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Proceedings of the National Academy of... Jul 2022The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.
Topics: Angiotensin-Converting Enzyme 2; Astrocytes; Cerebral Cortex; Humans; Organoids; Primary Cell Culture; SARS-CoV-2; Viral Tropism
PubMed: 35858406
DOI: 10.1073/pnas.2122236119 -
The New England Journal of Medicine Aug 2003
Topics: Humans; Influenza, Human; Severe Acute Respiratory Syndrome
PubMed: 12921089
DOI: No ID Found -
Journal of Clinical Research in... Feb 2020Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”....
Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”. Patients with severe disorders usually harbor homozygous or compound heterozygous mutations. In contrast, type A insulin resistance syndrome has been associated with heterozygous mutations; homozygous mutations are rarely responsible for this condition. We report a novel, homozygous mutation, p.Leu260Arg in exon 3, of the gene in a female adolescent patient with type A insulin resistance syndrome together with clinical details of her medical follow-up. Different mutations in the gene cause different phenotype and vary depending on the inheritance pattern. This report adds to the literature, increases understanding of the disease mechanism and aids in genetic counseling.
PubMed: 32018348
DOI: 10.4274/jcrpe.galenos.2020.2019.0213 -
Molecular Syndromology Jun 2020Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (). Here, we report 2 cases:...
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (). Here, we report 2 cases: one with DS and the other with RMS. The case with DS presented with intrauterine growth retardation, nipple hypertrophy, clitoromegaly, distended abdomen, hypertrichosis, and dysmorphic features. The second case showed severe acanthosis nigricans, hyperkeratosis, and hypertrichosis. In both cases, abnormal glucose homeostasis due to severe insulin resistance was observed. The diagnosis of DS and RMS was established based on clinical characteristics, abnormal glucose homeostasis, high serum insulin levels, and determination of pathogenic variants in the gene. The first case with DS has 2 novel homozygous variants, NM_000208.3, c.3122delA (p.N1041Mfs*16) and c.3419C>G (p.A1140G), and the second case with RMS has a previously reported homozygous variant NM_000208.3, c.3529+5G>A (IVS19+5G>A) in the gene.
PubMed: 32655340
DOI: 10.1159/000506722 -
Pediatrics Feb 2011Studies of the efficacy of inhaled nitric oxide (iNO) to prevent or treat respiratory failure in preterm infants have had variable and contradictory findings. (Review)
Review
CONTEXT
Studies of the efficacy of inhaled nitric oxide (iNO) to prevent or treat respiratory failure in preterm infants have had variable and contradictory findings.
OBJECTIVES
To systematically review the evidence on the use of iNO in infants born at ≤ 34 weeks' gestation who receive respiratory support.
METHODS
Medline, Embase, the Cochrane Central Register of Controlled Studies, PsycInfo, ClinicalTrials.gov, and proceedings of the 2009 and 2010 Pediatric Academic Societies meetings were searched in June 2010. Additional studies from reference lists of eligible articles, relevant reviews, and technical experts were considered. Two investigators independently screened search results and abstracted data from eligible articles. We focus here on mortality, bronchopulmonary dysplasia (BPD), the composite outcome of death or BPD, and neurodevelopmental impairment.
RESULTS
Fourteen randomized controlled trials, 7 follow-up studies, and 1 observational study were eligible for inclusion. Mortality rates in the NICU did not differ for infants treated with iNO compared with controls (risk ratio [RR]: 0.97 [95% confidence interval (CI): 0.82-1.15]). BPD at 36 weeks for iNO and control groups also did not differ for survivors (RR: 0.93 [95% CI: 0.86-1.003]). A small difference was found in favor of iNO in the composite outcome of death or BPD (RR: 0.93 [95% CI: 0.87-0.99]). There was no evidence to suggest a difference in the incidence of cerebral palsy (RR: 1.36 [95% CI: 0.88-2.10]), neurodevelopmental impairment (RR: 0.91 [95% CI: 0.77-1.12]), or cognitive impairment (RR: 0.72 [95% CI: 0.35-1.45]).
CONCLUSIONS
There was a 7% reduction in the risk of the composite outcome of death or BPD at 36 weeks for infants treated with iNO compared with controls but no reduction in death alone or BPD. There is currently no evidence to support the use of iNO in preterm infants with respiratory failure outside the context of rigorously conducted randomized clinical trials.
Topics: Administration, Inhalation; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nitric Oxide; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn
PubMed: 21220391
DOI: 10.1542/peds.2010-3428 -
Journal of Pediatric Endocrinology &... 2012Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and...
Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the alphabeta fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure.
Topics: Cardiomyopathy, Hypertrophic; Donohue Syndrome; Echocardiography; Fatal Outcome; Heart Failure; Humans; Infant, Newborn; Infant, Premature; Male; Mutation; Receptor, Insulin
PubMed: 22768670
DOI: 10.1515/jpem-2011-0448 -
Acta Diabetologica Oct 2014
Topics: Bartter Syndrome; Donohue Syndrome; Female; Humans; Insulin Resistance; Male; Mutation; Receptor, Insulin
PubMed: 24913309
DOI: 10.1007/s00592-014-0606-y -
Nature Immunology Apr 2024One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and...
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
Topics: Humans; Post-Acute COVID-19 Syndrome; COVID-19; Biomedical Research; Hospitalization; Immunoglobulin G
PubMed: 38589621
DOI: 10.1038/s41590-024-01778-0 -
Acta Paediatrica (Oslo, Norway : 1992) Jan 1994
Topics: Fetal Growth Retardation; Humans; Hypertrichosis; Infant, Newborn; Syndrome
PubMed: 8193466
DOI: 10.1111/j.1651-2227.1994.tb12945.x -
Cell Stem Cell Mar 2024Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2...
Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.
Topics: Humans; Schizophrenia; DiGeorge Syndrome; Phenotype
PubMed: 38382530
DOI: 10.1016/j.stem.2024.01.010