Features Of Down Syndrome Research Articles

Increased hippocampal epigenetic age in the Ts65Dn mouse model of Down Syndrome.

Down syndrome (DS) is a segmental progeroid genetic disorder associated with multi-systemic precocious aging phenotypes, which are particularly evident in the immune and nervous systems. Accordingly, people with DS show an increased biological age as measured by epigenetic clocks. The Ts65Dn trisomic mouse, which harbors extra-numerary copies of chromosome 21 (Hsa21)-syntenic regions, was shown to recapitulate several progeroid features of DS, but no biomarkers of age have been applied to it so far. In this pilot study, we used a mouse-specific epigenetic clock to measure the epigenetic age of hippocampi from Ts65Dn and euploid mice at 20 weeks. Ts65Dn mice showed an increased epigenetic age in comparison with controls, and the observed changes in DNA methylation partially recapitulated those observed in hippocampi from people with DS. Collectively, our results support the use of the Ts65Dn model to decipher the molecular mechanisms underlying the progeroid DS phenotypes.

Prenatal treatment with preimplantation factor improves early postnatal neurogenesis and cognitive impairments in a mouse model of Down syndrome

Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.

Spermatogonial depletion and a spermatogenesis defect in the Dp(16)1Yey mouse model of Down syndrome

In brief Little is known about the mechanism responsible for male infertility in Down syndrome. Duplication of Mmu16 chromosome (an orthologue of Hsa21, bearing Dyrk1A) in Dp(16)1Yey mice is responsible for impaired spermatogenesis through spermatogonial depletion and hypogonadotropic hypogonadism. Abstract Down syndrome (DS), or trisomy 21, is the most common chromosomal disorder in humans. Men with DS are infertile. The DYRK1A gene on Hsa21 is involved in several features of DS. Overexpression of the homolog dyrk1A disrupts primordial germ cell migration in zebrafish, and overexpression of Dyrk1A impairs gonadotropic axis function and the early stages of spermatogenesis in the mouse. Other genes on Hsa21 might be involved in the pathogenesis of infertility in DS. We investigated the Dp(16)1Yey mouse model of DS, which features segmental duplication of chromosome Mmu16 (orthologous to a large part of Hsa21 and carrying Dyrk1A and 112 other genes). Using an immunohistochemical assay for the spermatogonial marker STRA8, we observed spermatogonial depletion in the Dp(16)1Yey mouse. This was correlated with low mRNA expression of GFRα1 (a marker of the self-renewal stem cell pool) in an RT-qPCR assay and low protein expression of PLZF (a marker of differentiating stem cells) in a slot-blot assay. Spermatogenesis was present but impaired, with a low sperm count, low protamine-1 expression, a low testis weight, and a low seminiferous tubule diameter. Low circulating luteinizing hormone and follicle-stimulating hormone levels and an elevated testis anti-Müllerian hormone level (as measured in ELISAs) revealed the presence of hypogonadotropic hypogonadism. The Dp(16)1Yey mouse model of DS recapitulates observations made in zebrafish and mice overexpressing DYRK1A homologs. The presence of an excess of Mmu16 material perturbs spermatogenesis and the gonadotropic axis. More generally, DYRK1A’s role in human infertility (outside DS) remains to be characterized.

Dermatoglyphs in People with Down Syndrome and People with Normal Karyotype: A Comparison of Quantitative Characteristics

Background: All types of chromosomal aberrations have an impact on the development of dermatoglyphs, which changes both their quantitative and qualitative characteristics. This study aims to compare the quantitative characteristics of dermatoglyphs between individuals with Down syndrome and those with normal karyotypes in the Kosova Albanian population. Methods and Results: The quantitative characteristics of digitopalmar dermatoglyphs were analyzed on 104 individuals (54 men and 50 women) with Down syndrome from Kosova's Albanian population. The dermatoglyphs of 403 Albanians from Kosova with normal karyotypes (the control group) were also analyzed quantitatively. Using the method devised by Cummins and Midlo, dermatoglyph traces were obtained and analyzed. We analyzed the quantitative features of both the dermatoglyphs of the fingers and the dermatoglyphs of the palms of the hands. Moorhead and Seabright's peripheral blood culture technique was utilized to analyze the karyotypes of individuals with Down syndrome. A total of 40 dermatoglyphic variables were analyzed. When the quantitative dermatoglyphic features of men with Down syndrome and the control group were compared, significant differences were discovered in 20 of the dermatoglyphic variables. Significant differences were discovered in 21 of the dermatoglyphic variables when the features of women with Down syndrome and the control group were compared. One of the most distinctive characteristics of Down syndrome was the breadth of the atd angle, which should be taken into consideration. Compared to the control group's males and females, the males and females with Down syndrome exhibit wider atdT angles (161.91° vs. 92.60° [P<0.0001] and 165.48° vs. 94.75° [P<0.0001], respectively). Conclusion: The size of atd angles is the factor that most closely identifies people with Down syndrome.

Distinct neuroanatomical and neuropsychological features of Down syndrome compared to related neurodevelopmental disorders: a systematic review.

We critically review research findings on the unique changes in brain structure and cognitive function characteristic of Down syndrome (DS) and summarize the similarities and differences with other neurodevelopmental disorders such as Williams syndrome, 22q11.2 deletion syndrome, and fragile X syndrome. We conducted a meta-analysis and systematic literature review of 84 studies identified by searching PubMed, Google Scholar, and Web of Science from 1977 to October 2022. This review focuses on the following issues: (1) specific neuroanatomic and histopathological features of DS as revealed by autopsy and modern neuroimaging modalities, (2) language and memory deficits in DS, (3) the relationships between these neuroanatomical and neuropsychological features, and (4) neuroanatomic and neuropsychological differences between DS and related neurodevelopmental syndromes. Numerous post-mortem and morphometric neuroimaging investigations of individuals with DS have reported complex changes in regional brain volumes, most notably in the hippocampal formation, temporal lobe, frontal lobe, parietal lobe, and cerebellum. Moreover, neuropsychological assessments have revealed deficits in language development, emotional regulation, and memory that reflect these structural changes and are more severe than expected from general cognitive dysfunction. Individuals with DS also show relative preservation of multiple cognitive, linguistic, and social domains compared to normally developed controls and individuals with other neurodevelopmental disorders. However, all these neurodevelopment disorders exhibit substantial heterogeneity among individuals. People with Down syndrome demonstrate unique neurodevelopmental abnormalities but cannot be regarded as a homogenous group. A comprehensive evaluation of individual intellectual skills is essential for all individuals with neurodevelopment disorders to develop personalized care programs.

Analysis of strength and electromyographic activity of lower limbs of individuals with down syndrome assisted in physiotherapy and hippotherapy

Introductionone of the characteristics of Down Syndrome (DS) is muscle hypotonia. Different therapeutic approaches have a positive influence, between them Physiotherapy applications with different therapeutic approaches such as Hippotherapy have a positive effect on the physical health and quality of live of individuals with DS. Objectiveto evaluate the effects of both treatments on the strength and electromyographic activity of the lower limbs of children and adolescents with DS. Methodsfourteen individuals, aged between 10 and 18 years, participated in two groups: Physiotherapy group (n = 5) and Hippotherapy group (n = 9). Thirty interventions were performed for each type of therapy, once a week, lasting 30 min. Pre and post-interventions, the 30-Second Chair Stand Test (30s-CST) was used to assess the strength of the lower limbs and the surface electromyography equipment (EMG 800RF) to assess the lower limb myoelectric activity. Resultsthere was a reduction in the post-intervention electromyographic values for both treatments (p˂0.001), with significantly less myoelectric activity in Hippotherapy compared to Physiotherapy for all evaluated muscles (p˂0.001) and a significant increase in muscle strength for the Hippotherapy, post-intervention group (p = 0.0007). ConclusionPhysiotherapy and Hippotherapy are interventions that promote positive changes in the myoelectric activities of individuals with DS. However, only hippotherapy promoted an increase in strength of the lower limbs.

From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome.

Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer's disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools.

Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c+ B cells.

Down's syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS arealso prone to severe infectionsand autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata1,2. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels often exceeding those in patients with acute infection) and detected basal cellular activation: chronic IL-6 signalling in CD4 T cells and a high proportion of plasmablasts and CD11c+TbethighCD21low B cells (Tbet is also known as TBX21). This subset is known to be autoimmune-prone and displayed even greater autoreactive features in DS including receptors with fewer non-reference nucleotides and higher IGHV4-34 utilization. In vitro, incubation of naive B cells in the plasma of individuals with DS or with IL-6-activated T cells resulted in increased plasmablast differentiation compared withcontrol plasma or unstimulated T cells, respectively. Finally, we detected 365 auto-antibodies in the plasma of individuals with DS, which targeted the gastrointestinal tract, the pancreas, the thyroid, the central nervous system, and the immune system itself. Together, these data point to an autoimmunity-prone state in DS, in which a steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation all contribute to a breach in immune tolerance. Our findings also open therapeutic paths, as we demonstrate that T cell activation is resolved not only with broad immunosuppressants such as Jak inhibitors, but also with the more tailored approach of IL-6 inhibition.

Down syndrome patients with normal hearts: are they really normal?

Even though congenital heart disease is a common finding in down syndrome (DS) patients, some of them have anatomically normal hearts. However, the term "normal" might not be suitable, as these patients usually suffer from functional cardiac dysfunction. Several research highlighted that despite the absence of anatomical heart defects, subtle cardiac function derangements are present in DS patients. We aim to assess cardiac functions by Two-dimensional echocardiography and tissue Doppler imaging (TDI) in pediatric DS patients who have anatomically normal hearts. One hundred seventy-two patients with karyotyping confirmed DS with anatomically normal hearts and 165 healthy normal control children were enrolled in the current study. Their cardiac functions were assessed using both 2-dimensional echocardiography and TDI. Both patients and controls had structurally and anatomically normal hearts. In DS patients, the right side of the heart showed a significant reduction in both systolic and diastolic functions. Systolic dysfunction was evident by significantly decreased levels of Tricuspid annular plane systolic excursion and systolic wave by TDI. Diastolic dysfunction of the right ventricle was evident by prolonged deceleration time by conventional echocardiography and a significant decrease in annular tissue doppler velocity during early diastole/late diastole ratio by TDI. The E/De ratio was significantly increased. Even with anatomically normal hearts, DS patients should undergo cardiac function assessment by echocardiography & TDI. TDI is superior to conventional echocardiography in detecting subtle cardiac dysfunction especially left ventricular diastolic dysfunction in DS patients. TDI showed a significant decrease in the early/atrial ratio of mitral valve annulus and prolongation of left ventricle isometric relaxation time in DS children. Also, the left ventricle E/De ratio was prolonged denoting elevated filling pressures and diastolic dysfunction. This indicates that the TDI has higher sensitivity to detect diastolic dysfunction than conventional Echocardiography. Biventricular TDI-derived myocardial performance index was found to be significantly increased in DS children.

Cytogenetic analysis of autistic children with down syndrome features

INTRODUCTION: Autism is a heterogeneous neurodevelopmental disorder that influences a child's ability to think, learn, communicate, and interact socially and possess behavioral problems. It has also been observed to be associated with several medical conditions, including certain chromosomal disorders like Down syndrome (DS). Several studies have shown autistic individuals with DS. The main objective of the present study is to screen for chromosomal abnormalities in autistic children with DS characteristics in the North Karnataka population, India. MATERIALS AND METHODS: Chromosome analysis of peripheral blood of four DS children with autistic characteristics was performed to examine the chromosomal abnormalities, which were confirmed by fluorescent in situ hybridization. RESULTS: Childhood Autism Rating Scale score was calculated initially to assess the severity of autism. All four cases were found to have autism with DS. Out of four cases, three (75%) were found to be trisomy 21 and 1 (25%) had a trisomy 21 mosaic condition. CONCLUSION: Our study confirms the chromosomal abnormality present in autistic children with DS characteristics and these findings will contribute in several ways to the diagnosis and treatment of the genetic cause of autism with other comorbidities or vice versa.

Evaluation of clinical profile to diagnose Down syndrome with respect to karyotyping as gold standard: a cross-sectional study

Background: Down syndrome (DS) is a genetic disorder characterized with trisomy of chromosome 21 with a high prevalence among countries like India. DS patients present clinically with intellectual disability, congenital heart defect and other major abnormalities. Early diagnosis of DS and intervention with supportive care improves the patient care. To study the efficacy/use of Hall’s and Fried’s scoring system in diagnosing DS confirmed with karyotyping.Methods: The patients presented with dysmorphology, intellectual disability or other clinical features of DS are assessed for inclusion using Hall’s and Fried’s scoring in which patients with score ≥3 are included and considered positive. These patients are further confirmed with karyotyping. The results of Hall’s and Fried’s scoring are comparing against karyotyping results to check for its efficacy.Results: The cross-sectional study conducted found males as majorly affected sex (60.4%) for DS and the mean age of child at diagnosis as 6.69±4.84 months in infant stage and 61.86±60.16 months after infant stage. Flat face was present in 100% followed by up slanting palpebral fissures, protruding tongue, abundant neck skin and little digit clinodactyly. ID is seen in all the patients with CHD in 48.8% population and GI abnormalities in 9.3%. Among CHD’s, VSD is majorly seen followed by AVSD.Conclusions: The study found using combined criteria of both Fried’s and Hall’s score/criteria as an excellent screening test to suspect DS in community level compared to an individual score/criteria.

Medulloblastoma and Down Syndrome: An Extremely Rare Association.

Medulloblastoma has a reduced incidence in Down syndrome (DS). This protective characteristic has not been clarified yet. Here, we report the second case of SHH medulloblastoma and DS documented in the literature. A complete surgery was performed followed by reduced craniospinal irradiation dose and adjuvant chemotherapy. No evidence of tumor recurrence was observed. The overall survival was 9.1 years. No family history or physical stigma of other hereditary predisposition syndrome was found. In the elucidation of this extremely rare association, future case reports play an important role in defining the spectrum of brain tumors and their peculiar features in DS.

Clinical Characteristics of Down Syndrome with Congenital Heart Disease

Down syndrome (DS) or trisomy 21, causes overexpression of genes in most affected organs, including congenital heart disease (CHD). CHD is found in 40-60% of people with DS, with a high mortality rate in early life.Clinical signs and symptoms often found are essential indicators of early diagnosis of CHD. This study aimed todetermine the clinical characteristics of DS children with and without CHD. This study was a retrospective study.The study was conducted on August until October 2019. We took data from the inpatient and outpatient medicalrecords database for the years 2017-2019 in Dr. Kariadi Hospital, Semarang, Indonesia. Some informationincludes clinical signs and symptoms, nutritional status, comorbidities, and frequency of hospitalization in amonth were collected. A total of 66 patients were diagnosed with DS, consisting of 44 DS patients with CHDand 22 DS patients without CHD. There were no differences in nutritional status, interrupted breastfeeding, chestretraction, respiratory rate, thyroid disorder, hearing abnormalities, acute otitis media, and obstructive sleepapnea in both groups (p> 0.05). There were significant differences in the clinical characteristics of cyanosis(p=0.005), heart murmur (p=<0.001), and frequency of acute respiratory tract infection in a year (p=<0.001), andfrequency of hospitalization per month (p=0.039) in DS children with and without CHD. In conclusion, we foundsignificant difference in clinical characteristic in DS children with and without CHD.

Transient Myeloproliferative Syndrome associated with Down syndrome and Fetal Hydrops: Case Report

BACKGROUND: Transient myeloproliferative Syndrome can be defined as an abnormal proliferation of immature leukemic cells. It presents in newborns with Down syndrome or trisomy 21 mosaicism, as an uncontrolled proliferation of blasts in the megakaryocytic lineage; it resolves spontaneously during the first three months of life. One of the characteristic manifestations is Non-Immune Fetal Hydrops. CASE REPORT: Premature newborn patient adequate for gestational age, born by C-Section due to ultrasound diagnosis of NIHF. At birth, we evidenced phenotypic characteristics of Down syndrome; in addition, the clinical picture and physical examination (respiratory distress, bradycardia, hypotension, prolonged capillary refill, hypotonia, and thrombocytopenia) supported the diagnostic suspicion of neonatal sepsis. The initial management of the patient in the intensive care unit included: mechanical ventilation, vasopressor support, surfactant administration, intravenous antibiotic therapy, furosemide, fentanyl and midazolam, albumin, and vitamin k. EVOLUTION: During his hospital stay, the patient developed acute kidney injury. In addition, we detected leukocytosis and presence of immature cells, anemia and thrombocytopenia, with diagnostic suspicion of congenital leukemia versus MTS, confirmed by flow cytometry. Subsequently, the patient presented elevated bilirubin, with jaundice and subsequent multifactorial cholestasis. The patient was hospitalized for 48 days and after the resolution of the mentioned pathologies, he was discharged. At the follow up, 15 days after discharge, normalization of leucocyte, red blood cell and platelet values confirmed the TMS diagnosis. CONCLUSION: In this case report, the patient developed MTS in relation to Down syndrome and had a complicated clinical course due to all the complications derived from his prematurity, his congenital disease, and the presence of hydrops fetalis and other manifestations of MTS. In the present case, there were criteria of severity, poor prognosis and high risk of mortality, which advantageously do not affect his current clinical condition, but require continuous and strict clinical surveillance. Multidisciplinary management, a high index of suspicion, timely attention to the multiple manifestations and complications, and proper follow-up allowed for a favorable evolution and greater survival in this patient.

AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome.

Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies.

Blinatumomab Associated Seizure Risk in Patients with Down Syndrome and B-Lymphoblastic Leukemia: An Interim Report from Children's Oncology Group (COG) Study AALL1731

INTRODUCTIONChildren with Down Syndrome (DS) and B-lymphoblastic leukemia (B-ALL) are at an increased risk of both relapse and treatment-related mortality, compared to those without DS. On COG study AALL1731 for de novo B-ALL, patients with DS and higher risk features (DS-High) are non-randomly treated with a regimen replacing intensive elements of conventional chemotherapy with three 28-day cycles of blinatumomab, with the combined goals of reducing toxicity and enhancing anti-leukemic efficacy. The DS-High group includes all NCI high risk (HR) patients; NCI standard risk (SR) patients with end-induction minimal residual disease positivity (>0.01%), unfavorable cytogenetics, CNS3 status, steroid pre-treatment, neutral cytogenetics with CNS2 status, or testicular disease. Neurotoxicity is a known risk of blinatumomab, with an incidence of 4% in block 1 and 1% in block 2 among pediatric patients with relapsed ALL (Brown et al, JAMA 2021). However, the specific risk in patients with DS has not been described to date. Here, we provide an early report of increased seizure incidence associated with blinatumomab in older DS-High patients enrolled on AALL1731 to date.METHODSWe reviewed seizure incidence among patients with DS enrolled on AALL1731 from June 2019 to June 2021 who had proceeded to receive blinatumomab. Blinatumomab was administered at a dose of 15 mcg/m 2/day, using dexamethasone pre-medication in cycle 1. Infusions were interrupted for seizures, with resumption at 5 mcg/m 2/d permitted following full resolution for grade 1-3 seizures.RESULTSAmong DS NCI HR patients, 8 of 47 (17%) had a seizure during blinatumomab infusion (Table 1). All 8 seizures occurred in patients over 10 years old. Six of the 8 seizures occurred in the first cycle of blinatumomab, most in the first 3 days of the infusion. Four had concomitant fever or cytokine release syndrome. Seizures were grade 2 (n=2) or grade 3 (n=6), and all resolved with full neurologic recovery. Of the 8 patients, 5 elected to resume blinatumomab; no further seizures occurred in these patients. There was no indication of increased seizure risk among NCI SR DS-High patients (1 seizure among 11 patients), or among DS or non-DS patients receiving blinatumomab on other study strata (0 of 7 DS SR-Avg; 1 of 146 non-DS SR-Avg; and 2 of 120 non-DS SR-High).CONCLUSIONSThe incidence of seizures associated with blinatumomab in DS-ALL patients older than 10 years appears higher than previously reported in children without DS. The majority of seizures occurred within the first 3 days, all fully resolved with no sequelae, and no patient who resumed blinatumomab infusion at a lower rate experienced further seizures. Seizure prophylaxis may be advisable in DS patients while receiving blinatumomab, particularly those >10 years of age. Further follow-up and a larger sample size are needed to confirm incidence and identify risk factors predisposing DS patients to neurologic toxicity. [Display omitted] DisclosuresLi: Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder; Servier Pharmaceuticals: Consultancy. OffLabel Disclosure:This trial includes the use of blinatumomab in combination with chemotherapy for treatment of de novo B-lymphoblastic leukemia.

Maternal antibodies facilitate Amyloid-\u03b2 clearance by activating Fc-receptor-Syk-mediated phagocytosis

Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer’s disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-β (Aβ) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aβ overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aβ MAbs might promote the removal of early Aβ accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aβ1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation. MAbs reduce the offspring’s cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the FcγR1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early Aβ deposition, as occurs in EOAD and DS.

Structural magnetic resonance imaging demonstrates volumetric brain abnormalities in down syndrome: Newborns to young adults

Down syndrome (DS) is a genetic disorder caused by the presence of an extra full or partial copy of chromosome 21 and characterized by intellectual disability. We hypothesize that performing a retrospective analysis of 73 magnetic resonance imaging (MRI) examinations of participants with DS (aged 0 to 22 years) and comparing them to a large cohort of 993 brain MRI examinations of neurotypical participants (aged 0 to 32 years), will assist in better understanding what brain differences may explain phenotypic developmental features in DS, as well as to provide valuable confirmation of prospective literature findings clinically. Measurements for both absolute volumes and volumes corrected as a percentage of estimated total intracranial volume (%ETIV) were extracted from each examination. Our results presented novel findings such as volume increases (%ETIV) in the perirhinal cortex, entorhinal cortex, choroid plexus, and Brodmann’s areas (BA) 3a, 3b, and 44, as well as volume decreases (%ETIV) in the white matter of the cuneus, the paracentral lobule, the postcentral gyrus, and the supramarginal gyrus. We also confirmed volumetric brain abnormalities previously discussed in the literature. Findings suggest the presence of volumetric brain abnormalities in DS that can be detected clinically with MRI.

Down's syndrome and COVID-19: risk or protection factor against infection? A molecular and genetic approach.

Down syndrome (DS) is the most common genetic cause of learning difficulties and intellectual disabilities. DS patients often present with several congenital defects and chronic diseases, including immunity disorders. Elevated levels of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) have been seen, which appear to vary with age. At birth, patients present with combined immunodeficiency, with frequent infections that decrease with age. Furthermore, high levels of IL-4 and IL-10 with anti-inflammatory properties and low levels of IL-6 and TNF-α are described in children. The immune system is believed to play an essential role in SARS-CoV-2 pathogenesis, and it has been associated with elevated levels of pro-inflammatory cytokines and an exaggerated cytokine release syndrome (CRS) that may eventually trigger a severe situation called cytokine storm. On the other hand, genetic features seem to be involved in the predisposition to illness and its severity. Overexpression of DSCR1 and ZAKI-4 inhibits the translocation of activated T lymphocyte nuclear factor (NF-AT) to the nucleus, a main step in the inflammatory responsiveness. We discuss here the possible role of immunology and genetic features of DS in the infection and prognosis in COVID-19.

ENSINO E APRENDIZAGEM DE LÍNGUA ESTRANGEIRA (LE) PARA PESSOAS COM SÍNDROME DE DOWN ATRAVÉS DO MÉTODO AUDIOLINGUAL

A Síndrome de Down é uma alteração cromossômica causada pela existência de um cromossomo extra nas células do indivíduo (GONZÁLEZ, 2007). Indivíduos com Síndrome de Down apresentam atrasos intelectuais, dificuldades auditivas, problemas referentes à linguagem e à aprendizagem. O seu processo de desenvolvimento da linguagem é particularmente problemático devido a problemas referentes à memória de curto prazo e ao processamento auditivo. No entanto, apesar de tais dificuldades, a criança com Down tem direito a aprender línguas estrangeiras (LE) e capacidade para isso, embora seja necessário planejamento de atividades e atendimento diferenciados em sala de aula em comparação com aqueles utilizados com crianças sem Down. O principal objetivo deste artigo é analisar os benefícios e desafios do método audiolingual para o ensino de LE a aprendizes com Down. Para tanto, é feito um estudo exploratório sobre o conceito e as características da síndrome de Down, a aquisição de L2 na educação especial através da abordagem audiolingual (BUCKLEY, 2002; GOMES, 2012; GONZÁLEZ, 2007; PUESCHEL, 1993; BROWN, 2007; LARSEN-FREEMAN, 2001; RICHARDS e RODGERS, 1986).