats. The reduction in food intake by ICV-insulin was abolished in rats co-administered olanzapine suggesting rapid induction of central insulin resistance. A combination of ICV-insulin and olanzapine similarly reduced RER in the dark phase, independent of changes in food intake. Olanzapine treatment, alone or in combination with ICV-insulin, significantly reduced VCO
2 at regular intervals in the dark phase (specifically 3 h post-treatment), while VO2 was not significantly altered by either treatment. Finally, heat production was increased by olanzapine treatment in the light phase, though this effect was not consistent. The findings confirm that acute olanzapine treatment directly reduces RER and suggest that treatment with this drug may also override central insulin-mediated reductions in food intake at the hypothalamus (while still independently favoring fatty acid oxidation). Acute central insulin similarly reduces RER, but in contrast to olanzapine, this may represent a physiologically appropriate response to reduction in food intake., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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23. Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression.
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Benarroch L, Aubart M, Gross MS, Jacob MP, Arnaud P, Hanna N, Jondeau G, and Boileau C
- Abstract
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 ( FBN1 ) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1 . We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.
- Published
- 2018
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24. Atypical antipsychotics and effects on feeding: from mice to men.
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Benarroch L, Kowalchuk C, Wilson V, Teo C, Guenette M, Chintoh A, Nesarajah Y, Taylor V, Selby P, Fletcher P, Remington GJ, and Hahn MK
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- Animals, Appetite drug effects, Eating drug effects, Humans, Mice, Sex Factors, Antipsychotic Agents pharmacology, Feeding Behavior drug effects, Weight Gain drug effects
- Abstract
Rationale: So-called atypical antipsychotics (AAPs) are associated with varying levels of weight gain and associated metabolic disturbances, which in patients with serious mental illness (SMI) have been linked to non-compliance and poor functional outcomes. Mechanisms underlying AAP-induced metabolic abnormalities are only partially understood. Antipsychotic-induced weight gain may occur as a result of increases in food intake and/or changes in feeding., Objective: In this review, we examine the available human and preclinical literature addressing AAP-related changes in feeding behavior, to determine whether changes in appetite and perturbations in regulation of food intake could be contributing factors to antipsychotic-induced weight gain., Results: In general, human studies point to disruption by AAPs of feeding behaviors and food consumption. In rodents, increases in cumulative food intake are mainly observed in females; however, changes in feeding microstructure or motivational aspects of food intake appear to occur independent of sex., Conclusions: The findings from this review indicate that the varying levels of AAP-related weight gain reflect changes in both appetite and feeding behaviors, which differ by type of AAP. However, inconsistencies exist among the studies (both human and rodent) that may reflect considerable differences in study design and methodology. Future studies examining underlying mechanisms of antipsychotic-induced weight gain are recommended in order to develop strategies addressing the serious metabolic side effect of AAPs.
- Published
- 2016
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25. Quantitative levels of Deficiens and Globosa during late petal development show a complex transcriptional network topology of B function.
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Manchado-Rojo M, Delgado-Benarroch L, Roca MJ, Weiss J, and Egea-Cortines M
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- Acyclic Monoterpenes, Alkenes analysis, Alkenes metabolism, Antirrhinum anatomy & histology, Antirrhinum growth & development, Antirrhinum metabolism, Benzoates analysis, Benzoates metabolism, DEFICIENS Protein genetics, DEFICIENS Protein metabolism, Flowers growth & development, Flowers metabolism, Gene Expression, Gene Expression Regulation, Plant genetics, Gene Regulatory Networks, Genotype, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Models, Biological, Monoterpenes analysis, Monoterpenes metabolism, Mutation, Oils, Volatile analysis, Phenotype, Plant Leaves anatomy & histology, Plant Leaves genetics, Plant Leaves growth & development, Plant Leaves metabolism, Plant Proteins metabolism, Plants, Genetically Modified, RNA Interference, Antirrhinum genetics, Flowers genetics, Gene Expression Regulation, Developmental genetics, Oils, Volatile metabolism, Plant Proteins genetics
- Abstract
The transcriptional network topology of B function in Antirrhinum, required for petal and stamen development, is thought to rely on initial activation of transcription of DEFICIENS (DEF) and GLOBOSA (GLO), followed by a positive autoregulatory loop maintaining gene expression levels. Here, we show that the mutant compacta (co), whose vegetative growth and petal size are affected, plays a role in B function. Late events in petal morphogenesis such as development of conical cell area and scent emissions were reduced in co and def (nicotianoides) (def (nic) ), and absent in co def (nic) double mutants, suggesting a role for CO in petal identity. Expression of DEF was down-regulated in co but surprisingly GLO was not affected. We investigated the levels of DEF and GLO at late stages of petal development in the co, def (nic) and glo-1 mutants, and established a reliable transformation protocol that yielded RNAi-DEF lines. We show that the threshold levels of DEF or GLO required to obtain petal tissue are approximately 11% of wild-type. The relationship between DEF and GLO transcripts is not equal or constant and changes during development. Furthermore, down-regulation of DEF or GLO does not cause parallel down-regulation of the partner. Our results demonstrate that, at late stages of petal development, the B function transcriptional network topology is not based on positive autoregulation, and has additional components of transcriptional maintenance. Our results suggest changes in network topology that may allow changes in protein complexes that would explain the fact that not all petal traits appear early in development., (© 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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26. A molecular recombination map of Antirrhinum majus.
- Author
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Schwarz-Sommer Z, Gübitz T, Weiss J, Gómez-di-Marco P, Delgado-Benarroch L, Hudson A, and Egea-Cortines M
- Subjects
- Crosses, Genetic, DNA Transposable Elements genetics, Expressed Sequence Tags, Genetic Markers genetics, Mutation, Phenotype, Antirrhinum genetics, Chromosome Mapping methods, Chromosomes, Plant genetics, Recombination, Genetic
- Abstract
Background: Genetic recombination maps provide important frameworks for comparative genomics, identifying gene functions, assembling genome sequences and for breeding. The molecular recombination map currently available for the model eudicot Antirrhinum majus is the result of a cross with Antirrhinum molle, limiting its usefulness within A. majus., Results: We created a molecular linkage map of A. majus based on segregation of markers in the F2 population of two inbred lab strains of A. majus. The resulting map consisted of over 300 markers in eight linkage groups, which could be aligned with a classical recombination map and the A. majus karyotype. The distribution of recombination frequencies and distorted transmission of parental alleles differed from those of a previous inter-species hybrid. The differences varied in magnitude and direction between chromosomes, suggesting that they had multiple causes. The map, which covered an estimated of 95% of the genome with an average interval of 2 cM, was used to analyze the distribution of a newly discovered family of MITE transposons and tested for its utility in positioning seven mutations that affect aspects of plant size., Conclusions: The current map has an estimated interval of 1.28 Mb between markers. It shows a lower level of transmission ratio distortion and a longer length than the previous inter-species map, making it potentially more useful. The molecular recombination map further indicates that the IDLE MITE transposons are distributed throughout the genome and are relatively stable. The map proved effective in mapping classical morphological mutations of A. majus.
- Published
- 2010
- Full Text
- View/download PDF
27. The mutants compacta ähnlich, Nitida and Grandiflora define developmental compartments and a compensation mechanism in floral development in Antirrhinum majus.
- Author
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Delgado-Benarroch L, Weiss J, and Egea-Cortines M
- Subjects
- Antirrhinum cytology, Antirrhinum ultrastructure, Cell Division, Cell Proliferation, Cell Size, DNA, Plant metabolism, Flow Cytometry, Flowers cytology, Flowers ultrastructure, Phenotype, Reproduction, Antirrhinum genetics, Antirrhinum growth & development, Flowers genetics, Flowers growth & development, Mutation genetics
- Abstract
In order to improve our understanding of floral size control we characterised three mutants of Antirrhinum majus with different macroscopic floral phenotypes. The recessive mutant compacta ähnlich has smaller flowers affected mainly in petal lobe expansion, the dominant mutant Grandiflora has overall larger organs, whilst the semidominant mutation Nitida exhibits smaller flowers in a dose-dependent manner. We developed a cell map in order to establish the cellular phenotypes of the mutants. Changes in organ size were both organ- and region-specific. Nitida and compacta ähnlich affected cell expansion in proximal and distal petal regions, respectively, suggesting differential regulation between petal lobe regions. Although petal size was smaller in compacta ähnlich than in wild type, conical cells were significantly bigger, suggesting a compensation mechanism involved in petal development. Grandiflora had larger cells in petals and increased cell division in stamens and styles, suggesting a relationship between genes controlling organ size and organ identity. The level of ploidy in petals of Grandiflora and coan was found to be equivalent to wild type petals and leaves, ruling out an excess of growth via endoreduplication. We discuss our results in terms of current models about control of lateral organ size.
- Published
- 2009
- Full Text
- View/download PDF
28. Floral organ size control: interplay between organ identity, developmental compartments and compensation mechanisms.
- Author
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Delgado-Benarroch L, Weiss J, and Egea-Cortines M
- Subjects
- Cell Proliferation, Flowers cytology, Flowers ultrastructure, Organ Size, Cell Division, Flowers anatomy & histology, Flowers growth & development
- Abstract
Growth of lateral organs is a complex mechanism that starts with formation of lateral primordia. Basal developmental programs like polarity, organ identity and environmental cues influence the final organ size achieved via coordinated cell division and expansion. Recent evidence shows that the precise balance between these two processes, known as compensation mechanisms, seems to be influenced by the identity of the organ. Furthermore, studies of mutants affected in floral organ size suggest the existence of developmental compartments within different floral whorls that show distinct compensation behaviors.
- Published
- 2009
- Full Text
- View/download PDF
29. FORMOSA controls cell division and expansion during floral development in Antirrhinum majus.
- Author
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Delgado-Benarroch L, Causier B, Weiss J, and Egea-Cortines M
- Subjects
- Amino Acid Sequence, Antirrhinum cytology, Antirrhinum growth & development, Cell Cycle, Cell Division, Cell Size, Cyclin D, Cyclins genetics, Flowers cytology, Flowers ultrastructure, Gene Expression Regulation, Developmental, Gene Expression Regulation, Plant, In Situ Hybridization, Microscopy, Electron, Scanning, Molecular Sequence Data, Phylogeny, Plant Proteins classification, Plant Proteins physiology, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Antirrhinum genetics, Flowers genetics, Plant Proteins genetics
- Abstract
Control of organ size is the product of coordinated cell division and expansion. In plants where one of these pathways is perturbed, organ size is often unaffected as compensation mechanisms are brought into play. The number of founder cells in organ primordia, dividing cells, and the period of cell proliferation determine cell number in lateral organs. We have identified the Antirrhinum FORMOSA (FO) gene as a specific regulator of floral size. Analysis of cell size and number in the fo mutant, which has increased flower size, indicates that FO is an organ-specific inhibitor of cell division and activator of cell expansion. Increased cell number in fo floral organs correlated with upregulation of genes involved in the cell cycle. In Arabidopsis the AINTEGUMENTA (ANT) gene promotes cell division. In the fo mutant increased cell number also correlates with upregulation of an Antirrhinum ANT-like gene (Am-ANT) in inflorescences that is very closely related to ANT and shares a similar expression pattern, suggesting that they may be functional equivalents. Increased cell proliferation is thought to be compensated for by reduced cell expansion to maintain organ size. In Arabidopsis petal cell expansion is inhibited by the BIGPETAL (BPE) gene, and in the fo mutant reduced cell size corresponded to upregulation of an Antirrhinum BPE-like gene (Am-BPE). Our data suggest that FO inhibits cell proliferation by negatively regulating Am-ANT, and acts upstream of Am-BPE to coordinate floral organ size. This demonstrates that organ size is modulated by the organ-specific control of both general and local gene networks.
- Published
- 2009
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30. Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry.
- Author
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Leiva LE, Zelazco M, Oleastro M, Carneiro-Sampaio M, Condino-Neto A, Costa-Carvalho BT, Grumach AS, Quezada A, Patiño P, Franco JL, Porras O, Rodríguez FJ, Espinosa-Rosales FJ, Espinosa-Padilla SE, Almillategui D, Martínez C, Tafur JR, Valentín M, Benarroch L, Barroso R, and Sorensen RU
- Subjects
- Birth Rate, Data Collection, Demography, Female, Humans, Immunologic Deficiency Syndromes classification, Immunologic Deficiency Syndromes immunology, Latin America epidemiology, Male, Phenotype, Prevalence, Surveys and Questionnaires, Immunologic Deficiency Syndromes epidemiology, Registries
- Abstract
This is the second report on the continuing efforts of LAGID to increase the recognition and registration of patients with primary immunodeficiency diseases in 12 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Honduras, Mexico, Panama, Paraguay, Peru, Uruguay, and Venezuela. This report reveals that from a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%) with IgA deficiency reported as the most frequent phenotype. This category was followed by 22.6% other well-defined ID syndromes, 9.5% combined T- and B-cell inmunodeficiency, 8.6% phagocytic disorders, 3.3% diseases of immune dysregulation, and 2.8% complement deficiencies. All countries that participated in the first publication in 1998 reported an increase in registered primary immunodeficiency cases, ranging between 10 and 80%. A comparison of the estimated minimal incidence of X-linked agammaglobulinemia, chronic granulomatous disease, and severe combined immunodeficiency between the first report and the present one shows an increase in the reporting of these diseases in all countries. In this report, the estimated minimal incidence of chronic granulomatous disease was between 0.72 and 1.26 cases per 100,000 births in Argentina, Chile, Costa Rica, and Uruguay and the incidence of severe combined immunodeficiency was 1.28 and 3.79 per 100,000 births in Chile and Costa Rica, respectively. However, these diseases are underreported in other participating countries. In addition to a better diagnosis of primary immunodeficiency diseases, more work on improving the registration of patients by each participating country and by countries that have not yet joined LAGID is still needed.
- Published
- 2007
- Full Text
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31. Genetic control of floral size and proportions.
- Author
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Weiss J, Delgado-Benarroch L, and Egea-Cortines M
- Subjects
- Arabidopsis growth & development, Arabidopsis physiology, Biological Evolution, Body Patterning genetics, Cell Division genetics, Cell Size, Ecosystem, Flowers anatomy & histology, Gene Expression Regulation, Plant, Genes, Homeobox, Genes, Plant, Indoleacetic Acids metabolism, Models, Biological, Reproduction, Arabidopsis anatomy & histology, Arabidopsis genetics
- Abstract
Floral size is an ecologically important trait related to pollination success and genetic fitness. Independently of the sexual reproduction strategy, in many plants, floral size seems to be controlled by several genetic programs that are to some extent independent of vegetative growth. Flower size seems to be governed by at least two independent mechanisms, one controlling floral architecture that affects organ number and a second one controlling floral organ size. Different organ-dependent growth control may account for the final proportions of a flower as a whole. Genes controlling floral organ identity, floral symmetry and organ polarity as well as auxin and gibberellin response, also play a role in establishing the final size and architecture of the flower. The final size of an organ seems to be controlled by a systemic signal that might in some cases overcome transgenic modifications of cell division and expansion. Nevertheless, modification of basic processes like cell wall deposition might produce important changes in the floral organs. The coordination of the direction of cell division and expansion by unknown mechanisms poses a challenge for future research.
- Published
- 2005
- Full Text
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32. [Family education, a model for allergy prevention].
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Perdomo-Ponce D, Benarroch L, González-Cerrutti R, Barroso R, Carneiro F, and Meijomil P
- Subjects
- Asthma prevention & control, Bronchial Hyperreactivity prevention & control, Dermatitis, Atopic prevention & control, Food Hypersensitivity prevention & control, Humans, Infant, Newborn, Patient Compliance, Rhinitis prevention & control, Venezuela, Family Health, Health Education, Hypersensitivity prevention & control
- Abstract
It is frequent the lack of family adherence toward the therapeutic measures of the allergic diseases. The incidence in the therapeutic non compliance of the asthmatic patients vary from 20 to 80%. In the last decades, the symptomatic expression of the atopic diseases (AD) in the infancy, and in the adolescence of Venezuelans has been transformed into a health care problem, with an inaccessible therapeutic cost for the state and the family. The setup of the first allergic prevention program improved attitudes and perceptions toward bronchial asthma, allergic rhinitis, and atopic dermatitis, by the education of the risk family group, based on the results from previous investigations and adapted to the procedures and customs that govern our current society. A research project, through a multi-disciplinary group included an educational program model for the prevention of allergic diseases in a population from Caracas, Venezuelan allergic pregnant mothers, and their respective couples of a high and middle socioeconomic levels with no helminthic infections (n = 482), group A. Two subgroups were randomly selected for prospective evaluation: A1 (n = 20) without participation in the preventive program or control group, and A2 (n = 15) with participation in the program or intervened group, including strategies to be applied by the family, application of measures and reached goals; immunologic, pediatric, and nutritional sequential control; group B (n = 66), to validate the laboratory tests, and group C (n = 364) to validate immunoclinical diagnoses, in vivo immunodiagnostic tests to the parents and children (clinical history, skin prick tests for cow's milk, egg white, wheat, soybean, cladosporium and Dermatophagoides pteronnysinus), and in vitro tests (total serum IgE, Phadiatop, and Rast to the allergens previously selected). In conclusion, the program permits the identification of atopic risk children, sponsors the systematical application of intervention measures, economic, viable and projected toward the family affected, indicating a positive change through a self-family-management training and new conduct plans, facilitating the participation among the family, the community and the health team, that certifies, an optimistic therapy in the reduction of the clinical manifestations of the atopic diseases in young infants from this tropical population studied.
- Published
- 1996
33. The influence of environment and parasitism on the prevalence of asthma in two Venezuelan regions.
- Author
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Perdomo de Ponce D, Benarroch L, Aldrey O, Rodríguez D, Rosales A, Avila E, and Bianco N
- Subjects
- Asthma immunology, Asthma parasitology, Humans, Prevalence, Rural Population, Tropical Climate, Urban Population, Venezuela epidemiology, Asthma epidemiology, Helminthiasis complications
- Abstract
The point prevalence of bronchial asthma and the influence of environmental conditions among 100 individuals chosen from two Venezuelan regions, i.e., rural and urban, were investigated by history, routine laboratory tests, determination of total and specific IgE antibody to common allergens and spirometric tests. The point prevalence of bronchial asthma was 3.0% in rural subjects who were also highly parasitized by helminths and 3.6% in subjects from the urban region. A significative difference in skin responses to Dermatophagoides pteronnysinus was observed in urban asthmatics when compared with rural asthmatics. A similar response to selected allergens was found among both populations. The prevalence of infestation by Ascaris in rural asthmatics was high compared with that of rural controls. Total IgE levels were elevated for both populations, but significatively higher (p less than 0.05) for rural individuals. Results suggest a significative point prevalence of bronchial asthma in both regions, despite the helminth infestation of rural subjects. The effects of environmental factors, their concentration and time of exposure are considered as main factors responsible for allergic reactivity observed in the Venezuelan regions studied.
- Published
- 1991
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