down syndrome
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2022 ◽  
Juliane Grimm ◽  
Raj Bhayadia ◽  
Lucie Gack ◽  
Dirk Heckl ◽  
Jan-Henning Klusmann

Children with Down syndrome (DS) are predisposed to developing megakaryoblastic leukemia (ML-DS) and often experience severe toxicities from chemotherapy, highlighting the need for targeted therapies with beneficial risk profiles. The genomic landscape of ML-DS is characterized by a combination of mutations in signaling pathway genes and epigenetic modifiers, while aberrant lysine specific demethylase 1 (LSD1) and JAK-STAT activation have both been implicated in leukemogenesis. Here, we demonstrate that combined LSD1 and JAK1/2 inhibition exerts synergistic anti-leukemic effects specifically in ML-DS, both in vitro and in patient derived xenografts in vivo. The JAK1/2 inhibitor ruxolitinib enhanced the LSD1 inhibitor-induced differentiation, proliferation arrest and apoptosis in patient-derived leukemic blasts. At the transcriptional level, the combination synergistically repressed gene expression signatures essential for cell division. We further observed an immunogenic gene expression pattern in the form of increased cytokine signaling, which - by sensitizing ML-DS blasts to the JAK-STAT signaling blockade induced by ruxolitinib - could explain the increased susceptibility of ML-DS blasts to combination therapy. Taken together, we establish combined LSD1 and JAK-STAT inhibition as an efficacious therapeutic regimen specifically designed to target important steps in ML-DS leukemogenesis, paving the way for targeted therapies in this entity.

2022 ◽  
Laura Esparcia-Pinedo ◽  
Ayla Yarci-Carrion ◽  
Gloria Mateo-Jimenez ◽  
Noelia Ropero ◽  
Laura Gomez-Cabanas ◽  

Immune dysregulation in individuals with Down syndrome (DS) leads to an increased risk for hospitalization and death due to COVID-19 and may impair the generation of protective immunity after vaccine administration. The cellular and humoral responses of 55 DS patients who received a complete SARS-CoV-2 vaccination regime at one to three (V1) and six (V2) months were characterised. SARS-CoV-2-reactive CD4+ and CD8+ T lymphocytes with a predominant Th1 phenotype were observed at V1, and increased at V2. Likewise, a sustained increase of SARS-CoV-2-specific circulating Tfh (cTfh) cells was observed one to three months after vaccine administration. Specific IgG antibodies against SARS-CoV-2 S protein were detected in 96% and 98% of subjects at V1 and V2, respectively, though IgG titers decreased significantly between both timepoints.

2022 ◽  
Vol 11 (1) ◽  
pp. e50011125342
Geiziane Leite Rodrigues Melo ◽  
Milton Rocha Moraes ◽  
Weldson Ferreira Abreu ◽  
Rafael Reis Olher ◽  
Lysleine Alves Deus ◽  

Este estudo teve como objetivo comparar as respostas cardiovasculares e de óxido nítrico (NO) à contração isométrica voluntária máxima (CIVM) com diferentes grupos musculares (leg press [LEP] e preensão manual isométrica [IHG]) de adolescentes com e sem síndrome de Down (SD). Alem de comparar a força IHG absoluta e relativa entre os grupos. Onze adolescentes com SD (14,1 ± 1,0 anos) e dez sem SD (13,7 ± 1,25 anos) realizaram duas sessões experimentais de exercícios LEP e IHG: 1) sessão de familiarização e 2) 3 tentativas x 5 segundos de contração na CIVM com 3- intervalo mínimo de descanso. A pressão arterial (PA), a frequência cardíaca (FC) e o NO foram coletados em repouso, imediatamente após a sessão de exercício e 10 minutos após o exercício. A dosagem de NO na saliva foi realizada pelo método colorimétrico de Griess. Não houve diferenças para respostas cardiovasculares e NO entre os grupos para CIVM. No entanto, o SD teve uma resposta cardiovascular menor, mas não significativamente, em repouso e após os testes de CIVM do que aqueles sem SD. O grupo SD apresentou maior concentração de NO em repouso, recuperação e após IHG quando comparado ao grupo não SD (P <0,05). Além disso, adolescentes com SD apresentaram menor nível de força de IHG absoluta e relativa quando comparados àqueles sem SD (P = 0,001). Indivíduos com SD apresentam menor resposta cardiovascular em repouso e após testes de CIVM e maior resposta de NO após o exercício quando comparados ao grupo sem SD.

2022 ◽  
Vol 14 (627) ◽  
Katharina Lambert ◽  
Keagan G. Moo ◽  
Azlann Arnett ◽  
Gautam Goel ◽  
Alex Hu ◽  

Permutational analysis of the immune system reveals advanced immune aging in individuals with Down syndrome and in individuals with type 1 diabetes.

2022 ◽  
Vol Publish Ahead of Print ◽  
Taylor Dreher ◽  
Kristine Wolter-Warmerdam ◽  
Samantha Holland ◽  
Terry Katz ◽  
Lina Patel

2022 ◽  
Vol 22 (1) ◽  
Savitree Pranpanus ◽  
Kanokkarn Keatkongkaew ◽  
Manaphat Suksai

Abstract Background To establish the reference ranges and evaluate the efficacy of the fetal facial sonomarkers prenasal thickness (PT), nasal bone length (NBL), PT/NBL ratio and NBL/PT ratio for Down syndrome screening in the second trimester of high-risk pregnancies using two-dimensional (2D) ultrasound. Methods A prospective study was done in Thai pregnant women at high risk for structural and chromosomal abnormalities between May 2018 and May 2019. The main exclusion criteria were any fetal anatomical anomaly detected on ultrasonography or postpartum examination, abnormal chromosome or syndrome other than Down syndrome. Ultrasounds were performed in 375 pregnant women at 14 to 22 weeks’ gestation and the fetal facial parameters were analyzed. Down syndrome results were confirmed by karyotyping. The reference ranges of these facial ultrasound markers were constructed based on the data of our population. The Down syndrome screening performance using these facial ultrasound markers was evaluated. Results In total, 340 euploid fetuses and 11 fetuses with Down syndrome met the inclusion criteria. The PT, NBL, and PT/NBL ratios in the euploid fetuses gradually increased with gestation progression while the NBL/PT ratio gradually decreased between 14–22 weeks’ gestation. The NBL, PT/NBL ratio, and NBL/PT ratio all had 100% sensitivity and PT had 91% sensitivity. These facial markers had 100% negative predictive value for Down syndrome screening in the second trimester. The Bland–Altman analysis showed the intra- and inter-observer variations of PT and NBL had high intraclass correlation coefficients (ICC) in both operators, with ICCs of 0.98 and 0.99 and inter-observer ICCs of 0.99 for both operators. Conclusion The facial ultrasound markers are very useful for second trimester Down syndrome screening in our population. These facial ultrasound markers were easily identifiable and highly consistent either intra- or inter-operator by using widely-available 2D ultrasound. However, the reference ranges for these markers need to be constructed based on individual populations. Trial registration Registration number: REC 61–029-12–3. Date of registration: 18 May 2018.

2022 ◽  
Vol 18 (1) ◽  
pp. 196-208
Luana Pereira de Novais Silva ◽  
Jhenifer Prescilla Dias Fuzinelli ◽  
Rosemary Aparecida de Almeida Moraes ◽  
Fabiana Frolini Marques Mangili

Faced with the theme of inclusion, discussions about the importance of the family-school relationship are relevant with regard to the socialization of children with Down Syndrome. In this perspective, the main objective of this essay was to explore the scientific literature about the challenges faced by parents, family and teachers in the process of inclusion of children with Down syndrome. Specifically, this article sought to propose discussions on the importance of community awareness and collaboration to change the paradigm of inclusion. Therefore, scientific articles, books and academic papers found in the Google Scholar database were selected, between the period 2011 to 2021, based on the following keywords: People with disabilities; Down's syndrome; Inclusion; History of people with disabilities; Diagnosis of a child with a disability and; Family-School Relationship. Among the main factors influencing the inclusion process of children with Down's Syndrome, beliefs and stigmas of parents, family members, school professionals and society about the child's ability to deal with other people and learn, stand out. family support and the lack of support/guidance from an interdisciplinary team. The inclusion of people with disabilities still faces barriers and challenges that need to be overcome, however, through the active participation of the scientific community and political-social movements, studies on the theme of inclusion show that changes in this scenario have occurred gradually.

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