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Aging - Envejecimiento

TÍTULO / TITLE:   - Characterization of monomeric and soluble aggregated Aβ in Downs syndrome and Alzheimer s disease brains

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REVISTA / JOURNAL:    - Neurosci Lett. 2021 May 29;754:135894. doi: 10.1016/j.neulet.2021.135894. Epub 2021 Apr 10. Free art

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AUTORES / AUTHORS: - Eleni Gkanatsiou et al.

INSTITUCIÓN / INSTITUTION: - Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden 

RESUMEN / SUMMARY: - The major characteristics of Alzheimers disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Downs syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IPd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IPd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides

TÍTULO / TITLE:   - Regulator of calcineurin 1 is a novel RNA-binding protein to regulate neuronal apoptosis

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REVISTA / JOURNAL:    - Mol Psychiatry.2021 Apr;26(4):1361-1375. doi: 10.1038/s41380-019-0487-0.Epub 2019 Aug 27.

Enlace a la Editora de la Revista https://doi.org/10.1038/s41380-019-0487-0

AUTORES / AUTHORS: - Yan Yun et al.

INSTITUCIÓN / INSTITUTION: - Department of Neurology, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, 250012, Jinan, Shandong Province, China. 

RESUMEN / SUMMARY: - Posttranscriptional regulation of gene expression plays an important role in the maturation, transport, stability and translation of coding and noncoding RNAs. RNA-binding protein (RBP) is a key factor of the regulation. Regulator of calcineurin 1 (RCAN1) is a multifunctional protein involved in neurodegeneration, mitochondrial dysfunction, inflammation and protein glycosylation, and plays an important role in the pathogenesis of Down syndrome and Alzheimers disease. In this report, we discovered that RCNA1 is a novel RNA-binding protein. A 23 nucleotide sequence of adenine nucleotide translocator (ANT1) mRNA was identified as the binding motif of RCAN1. Furthermore, we found that R1SR13, as the RNA aptamer of RCAN1 identified by SELEX, blocked RCAN1-induced inhibition of the nuclear factor of activated T cells (NFAT) and NF-κB signaling pathways, and reduced neuronal apoptosis. Taken together, our results demonstrate that RCAN1 is a novel RNA-binding protein and the RNA aptamer of RCAN1 plays a neuroprotective role.

TÍTULO / TITLE:   - The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation

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REVISTA / JOURNAL:    - J Alzheimers Dis.2021;81(4):1505-1527. doi: 10.3233/JAD-201427.

Enlace a la Editora de la Revista https://doi.org/10.3233/jad-201427

AUTORES / AUTHORS: - Alain D Dekker et al.

INSTITUCIÓN / INSTITUTION: - Department of Neurology and Alzheimer Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 

RESUMEN / SUMMARY: - Background: People with Down syndrome (DS) are at high risk to develop Alzheimers disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. Objective: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. Methods: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).Results: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. Conclusion: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.

TÍTULO / TITLE:   - The Association between Physical Activity and CAMDEX-DS Changes Prior to the Onset of Alzheimers Disease in Down Syndrome

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REVISTA / JOURNAL:    - J Clin Med. 2021 Apr 27;10(9):1882. doi: 10.3390/jcm10091882. DOI:10.3390/jcm10091882 Free PMC art

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AUTORES / AUTHORS: - Sarah E Pape et al

INSTITUCIÓN / INSTITUTION: - Institute of Psychiatry, Psychology, and Neuroscience, Kings College London, London SE5 8AF, UK 

RESUMEN / SUMMARY: - Abstract. Background:People with Down syndrome are at ultra-high risk of developing Alzheimer s dementia. At present, there are no preventative or curative treatments. Evidence from sporadic Alzheimer s disease literature suggests that lifestyle factors including physical activity may help maintain cognitive and functional skills and reduce dementia risk. Our study aimed to explore the association between regular exercise undertaken by participants with Down syndrome and changes in dementia-related domains of cognition and function. This was to consider whether physical activity may be a protective measure to delay cognitive decline and dementia in Down syndrome. Methods:�Demographic, lifestyle, and health information was collected at baseline and at a two year follow up from 214 adults with Down syndrome without dementia, who also underwent assessment using the Cambridge Examination for Mental Disorders of Older People with Down Syndrome and Others with Intellectual Disabilities (CAMDEX-DS) and genetic analysis. Logistic regression models were used to examine the potential associations between decline in CAMDEX-DS domains and exercise whilst controlling for key variables. Results:At baseline, engaging in moderate intensity exercise was associated with a 47% reduced risk of everyday skills decline and engaging in high intensity exercise was associated with a 62% reduced risk of decline in personality and behaviour. At follow-up, high levels of exercise were associated with an 87% reduced risk of decline in personality and behaviour. Moderate intensity exercise at baseline was associated with a 62% reduction in risk of decline during the follow-up period in memory and orientation. Discussion:Based on our data it appears that regular moderate and high intensity exercise could reduce the risk of clinically detectable decline in a Down syndrome population with possible long-term benefits. People with Down syndrome may engage in less physical activity than their peers

TÍTULO / TITLE:   - Cross-Sectional Exploration of Plasma Biomarkers of Alzheimers Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study

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REVISTA / JOURNAL:    - J Clin Med. 2021 Apr 28;10(9):1907. doi: 10.3390/jcm10091907. DOI:�10.3390/jcm10091907. Free PMC ar

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AUTORES / AUTHORS: - James A Hendrix et al

INSTITUCIÓN / INSTITUTION: - LuMind IDSC, 20 Mall Road, Suite 200, Burlington, MA 01803-4126, USA.  

RESUMEN / SUMMARY: - With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimers disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

TÍTULO / TITLE:   - PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimers disease progression in Down syndrome

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REVISTA / JOURNAL:    - Neuroimage.2021 Mar;228:117728.doi: 10.1016/j.neuroimage.2021.117728.Epub 2021 Jan 7. DOI:10.10

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AUTORES / AUTHORS: - Matthew D Zammit et al.

INSTITUCIÓN / INSTITUTION: - University of Wisconsin-Madison, Waisman Center, 1500 Highland Avenue, Madison, WI 53705, United States.  

RESUMEN / SUMMARY: - Introduction: Adults with Down syndrome (DS) are predisposed to Alzheimer´s disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. Methods: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aβ burden was quantified using the amyloid load metric (AβL). Modeled PiB images were generated from the longitudinal AβL data to visualize which regions are most susceptible to Aβ accumulation in DS. AβL change was evaluated across Aβ(-), Aβ-converter, and Aβ(+) groups to assess longitudinal Aβ trajectories during different stages of AD-pathology progression. AβL change values were used to identify Aβ-accumulators within the Aβ(-) group prior to reaching the Aβ(+) threshold (previously reported as 20 AβL) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(-) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status. Results: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aβ accumulation in DS. The Aβ(-) group had a mean AβL change of 0.38 (0.58) AβL/year, while the Aβ-converter and Aβ(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AβL/year, respectively. Within the A&#

TÍTULO / TITLE:   - The reliability and validity of DSM 5 diagnostic criteria for neurocognitive disorder and relationship with plasma neurofilament light in a down syndrome population

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REVISTA / JOURNAL:    - Sci Rep. 2021 Jun 29;11(1):13438. doi: 10.1038/s41598-021-92887-5.Free PMC article

Enlace a la Editora de la Revista https://doi.org/10.1038/s41598-021-92887-5

AUTORES / AUTHORS: - Sarah E Pape et al

INSTITUCIÓN / INSTITUTION: - Institute of Psychiatry, Psychology, and Neuroscience, Kings College London, London, UK. 

RESUMEN / SUMMARY: - The validity of dementia diagnostic criteria depends on their ability to distinguish dementia symptoms from pre-existing cognitive impairments. The study aimed to assess inter-rater reliability and concurrent validity of DSM-5 criteria for neurocognitive disorder in Down syndrome. The utility of mild neurocognitive disorder as a distinct diagnostic category, and the association between clinical symptoms and neurodegenerative changes represented by the plasma biomarker neurofilament light were also examined. 165 adults with Down syndrome were included. Two clinicians independently applied clinical judgement, DSM-IV, ICD-10 and DSM-5 criteria for dementia (or neurocognitive disorder) to each case. Inter-rater reliability and concurrent validity were analysed using the kappa statistic. Plasma neurofilament light concentrations were measured for 55 participants as a marker of neurodegeneration and between group comparisons calculated. All diagnostic criteria showed good inter-rater reliability apart from mild neurocognitive disorder which was moderate (k = 0.494). DSM- 5 criteria had substantial concurrence with clinical judgement (k = 0.855). When compared to the no neurocognitive disorder group, average neurofilament light concentrations were higher in both the mild and major neurocognitive disorder groups. DSM-5 neurocognitive disorder criteria can be used reliably in a Down syndrome population and has higher concurrence with clinical judgement than the older DSM-IV and ICD-10 criteria. Whilst the inter-rater reliability of the mild neurocognitive disorder criteria was modest, it does appear to identify people in an early stage of dementia with underlying neurodegenerative changes, represented by higher average NfL levels.

TÍTULO / TITLE:   - A multicentre validation study of the diagnostic value of plasma neurofilament light

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REVISTA / JOURNAL:    - Nat Commun.2021 Jun 7;12(1):3400. DOI:10.1038/s41467-021-23620-z. Free PMC article

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AUTORES / AUTHORS: - Nicholas J Ashton et al.

INSTITUCIÓN / INSTITUTION: - Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, M lndal, Sweden 

RESUMEN / SUMMARY: - Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

Cardiology - Cardiología

TÍTULO / TITLE:   - Comparative genome-wide DNA methylation analysis in myocardial tissue from donors with and without Down syndrome

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REVISTA / JOURNAL:    - Gene.2021 Jan 5;764:145099.doi: 10.1016/j.gene.2020.145099.Epub 2020 Aug 27.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.gene.2020.145099

AUTORES / AUTHORS: - Romina B Cejas et al.

INSTITUCIÓN / INSTITUTION: - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, United States. 

RESUMEN / SUMMARY: - Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.

TÍTULO / TITLE:   - Characteristics of the pulmonary circulation in infants with complete atrioventricular septal defect

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REVISTA / JOURNAL:    - Cardiol Young.2021 Apr;31(4):556-561. doi: 10.1017/S1047951120004424.Epub 2020 Dec 11.

Enlace a la Editora de la Revista https://doi.org/10.1017/s1047951120004424

AUTORES / AUTHORS: - Hirohito Doi et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Kitakyushu, Japan. 

RESUMEN / SUMMARY: - Objective: Infants with complete atrioventricular septal defect occasionally accompany pulmonary hypertension; however, the pulmonary circulation can be altered by pulmonary vascular conditions as well as the left heart lesions. This study aimed to explore whether the left heart lesions were related to the pulmonary circulation among them.Methods: We performed echocardiography and cardiac catheterisation in 42 infants with complete atrioventricular septal defect and studied relationships between the pulmonary haemodynamic parameters and the left heart morphology. Results: Age and weight at preoperative evaluation were 65 days (47-114) (the median following interquartile range) and 5.5 kg (4.0-7.1), respectively. There were 27 individuals with Down syndrome. Gestational age was 38 weeks (37-39). Catheterisation showed mean pulmonary arterial pressure: 36 (29-46) mmHg, the ratio of pulmonary to systemic blood flow: 3.45 (2.79-4.98), pulmonary vascular resistance: 2.20 Wood units·m2 (1.53-3.65), and pulmonary arterial compliance: 2.78 (1.86-4.10) ml/Hg/m2. Echocardiography showed the Rastelli classification type A in 28 and type C in 14, moderate or severe left atrioventricular valve regurgitation in 19 patients (45%), atrioventricular valve index of 0.67 (0.56-0.79), left ventricular end-diastolic volume z score of 4.46 (1.96-7.78), and aortic valve diameter z score of -0.70 (-1.91 to 0.20). Multivariable regression analysis revealed that preoperative pulmonary vascular resistance was significantly correlated to gestational age (p = 0.002), and that preoperative pulmonary arterial compliance was significantly correlated to gestational age (p = 0.009) and Down syndrome (p = 0.036). Conclusions: The pulmonary circulation does not depend upon the presence of left heart lesions but gestational age and Down syndrome in infants with complete atrioventricular septal defect.

TÍTULO / TITLE:   - Prenatal Ultrasound Analysis of Umbilical-Portal-Systemic Venous Shunts Concurrent With Trisomy 21

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REVISTA / JOURNAL:    - J Ultrasound Med.2021 Jul;40(7):1307-1312.doi: 10.1002/jum.15507.Epub 2020 Sep 20.

Enlace a la Editora de la Revista https://doi.org/10.1002/jum.15507

AUTORES / AUTHORS: - Xiangyi Dong et al.

INSTITUCIÓN / INSTITUTION: - Department of Ultrasound, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. 

RESUMEN / SUMMARY: - Objectives: A classification termed umbilical-portal-systemic venous shunt (UPSVS) for an abnormal umbilical vein (UV), portal vein (PV), and ductus venosus (DV) was proposed recently. According to this classification, there are 3 types of UPSVSs: types I, II, and III. Trisomy 21 associated with UV-PV-DV anomalies has been described, but the incidence of trisomy 21 in UPSVS cases, the relationship between UPSVS types and trisomy 21, and the pregnancy outcome are poorly documented. This study aimed to address these issues. Methods: All UPSVS cases diagnosed at our department from 2016 to 2019 were retrospectively studied. The English literature describing UV-PV-DV anomalies and trisomy 21 from 2000 to 2019 was searched, and the retrieved cases were analyzed. Results: Four of 20 UPSVS cases identified by us also had trisomy 21, with 2 type I and 2 type II UPSVSs. Ultrasound markers of Down syndrome were observed in all 4 cases that underwent termination of pregnancy (TOP). The literature search retrieved 12 reports including 279 patients, with 29 also having trisomy 21, giving a pooled trisomy 21 incidence rate of 10.4%. Of the 29 cases, 16 had type I, and 9 had type II, whereas UPSVS types in 4 were undeterminable, and 22 cases underwent TOP. Conclusions: There is a high incidence of trisomy 21 in UPSVS cases. Trisomy 21 is associated with a type I or II UPSVS. Most cases with the combined defect underwent TOP. These findings may be used to direct prenatal counseling and management of the combined condition.

TÍTULO / TITLE:   - Dysautonomia: A Forgotten Condition - Part 1

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REVISTA / JOURNAL:    - rq Bras Cardiol.2021 Apr;116(4):814-835. doi: 10.36660/abc.20200420. DOI:10.36660/abc.20200420 Fr

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AUTORES / AUTHORS: - Eduardo Arrais Rochaet al.

INSTITUCIÓN / INSTITUTION: - Hospital Universitário Walter Cantídio da Universidade Federal do Ceará (UFC) - Programa de Pós-graduação em Ciências Cardiovasculares da Faculdade de Medicina da UFC, Fortaleza, CE - Brasil.  

RESUMEN / SUMMARY: - Dysautonomia covers a range of clinical conditions with different characteristics and prognoses. They are classified as Reflex Syndromes, Postural Orthostatic Tachycardia Syndrome (POTS), Chronic Fatigue Syndrome, Neurogenic Orthostatic Hypotension (nOH) and Carotid Sinus Hypersensitivity Syndrome. Reflex (vasovagal) syndromes will not be discussed in this article. Reflex (vasovagal) syndromes are mostly benign and usually occur in patients without an intrinsic autonomic nervous system (ANS) or heart disease. Therefore, they are usually studied separately. Cardiovascular Autonomic Neuropathy (CAN) is the term most currently used to define dysautonomia with impairment of the sympathetic and/or parasympathetic cardiovascular autonomic nervous system. It can be idiopathic, such as multisystemic atrophy or pure autonomic failure, or secondary to systemic pathologies such as diabetes mellitus, neurodegenerative diseases, Parkinson s disease, dementia syndromes, chronic renal failure, amyloidosis and it may also occur in the elderly. The presence of Cardiovascular Autonomic Neuropathy (CAN) implies greater severity and worse prognosis in various clinical situations. Detection of Orthostatic Hypotension (OH) is a late sign and means greater severity in the context of dysautonomia, defined as Neurogenic Orthostatic Hypotension (nOH). It must be differentiated from hypotension due to hypovolemia or medications, called non-neurogenic orthostatic hypotension (nnOH). OH can result from benign causes, such as acute, chronic hypovolemia or use of various drugs. However, these drugs may only reveal subclinical pictures of Dysautonomia. All drugs of patients with dysautonomic conditions should be reevaluated. Precise diagnosis of CAN and the investigation of the involvement of other organs or systems is extremely important in the clinical suspicion of pandysautonomia. In diabetics, in addition to age and time of disease, other factors are associated with a higher incidence of CAN,

Dermatology - Dermatología

TÍTULO / TITLE:   - Hidradenitis suppurativa and chromosomal abnormalities: a case report and systematic review of the literature

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REVISTA / JOURNAL:    - Int J Dermatol.2021 Mar;60(3):261-271. doi: 10.1111/ijd.15111.Epub 2020 Aug 9.

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AUTORES / AUTHORS: - Monica Shah et al.

INSTITUCIÓN / INSTITUTION: - Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. 

RESUMEN / SUMMARY: - Hidradenitis suppurativa (HS) is a chronic inflammatory follicular disorder that involves painful nodules, abscesses, and tunnels of intertriginous sites. Although the etiology has not been fully elucidated, recent studies have highlighted its association with chromosomal abnormalities.We present a rare case of HS in a patient with Trisomy 1q;13 and systematically summarize the association between HS and chromosomal abnormalities. A search was conducted using MEDLINE and EMBASE in OVID database. Original studies reporting HS among human subjects with chromosomal abnormalities were included. Patient demographics, disease symptomology, clinical features, and treatment histories were extracted and summarized.Thirteen studies describing 428 cases met the inclusion criteria. Of the 13 articles, nine studies reported patients with HS and Down syndrome (DS), one article investigated HS and Smith-Magenis syndrome (SMS), and three articles analyzed HS and Patau syndrome (PS). While increased prevalence of HS was found in populations with DS, with suggested mechanisms involving amyloid precursor protein cleavage product, keratinocyte proliferation, and follicular plugging, the associations between HS and both SMS and PS remain inconclusive because of limited studies with small sample size.Although evidence suggests that the genetic regulation of chromosome 21 may be implicated in the association between HS and DS, this association may be confounded by additional factors that increase the risk of HS. Further research with larger sample sizes must be conducted to strengthen our understanding of the association between HS and chromosomal abnormalities.

TÍTULO / TITLE:   - Hidradenitis suppurativa and Down syndrome: A systematic review and meta-analysis

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REVISTA / JOURNAL:    - Pediatr Dermatol.2020 Nov;37(6):1044-1050. doi: 10.1111/pde.14326.Epub 2020 Sep 6.

Enlace a la Editora de la Revista https://doi.org/10.1111/pde.14326

AUTORES / AUTHORS: - Megan Lam et al.

INSTITUCIÓN / INSTITUTION: - Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada. 

RESUMEN / SUMMARY: - Background: Hidradenitis suppurativa (HS), characterized by inflammatory nodules, sinus tracts, and abscesses, has been linked to several factors, including immune dysfunction and obesity, which are thought to contribute to its development. Several follicular disorders have also been associated with Down syndrome (DS), a common chromosomal disorder, including HS, although studies on this topic are limited. Objectives: To characterize HS in Down syndrome patients and to further examine the association between HS and DS compared to HS patients without DS. Methods: We systematically searched MEDLINE, Embase, Web of Science, and CENTRAL electronic databases from their dates of conception to February 2020. Random-effects meta-analyses were performed analyzing (a) HS characteristics between DS and non-DS participants, and (b) prevalence or association between HS and DS compared to non-DS individuals. Results: Twelve studies were included in this systematic review, with a total of 358 participants presenting with both HS and DS. Pooled analysis of mean differences between DS and non-DS participants presenting with HS found a significantly younger age of HS symptom onset for DS patients (-6.24; 95% CI, -10.01--2.24). A meta-analysis examining the association between HS and DS found a significantly increased likelihood of HS in DS patients (OR 9.61; 95% CI, 5.70-16.20). Conclusions: Our findings suggest an association between HS and DS, with DS patients suffering from an earlier onset of HS symptoms compared to non-DS patients.

Ear/Nasal - Otorrinolaringología

TÍTULO / TITLE:   - Respiratory and otolaryngological disorders in Down syndrome from one center in Brazil

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Aug;185(8):2356-2360. doi: 10.1002/ajmg.a.62244.Epub 2021 May 28.

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.62244

AUTORES / AUTHORS: - Beatriz Elizabeth Bagatin Veleda Bermudezet al

INSTITUCIÓN / INSTITUTION: - Down Syndrome Outpatient Clinic, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil. 

RESUMEN / SUMMARY: - Down syndrome (DS) is the most common chromosomal condition. Anatomical and functional variations in the upper and lower airways are component manifestations of the syndrome and increase the risk of various medical problems. The objective of this study was to determine the prevalence of otorhinolaryngological and respiratory diseases in a DS outpatient clinic over a 3-year period. Medical records data from 1207 patients were retrospectively reviewed. Newborn Hearing Screening was positive in 7.1% of patients. Brainstem auditory evoked potential was performed in 1101 children and showed a hearing loss of 19.8% in the first year. It was positive in 21% of 1021 exams. Audiometry was altered in 64 of 994 exams (6.4%), showing a conductive loss in 90%. Adenotonsillectomy was performed in 308 (25.5%) patients, and 169 (14.0%) required serous otitis ventilation tubes. Asthma was observed in 140 (11.6%) patients, and allergic rhinitis in 544 (56.6%). There were hospitalizations for invasive infection in 480 (39.8%) children, and two (0.2%) patients had severe septicemia from pulmonary focus. Five (0.4%) infants had laryngotracheomalacia, and one patient had anomalous right tracheal bronchus. Recognizing the prevalence of respiratory and otorhinolaryngological disorders in patients with DS allows the promotion of optimal follow-up and early treatment, preventing the development of sequelae.

TÍTULO / TITLE:   - Repeat tympanostomy tubes in children with Down syndrome

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REVISTA / JOURNAL:    - https://doi.org/10.1016/j.ijporl.2021.110811

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AUTORES / AUTHORS: - Mahmoud Omar et al.

INSTITUCIÓN / INSTITUTION: - UPMC Children s Hospital of Pittsburgh, Department of Otolaryngology, Pittsburgh, PA, USA. 

RESUMEN / SUMMARY: - Objectives: Children with Down syndrome (DS) have a higher incidence of tympanostomy tube insertion (TTI) than children in the general population. As there were no studies investigating factors that are associated with multiple TTIs in children with DS, we sought to determine what factors increase or decrease the likelihood of repeat TTI in children with DS. Methods: A retrospective case-control study was performed on consecutive children with DS from 2007 to 2018 with first TTI at a large tertiary children s hospital and follow-up duration at least 27 months since first TTI. Results: 277 patients met the inclusion criteria. Repeat TTI rate was 61.4%. Having an indication of chronic otitis media with effusion (COME) at first TTI was an adjusted risk factor for increased rate of repeat TTI (OR: 2.01, 95%CI: 1.15-3.51, p = .014), while being older at first TTI was an adjusted protective factor for decreased rate of repeat TTI (OR: 0.84, 95%CI: 0.74-0.95, p = .004). Adenotonsillectomy at or before first TTI was not an adjusted protective factor for decreased rate of repeat TTI (OR: 0.915, 95%CI: 0.448-1.872, p = .809) and bilateral intra-operative fluid was not an adjusted risk factor for repeat TTI (OR: 1.97, 95%CI: 0.99-3.90, p = .054). Conclusion: Children with DS were more likely to undergo repeat TTI if they were of younger age and if the indication for surgery was COME. The repeat TTI rate for children with DS was high at 61.4%. Prospective studies are warranted to more precisely investigate factors associated with repeat TTIs in this unique patient population.

Endocrinology/Nutrition - Endocrinología/Nutrición

TÍTULO / TITLE:   - Thyroid disorder in children and young people with Down syndrome: DSMIG guideline review

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REVISTA / JOURNAL:    - Arch Dis Child Educ Pract Ed.2021 Feb 8;edpract-2020-321080.doi: 10.1136/archdischild-2020-321080.

Enlace a la Editora de la Revista mailto:becksdrd@gmail.com

AUTORES / AUTHORS: - Rebecca Amy Dalrymple

INSTITUCIÓN / INSTITUTION: - Department of Community Child Health, The West Centre, Glasgow, UK  

RESUMEN / SUMMARY: - No abstract available

TÍTULO / TITLE:   - Late-Onset Isolated Corticotrope Deficiency in a Woman with Down Syndrome

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REVISTA / JOURNAL:    - Case Rep Endocrinol.2021 Apr 27;2021:5562831.doi: 10.1155/2021/5562831.eCollection 2021. DOI:10

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AUTORES / AUTHORS: - Ibtissem Oueslati et al.

INSTITUCIÓN / INSTITUTION: - Department of Endocrinology, La Rabta University Hospital, University of Tunis-El Manar, Faculty of Medicine, Tunis, Tunisia.PMID: 34007493 

RESUMEN / SUMMARY: - Isolated corticotrope deficiency is a rare cause of secondary adrenocortical insufficiency. Its occurrence in patients with Down syndrome is exceptional. Herein, we report a case of an isolated corticotrope deficiency diagnosed at the age of 33 years in a woman with Down syndrome and discuss its possible mechanisms. A 33-year-old woman with Down syndrome was referred to our department for the investigation of low blood pressure. She complained of asthenia, dizziness, and palpitation with arterial hypotension for the past 4 years. The thyroid function was normal and anti-thyroperoxidase antibodies were negative. The peak of cortisol level in response to the insulin-induced hypoglycemia test was 9.4 μg/dl. ACTH level was normal, indicating corticotrope deficiency. Other pituitary hormones were normal. Magnetic resonance imaging scan revealed a partially empty sella turcica. Genetic analysis showed no mutations and no copy number variants of the TBX19 and NFKB2 genes. The mechanism of isolated corticotrope deficiency is unclear, but it may be induced by autoimmune mechanism in similar to other disorders of patients with Down syndrome.

Epidemiology - Epidemiología

TÍTULO / TITLE:   - Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome

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REVISTA / JOURNAL:    - J Pediatr. 2021 Jul;234:172-180.e3. doi: 10.1016/j.jpeds.2021.03.001. Epub 2021 Mar 6.PMID:33684394

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AUTORES / AUTHORS: - Marlow EC et al.

INSTITUCIÓN / INSTITUTION: - Graduate Group in Epidemiology, University of California, Davis, Davis, CA; Department of Public Health Sciences, University of California, Davis, Davis, CA. 

RESUMEN / SUMMARY: - Objective: To assess leukemia risks among children with Down syndrome in a large, contemporary cohort. Study design: Retrospective cohort study including 3 905 399 children born 1996-2016 in 7 US healthcare systems or Ontario, Canada, and followed from birth to cancer diagnosis, death, age 15 years, disenrollment, or December 30, 2016. Down syndrome was identified using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. Cancer diagnoses were identified through linkages to tumor registries. Incidence and hazard ratios (HRs) of leukemia were estimated for children with Down syndrome and other children adjusting for health system, child s age at diagnosis, birth year, and sex. Results: Leukemia was diagnosed in 124 of 4401 children with Down syndrome and 1941 of 3 900 998 other children. In children with Down syndrome, the cumulative incidence of acute myeloid leukemia (AML) was 1405/100 000 (95% CI 1076-1806) at age 4 years and unchanged at age 14 years. The cumulative incidence of acute lymphoid leukemia in children with Down syndrome was 1059/100 000 (95% CI 755-1451) at age 4 and 1714/100 000 (95% CI 1264-2276) at age 14 years. Children with Down syndrome had a greater risk of AML before age 5 years than other children (HR 399, 95% CI 281-566). Largest HRs were for megakaryoblastic leukemia before age 5 years (HR 1500, 95% CI 555-4070). Children with Down syndrome had a greater risk of acute lymphoid leukemia than other children regardless of age (<5 years: HR 28, 95% CI 20-40, ≥5 years HR 21, 95% CI 12-38). Conclusions: Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported. 

Gastroenterology - Gastroenterología

TÍTULO / TITLE:   - Masticatory function in children with Down syndrome

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REVISTA / JOURNAL:    - Physiol Behav.2021 Jun 1;235:113390. doi: 10.1016/j.physbeh.2021.113390.Epub 2021 Mar 16.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.physbeh.2021.113390

AUTORES / AUTHORS: - Ana Wintergerst,Marcela Patricia Lpez-Morales

INSTITUCIÓN / INSTITUTION: - División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Av. Universidad 3000, Col. Universidad Nacional Autónoma de México, CP 04510 Ciudad de México, México.  

RESUMEN / SUMMARY: - The objective was to study masticatory function of 8 to 10-year-old children with Down syndrome (DS) through the evaluation of maximum occlusal force and masticatory performance (via medium particle size) and compare it to that of children of the same age without DS. Methods: A convenience sample of eight, 8-10-year-old children with DS were included in this cross-sectional study. The study had ethical approval and parents provided informed consent. Exclusion criteria were large carious lesions, dental pain or previous orthodontic/orthopedic treatment. Masticatory performance was evaluated with an artificial test food (Optosil Comfort®) after 20 cycles and at swallowing threshold. The chewed material was collected, dried and sieved. The material on each sieve was weighed; the weights were used to calculate medium particle size. Maximum occlusal force (1st permanent molars) was determined using the GM10 Nagano Keiki Co.™ portable transducer. The number of cycles until swallowing threshold, cycle and sequence durations were also compared. The data for the reference group (n = 32) came from a previous study in children of the same age. Descriptive statistics as well as comparisons with Mann-Whitney tests and simple and multiple regression analysis were performed. Cutoff was set at p≤.05. Results: Medium particle size is larger by 44% after 20 chewing cycles and 75% at swallowing threshold (p<.05) in children with DS. Median maximum occlusal force was 254 kN in DS children and 499 kN in children without the syndrome (p<.001). 48% of the variance in maximum occlusal force is explained by having DS. There were also significant differences in sequence and cycle durations. All significant differences had large effect sizes (˃1). Although the children with DS chewed more cycles before swallowing threshold the difference was not significant. Conclusions: Children with DS have approximately 50% of the masticatory performance and maximum occlusal force of children of

Genetics - Genética

TÍTULO / TITLE:   - Human disease genes website series: An international, open and dynamic library for up-to-date clinical information

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Apr;185(4):1039-1046. doi: 10.1002/ajmg.a.62057.Epub 2021 Jan 13.

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.62057

AUTORES / AUTHORS: - Alexander J M Dingemans et al.

INSTITUCIÓN / INSTITUTION: - Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands. 

RESUMEN / SUMMARY: - Since the introduction of next-generation sequencing, an increasing number of disorders have been discovered to have genetic etiology. To address diverse clinical questions and coordinate research activities that arise with the identification of these rare disorders, we developed the Human Disease Genes website series (HDG website series): an international digital library that records detailed information on the clinical phenotype of novel genetic variants in the human genome (https://humandiseasegenes.info/). Each gene website is moderated by a dedicated team of clinicians and researchers, focused on specific genes, and provides up-to-date-including unpublished-clinical information. The HDG website series is expanding rapidly with 424 genes currently adopted by 325 moderators from across the globe. On average, a gene website has detailed phenotypic information of 14.4 patients. There are multiple examples of added value, one being the ARID1B gene website, which was recently utilized in research to collect clinical information of 81 new patients. Additionally, several gene websites have more data available than currently published in the literature. In conclusion, the HDG website series provides an easily accessible, open and up-to-date clinical data resource for patients with pathogenic variants of individual genes. This is a valuable resource not only for clinicians dealing with rare genetic disorders such as developmental delay and autism, but other professionals working in diagnostics and basic research. Since the HDG website series is a dynamic platform, its data also include the phenotype of yet unpublished patients curated by professionals providing higher quality clinical detail to improve management of these rare disorders.

TÍTULO / TITLE:   - The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

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REVISTA / JOURNAL:    - Nat Commun.2021 Feb 5;12(1):821.doi: 10.1038/s41467-021-21064-z. DOI:10.1038/s41467-021-21064-z.

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AUTORES / AUTHORS: - Ivo S Muskens et al.

INSTITUCIÓN / INSTITUTION: - Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 

RESUMEN / SUMMARY: - Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

TÍTULO / TITLE:   - SON is necessary for proper vertebrate blood development

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REVISTA / JOURNAL:    - PLoS One.2021 Feb 25;16(2):e0247489. doi: 10.1371/journal.pone.0247489.eCollection 2021.

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AUTORES / AUTHORS: - Rebecca L Belmonte et al

INSTITUCIÓN / INSTITUTION: - Department of Biological Sciences, California State University Chico, Chico, California, United States of America. 

RESUMEN / SUMMARY: - The gene SON is on human chromosome 21 (21q22.11) and is thought to be associated with hematopoietic disorders that accompany Down syndrome. Additionally, SON is an RNA splicing factor that plays a role in the transcription of leukemia-associated genes. Previously, we showed that mutations in SON cause malformations in human and zebrafish spines and brains during early embryonic development. To examine the role of SON in normal hematopoiesis, we reduced expression of the zebrafish homolog of SON in zebrafish at the single-cell developmental stage with specific morpholinos. In addition to the brain and spinal malformations we also observed abnormal blood cell levels upon son knockdown. We then investigated how blood production was altered when levels of son were reduced. Decreased levels of son resulted in lower amounts of red blood cells when visualized with lcr: GFP transgenic fish. There were also reduced thrombocytes seen with cd41:GFP fish, and myeloid cells when mpx:GFP fish were examined. We also observed a significant decrease in the quantity of T cells, visualized with lck:GFP fish. However, when we examined their hematopoietic stem and progenitor cells (HSPCs), we saw no difference in colony-forming capability. These studies indicate that son is essential for the proper differentiation of the innate and adaptive immune system, and further investigation determining the molecular pathways involved during blood development should elucidate important information about vertebrate HSPC generation, proliferation, and differentiation.

Growth/Development - Crecimiento/Desarrollo

TÍTULO / TITLE:   - Reference serum creatinine levels according to sex, age, and height in children with Down syndrome

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REVISTA / JOURNAL:    - Eur J Pediatr.2021 Apr 15.doi: 10.1007/s00431-021-04078-z.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1007/s00431-021-04078-z

AUTORES / AUTHORS: - Tomohiko Nishino et al.

INSTITUCIÓN / INSTITUTION: - Division of Nephrology, Saitama Children s Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama-City, Saitama, 330 8777, Japan.  

RESUMEN / SUMMARY: - Standard serum creatinine (S-Cr) levels in healthy children fluctuate with age and sex. However, it is unclear if this fluctuation in S-Cr levels is present for children with Down syndrome (DS) who show atypical growth rate. Therefore, we aimed to establish specific reference S-Cr levels for DS and compare them with the prevailing standard levels. We retrospectively reviewed 984 children with DS aged 3 months to 18 years who visited our medical center. Patients with diseases affecting S-Cr levels were excluded. We calculated the reference S-Cr levels according to sex, age, and length/height using medical records. A total of 3765 examinations of 568 children with DS were registered for this study. Ages and S-Cr levels were examined for boys (y = 0.032x + 0.20; r = 0.868, P < 0.0001), and girls (y = 0.024x + 0.23; r = 0.835, P < 0.0001). S-Cr levels in children aged >9 years were significantly higher in boys than in girls. The 430 children with DS aged 2-8 years were examined 1867 times. Height and S-Cr levels showed a significantly strong positive correlation (r = 0.670, P < 0.001) with regression equation y = 0.37x. The quintic equations calculated with S-Cr levels and length/height for boys (336 children, 2043 tests, r = 0.887) and girls (232 children, 1722 tests, r = 0.805) werey = - 6.132x5 + 32.78x4 - 67.86x3 + 68.31x2 - 33.14x + 6.41, and y = 0.09542x5 + 1.295x4 - 6.401x3 + 10.35x2 - 6.746x + 1.772. All calculated results varied from the standard levels for healthy children.Conclusion: This study established reference S-Cr levels and quintic equations specific for children with DS. These reference levels would be potentially useful in evaluating S-Cr levels and renal function in this population. What is Known: •Standard serum creatinine levels vary with age and sex to reflect muscle mass. •Reference serum creatinine levels specific to children with Down syndrome who show growth rates different from those of healthy children have not been established. What is Ne

Hematology/Oncology - Hematología/Oncología

TÍTULO / TITLE:   - Acute lymphoblastic leukemia and Down syndrome: 6-mercaptopurine and methotrexate metabolites during maintenance therapy

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REVISTA / JOURNAL:    - Leukemia. 2021 Mar;35(3):863-866. doi: 10.1038/s41375-020-0946-2. Epub 2020 Jul 4.PMID:32623444

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AUTORES / AUTHORS: - stergaard A, et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark. 

RESUMEN / SUMMARY: - Abstract not available.

TÍTULO / TITLE:   - Enhancer polymorphisms at the IKZF1 susceptibility locus for acute lymphoblastic leukemia impact B-cell proliferation and differentiation in both Down syndrome and non-Down syndrome genetic background

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REVISTA / JOURNAL:    - PLoS One.2021Jan7;16(1):e0244863. doi: 10.1371/journal.pone.0244863.eCollection 2021.PMID:33411777.

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AUTORES / AUTHORS: - Gant VU et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, United States of America. 

RESUMEN / SUMMARY: - Children with Down syndrome have an approximately 10-fold increased risk of developing acute lymphoblastic leukemia and this risk is influenced by inherited genetic variation. Genome-wide association studies have identified IKZF1 as a strong acute lymphoblastic leukemia susceptibility locus in children both with and without Down syndrome, with association signals reported at rs4132601 in non-Down syndrome and rs58923657 in individuals with Down syndrome (r2 = 0.98 for these two loci). Expression quantitative trait locus analysis in non-Down syndrome lymphoblastoid cell lines has demonstrated an association between the rs4132601 risk allele and decreased IKZF1 mRNA levels. In this study, we provide further mechanistic evidence linking the region encompassing IKZF1-associated polymorphisms to pro-leukemogenic effects in both human lymphoblastoid cell lines and murine hematopoietic stem cells. CRISPR/Cas9-mediated deletion of the region encompassing the rs17133807 major allele (r2 with rs58923657 = 0.97) resulted in significant reduction of IKZF1 mRNA levels in lymphoblastoid cell lines, with a greater effect in Down syndrome versus non-Down syndrome cells. Since rs17133807 is highly conserved in mammals, we also evaluated the orthologous murine locus at rs263378223, in hematopoietic stem cells from the Dp16(1)Yey mouse model of Down syndrome as well as non-Down syndrome control mice. Homozygous deletion of the region encompassing rs263378223 resulted in significantly reduced Ikzf1 mRNA, confirming that this polymorphism maps to a strong murine Ikzf1 enhancer, and resulted in increased B-lymphoid colony growth and decreased B-lineage differentiation. Our results suggest that both the region encompassing rs17133807 and its conserved orthologous mouse locus have functional effects that may mediate increased leukemia susceptibility in both the Down syndrome and non-Down syndrome genetic backgrounds.

TÍTULO / TITLE:   - Outcome and Prognostic Features in Pediatric Acute Megakaryoblastic Leukemia Without Down Syndrome: A Retrospective Study in China

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REVISTA / JOURNAL:    - Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):e301-e308. doi: 10.1016/j.clml.2020.11.001.PMID:33257285

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AUTORES / AUTHORS: - Wang Y et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Peking University People s Hospital, Peking University, Beijing, China. 

RESUMEN / SUMMARY: - Background: Acute megakaryoblastic leukemia (AMKL) is a biologically heterogeneous subtype of acute myeloid leukemia that originates from megakaryocytes. Patients with AMKL with non-Down syndrome (DS) had a poorer prognosis. However, clear prognostic indicators and treatment recommendations for this subgroup remain controversial. Patients and methods: Herein, we performed a retrospective study on 40 patients (age ≤ 18 years) with non-Down syndrome AMKL at our institution. We assessed the effect of different prognostic factors, such as their cytogenetic abnormalities, early treatment response, and the role of hematopoietic stem cell transplantation (HSCT) as post-remission treatment on the outcomes. Results: The complete remission (CR) rate of the patients was 57.9% and 81.1%, respectively, at the end of induction therapy 1 and 2. The overall survival (OS) and event-free survival rates at 2 years were 41% ± 13% and 41% ± 10%, respectively. An analysis of the cytogenetic features showed that patients with +21 or hyperdiploid (> 50 chromosomes) had significantly better OS than those in other cytogenetic subgroups (Plog-rank = .048 and Plog-rank = .040, respectively). Besides cytogenetics, an excellent early treatment response (CR and minimal residual disease < 1% after induction therapy 1) also provided a significant survival benefit in univariate analysis in our study. However, multivariate analysis indicated that allogeneic HSCT was the only independent prognostic marker (relative risk, 11.192; 95% confidence interval, 2.045-61.241; P = .005 for OS and relative risk, 5.400; 95% confidence interval, 1.635-17.832; P = .006 for event-free survival, respectively). Conclusion: AMKL in patients with non-Down syndrome has a poor outcome. With poor OS but CR rates comparable with other acute myeloid leukemia subtypes, allogenic HSCT may be a better option for post-remission therapy than conventional chemotherapy, especially for those having a poor response to induction

TÍTULO / TITLE:   - Blast cells in acute megakaryoblastic leukaemia with Down syndrome are characterized by low CLEC12A expression

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REVISTA / JOURNAL:    - BrJ Haematol.2021Jan;192(1):e7-e11.doi: 10.1111/bjh.17122.Epub 2020 Oct23.PMID:33095915Clinical Tria

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AUTORES / AUTHORS: - Matsuo H, et al.

INSTITUCIÓN / INSTITUTION: - Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 

RESUMEN / SUMMARY: - Abstract not available. 

TÍTULO / TITLE:   - Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome

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REVISTA / JOURNAL:    - J Pediatr.2021 Jul;234:172-180.e3. doi:10.1016/j.jpeds.2021.03.001. Epub 2021 Mar 6.PMID:33684394

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AUTORES / AUTHORS: - Marlow EC et al

INSTITUCIÓN / INSTITUTION: - Graduate Group in Epidemiology, University of California, Davis, Davis, CA; Department of Public Health Sciences, University of California, Davis, Davis, CA. 

RESUMEN / SUMMARY: - Objective: To assess leukemia risks among children with Down syndrome in a large, contemporary cohort. Study design: Retrospective cohort study including 3 905 399 children born 1996-2016 in 7 US healthcare systems or Ontario, Canada, and followed from birth to cancer diagnosis, death, age 15 years, disenrollment, or December 30, 2016. Down syndrome was identified using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. Cancer diagnoses were identified through linkages to tumor registries. Incidence and hazard ratios (HRs) of leukemia were estimated for children with Down syndrome and other children adjusting for health system, child s age at diagnosis, birth year, and sex. Results: Leukemia was diagnosed in 124 of 4401 children with Down syndrome and 1941 of 3 900 998 other children. In children with Down syndrome, the cumulative incidence of acute myeloid leukemia (AML) was 1405/100 000 (95% CI 1076-1806) at age 4 years and unchanged at age 14 years. The cumulative incidence of acute lymphoid leukemia in children with Down syndrome was 1059/100 000 (95% CI 755-1451) at age 4 and 1714/100 000 (95% CI 1264-2276) at age 14 years. Children with Down syndrome had a greater risk of AML before age 5 years than other children (HR 399, 95% CI 281-566). Largest HRs were for megakaryoblastic leukemia before age 5 years (HR 1500, 95% CI 555-4070). Children with Down syndrome had a greater risk of acute lymphoid leukemia than other children regardless of age (<5 years: HR 28, 95% CI 20-40, ≥5 years HR 21, 95% CI 12-38). Conclusions: Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported. 

TÍTULO / TITLE:   - DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

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REVISTA / JOURNAL:    - J Clin Invest.2021 Jan 4;131(1):e135937.doi: 10.1172/JCI135937.

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AUTORES / AUTHORS: - Rahul S Bhansali et al.

INSTITUCIÓN / INSTITUTION: - Department of Medicine, Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA. 

RESUMEN / SUMMARY: - DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer s disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.

TÍTULO / TITLE:   - Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia

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REVISTA / JOURNAL:    - Leukemia. 2021 Jan 22. doi: 10.1038/s41375-021-01128-1. Online ahead of print. PMID:33483616

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AUTORES / AUTHORS: - Goemans BF, et al.

INSTITUCIÓN / INSTITUTION: - Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.  

RESUMEN / SUMMARY: - Abstract not available.

TÍTULO / TITLE:   - Neonatal Leukemia

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REVISTA / JOURNAL:    - Clin Perinatol.2021 Mar;48(1):15-33.doi: 10.1016/j.clp.2020.11.002.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.clp.2020.11.002

AUTORES / AUTHORS: -

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. 

RESUMEN / SUMMARY: - Neonates are at risk for 3 major forms of leukemia in the first year of life: acute leukemia, juvenile myelomonocytic leukemia, and transient abnormal myelopoiesis associated with Down syndrome. These disorders are rare but generate interest due to aggressive clinical presentation, suboptimal response to current therapies, and fascinating biology. Each can arise as a result of unique constitutional and acquired genetic events. Genetic insights are pointing the way toward novel therapeutic approaches. This article reviews key epidemiologic, clinical, and molecular features of neonatal leukemias, focusing on risk stratification, treatment, and strategies for developing novel molecularly targeted approaches to improve future outcomes.

TÍTULO / TITLE:   - Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution

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REVISTA / JOURNAL:    - Int J Hematol.2021 May;113(5):662-667. doi: 10.1007/s12185-020-03066-7.Epub 2021 Jan 4.

Enlace a la Editora de la Revista https://doi.org/10.1007/s12185-020-03066-7

AUTORES / AUTHORS: - Genki Yamato et al

INSTITUCIÓN / INSTITUTION: - Department of Hematology/Oncology, Gunma Children s Medical Center, Shibukawa, Gunma, Japan. 

RESUMEN / SUMMARY: - Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5-10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia.

TÍTULO / TITLE:   - Mapping the cellular origin and early evolution of leukemia in Down syndrome

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REVISTA / JOURNAL:    - Science.2021 Jul 9;373(6551):eabf6202.doi: 10.1126/science.abf6202.

Enlace a la Editora de la Revista https://doi.org/10.1126/science.abf6202

AUTORES / AUTHORS: - Elvin Wagenblast et al.

INSTITUCIÓN / INSTITUTION: - Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.  

RESUMEN / SUMMARY: - Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

TÍTULO / TITLE:   - A Novel Chromosomal Aberration in the Pathogenesis of Transient Leukemia of Down Syndrome

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REVISTA / JOURNAL:    - Indian J Pediatr.2021 Jun;88(6):615.doi: 10.1007/s12098-021-03699-4.Epub 2021 Mar 15.

Enlace a la Editora de la Revista https://doi.org/10.1007/s12098-021-03699-4

AUTORES / AUTHORS: - Aakash Chandran Chidambaram et al

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India. 

RESUMEN / SUMMARY: - Abstract not available

TÍTULO / TITLE:   - RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

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REVISTA / JOURNAL:    - Oncogene 2021 Jan;40(4):746-762. doi: 10.1038/s41388-020-01567-7.Epub 2020 Nov 27.

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AUTORES / AUTHORS: - David Koschut et al.

INSTITUCIÓN / INSTITUTION: - Lee Kong Chian School of Medicine, Nanyang Technological University,Singapore, Singapore 

RESUMEN / SUMMARY: - Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL.

TÍTULO / TITLE:   - Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome

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REVISTA / JOURNAL:    - Leukemia.2021 May;35(5):1480-1484.doi: 10.1038/s41375-021-01171-y.Epub 2021 Mar 3.

Enlace a la Editora de la Revista https://doi.org/10.1038/s41375-021-01171-y

AUTORES / AUTHORS: - Genki Yamato et al.

INSTITUCIÓN / INSTITUTION: - Department of Hematology/Oncology, Gunma Children s Medical Center, Gunma, Japan 

RESUMEN / SUMMARY: - Abstract not available

TÍTULO / TITLE:   - The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

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REVISTA / JOURNAL:    - Nat Commun.2021 Feb 5;12(1):821.doi: 10.1038/s41467-021-21064-z.

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AUTORES / AUTHORS: - Ivo S Muskens et al.

INSTITUCIÓN / INSTITUTION: - Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 

RESUMEN / SUMMARY: - Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

TÍTULO / TITLE:   - Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome

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REVISTA / JOURNAL:    - Leukemia.2021 Feb 15.doi: 10.1038/s41375-021-01157-w.

Enlace a la Editora de la Revista https://doi.org/10.1038/s41375-021-01157-w

AUTORES / AUTHORS: - Takashi Taga et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan. 

RESUMEN / SUMMARY: - Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 93.3% and 95.0% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 96.2% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD or GATA1-MRD with EFS were 10.98 (p = 0.01) and 27.68 (p < 0.01), respectively. Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.

TÍTULO / TITLE:   - Aberrant myelomonocytic CD56 expression in Down syndrome is frequent and not associated with leukemogenesis

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REVISTA / JOURNAL:    - Ann Hematol.2021 Jul;100(7):1695-1700. doi: 10.1007/s00277-021-04531 x.Epub 2021 Apr 23

Enlace a la Editora de la Revista https://doi.org/10.1007/s00277-021-04531-x

AUTORES / AUTHORS: - Manisha Gadgeel et al.

INSTITUCIÓN / INSTITUTION: - Children s Hospital of Michigan, Division of Hematology/Oncology, Hematology/Oncology Flow Cytometry Laboratory, Detroit, MI, USA. 

RESUMEN / SUMMARY: - Children with Down syndrome (DS) are at an increased risk of developing transient abnormal myelopoiesis (TAM) and acute leukemia. Aberrant expression of CD56 has been observed on myeloid leukemic blasts in DS patients. In general, CD56 expression in acute myeloid leukemia (AML) is considered a promoter of leukemogenesis. We did a retrospective flow cytometric study to investigate mature myelomonocytic cell CD56 expression patterns in TAM, non-TAM, and leukemia cases with DS. Flow cytometric analysis showed that granulocyte and monocyte aberrant/dysplastic CD56 expression is an inherent characteristic of most DS patients irrespective of the presence of TAM or leukemia. Increased CD56 expression in monocyte and granulocyte populations in DS could be multifactorial; greater expression of RUNX1 secondary to the gene dose effect of trisomy 21 along with the maturational state of the cells are the potential contributors. Unlike AML seen in non-DS patients, CD56 overexpression in DS AML cases does not appear to play a role in leukemogenesis.

TÍTULO / TITLE:   - Patient with Down syndrome and relapsed acute lymphoblastic leukemia with sustained remission despite only partial R3 chemotherapy

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REVISTA / JOURNAL:    - Clin Case Rep.2021 Feb 12;9(3):1118-1122.doi: 10.1002/ccr3.3678.eCollection 2021 Mar.

Enlace a la Editora de la Revista https://doi.org/10.1002/ccr3.3678

AUTORES / AUTHORS: - Zhongbo Hu et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics Division of Pediatric Hematology Oncology Rainbow Babies and Children s Hospital at University Hospitals Cleveland Medical Center Cleveland OH USA.  

RESUMEN / SUMMARY: - DS-ALL has a higher rate of relapse and treatment-related mortality. The newer immunotherapies are potentially better options. Relapsed ALL with positive MRD has a poor prognosis. Transient long-term remission after ALL relapse due to partial chemotherapy combined severe infection is rare.

TÍTULO / TITLE:   - Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification

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REVISTA / JOURNAL:    - PLoS One.2021 Mar 29;16(3):e0247595.doi: .1371/journal.pone.0247595.eCollection 2021.

Enlace a la Editora de la Revista https://doi.org/10.1371/journal.pone.0247595

AUTORES / AUTHORS: - Shiori Matsuo et al.

INSTITUCIÓN / INSTITUTION: - Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan. 

RESUMEN / SUMMARY: - Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in GATA binding protein 1 (GATA1) have been identified as the cause of these diseases, and the expression levels of the resulting protein, short-form GATA1 (GATA1s), are known to correlate with the severity of TAM. On the other hand, despite the presence of GATA1 mutations in almost all cases of DS-AMKL, the incidence of DS-AMKL in TAM patients is inversely correlated with the expression of GATA1s. This discovery has required the need to clarify the role of GATA1s in generating the cells of origin linked to the risk of both diseases. Focusing on this point, we examined the characteristics of GATA1 mutant trisomy-21 pluripotent stem cells transfected with a doxycycline (Dox)-inducible GATA1s expression cassette in a stepwise hematopoietic differentiation protocol. We found that higher GATA1s expression significantly reduced commitment into the megakaryocytic lineage at the early hematopoietic progenitor cell (HPC) stage, but once committed, the effect was reversed in progenitor cells and acted to maintain the progenitors. These differentiation stage-dependent reversal effects were in contrast to the results of myeloid lineage, where GATA1s simply sustained and increased the number of immature myeloid cells. These results suggest that although GATA1 mutant cells cause the increase in myeloid and megakaryocytic progenitors regardless of the intensity of GATA1s expression, the pathways vary with the expression level. This study provides experimental support for the paradoxical clinical features of GATA1 mutations in the two diseases.

TÍTULO / TITLE:   - Transient abnormal myelopoiesis in pediatrics with trisomy 21

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REVISTA / JOURNAL:    - Clin Case Rep.2020 Nov 29;9(2):605-608. doi: 10.1002/ccr3.3589.eCollection 2021 Feb.

Enlace a la Editora de la Revista https://doi.org/10.1002/ccr3.3589

AUTORES / AUTHORS: - Nadereh Taee et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics Faculty of Medicine Lorestan University of Medical Sciences Khorramabad Iran. 

RESUMEN / SUMMARY: - Transient abnormal myelopoiesis is common among Down syndrome patients. Although no therapeutic measures are required, close monitoring of comorbidities such as gastrointestinal bleeding is required. Long-term follow-up is promising for a healthy future and reduced requirement of unnecessary therapeutic measures including chemotherapy and remission of the pathology.

TÍTULO / TITLE:   - Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia

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REVISTA / JOURNAL:    - J Clin Invest.2021 Jan 4;131(1):e142627.doi: 10.1172/JCI142627.

Enlace a la Editora de la Revista https://doi.org/10.1172/jci142627

AUTORES / AUTHORS: - Jung-Hyun Kim et al.

INSTITUCIÓN / INSTITUTION: - Pathobiology, Human Genetics, and Cellular and Molecular Medicine Graduate Programs, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 

RESUMEN / SUMMARY: - DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.

TÍTULO / TITLE:   - Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

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REVISTA / JOURNAL:    - Expert Rev Mol Med.2021 Apr 27;23:e5. doi: 10.1017/erm.2021.6

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AUTORES / AUTHORS: - https://doi.org/10.1017/erm.2021.6

INSTITUCIÓN / INSTITUTION: - Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CSUtrecht, the Netherlands.  

RESUMEN / SUMMARY: - Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because of their young age. Children with Down syndrome (DS) have an even higher risk of developing leukaemia during the first years of life. The presence of a constitutive trisomy of chromosome 21 (T21) in DS acts as a genetic driver for leukaemia development, however, additional oncogenic mutations are required. Therefore, T21 provides the opportunity to better understand leukaemogenesis in children. Here, we describe the increased risk of leukaemia in DS during childhood from a somatic evolutionary view. According to this idea, cancer is caused by a variation in inheritable phenotypes within cell populations that are subjected to selective forces within the tissue context. We propose a model in which the increased risk of leukaemia in DS children derives from higher rates of mutation accumulation, already present during fetal development, which is further enhanced by changes in selection dynamics within the fetal liver niche. This model could possibly be used to understand the rate-limiting steps of leukaemogenesis early in life.

TÍTULO / TITLE:   - The in vitro effects of hepatoblastoma cells on the growth and differentiation of blasts in transient abnormal myelopoiesis associated with Down syndrome

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REVISTA / JOURNAL:    - Leuk Res.2021 Jun;105:106570.doi: 10.1016/j.leukres.2021.106570.Epub 2021 Mar 31.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.leukres.2021.106570

AUTORES / AUTHORS: - Jun Miyauchi,Hiroyuki Kawaguchi

INSTITUCIÓN / INSTITUTION: - Department of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Chiba-ken, Japan. 

RESUMEN / SUMMARY: - Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome, which spontaneously resolves within several weeks or months after birth, may represent a special form of leukemia developing in the fetal liver (FL). To explore the role of hepatoblasts, one of the major constituents of the FL hematopoietic microenvironment, in the pathogenesis of TAM, we investigated the influence of a human hepatoblastoma cell line, HUH-6, on the in vitro growth and differentiation of TAM blasts. In a coculture system with membrane filters, which hinders cell-to-cell contact between TAM blasts and HUH-6 cells, the growth and megakaryocytic differentiation of TAM blast progenitors were increased in the presence of HUH-6 cells. The culture supernatant of HUH-6 cells contained hematopoietic growth factors, including stem cell factor (SCF) and thrombopoietin (TPO). The neutralizing antibody against SCF abrogated the growth-stimulating activity of the culture supernatant of HUH-6 cells, demonstrating that, among the growth factors produced by HUH-6 cells, SCF may be the major growth stimulator and that TPO may be involved in megakaryocytic differentiation, rather than growth, of TAM blasts. This suggests that hepatoblasts function in the regulation of the growth and differentiation of TAM blasts in the FL through the production of hematopoietic growth factors, including SCF and TPO, and are involved in the leukemogenesis of TAM.

TÍTULO / TITLE:   - Cohesin mutations in myeloid malignancies

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REVISTA / JOURNAL:    - Blood.2021 Jun 22;blood.2019004259.doi: 10.1182/blood.2019004259.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1182/blood.2019004259

AUTORES / AUTHORS: -

INSTITUCIÓN / INSTITUTION: - Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA. 

RESUMEN / SUMMARY: - Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation and DNA damage repair, and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1 and SMC3, as well as its modulators PDS5A/B, WAPL and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down Syndrome-associated acute megakaryoblastic leukemia (DS-AMKL), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and de-novo and secondary acute myeloid leukemia (AML). The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC), which are associated w. th changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Here, we will review the role of the cohesin complex in healthy and malignant hematopoiesis. We will discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.

TÍTULO / TITLE:   - Medulloblastoma Associated with Down Syndrome: From a Rare Event Leading to a Pathogenic Hypothesis

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REVISTA / JOURNAL:    - Diagnostics (Basel).2021 Feb 7;11(2):254.doi: 10.3390/diagnostics11020254

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AUTORES / AUTHORS: - Alessandra Boni et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy. 

RESUMEN / SUMMARY: - Down syndrome (DS) is the most common chromosome abnormality with a unique cancer predisposition syndrome pattern: a higher risk to develop acute leukemia and a lower incidence of solid tumors. In particular, brain tumors are rarely reported in the DS population, and biological behavior and natural history are not well described and identified. We report a case of a 10-year-old child with DS who presented with a medulloblastoma (MB). Histological examination revealed a classic MB with focal anaplasia and the molecular profile showed the presence of a CTNNB1 variant associated with the wingless (WNT) molecular subgroup with a good prognosis in contrast to our case report that has shown an early metastatic relapse. The nearly seven-fold decreased risk of MB in children with DS suggests the presence of protective biological mechanisms. The cerebellum hypoplasia and the reduced volume of cerebellar granule neuron progenitor cells seem to be a possible favorable condition to prevent MB development via inhibition of neuroectodermal differentiation. Moreover, the NOTCH/WNT dysregulation in DS, which is probably associated with an increased risk of leukemia, suggests a pivotal role of this pathway alteration in the pathogenesis of MB; therefore, this condition should be further investigated in future studies by molecular characterizations.

TÍTULO / TITLE:   - Blinatumomab as a successful and safe therapy in Down syndrome patients with relapsed/refractory b-precursor acute lymphoblastic leukaemia: Case reports and literature review

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REVISTA / JOURNAL:    - Pediatr Blood Cancer.2021 Jul;68(7):e29044.

Enlace a la Editora de la Revista https://doi.org/10.1002/pbc.29044

AUTORES / AUTHORS: - Federica Sora et al.

INSTITUCIÓN / INSTITUTION: - Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 

RESUMEN / SUMMARY: - Abstract not available

TÍTULO / TITLE:   - SON is necessary for proper vertebrate blood development

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REVISTA / JOURNAL:    - PLoS One.2021 Feb 25;16(2):e0247489. eCollection 2021.

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AUTORES / AUTHORS: - Rebecca L Belmonte et al

INSTITUCIÓN / INSTITUTION: - Department of Biological Sciences, California State University Chico, Chico, California, United States of America. 

RESUMEN / SUMMARY: - The gene SON is on human chromosome 21 (21q22.11) and is thought to be associated with hematopoietic disorders that accompany Down syndrome. Additionally, SON is an RNA splicing factor that plays a role in the transcription of leukemia-associated genes. Previously, we showed that mutations in SON cause malformations in human and zebrafish spines and brains during early embryonic development. To examine the role of SON in normal hematopoiesis, we reduced expression of the zebrafish homolog of SON in zebrafish at the single-cell developmental stage with specific morpholinos. In addition to the brain and spinal malformations we also observed abnormal blood cell levels upon son knockdown. We then investigated how blood production was altered when levels of son were reduced. Decreased levels of son resulted in lower amounts of red blood cells when visualized with lcr: GFP transgenic fish. There were also reduced thrombocytes seen with cd41:GFP fish, and myeloid cells when mpx:GFP fish were examined. We also observed a significant decrease in the quantity of T cells, visualized with lck:GFP fish. However, when we examined their hematopoietic stem and progenitor cells (HSPCs), we saw no difference in colony-forming capability. These studies indicate that son is essential for the proper differentiation of the innate and adaptive immune system, and further investigation determining the molecular pathways involved during blood development should elucidate important information about vertebrate HSPC generation, proliferation, and differentiation.

TÍTULO / TITLE:   - Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies

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REVISTA / JOURNAL:    - Cold Spring Harb Mol Case Stud. doi: 10.1101/mcs.a005975.Print 2021 Apr.

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AUTORES / AUTHORS: - Emilie Lalonde et al.

INSTITUCIÓN / INSTITUTION: - Department of Pathology and Laboratory Medicine, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. 

RESUMEN / SUMMARY: - Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a NUP98-KDM5A or a KMT2A-MLLT6 fusion, and the remaining harbored a CBFA2T3-GLIS2 fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic GATA1 mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.

TÍTULO / TITLE:   - Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic L

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REVISTA / JOURNAL:    - JAMA.2021 Mar 2;325(9):833-842.doi: 10.1001/jama.2021.0669.

Enlace a la Editora de la Revista https://doi.org/10.1001/jama.2021.0669

AUTORES / AUTHORS: - Patrick A Brown et al.

INSTITUCIÓN / INSTITUTION: - Department of Pathology and Laboratory Medicine, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. 

RESUMEN / SUMMARY: - Importance: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. Objective: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. Design, setting, and participants: This trial was a randomized phase 3 clinical trial conducted by the Children s Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). Interventions: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. Main outcome and measures: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. Results: Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping r

TÍTULO / TITLE:   - Lower BCL11B expression is associated with adverse clinical outcome for patients with myelodysplastic syndrome

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REVISTA / JOURNAL:    - Biomark Res.2021 Jun 10;9(1):46. doi: 10.1186/s40364-021-00302-y.

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AUTORES / AUTHORS: - Xin Huang et al.

INSTITUCIÓN / INSTITUTION: - Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan University, 510632, Guangzhou, PR China. 

RESUMEN / SUMMARY: - Myelodysplastic syndrome (MDS) is an aggressive and genetically heterogeneous disease with poor prognosis. Cellular immune disorder is a common characteristic of this disease and is thought to be related to clinical outcome. Alterations in T cell clonal expansion and T cell dysfunction has been detected in MDS patients. Little is known about whether there are immune biomarkers to evaluate the T cell alterations with clinical outcome. Previous studies have demonstrated that B-cell leukemia/lymphoma 11B (BCL11B) plays an important role in regulating T cell development and proliferation. In this study, the prognostic value of BCL11B for MDS patients was explored by analyzing RNA-seq data from 270 patients in two datasets in the Gene Expression Omnibus (GEO) database and real-time quantitative PCR data (qRT-PCR) of 31 bone marrow (BM) samples of MDS and 6 BM samples of patients with MDS progress to secondary acute myeloid leukemia (sAML) from our clinical center. The results demonstrated that BCL11B is significantly down-regulated in MDS patients as compared with healthy individuals (HIs). Importantly, lower BCL11B expression was found in MDS patients who were of high/very high risk, older than 60 y, or male and patients with sAML. Furthermore, low BCL11B expression appeared to be associated with poor overall survival (OS) for MDS patients, though the data were not yet significant enough at this point. In addition, BCL11B low-expressing MDS patients had shorter restricted mean survival time (RMST) than those with high BCL11B expression. Interestingly, BCL11B positively correlated with naive and activated memory CD4 + T cells, CD8 + T cells, and the T cell receptor complex genes CD3E and CD3G, but it negatively correlated with regulatory T cells (Treg). Additionally, co-occurrence of low BCL11B expression and CD3E and CD3G was associated with poor OS and shorter RMST. In conclusion, lower BCL11B expression in BM samples of MDS patients was associated with adverse clinica

Infectious diseases - Infecciones

TÍTULO / TITLE:   - Catheter-related blood stream infection caused by Mycobacterium chelonae in a child with myeloid leukemia associated with Down syndrome

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REVISTA / JOURNAL:    - Clin Case Rep.2020 Dec 18;9(2):835-840.doi: 10.1002/ccr3.3646.eCollection 2021 Feb.

Enlace a la Editora de la Revista https://doi.org/10.1002/ccr3.3646

AUTORES / AUTHORS: - Tomoko Fujikawa et al.

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan 

RESUMEN / SUMMARY: - Rapidly growing nontuberculous mycobacteria should be considered if GPRs gram-positive rods are detected in blood cultures 2-3 days after the blood sample collection.

TÍTULO / TITLE:   - Trisomy 21 impairs PGE2 production in dermal fibroblasts

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REVISTA / JOURNAL:    - Prostaglandins Other Lipid Mediat .2021 Apr;153:106524. doi: 10.1016/j.prostaglandins.2020.106524.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.prostaglandins.2020.106524

AUTORES / AUTHORS: - John O Marentette et al

INSTITUCIÓN / INSTITUTION: - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, USA; Linda Crnic Institute for Down Syndrome, Aurora, Colorado, USA  

RESUMEN / SUMMARY: - The triplication of human chromosome 21 results in Down syndrome (DS), the most common genetic form of intellectual disability. This aneuploid condition also results in an enhanced risk of a spectrum of comorbid conditions, such as leukemia, early onset Alzheimer s disease, and diabetes. Individuals with DS also display an increased incidence of wound healing complications and resistance to solid tumor development. Due to this unique phenotype and the involvement of eicosanoids in key comorbidities like poor healing and tumor development, we hypothesized that cells from DS individuals would display altered eicosanoid production. Using age- and sex-matched dermal fibroblasts we interrogated this hypothesis. Briefly, assessment of over 90 metabolites derived from cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome p450 systems revealed a possible deficiency in the COX system. Basal gene expression and Western blotting experiments showed significantly decreased gene expression of COX1 and 2, and COX2 protein abundance in DS fibroblasts compared to euploid controls. Further, using two different stressors, scratch wound or LPS, we found that DS fibroblasts could not upregulate COX2 abundance and prostaglandin E2 production. Together, these findings show that dermal fibroblasts from DS individuals have a deficient COX2 response, which may contribute to wound healing complications and tumor resistance in DS.

TÍTULO / TITLE:   - Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome

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REVISTA / JOURNAL:    - Front Immunol.2021 Jun 25;12:621440. doi: 10.3389/fimmu.2021.621440.eCollection 2021.

Enlace a la Editora de la Revista https://doi.org/10.3389/fimmu.2021.621440

AUTORES / AUTHORS: - Tomer Illouz et al.

INSTITUCIÓN / INSTITUTION: - The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel. 

RESUMEN / SUMMARY: - The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.

Molecular biology/Biochemistry - Biología molecular/Bioquímica

TÍTULO / TITLE:   - Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

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REVISTA / JOURNAL:    - Int J Mol Sci..2021 Jun 3;22(11):6047.doi: 10.3390/ijms22116047.

Enlace a la Editora de la Revista https://doi.org/10.3390/ijms22116047

AUTORES / AUTHORS: - Mattias F Lindberg, Laurent Meijer

INSTITUCIÓN / INSTITUTION: - Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France. 

RESUMEN / SUMMARY: - Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer s disease and related diseases, tauopathies, dementia, Pick s disease, Parkinson s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

TÍTULO / TITLE:   - Cohesin mutations in myeloid malignancies

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REVISTA / JOURNAL:    - Blood.2021 Jun 22;blood.2019004259.doi: 10.1182/blood.2019004259.Online ahead of print.

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AUTORES / AUTHORS: - Joahnn-Christoph Jann,Zuzana Tothova

INSTITUCIÓN / INSTITUTION: - Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA. 

RESUMEN / SUMMARY: - Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation and DNA damage repair, and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1 and SMC3, as well as its modulators PDS5A/B, WAPL and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down Syndrome-associated acute megakaryoblastic leukemia (DS-AMKL), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and de-novo and secondary acute myeloid leukemia (AML). The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC), which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Here, we will review the role of the cohesin complex in healthy and malignant hematopoiesis. We will discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.

Neurobiology - Neurobiología

TÍTULO / TITLE:   - : Signalling pathways contributing to learning and memory deficits in the Ts65Dn mouse model of Down syndrome

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REVISTA / JOURNAL:    - Neuronal Signal.2021 Mar 12;5(1):NS20200011.doi: 10.1042/NS20200011.eCollection 2021 Apr.

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AUTORES / AUTHORS: - Aime Freeburn et al.

INSTITUCIÓN / INSTITUTION: - Discipline of Pharmacology and Therapeutics, National University of Ireland, Galway, Republic of Ireland. 

RESUMEN / SUMMARY: - Down syndrome (DS) is a genetic trisomic disorder that produces life-long changes in physiology and cognition. Many of the changes in learning and memory seen in DS are reminiscent of disorders involving the hippocampal/entorhinal circuit. Mouse models of DS typically involve trisomy of murine chromosome 16 is homologous for many of the genes triplicated in human trisomy 21, and provide us with good models of changes in, and potential pharmacotherapy for, human DS. Recent careful dissection of the Ts65Dn mouse model of DS has revealed differences in key signalling pathways from the basal forebrain to the hippocampus and associated rhinal cortices, as well as changes in the microstructure of the hippocampus itself. In vivo behavioural and electrophysiological studies have shown that Ts65Dn animals have difficulties in spatial memory that mirror hippocampal deficits, and have changes in hippocampal electrophysiological phenomenology that may explain these differences, and align with expectations generated from in vitro exploration of this model. Finally, given the existing data, we will examine the possibility for pharmacotherapy for DS, and outline the work that remains to be done to fully understand this system

TÍTULO / TITLE:   - Time-dependent diffusion MRI probes cerebellar microstructural alterations in a mouse model of Down syndrome

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REVISTA / JOURNAL:    - Brain Commun.2021 Apr 5;3(2):fcab062. doi: 10.1093/braincomms/fcab062.eCollection 2021. DOI:10.10

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AUTORES / AUTHORS: - Dan Wu et al.

INSTITUCIÓN / INSTITUTION: - Key Laboratory for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang 310027, China. 

RESUMEN / SUMMARY: - The cerebellum is a complex system with distinct cortical laminar organization. Alterations in cerebellar microstructure are common and associated with many factors such as genetics, cancer and ageing. Diffusion MRI (dMRI) provides a non-invasive tool to map the brain structural organization, and the recently proposed diffusion-time (td )-dependent dMRI further improves its capability to probe the cellular and axonal/dendritic microstructures by measuring water diffusion at multiple spatial scales. The td -dependent diffusion profile in the cerebellum and its utility in detecting cerebellar disorders, however, are not yet elucidated. Here, we first deciphered the spatial correspondence between dMRI contrast and cerebellar layers, based on which the cerebellar layer-specific td -dependent dMRI patterns were characterized in both euploid and Ts65Dn mice, a mouse model of Down syndrome. Using oscillating gradient dMRI, which accesses diffusion at short td s by modulating the oscillating frequency, we detected subtle changes in the apparent diffusivity coefficient of the cerebellar internal granular layer and Purkinje cell layer of Ts65Dn mice that were not detectable by conventional pulsed gradient dMRI. The detection sensitivity of oscillating gradient dMRI increased with the oscillating frequency at both the neonatal and adult stages. The td -dependence, quantified by ΔADC map, was reduced in Ts65Dn mice, likely associated with the reduced granule cell density and abnormal dendritic arborization of Purkinje cells as revealed from histological evidence. Our study demonstrates superior sensitivity of short-td diffusion using oscillating gradient dMRI to detect cerebellar microstructural changes in Down syndrome, suggesting the potential application of this technique in cerebellar disorders.

Neurology - Neurología

TÍTULO / TITLE:   - RELA Fusion-Positive Ependymoma in a Child with Down Syndrome: A Case Report

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REVISTA / JOURNAL:    - Pediatr Neurosurg.2021;56(2):146-151.Epub 2021 Mar 9.

Enlace a la Editora de la Revista https://doi.org/10.1159/000511673

AUTORES / AUTHORS: - Julie L Chan et al.

INSTITUCIÓN / INSTITUTION: - Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 

RESUMEN / SUMMARY: - Introduction: Down syndrome (DS) is the most common multiple malformation syndrome in humans and is associated with an increased risk of childhood malignancy, particularly leukemia. Incidence of brain tumors in patients with DS is limited to sporadic cases. We report the first case of a RELA fusion-positive ependymoma in a 3-year-old boy with DS. Case presentation: Imaging prompted by new left-sided hemiparesis demonstrated an 8-cm hemorrhagic right temporal-parietal mass. Subsequent image-complete resection confirmed a RELA fusion-positive anaplastic ependymoma with 90% OLIG2 staining. Postoperatively, the patient, unfortunately, experienced fatal recurrence and drop metastases with leptomeningeal involvement. Conclusion: To our knowledge, this is the first reported case of a confirmed RELA fusion-positive ependymoma in a child with DS. We discuss this finding in the context of intracranial tumors in children with DS, as well as the finding of 90% positive OLIG2 expression and its potential as a prognostic marker.

Physiotherapy - Fisioterapia

TÍTULO / TITLE:   - Multi-segmental postural control patterns in Down syndrome

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REVISTA / JOURNAL:    - Clin Biomech (Bristol, Avon).2021 Feb;82:105271. doi: 10.1016/j.clinbiomech.2021.105271.Epub 2021

Enlace a la Editora de la Revista https://doi.org/10.1016/j.clinbiomech.2021.105271

AUTORES / AUTHORS: - Matteo Zago

INSTITUCIÓN / INSTITUTION: - Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy. 

RESUMEN / SUMMARY: - atients with Down Syndrome (DS) exhibit less efficient and unstable standing postural control. The specificities of somatosensorial deficits might result in a different utilization of resources and in distinct whole-body kinematic patterns, to date still unexplored. In this paper we aim at addressing multi-segmental coordination patterns in people with DS while maintaining standing balance under different visual conditions (open and closed eyes). Methods: This cross-sectional observational cohort study involved two groups of 23 patients with DS and 12 healthy controls. A 30-s standing balance test allowed to extract (i) the length of the trajectory of the center-of-pressure sway and 95% confidence ellipse area from Ground Reaction forces, and (ii) Principal Movement (PM) components from full-body motion kinematics; the latter were obtained exploiting a Principal Component Analysis-based approach, also embracing a motor-control perspective through the evaluation of the number of modifications applied by the neuromuscular controller on segments acceleration. Findings: Trajectory length was significantly higher in patients; 95% ellipse confidence area did not differ between groups/condition. Postural movement components differed in people with DS from healthy controls not only in the "observable", behavioural phenotype (PM3 and PM8), but also in the amount of activation of the associated control (PM1 to PM8, over-activated in DS) in all spatial directions. Interpretation: Results reinforced the prevalence of a medio-lateral hip strategy (instead of an ankle strategy) in maintaining postural stability. Most important, they revealed a less frequent activation of postural patterns in all spatial directions.

TÍTULO / TITLE:   - The Effects of 20 Weeks of Side-Alternating Vibration Therapy on Physical Function, Bone and Muscle Health in Adolescents with Down Syndrome

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REVISTA / JOURNAL:    - Phys Occup Ther Pediatr.2021;41(1):44-55. doi: 10.1080/01942638.2020.1758983.Epub 2020 Apr 28.

Enlace a la Editora de la Revista https://doi.org/10.1080/01942638.2020.1758983

AUTORES / AUTHORS: - Silmara Gusso et al.

INSTITUCIÓN / INSTITUTION: - : Liggins Institute, University of Auckland, Auckland, New Zealand. 

RESUMEN / SUMMARY: - Aims: To evaluate the effects of side-alternating vibration therapy on physical function and body composition in adolescents with Down syndrome. Methods: Fourteen adolescents (8 males) with Down syndrome (mean ± SD age: 15.5 ± 2.3 years) performed vibration treatment nine minutes daily, four times per week, for 20 weeks on a Galileo vibration platform. Data were collected at baseline and after 20 weeks of intervention. Assessments included six-minute walk test, muscle function (force plate), whole-body dual-energy X-ray absorptiometry and peripheral quantitative computed tomography of the non-dominant tibia. Results: After 20 weeks, participants increased their distance walked in the six-minute walk test (p = 0.009), 2-leg single jump efficiency (p = 0.024) and jump velocity (p = 0.046). Participants also increased their power (p = 0.034) and reduced the time taken during the chair rise test (p < 0.001). At the total body level, increases were seen in bone mineral density (p = 0.004), bone mineral content (p = 0.043), fat free mass (p = 0.013) and lean mass (p = 0.021). Conclusion: Side-alternating vibration therapy was associated with increases in physical function and muscle mass with no effects on bone health in adolescents with Down syndrome.

TÍTULO / TITLE:   - Efficacy and safety of methylphenidate on attention deficit hyperactivity disorder in children with Down syndrome

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REVISTA / JOURNAL:    - J Intellect Disabil Res.2021 Apr 20. doi: 10.1111/jir.12832.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1111/jir.12832

AUTORES / AUTHORS: - M Roche et al

INSTITUCIÓN / INSTITUTION: - 1CRB BioJeL, Institut Jérôme Lejeune, Paris, France. 

RESUMEN / SUMMARY: - Background: Attention deficit hyperactivity disorder (ADHD) is a common co-morbidity that affects up to 44% of children with Down syndrome (DS). There is a need for reliable, good quality research on the use of methylphenidate within this population. The objective of this study is to report our experience regarding the management of ADHD in these children using methylphenidate. Methods: This study is a retrospective observation of 21 children with DS, followed at Jérôme Lejeune Institute between 2000 and 2018. The diagnosis of ADHD was made using the Diagnostic and Statistical Manual of Mental Disorders criteria. Efficacy was measured as response or non-response on two main symptoms: attention/concentration and hyperactivity/impulsivity. Safety was evaluated by the presence or absence of side effects. Results: Sixteen out of the 21 children (76%) showed improvement with methylphenidate. The average age of treatment onset in responding children was 8 years and 10 months versus 6 years and 3 months in non-responders (P = 0.05). Average dose/weight was significantly different in responders and non-responders (0.82 vs. 0.54 mg/kg/day, respectively; P = 0.03). Twelve children out of 21 (57%) experienced side effects; only three experienced side effects severe enough to require treatment interruption. Most common side effects were loss of appetite and difficulties in falling asleep. Conclusion: Methylphenidate was effective and safe in treating ADHD in 76% of cases in children with DS, with few serious side effects to report. Early diagnosis of ADHD is important to improve the quality of life, learning, inclusion and socialisation of children with DS.

Prenatal diagnosis - Diagnóstico

TÍTULO / TITLE:   - Delivering a new diagnosis of Down syndrome: Parent experience

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Jul 1. doi: 10.1002/ajmg.a.62408.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.62408

AUTORES / AUTHORS: - April Lehman et al

INSTITUCIÓN / INSTITUTION: - Division of Genetic, Genomic and Metabolic Disorders, Detroit Medical Center Children s Hospital of Michigan, and Central Michigan University, Detroit, Michigan, USA. 

RESUMEN / SUMMARY: - Down syndrome is one of the most common chromosomal abnormalities. In 2014, in conjunction with the passing of House Bill 552, the Ohio Department of Health released a Down syndrome fact sheet to be given to parents at time of diagnosis to answer basic questions regarding the diagnosis. Our survey helps us to understand parental experience in receiving a new Down syndrome diagnosis including information provided. An electronic survey was created and distributed to members of established Down syndrome parent groups in Ohio. Questions assessed the parental experience at the time of receiving a Down syndrome. We also looked at parent perceptions after the implementation of a Down syndrome fact sheet. Responses were collected regarding experience at the time of diagnosis and broadly categorized into a trichotomy of positive experience (>5), neutral experience (=5), and negative experience (<5). Parents report an overall negative experience when receiving a new diagnosis of Down syndrome (mean of 4 on scale of 0-10), which did not increase after 2014 (p >0.05). Eighty-five percent of parents with children born in 2014 or after report that they did not receive the Ohio Department of Health Down syndrome fact sheet. Legislation regarding a diagnosis of Down syndrome exists in 20 states with significant variability, readability of those fact sheets. Legislation requiring accurate information be given to families was not always followed, and printed literature alone did not correlate with improved parent experience; additional efforts are necessary to ensure that the experience receiving a diagnosis of Down syndrome is not a negative one.

TÍTULO / TITLE:   - Prenatal Screening of Trisomy 21: Could Oxidative Stress Markers Play a Role?

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REVISTA / JOURNAL:    - J Clin Med.2021 May 28;10(11):2382. doi: 10.3390/jcm10112382.

Enlace a la Editora de la Revista https://doi.org/10.3390/jcm10112382

AUTORES / AUTHORS: - ngelika Buczyńska

INSTITUCIÓN / INSTITUTION: - Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland.  

RESUMEN / SUMMARY: - Despite significant progress in trisomy 21 (T21) diagnostic tools, amniocentesis is still used for the confirmation of an abnormal fetal karyotype. Invasive tests carry the potential risk of miscarriage; thus, screening biomarkers are commonly used before undergoing invasive procedures. In our study, we investigated the possible application of oxidative stress markers in the prenatal screening of trisomy 21. The DNA/RNA oxidative stress damage products (OSDPs), advanced glycation end (AGE) products, ischemia-modified albumin (IMA), alfa-1-antitrypsin (A1AT), asprosin, and vitamin D concentrations were measured in both maternal plasma and amniotic fluid in trisomy 21 (T21) and euploid pregnancies. The obtained results indicated increased levels of DNA/RNA OSDPs and asprosin with simultaneous decreased levels of vitamin D and A1AT in the study group. The diagnostic utility of the plasma measurement based on the area under the received operative characteristic (ROC) curve (AUC) calculation of asprosin (AUC = 0.965), IMA (AUC = 0.880), AGE (AUC = 0.846) and DNA/RNA OSDPs (AUC = 0.506) in T21 screening was demonstrated. The obtained results indicate a potential role for the application of oxidative stress markers in the prenatal screening of T21 with the highest screening utility of plasma asprosin.

Psychiatry - Psiquiatría

TÍTULO / TITLE:   - Psychotropic medication use for adults and older adults with intellectual disability; selective review, recommendations and future directions

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REVISTA / JOURNAL:    - Prog Neuropsychopharmacol Biol Psychiatry.2021 Jan 10;104:110017. doi: 10.1016/j.pnpbp.2020.110017.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.pnpbp.2020.110017

AUTORES / AUTHORS: - Stephen I Deutsch1,Jessica A Burket2

INSTITUCIÓN / INSTITUTION: - Department of Psychiatry and Behavior Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, Virginia 23507, USA 

RESUMEN / SUMMARY: - A growing expert consensus has emerged to guide prescribing behavior and monitoring of psychotropic medications in adults and older adults with intellectual disability (ID). However, there is little empirically-derived evidence to inform physician selection of specific categories of psychotropic medication for treatment of "challenging" behaviors in this vulnerable population (such as aggression to self, others and objects; self-injurious behaviors; repetitive stereotypic behaviors; and hyperactivity). Difficulties with application of formal definitional diagnostic criteria and reliable assignment of psychiatric diagnoses to adults with ID, which is often difficult due to their poor communication skills, contribute to confusion and uncertainty surrounding medication selection. Long-term administration of antipsychotic medications are commonly prescribed for challenging behaviors in spite of their questionable long-term efficacy, leading some to suggest that their "episodic" short-term administration for imminent dangerousness to self and others or when difficult-to-find residential placements are threatened is preferred to their long-term administration. Further, literature supports engagement of interdisciplinary treatment teams to seek causes for challenging behaviors, formulate non-pharmacological psychosocial and behavioral plans for their amelioration and, if medications are initiated, convene regular medication monitoring to identify "drug-related problems". Medication monitoring is important because medication-related adverse events cause or contribute to challenging behaviors, which can sometimes be improved by dose reduction, medication discontinuation and/or elimination of polypharmacy and co-pharmacy. Importantly, medications themselves may interfere with self-reported measures of Quality of Life. The data clearly highlight the need for well-designed randomized controlled clinical trials in samples that are homogeneous with respect to severity of ID and r

Quality of life - Calidad de vida

TÍTULO / TITLE:   - Mind-Mindedness and Stress in Parents of Children with Developmental Disorders

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REVISTA / JOURNAL:    - J Autism Dev Disord.2021 Feb;51(2):600-612. doi: 10.1007/s10803-020-04570-9.

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AUTORES / AUTHORS: - Fionnuala Larkin et al.

INSTITUCIÓN / INSTITUTION: - Department of Psychology, University of York, Heslington, York, YO10 5DD, England.  

RESUMEN / SUMMARY: - Relations between mind-mindedness (assessed using the describe-your-child interview) and stress were investigated in parents of children with developmental disorders (ADHD, n = 51, ASD, n = 23, Down s Syndrome, n = 38, and 22q11.2 Deletion Syndrome, 22q11.2DS, n = 32) and typically-developing children (n = 89). Mind-mindedness did not differ across diagnostic groups, and mind-mindedness predicted parenting stress across groups. Parenting stress was lowest in the typically-developing and Down s Syndrome groups. Across all groups, mind-minded and positive descriptions predicted lower parenting stress, and negative descriptions predicted higher stress. In the developmental disorder groups, describing the children with reference to their disorder was negatively correlated with mind-mindedness. Results are discussed with regard to interventions for families where children have developmental disorders.

TÍTULO / TITLE:   - Prevalence of Common Disease Conditions in a Large Cohort of Individuals With Down Syndrome in the United States

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REVISTA / JOURNAL:    - J Patient Cent Res Rev.2021 Apr 19;8(2):86-97. doi: 10.17294/2330-0698.1824.eCollection Spring2021

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AUTORES / AUTHORS: - Brian Chicoine et al.

INSTITUCIÓN / INSTITUTION: - Advocate Medical Group Adult Down Syndrome Center, Park Ridge, IL 

RESUMEN / SUMMARY: - Purpose: Given the current life expectancy and number of individuals living with Down syndrome (DS), it is important to learn common occurrences of disease conditions across the developmental lifespan. This study analyzed data from a large cohort of individuals with DS in an effort to better understand these disease conditions, inform future screening practices, tailor medical care guidelines, and improve utilization of health care resources. Methods: This retrospective, descriptive study incorporated up to 28 years of data, compiled from 6078 individuals with DS and 30,326 controls matched on age and sex. Data were abstracted from electronic medical records within a large Midwestern health system. Results: In general, individuals with DS experienced higher prevalence of testicular cancer, leukemias, moyamoya disease, mental health conditions, bronchitis and pneumonia, gastrointestinal conditions, thyroid disorder, neurological conditions, atlantoaxial subluxation, osteoporosis, dysphagia, diseases of the eyes/adnexa and of the ears/mastoid process, and sleep apnea, relative to matched controls. Individuals with DS experienced lower prevalence of solid tumors, heart disease conditions, sexually transmitted diseases, HIV, influenza, sinusitis, urinary tract infections, and diabetes. Similar rates of prevalence were seen for lymphomas, skin melanomas, stroke, acute myocardial infarction, hepatitis, cellulitis, and osteoarthritis. Conclusions: While it is challenging to draw a widespread conclusion about comorbidities in individuals with Down syndrome, it is safe to conclude that care for individuals with DS should not automatically mirror screening, prevention, or treatment guidelines for the general U.S. population. Rather, care for those with DS should reflect the unique needs and common comorbidities of this population.

TÍTULO / TITLE:   - Neonatal complications of Down syndrome and factors necessitating intensive care

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Feb;185(2):336-343. doi: 10.1002/ajmg.a.61948.Epub 2020 Oct 31.

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.61948

AUTORES / AUTHORS: - Katelyn Seither et al.

INSTITUCIÓN / INSTITUTION: - Perinatal Institute, Division of Neonatology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio, USA. 

RESUMEN / SUMMARY: - Limited knowledge exists about how frequently newborns with Down syndrome receive a prenatal diagnosis, require intensive care, and what surgical and medical factors are contributory. A retrospective cohort study was performed for patients with a diagnosis of Down syndrome born in 2013 and 2014 who sought care at Cincinnati Children s Hospital Medical Center during the first year of life. Data were extracted from the electronic medical record through the first year of life including need for intensive care as a newborn, prenatal diagnosis, and medical and surgical complications. Of the 129 patients in the study, 65% required intensive care as newborns. The presence of a structural abnormality that required surgical correction in the neonatal period and certain types of congenital heart disease not requiring surgical intervention in the neonatal period were positively associated with the need for intensive care. A minority of infants, 8%, had a confirmed prenatal diagnosis. A majority of newborns with Down syndrome required intensive care following birth while a minority had any concern for the diagnosis prenatally. Improving prenatal diagnostic rates would allow for better prenatal counseling and delivery planning, while targeting therapeutic interventions for this population is needed to improve outcomes.

TÍTULO / TITLE:   - Health care transition for individuals with Down syndrome: A needs assessment

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Jun 24.doi: 10.1002/ajmg.a.62403.Online ahead of print

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.62403

AUTORES / AUTHORS: - Jordan Seth VanZant,Andrew A McCormick

INSTITUCIÓN / INSTITUTION: - Department of Pediatrics, UPMC Children s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA. 

RESUMEN / SUMMARY: - Transition to adulthood is a multifaceted process that requires integration of numerous domains within a young person s life, including their health care. For children with special health care needs, the transition process can be markedly more difficult to navigate. This is especially true for children with Down syndrome (DS) who receive fewer transition planning services. The aim of this needs assessment was to identify current trends, potential gaps, and areas for targeted intervention within the current transition landscape for individuals with DS. We utilized DS-Connect, a National Institutes of Health (NIH) funded family/self-advocate survey repository, as a platform to recruit respondents to the "Transition to Adulthood" survey. Sixty-five respondents (64 parents and 1 caregiver) completed the survey. Responses indicated that 42% of respondents reported comfort in the transition process, but 5% or less reported completing one of the core transition outcomes: transition readiness assessment, portable medical summary, or written transition plan. These findings translated across other domains of respondents lives. While many individuals with DS and their caregivers are aware of the transition process, there appears to be a disconnect between the introduction of transition concepts and an actualization of transition outcomes necessary for success.

TÍTULO / TITLE:   - Down syndrome caregivers support needs: a mixed-method participatory approach

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REVISTA / JOURNAL:    - J Intellect Disabil Res.2021 Jan;65(1):60-76. doi: 10.1111/jir.12791.Epub 2020 Nov 3.

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AUTORES / AUTHORS: - K M Hart,N Neil

INSTITUCIÓN / INSTITUTION: - Faculty of Education, Western University, London, Ontario, Canada. 

RESUMEN / SUMMARY: - Background: The purpose of the study was to explore the support needs of caregivers of children with Down syndrome from their perspective using a mixed-method participatory research approach.. Methods: Concept mapping methodology was used to obtain caregiver perspectives. Twenty-one caregivers answered the question Are parents of individuals with Down syndrome supported, why or why not? Caregivers were involved in the analysis of the data through concept mapping procedures.. Results: Sorted data were analysed with multidimensional scaling and cluster analysis. Participants generated eight thematic clusters representing the support needs of caregivers of children with Down syndrome. The themes included online and social support, support system gaps, areas where support is lacking, Down syndrome community support, financial support, advocacy needs, educational support and concerns for community programming.. Conclusions: Themes align with previous research on support needs of parents of children with developmental disabilities. The study highlights the need for more local organisations to offer support that is affordable and accessible for families. Results will support future programme planning for services for individuals caring for those with Down syndrome.

TÍTULO / TITLE:   - Medical conditions of children and young people with Down syndrome

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REVISTA / JOURNAL:    - J Intellect Disabil Res.2021 Feb;65(2):199-209. doi: 10.1111/jir.12804.Epub 2021 Jan 10.

Enlace a la Editora de la Revista https://doi.org/10.1111/jir.12804

AUTORES / AUTHORS: - D Valentini et al.

INSTITUCIÓN / INSTITUTION: - Pediatric Unit, Bambino Gesù Children s Hospital-IRCCS, Rome, Italy. 

RESUMEN / SUMMARY: - Background: The life expectancy of people with Down syndrome (DS) has significantly increased in the last decades. We describe the congenital malformations and main comorbidities of a cohort of children and young people with DS and analyse their differences according to age and gender groups.. Methods: This retrospective cross-sectional study was conducted at DS centre of Bambino Gesù Children s Hospital in Rome (Italy). The period for reviewing all electronic health records ran from July 2016 to September 2017. We collected data on clinical conditions and compared them with the general paediatric population. Moreover, we compared the main comorbidities, dental diseases and body mass index data between age groups. Results: Seven hundred sixty-three children and young people with DS included in this study were aged 7.45 ± 5.49 years. Gender distribution included 58.19% male patients. The majority of our population (71.04%) came from central regions of Italy. Respiratory diseases (19%), congenital heart defects (72.23%), malocclusions (58.62%), astigmatism (20.31%), farsightedness (16.51%), near-sightedness (12.19%) and autoimmune hypothyroidism (3.28%) were more frequent in our population compared with the typical paediatric population. Upper respiratory tract infections and underweight were significantly more frequent in the youngest children, whereas dental diseases, refractive errors, obesity and autoimmune hypothyroidism increased over age.. Conclusions: Children and young people with DS present a high prevalence of potentially treatable medical conditions making multidisciplinary teams a mandatory need for this population.

Respiratory - Respiratorio

TÍTULO / TITLE:   - Efficacy and adherence of noninvasive ventilation treatment in children with Down syndrome

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REVISTA / JOURNAL:    - Pediatr Pulmonol.2021 Jun;56(6):1704-1715. doi: 10.1002/ppul.25308.Epub 2021 Mar 17.

Enlace a la Editora de la Revista https://doi.org/10.1002/ppul.25308

AUTORES / AUTHORS: - Lauren MacDonagh et al.

INSTITUCIÓN / INSTITUTION: - School of Medicine, Department of Health Sciences, University College Dublin, Belfield, Dublin, Ireland. 

RESUMEN / SUMMARY: - Abstract. Objective: Children with Down syndrome (DS) have an increased prevalence of obstructive sleep apnea (OSA). Noninvasive ventilation (NIV) is a common modality of OSA treatment in this cohort. This study aimed to measure adherence and efficiency of NIV delivery in children with DS. Study design: This was a retrospective cohort study involving 106 children with confirmed OSA and home NIV with downloadable data capacity. Children were divided into DS (n = 44) and non-DS cohorts (n = 62). Adherence, clinical outcomes apnea-hypopnoea index (AHI), positive airway pressure delivery, and leakage were recorded and compared between DS and non-DS cohorts and within the DS cohort based on past surgical history. Results: Significantly greater NIV usage was observed in the DS cohort, they showed more consistent use with an increased percentage of days used relative to their non-DS counterparts (78.95 ± 2.26 vs. 72.11 ± 2.14, p = .031). However, despite greater usage, poorer clinical outcomes in the form of increased AHI (p = .0493) was observed in the DS cohort, where significantly greater leakage was also shown 41.00 ± 1.61 L/min versus 36.52 ± 1.18 L/min (p = .022). Twenty children with DS had prior cardiac surgery; compliance across all parameters was significantly reduced relative to those without. Conclusion: These data confirm that satisfactory NIV adherence is achievable in children with DS. However, we have identified excessive system leak at the machine-patient interface as a factor, which could undermine NIV efficacy in children with DS.

TÍTULO / TITLE:   - Children with Down syndrome and sleep disordered breathing display impairments in ventilatory control

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REVISTA / JOURNAL:    - Sleep Med.2021 Jan;77:161-169. doi: 10.1016/j.sleep.2020.12.005.Epub 2020 Dec 8.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.sleep.2020.12.005

AUTORES / AUTHORS: - Leon S Siriwardhana et al.

INSTITUCIÓN / INSTITUTION: - 1The Ritchie Centre, Department of Paediatrics, Monash University and Hudson Institute of Medical Research, Melbourne, Australia. 

RESUMEN / SUMMARY: - Objectives: To investigate the role of ventilatory control instability (i.e. loop gain) in children with Down syndrome and sleep disordered breathing. Methods: Children (3-19 years) with Down syndrome and sleep disordered breathing (n = 14) were compared with typically developing children (n = 14) matched for age, sex and sleep disordered breathing severity. All children underwent overnight polysomnography. Spontaneous sighs were identified and a 180s analysis window (60s pre-sigh to 120s post-sigh) containing flow measurements and oxygen saturation were created. Loop gain, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. Results; Loop gain was significantly higher in children with Down syndrome compared to matched typically developing children (median loop gain [interquartile range]: 0.36 [0.33, 0.55] vs 0.32 [0.24, 0.38]; P = 0.0395). While children with Down syndrome also had significantly lower average oxygen saturation associated within each analysis window compared to typically developing children (mean ± standard deviation: 96.9 ± 1.3% vs 98.0 ± 1.0%; P = 0.0155), loop gain was not related to polysomnographic measures of hypoxia. Conclusions: Higher loop gain in children with Down syndrome and sleep disordered breathing indicates that these children have more unstable ventilatory control, compared to age, sex and sleep disordered breathing severity matched typically developing children. This may be due to an inherent impairment in ventilatory control in children with Down syndrome contributing to their increased risk of sleep disordered breathing which may inform alternative treatment options for this population.

TÍTULO / TITLE:   - Sleep Architecture in Children With Down Syndrome With and Without Obstructive Sleep Apnea

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REVISTA / JOURNAL:    - Otolaryngol Head Neck Surg.2021 May;164(5):1108-1115. doi: 10.1177/0194599820960454.Epub 2020 Oct

Enlace a la Editora de la Revista https://doi.org/10.1177/0194599820960454

AUTORES / AUTHORS: - Christine H Heubi et al

INSTITUCIÓN / INSTITUTION: - Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio, USA. 

RESUMEN / SUMMARY: - Objective: To characterize polysomnographic sleep architecture in children with Down syndrome and compare findings in those with and without obstructive sleep apnea. Study design: Case series with retrospective review.. Setting: Single tertiary pediatric hospital (2005-2018). Methods: We reviewed the electronic health records of patients undergoing polysomnography who were referred from a specialized center for children with Down syndrome (age, ≥12 months). Continuous positive airway pressure titration, oxygen titration, and split-night studies were excluded.. Results: A total of 397 children were included (52.4% male, 81.6% Caucasian). Mean age at the time of polysomnography was 4.7 years (range, 1.4-14.7); 79.4% had obstructive sleep apnea. Sleep variables were reported as mean (SD) values: sleep efficiency, 85% (11%); sleep latency, 29.8 minutes (35.6); total sleep time, 426 minutes (74.6); rapid eye movement (REM) latency, 126.8 minutes (66.3); time spent in REM sleep, 22% (7%); arousal index, 13.3 (5); and time spent supine, 44% (28%). There were no significant differences between those with obstructive sleep apnea and those without. Sleep efficiency <80% was seen in 32.5%; 34.3% had a sleep latency >30 minutes; 15.9% had total sleep time <360 minutes; and 75.6% had an arousal index >10/h. Overall, 69.2% had ≥2 metrics of poor sleep architecture. REM sleep time <20% was seen in 35.3%. REM sleep time decreased with age. Conclusion: In children with Down syndrome, 32.5% had sleep efficiency <80%; 75.6% had an elevated arousal index; and 15.9% had total sleep time <360 minutes. More than a third of the patients had ≥3 markers of poor sleep architecture. There was no difference in children with or without obstructive sleep apnea.

TÍTULO / TITLE:   - Respiratory and otolaryngological disorders in Down syndrome from one center in Brazil

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REVISTA / JOURNAL:    - Am J Med Genet A.2021 Aug;185(8):2356-2360. doi: 10.1002/ajmg.a.62244.Epub 2021 May 28.

Enlace a la Editora de la Revista https://doi.org/10.1002/ajmg.a.62244

AUTORES / AUTHORS: - Beatriz Elizabeth Bagatin Veleda Bermudezet al

INSTITUCIÓN / INSTITUTION: - Down Syndrome Outpatient Clinic, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil. 

RESUMEN / SUMMARY: - Down syndrome (DS) is the most common chromosomal condition. Anatomical and functional variations in the upper and lower airways are component manifestations of the syndrome and increase the risk of various medical problems. The objective of this study was to determine the prevalence of otorhinolaryngological and respiratory diseases in a DS outpatient clinic over a 3-year period. Medical records data from 1207 patients were retrospectively reviewed. Newborn Hearing Screening was positive in 7.1% of patients. Brainstem auditory evoked potential was performed in 1101 children and showed a hearing loss of 19.8% in the first year. It was positive in 21% of 1021 exams. Audiometry was altered in 64 of 994 exams (6.4%), showing a conductive loss in 90%. Adenotonsillectomy was performed in 308 (25.5%) patients, and 169 (14.0%) required serous otitis ventilation tubes. Asthma was observed in 140 (11.6%) patients, and allergic rhinitis in 544 (56.6%). There were hospitalizations for invasive infection in 480 (39.8%) children, and two (0.2%) patients had severe septicemia from pulmonary focus. Five (0.4%) infants had laryngotracheomalacia, and one patient had anomalous right tracheal bronchus. Recognizing the prevalence of respiratory and otorhinolaryngological disorders in patients with DS allows the promotion of optimal follow-up and early treatment, preventing the development of sequelae.

TÍTULO / TITLE:   - Redefining Success by Focusing on Failures After Pediatric Hypoglossal Stimulation in Down Syndrome

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REVISTA / JOURNAL:    - Laryngoscope.2021 Jul;131(7):1663-1669. doi: 10.1002/lary.29290.Epub 2020 Dec 2.

Enlace a la Editora de la Revista https://doi.org/10.1002/lary.29290

AUTORES / AUTHORS: - Phoebe K Yu et al.

INSTITUCIÓN / INSTITUTION: - Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.PMID: 33264427 

RESUMEN / SUMMARY: - Objectives/hypothesis: Patients with Down syndrome have a high incidence of obstructive sleep apnea (OSA) and limited treatment options. Hypoglossal stimulation has shown efficacy but has not yet been approved for pediatric populations. Our objective is to characterize the therapy response of adolescent patients with down syndrome and severe OSA who underwent hypoglossal stimulation. Study design: Prospective longitudinal trial.. Methods: We are conducting a multicenter single-arm trial of hypoglossal stimulation for adolescent patients with Down syndrome and severe OSA. Interim analysis was performed to compare objective sleep and quality of life outcomes at 12 months postoperatively for the first 20 patients.. Results: The mean age was 15.5 and baseline AHI 24.2. Of the 20 patients, two patients (10.0%) had an AHI under 1.5 at 12 months; nine patients of 20 (45.0%) under five; and 15 patients of 20 (75.0%) under 10. The mean decrease in AHI was 15.1 (P < .001). Patients with postoperative AHI over five had an average baseline OSA-18 survey score of 3.5 with an average improvement of 1.7 (P = .002); in addition, six of these patients had a relative decrease of apneas compared to hypopneas and seven had an improvement in percentage of time with oxygen saturation below 90%. Conclusions: Patients with persistently elevated AHI 12 months after hypoglossal implantation experienced improvement in polysomnographic and quality of life outcomes. These results suggest the need for a closer look at physiologic markers for success beyond reporting AHI as the gold standard.

Therapeutics - Terapéutica

TÍTULO / TITLE:   - Blinatumomab as a successful and safe therapy in Down syndrome patients with relapsed/refractory b-precursor acute lymphoblastic leukaemia: Case reports and literature review

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REVISTA / JOURNAL:    - Pediatr Blood Cancer.2021 Jul;68(7):e29044. doi: 10.1002/pbc.29044.Epub 2021 Apr 12

Enlace a la Editora de la Revista https://doi.org/10.1002/pbc.29044

AUTORES / AUTHORS: - Federica Sora et al

INSTITUCIÓN / INSTITUTION: - Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 

RESUMEN / SUMMARY: - Abstract not available

TÍTULO / TITLE:   - Efficacy and safety of methylphenidate on attention deficit hyperactivity disorder in children with Down syndrome

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REVISTA / JOURNAL:    - J Intellect Disabil Res.2021 Apr 20. doi: 10.1111/jir.12832.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1111/jir.12832

AUTORES / AUTHORS: - M Roche et al.

INSTITUCIÓN / INSTITUTION: - CRB BioJeL, Institut Jérôme Lejeune, Paris, France. 

RESUMEN / SUMMARY: - Background: Attention deficit hyperactivity disorder (ADHD) is a common co-morbidity that affects up to 44% of children with Down syndrome (DS). There is a need for reliable, good quality research on the use of methylphenidate within this population. The objective of this study is to report our experience regarding the management of ADHD in these children using methylphenidate. Methods: This study is a retrospective observation of 21 children with DS, followed at Jérôme Lejeune Institute between 2000 and 2018. The diagnosis of ADHD was made using the Diagnostic and Statistical Manual of Mental Disorders criteria. Efficacy was measured as response or non-response on two main symptoms: attention/concentration and hyperactivity/impulsivity. Safety was evaluated by the presence or absence of side effects. Results: Sixteen out of the 21 children (76%) showed improvement with methylphenidate. The average age of treatment onset in responding children was 8 years and 10 months versus 6 years and 3 months in non-responders (P = 0.05). Average dose/weight was significantly different in responders and non-responders (0.82 vs. 0.54 mg/kg/day, respectively; P = 0.03). Twelve children out of 21 (57%) experienced side effects; only three experienced side effects severe enough to require treatment interruption. Most common side effects were loss of appetite and difficulties in falling asleep. Conclusion: Methylphenidate was effective and safe in treating ADHD in 76% of cases in children with DS, with few serious side effects to report. Early diagnosis of ADHD is important to improve the quality of life, learning, inclusion and socialisation of children with DS.

Urinary/Renal - Urinario/Renal

TÍTULO / TITLE:   - Reference serum creatinine levels according to sex, age, and height in children with Down syndrome

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REVISTA / JOURNAL:    - Eur J Pediatr.2021 Apr 15.doi: 10.1007/s00431-021-04078-z.Online ahead of print.

Enlace a la Editora de la Revista https://doi.org/10.1007/s00431-021-04078-z

AUTORES / AUTHORS: - Tomohiko Nishino et al

INSTITUCIÓN / INSTITUTION: - Division of Nephrology, Saitama Children s Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama-City, Saitama, 330 8777, Japan. 

RESUMEN / SUMMARY: - Standard serum creatinine (S-Cr) levels in healthy children fluctuate with age and sex. However, it is unclear if this fluctuation in S-Cr levels is present for children with Down syndrome (DS) who show atypical growth rate. Therefore, we aimed to establish specific reference S-Cr levels for DS and compare them with the prevailing standard levels. We retrospectively reviewed 984 children with DS aged 3 months to 18 years who visited our medical center. Patients with diseases affecting S-Cr levels were excluded. We calculated the reference S-Cr levels according to sex, age, and length/height using medical records. A total of 3765 examinations of 568 children with DS were registered for this study. Ages and S-Cr levels were examined for boys (y = 0.032x + 0.20; r = 0.868, P < 0.0001), and girls (y = 0.024x + 0.23; r = 0.835, P < 0.0001). S-Cr levels in children aged >9 years were significantly higher in boys than in girls. The 430 children with DS aged 2-8 years were examined 1867 times. Height and S-Cr levels showed a significantly strong positive correlation (r = 0.670, P < 0.001) with regression equation y = 0.37x. The quintic equations calculated with S-Cr levels and length/height for boys (336 children, 2043 tests, r = 0.887) and girls (232 children, 1722 tests, r = 0.805) were y = - 6.132x5 + 32.78x4 - 67.86x3 + 68.31x2 - 33.14x + 6.41, and y = 0.09542x5 + 1.295x4 - 6.401x3 + 10.35x2 - 6.746x + 1.772. All calculated results varied from the standard levels for healthy children. Conclusion: This study established reference S-Cr levels and quintic equations specific for children with DS. These reference levels would be potentially useful in evaluating S-Cr levels and renal function in this population. What is Known: •Standard serum creatinine levels vary with age and sex to reflect muscle mass. •Reference serum creatinine levels specific to children with Down syndrome who show growth rates different from those of healthy children have not been established. What is

Education - Educación

TÍTULO / TITLE:   - Parent-based training of basic number skills in children with Down syndrome using an adaptive computer game

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REVISTA / JOURNAL:    - Res Dev Disabil.2021 May;112:103919. doi: 10.1016/j.ridd.2021.103919.Epub 2021 Mar 6.

Enlace a la Editora de la Revista https://doi.org/10.1016/j.ridd.2021.103919

AUTORES / AUTHORS: - Silvia Lanfranchi et al.

INSTITUCIÓN / INSTITUTION: - University of Padova, Italy.  

RESUMEN / SUMMARY: - Background: Numeracy is an area of difficulty for children with Down syndrome (DS). It has been demonstrated that The Number Race, a non-commercial adaptive computer game designed to foster basic mathematical abilities, represents a promising instrument to enhance these skills in children with DS when delivered by an expert in a clinical setting. Aims: In the present study, we assessed the efficacy of The Number Race when administered at home by properly instructed and remotely supervised parents. Methods and procedures: Basic numerical skills were assessed before and after training, as well as at three-months follow-up. Performance of children with DS who worked at home with the parent (PG) was compared with that of children who received the training by an expert (EG). For both groups, the training lasted ten weeks, with two weekly sessions of 20-30 min. Outcomes and results: Results show that both groups improved across various measures of numerical proficiency, including the overall score of the numeracy assessment battery, while only the EG showed an improvement in a measure of mental calculation. The improvements were maintained three months after the end of the training. Conclusions and implications: These findings confirm the efficacy of The Number Race and extend it to an home-based setting, whereby parents administer the training with external supervision.

TÍTULO / TITLE:   - Feasibility of a syndrome-informed micro-intervention for infants with Down syndrome

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REVISTA / JOURNAL:    - J Intellect Disabil Res.2021 Apr;65(4):320-339. doi: 10.1111/jir.12814.Epub 2021 Jan 31.

Enlace a la Editora de la Revista https://doi.org/10.1111/jir.12814

AUTORES / AUTHORS: - D J Fidler et al.

INSTITUCIÓN / INSTITUTION: - Human Development and Family Studies, Colorado State University, Fort Collins, CO, USA. 

RESUMEN / SUMMARY: - Background: Infants with Down syndrome (DS) are at risk for a range of phenotypic outcomes, including delays in the onset of reaching behaviour, a critical skill that facilitates early learning. This parallel-group feasibility and pilot study presents findings from a parent-mediated micro-intervention that aimed to support the development of reaching behaviour in a sample of infants with DS.. Methods: Participants were 73 infants with DS and their caregivers. Infants who qualified for the home-based intervention (based on manual skill performance on Bayley Scales of Infant and Toddler Development, Third Edition items) were randomly assigned individually or by geographical region to a treatment or an alternative treatment condition that involved toy-based interactions with caregivers. Infants in the treatment condition experienced facilitated reaching during the toy-based interactions through the use of Velcro-affixed mittens and toys. Results: Forty-two infants met criteria to participate in the intervention, and 37 participated in both baseline and post-treatment visits. At post-treatment, infants in the treatment condition demonstrated shorter latencies to make contact with objects and showed higher frequencies of reach attempts and swats at objects than infants in the alternative treatment group. These findings were more pronounced when examining a chronological age-restricted subgroup of infants 5 to 10 months. Conclusions: Findings suggest that a syndrome-informed approach to targeted intervention may be a promising application of phenotyping science in DS and other neurogenetic conditions associated with intellectual disability.

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