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Gene Jun 2024Transducin β-like 1 X-linked receptor 1 (mouse Tbl1xr1) or TBL1X/Y related 1 (human TBL1XR1), part of the NCoR/SMRT corepressor complex, is involved in nuclear receptor...
Transducin β-like 1 X-linked receptor 1 (mouse Tbl1xr1) or TBL1X/Y related 1 (human TBL1XR1), part of the NCoR/SMRT corepressor complex, is involved in nuclear receptor signaling. Variants in TBL1XR1 cause a variety of neurodevelopmental disorders including Pierpont syndrome caused by the p.Tyr446Cys variant. We recently reported a mouse model carrying the Tbl1xr1 variant as a model for Pierpont syndrome. To obtain insight into mechanisms involved in altered brain development we studied gene expression patterns in the cortex of mutant and wild type (WT) mice, using RNA-sequencing, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene correlation network analysis (WGCNA) and hub gene analysis. We validated results in mutated mouse cortex, as well as in BV2 and SK-N-AS cell lines, in both of which Tbl1xr1 was knocked down by siRNA. Two DEGs (adj.P. Val < 0.05) were found in the cortex, Mpeg1 (downregulated in mutant mice) and 2900052N01Rik (upregulated in mutant mice). GSEA, WGCNA and hub gene analysis demonstrated changes in genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1 mice. The lowered expression of ion channel genes Kcnh3 and Kcnj4 mRNA was validated in the mutant mouse cortex, and increased expression of TRIM9, associated with neuroinflammation, was confirmed in the SK-N-AS cell line. Conclusively, our results show altered expression of genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1 mice. These may partly explain the impaired neurodevelopment observed in individuals with Pierpont syndrome and related TBL1XR1-related disorders.
PubMed: 38885822
DOI: 10.1016/j.gene.2024.148707 -
MedRxiv : the Preprint Server For... Jun 2024In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD)...
In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.
PubMed: 38883742
DOI: 10.1101/2024.06.01.24308050 -
Cureus May 2024Down syndrome (DS) is the most common chromosomal disorder in live-born infants, often associated with intellectual disability and various medical conditions, including...
Down syndrome (DS) is the most common chromosomal disorder in live-born infants, often associated with intellectual disability and various medical conditions, including thyroid dysfunction. Hashimoto's thyroiditis (HT), an autoimmune subtype, is a leading cause of acquired hypothyroidism in DS children. Severe hypothyroidism can precipitate myxedema, a critical condition linked to complications like pericardial effusion and cardiac tamponade. This case study presents a nine-year-old male with DS who was admitted for acute respiratory distress exhibiting classic signs of myxedema. Initial investigations revealed severe hypothyroidism and significant pericardial effusion. Surgical pericardiotomy drained 800 mL of fluid, confirming myxedema secondary to HT. Levothyroxine therapy led to progressive improvement, resolving myxedematous infiltrate and associated symptoms within a month. Follow-up at 12 months demonstrated sustained improvement with normalized thyroid function and no clinical disease activity. This case highlights an atypical presentation of HT in a DS child with cardiac pre-tamponade.
PubMed: 38883046
DOI: 10.7759/cureus.60367 -
MicroPublication Biology 2024In humans, trafficking of the GABA(A) receptor by GABARAP can lead to obsessive behaviors and learning deficits often in seen in neurological disorders such as...
In humans, trafficking of the GABA(A) receptor by GABARAP can lead to obsessive behaviors and learning deficits often in seen in neurological disorders such as Tourette's Syndrome. We find that in , , the ortholog of the human gene, is necessary in the nervous system for learning and suppression of excessive grooming. These results suggest that knocking down in neurons of produces a phenotype similar to that seen in human patients, potentially allowing for use of an knockdown background as a suitable invertebrate model for related neurological conditions.
PubMed: 38882929
DOI: 10.17912/micropub.biology.001116 -
Frontiers in Oral Health 2024Children with special health care needs including Down Syndrome, Autism Spectrum Disorder and Down Syndrome experience difficulties in receiving dental treatment. Silver...
BACKGROUND
Children with special health care needs including Down Syndrome, Autism Spectrum Disorder and Down Syndrome experience difficulties in receiving dental treatment. Silver Diamine Fluoride (SDF) and Silver Fluoride (SF) are a minimally invasive treatments options to arrest dental caries without sedation; local or general anaesthesia (GA).
AIM
Evaluation of Brazilian's parents' acceptance of the use of SF in CSHCN.
METHODS
After receiving education on SF, 100 Parents of CSHCN completed a questionnaire concerning their acceptance of SF, in different dental situation.
RESULT
Majority of parents (74,5%) agreed to the use of SF for their children. SF was more acceptable on posterior teeth (74,5%) when compared to its use on anterior teeth (43,1%). Parents accepted to use SF in order: to reduce infection and pain (82,4%); to avoid dental injection (72,5%) and treatment under GA (84,3%). The Majority of parents accepted the properties of SF (82,4%) and Silver (80,4%).
CONCLUSION
Silver Fluoride was accepted as a treatment option for caries, by Brazilian parents of CSHCN. SF should be considered as a treatment option for caries limited to dentine for CSHCN, taking into consideration the individual needs and opinions with regard to aesthetics and exposure to fluoride and silver.
PubMed: 38872987
DOI: 10.3389/froh.2024.1377949 -
Journal of Neurodevelopmental Disorders Jun 2024Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living,...
BACKGROUND
Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD.
METHODS
Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (m = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization).
RESULTS
Over a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model.
CONCLUSIONS
The present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.
Topics: Humans; Male; Child; Adolescent; Female; Adaptation, Psychological; Young Adult; Adult; Intellectual Disability; Developmental Disabilities; Cognition; Longitudinal Studies; Activities of Daily Living; Socialization; Down Syndrome; Fragile X Syndrome
PubMed: 38872099
DOI: 10.1186/s11689-024-09542-z -
Clinical Practice and Cases in... May 2024Spontaneous esophageal rupture, or Boerhaave syndrome, and upside-down stomach are rare pathologies associated with grave sequelae. Boerhaave syndrome can have a...
INTRODUCTION
Spontaneous esophageal rupture, or Boerhaave syndrome, and upside-down stomach are rare pathologies associated with grave sequelae. Boerhaave syndrome can have a mortality rate as high as 44%. Upside-down stomach accounts for less than 5% of hiatal hernias and can lead to incarceration and volvulus.
CASE REPORT
An 80-year-old woman presented to the emergency department with sudden onset, severe epigastric pain. Physical examination revealed normal vital signs with mild epigastric tenderness. Imaging obtained revealed a large hiatal hernia and findings concerning for esophageal perforation. The patient was started on 3.375 grams of intravenous piperacillin/tazobactam, and transfer to a tertiary care facility was initiated. After transfer, esophagography confirmed a perforation near the gastroesophageal junction and findings consistent with an upside-down stomach. The patient underwent successful repair of the esophageal perforation and gastropexy followed by intensive care unit admission and ultimately discharge.
CONCLUSION
Boerhaave syndrome and upside-down stomach are two conditions with high associated morbidity and mortality requiring prompt intervention. Information obtained in the history and physical examination including acute onset of chest pain after vomiting, tachypnea, subcutaneous emphysema, and hypoxia can assist in the diagnosis of the described pathologies. These signs and symptoms can be subtle on examination but are important in raising clinical suspicion for an otherwise rare etiology for acute onset chest pain.
PubMed: 38869327
DOI: 10.5811/cpcem.20907 -
Health Science Reports Jun 2024Patellofemoral pain (PFP) is common in males, causing reduced physical activity and chronic pain. One proposed cause of PFP is aberrant biomechanics during tasks loading...
BACKGROUND AND AIMS
Patellofemoral pain (PFP) is common in males, causing reduced physical activity and chronic pain. One proposed cause of PFP is aberrant biomechanics during tasks loading the patellofemoral joint. Consistent evidence exists for females with PFP, but it is uncertain if males with PFP have altered biomechanics. This study investigated the kinematics of males with PFP compared to pain-free males during forward step-down (StDn) and single-leg squat (SLSq).
METHODS
A cross-sectional study including 40 males aged 20-39 years (28.28 ± 5.46) was conducted (20 PFP, 20 pain-free). Participants performed StDn and SLSq while motion was captured with a video-based motion capture system (Motion Analysis Corporation). Triplanar peak angles and angular ranges of motion (ROM) of the trunk, pelvis, and weight-bearing hip, knee, and ankle were dependent variables. Mixed-model ANOVA tests were used to determine the presence of significant interactions and main effects of group and task.
RESULTS
Males with PFP had significantly lower peak knee adduction angles compared to pain-free males ( = 0.01). Significant group x task interactions were found for hip and pelvis ROM ( < 0.05). PFP participants had increased hip and pelvis ROM during StDn in the frontal and transverse planes but reduced or nearly equal ROM for these variables during SLSq. Peak hip adduction, hip internal rotation, contralateral pelvic drop and anterior tilt, trunk flexion, and ankle dorsiflexion were greater during StDn compared to SLSq ( < 0.05). ROM of the hip, pelvis, trunk, and ankle were greater during StDn compared to SLSq ( < 0.05).
CONCLUSION
Males with PFP had reduced peak knee adduction angles in StDn and SLSq. Males with PFP demonstrated increased hip and pelvis ROM during StDn versus SLSq, particularly in the frontal and transverse planes. Clinicians should consider StDn as a clinical test since aberrant movement may be easier to detect than in SLSq.
PubMed: 38868539
DOI: 10.1002/hsr2.2193 -
Acta Neuropathologica Communications Jun 2024Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and...
Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.
Topics: Humans; Down Syndrome; tau Proteins; Cryoelectron Microscopy; Middle Aged; Alzheimer Disease; Female; Adult; Male; Neurofibrillary Tangles; Brain
PubMed: 38867338
DOI: 10.1186/s40478-024-01806-y