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Science Advances Jun 2024Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2-induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier...
Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2-induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier function and immune response modulation and expresses the ACE2 receptor and the chromosome 21-encoded TMPRSS2 protease, suggesting its substantial role in establishing SARS-CoV-2 infection in the brain. To explore this, we established brain organoids from DS and isogenic euploid iPSC that consist of a core of functional cortical neurons surrounded by a functional ChP-like epithelium (ChPCOs). DS-ChPCOs recapitulated abnormal DS cortical development and revealed defects in ciliogenesis and epithelial cell polarity in ChP-like epithelium. We then demonstrated that the ChP-like epithelium facilitates infection and replication of SARS-CoV-2 in cortical neurons and that this is increased in DS. Inhibiting TMPRSS2 and furin activity reduced viral replication in DS-ChPCOs to euploid levels. This model enables dissection of the role of ChP in neurotropic virus infection and euploid forebrain development and permits screening of therapeutics for SARS-CoV-2-induced neuropathogenesis.
Topics: Choroid Plexus; Organoids; Humans; SARS-CoV-2; COVID-19; Serine Endopeptidases; Down Syndrome; Brain; Neurons; Virus Replication; Induced Pluripotent Stem Cells; Furin; Angiotensin-Converting Enzyme 2; Viral Tropism
PubMed: 38838150
DOI: 10.1126/sciadv.adj4735 -
Epilepsia Open Jun 2024Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency,... (Review)
Review
Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency, severity, and type of epileptic seizures vary according to the macro- and microrearrangements present. Even within a single chromosomal anomaly, we most often deal with a phenotypic spectrum. The aim of the study was to look for chromosomal rearrangements with a characteristic electroencephalographic pattern. Only a few disorders have peculiar electroclinical abnormalities: 1p36, 4p16, 6q terminal or trisomy 12p, Angelman syndrome, inv dup 15, 15q13.3 deletions, ring 20, Down syndrome, or Xp11.22-11.23 duplication. We also reviewed studies on epileptic seizures and typical electroencephalographic patterns described in certain chromosomal rearrangements, focusing on the quest for potential electroclinical biomarkers. The comprehensive review concludes with clinical presentations of the most common micro and macro chromosomal rearrangements, such as 17q21.31 microdeletion, 6q terminal deletion, 15q inv dup syndrome, 2q24.4 deletion, Xp11.22-11.23 duplication, 15q13.3 microdeletion, 1p36 terminal deletion, 5q14.3 microdeletion, and Xq28 duplication. The papers reviewed did not identify any specific interictal electroencephalographic patterns that were unique and significant biomarkers for a given chromosomal microrearrangement. The types of seizures described varied, with both generalized and focal seizures of various morphologies being reported. Patients with chromosomal anomalies may also meet the criteria for specific epileptic syndromes such as Infantile Epilepsy Spasms Syndrome (IESS, West syndrome): 16p13.11, 15q13.3 and 17q21.31 microdeletions, 5q inv dup. syndrome; Dravet syndrome (2q24.4 deletion), Lennox-Gastaut syndrome (15q11 duplication. 1q13.3, 5q inv dup.); or Self-Limited Epilepsy with Autonomic Features (SeLEAS, Panayiotopoulos syndrome: terminal deletion of 6q.n), Self-Limited Epilepsy with Centrotemporal Spikes (SeLECT): fragile X syndrome. It is essential to better characterize groups of patients to more accurately define patterns of epilepsy and EEG abnormalities. This could lead to new treatment strategies. Future research is required to better understand epileptic syndromes and chromosomal rearrangements. PLAIN LANGUAGE SUMMARY: This paper presents EEG recording abnormalities in patients with various gene abnormalities that can cause epilepsy. The authors summarize these EEG variations based on a literature review to see if they occur frequently enough in other chromosomal abnormalities (in addition to those already known) to be a clue for further diagnosis.
PubMed: 38837855
DOI: 10.1002/epi4.12951 -
Intractable & Rare Diseases Research May 2024We conducted a cross-sectional study to describe the health care problems of children with Down syndrome in Central Java, Indonesia. A total of 162 children (81 boys, 81...
We conducted a cross-sectional study to describe the health care problems of children with Down syndrome in Central Java, Indonesia. A total of 162 children (81 boys, 81 girls) with Down syndrome were included. Congenital heart defects and hypothyroidism were found in about 50%, followed by vision and hearing problems in 27.7% and 17.3%, respectively. Almost half of cases were diagnosed after the first month of age. Advanced maternal age was identified in more than 50%, and less than 10% was based on karyotype analysis. This study describes the essential issues such as critical co-morbidities, delayed diagnosis, advanced maternal age, and lack of (accessibility to) genetic testing facilities; thus, better health care and management is needed.
PubMed: 38836178
DOI: 10.5582/irdr.2023.01103 -
Frontiers in Aging Neuroscience 2024Down syndrome (DS) is a segmental progeroid genetic disorder associated with multi-systemic precocious aging phenotypes, which are particularly evident in the immune and...
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.
PubMed: 38836050
DOI: 10.3389/fnagi.2024.1401109 -
BMC Psychiatry Jun 2024Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine...
BACKGROUND
Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine (Suxamethonium). Despite the frequent use of succinylcholine with electroconvulsive therapy (ECT), there has been no reported case of potentially lethal malignant hyperthermia following ECT. In addition, the time interval between the administration of succinylcholine and the onset of malignant hyperthermia has not been outlined in the context of ECT.
CASE PRESENTATION
We present the case of a 79-year-old woman suffering from severe depression, who experienced severe malignant hyperthermia due to succinylcholine administration during an ECT session. She presented with a high fever of 40.2 °C, tachycardia of 140/min, hypertension with a blood pressure exceeding 200 mmHg, significant muscle rigidity, and impaired consciousness. These symptoms emerged two hours after ECT, which occurred in a psychiatric ward rather than an operating room, and reached their peak in less than 24 h. She was given 60 mg of dantrolene, which quickly reduced the muscular rigidity. Subsequently, she received two additional doses of 20 mg and 60 mg of dantrolene, which brought her fever down to 36.2 °C and completely eased her muscle rigidity within two days after ECT.
CONCLUSIONS
This is the first reported case of potentially lethal malignant hyperthermia after ECT. In addition, it highlights the delayed onset of malignant hyperthermia following an ECT procedure, emphasizing the necessity for psychiatrists to recognize its onset even after the treatment. In the light of potentially lethal consequences of malignant hyperthermia, it is critically important for psychiatrists to closely monitor both intraoperative and postoperative patient's vital signs and characteristic physical presentations, promptly identify any symptomatic emergence, and treat it immediately with dantrolene.
Topics: Humans; Succinylcholine; Electroconvulsive Therapy; Aged; Malignant Hyperthermia; Female; Neuromuscular Depolarizing Agents; Dantrolene; Psychiatrists
PubMed: 38834964
DOI: 10.1186/s12888-024-05846-5 -
Journal of Surgical Case Reports Jun 2024Morgagni hernia (MH) is a rare form of congenital diaphragmatic hernia, typically occurring predominantly on the right side and exhibiting a higher prevalence in...
Morgagni hernia (MH) is a rare form of congenital diaphragmatic hernia, typically occurring predominantly on the right side and exhibiting a higher prevalence in females. Usually diagnosed incidentally, MH may coexist with congenital heart defects, chest wall abnormalities and certain genetic syndromes such as Down syndrome. A 4-year-old boy with Down syndrome underwent simultaneous repair of MH and closure of a ventricular septal defect (VSD). A vertical midline sternotomy was performed, and the VSD was repaired using the right atrium approach. Subsequently, MH repair was conducted. Three weeks after the surgery, this patient developed a complete heart block, which lead to the implantation of a VVI pacemaker.
PubMed: 38832060
DOI: 10.1093/jscr/rjae301 -
PeerJ 2024To investigate the effect of GnRH agonist (GnRH-a) down-regulation prior to hormone replacement treatment (HRT) to prepare the endometrium in frozen embryo transfer...
Effect of GnRH agonist down-regulation combined with hormone replacement treatment on reproductive outcomes of frozen blastocyst transfer cycles in women of different ages.
OBJECTIVE
To investigate the effect of GnRH agonist (GnRH-a) down-regulation prior to hormone replacement treatment (HRT) to prepare the endometrium in frozen embryo transfer (FET) cycles in women of different ages.
METHODS
This was a retrospective study, and after excluding patients with adenomyosis, endometriosis, severe endometrial adhesions, polycystic ovary syndrome (PCOS), and repeated embryo implantation failures, a total of 4,091 HRT cycles were collected. Patients were divided into group A (<35 years old) and group B (≥35 years old), and each group was further divided into HRT and GnRHa-HRT groups. The clinical outcomes were compared between groups.
RESULTS
There was no statistically significant difference in clinical outcomes between the HRT and GnRHa-HRT groups among women aged <35 years. In women of advanced age, higher rates of clinical pregnancy and live birth were seen in the GnRHa-HRT group. Logistic regression analysis showed that female age and number of embryos transferred influenced the live birth rate in FET cycles, and in women aged ≥ 35 years, the use of GnRH-a down-regulation prior to HRT improved pregnancy outcomes.
CONCLUSIONS
In elderly woman without adenomyosis, endometriosis, PCOS, severe uterine adhesions, and RIF, hormone replacement treatment with GnRH agonist for pituitary suppression can improve the live birth rate of FET cycles.
Topics: Humans; Female; Embryo Transfer; Retrospective Studies; Adult; Gonadotropin-Releasing Hormone; Pregnancy; Down-Regulation; Hormone Replacement Therapy; Age Factors; Pregnancy Outcome; Pregnancy Rate; Embryo Implantation
PubMed: 38832029
DOI: 10.7717/peerj.17447 -
EFORT Open Reviews Jun 2024Distal radius fractures (DRFs) represent up to 18% of all fractures in the elderly population, yet studies on the rate of complications following surgery are lacking in...
PURPOSE
Distal radius fractures (DRFs) represent up to 18% of all fractures in the elderly population, yet studies on the rate of complications following surgery are lacking in the literature. This systematic review aimed to quantify the rate of complications and reinterventions in patients treated with volar plate for distal radius fractures, and analyze if there was any predisposing factor.
METHODS
A comprehensive literature search was performed on three databases up to January 2023, following PRISMA guidelines. Studies describing volar plate complications and hardware removal were included. A systematic review was performed on complications and rate of reintervention. Assessment of risk of bias and quality of evidence was performed with the 'Down and Black's Checklist for measuring quality'.
RESULTS
About112 studies including 17 288 patients were included. The number of complications was 2434 in 2335 patients; the most frequent was carpal tunnel syndrome (CTS), representing 14.3% of all complications. About 104 studies reported the number of reinterventions, being 1880 with a reintervention rate of 8.5%. About 84 studies reported the reason of reintervention; the most common were patient's will (3.0%), pain (1.1%), CTS (1.2%), and device failure (1.1%).
CONCLUSION
The complication rate after DRFs is 13.5%, with the main complication being CTS (14.3%), followed by pain and tendinopathy. The reintervention rate is 8.5%, mainly due to the patient's willingness, and all these patients had plate removal. Correct positioning of the plate and correct information to the patient before surgery can reduce the number of hardware removal, thereby reducing costs and the risk of complications associated with VLP for distal radius fractures.
PubMed: 38828969
DOI: 10.1530/EOR-23-0188 -
The Journal of Clinical Investigation Jun 2024Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a...
Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10-8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10-8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10-27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10-5) and ZNF467 (P = 2.9 × 10-4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Young Adult; Adaptor Proteins, Signal Transducing; Bone Morphogenetic Proteins; Cell Adhesion Molecules; Down Syndrome; Endothelial Cells; Genetic Markers; Phenotype; Wnt Signaling Pathway
PubMed: 38828726
DOI: 10.1172/JCI167811 -
BioRxiv : the Preprint Server For... May 2024Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of...
Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and overexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits and was trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic are important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.
PubMed: 38826419
DOI: 10.1101/2024.05.24.595804