Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased survival of very preterm infants and extremely preterm infants does not imply an increase in neurodevelopmental sequelae. However, preterm infants remain at high risk of severe cerebral palsy with neuromotor dysfunction and mental retardation. Necrotic or hemorrhagic lesions occurring in the periventricular ring of telencephalic white matter are the most threatening events for the developing brain of these infants. Recent progress in neuroepidemiology, developmental neurobiology and imaging methods has made it possible to revisit the pathophysiology of brain lesions on a multifactorial basis. Treatment and early detection of infections is a priority. Neuroprotective agents capable of arresting neuron cell death (antagonists of the excitotoxic cascade, free-radical antagonists, proinflammatory cytokine antagonists, growth factors) are new strategies for the prevention of cerebral palsy.
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PMID:[Grand prematurity, risk of neuropsychic handicaps and neuroprotection]. 1084 25

The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.
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PMID:Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. 1462 Aug 78

Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor alpha inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = .16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis.
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PMID:Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. 1516 89

In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a "tree in winter" appearance. This developmental failure is thought to result in mental retardation. In adults with Down syndrome, neuronal loss is dramatic and neurofibrillary and neuritic Abeta plaque pathologies are consistent with Alzheimer disease. These pathological changes are thought to underlie the neuropsychological and physiological changes in older individuals with Down syndrome. Two chromosome 21-based gene products, beta-amyloid precursor protein (betaAPP) and S100B, have been implicated in these neuronal and interstitial changes. Although not necessary for mental retardation and other features, betaAPP gene triplication is necessary, although perhaps not sufficient, for development of Alzheimer pathology. S100B is overexpressed throughout life in Down patients, and mice with extra copies of the S100B gene have dendritic abnormalities. S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis. Interleukin-1 (IL-1) is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome. IL-1 upregulates betaAPP and S100B expression and drives numerous neurodegenerative and self-amplifying cascades that support a neuroinflammatory component in the pathogenesis of sporadic and Down syndrome-related Alzheimer disease.
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PMID:Trisomy 21 and the brain. 1529 Aug 93

Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.
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PMID:Neuroglial activation and neuroinflammation in the brain of patients with autism. 1554 55

Down's syndrome (DS) associates with genetic-dependent dysregulation of the interferon (IFN) system. We used intracellular cytokine staining to analyse the percentages of IFN-gamma- and interleukin (IL)-4-producing T cells in the peripheral blood of patients with DS, individuals with mental retardation (MR), and healthy controls (HCs). The percentages of IFN-gamma-producing CD4(+) and CD8(+) T cells (IFGCs), namely Th1 (mean, 21.4+/-S.D. 1.3) and Tc1 (12.6+/-1.1), and the Th1/Th2 ratio (6.1+/-0.2) in DS were significantly higher than in MR (15.9+/-1.3, 7.9+/-0.6, 4.8+/-0.3) and in HCs (15.6+/-1.9, 7.2+/-1.1, 4.6+/-0.6). Most of the DS patients with high IFGC percentages were seropositive for anti-transglutaminase IgA. We found no correlation between sex, age, APOE genotypes, coexisting autoimmune diseases, susceptibility to infections, or degree of cognitive impairment and high IFGC percentages. This abnormality might thus contribute to immune dysfunction in DS without manifest clinical correlates.
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PMID:Interferon-gamma- and interleukin-4-producing T cells in Down's syndrome. 1628 22

Disturbance to early brain development is implicated in several neuropsychiatric disorders including autism, schizophrenia, and mental retardation. Epidemiological studies have indicated that the risk of developing these disorders is enhanced by prenatal maternal infection, presumably as a result of neurodevelopmental defects triggered by cytokine-related inflammatory events. Here, we demonstrate that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior. Specifically, the relative expression of pro- and anti-inflammatory cytokines in the fetal brains in response to maternal immune challenge may be an important determinant among other developmental factors for the precise pathological profile emerging in later life. Thus, the middle and late gestation periods correspond to two windows with differing vulnerability to adult behavioral dysfunction, brain neuropathology in early adolescence, and of the acute cytokine responses in the fetal brain.
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PMID:The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. 1687 86

Cytomegalovirus (CMV) is the leading cause of congenital viral infection, with an incidence of 0.5-3% of live births worldwide. Clinical evidence has shown hearing and vision loss, mental retardation and sometimes death in affected newborns. Primary maternal CMV infection during gestation poses a 40% risk of intrauterine transmission in contrast to recurrent infection. European laboratories have made significant progress in the last decade in solving diagnostic problems linked to infection in pregnancy. With the advances in CMV serology, such as detection of anti-CMV IgM by enzyme immunoassays (EIA), confirmed by Western blot, together with seroconversion and anti-CMV IgG avidity evaluation in pregnant mothers, can help to identify recent infection. Preventative measures such as screening for CMV in the routine serological work-up of pregnant women have been introduced in countries such as Spain and Italy. The development of specific T cell-mediated immune responses in mothers, fetus and neonates is now emerging with regard to antigen-specific CD4 and CD8 T cells, differentiation status, proliferative and cytokine responses. A protective vaccine against CMV is a major public health priority and the study of vaccines in animal model systems has identified potential strategies for interrupting transmission and preventing disease in newborns. Congenital CMV infection has a variable outcome and therefore novel diagnostic methods are required to identify those at risk and therapeutic interventions are needed to improve the long-term prognosis of those infected. CMV was first isolated in 1957. We are now 50 years on, so procrastination is not an option.
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PMID:Translational mini-review series on infectious disease: congenital cytomegalovirus infection: 50 years on. 1763 29

Fifteen years of evidence have established that the cytokine erythropoietin offers promise as a treatment for brain injury. In particular, neonatal brain injury may be reduced or prevented by early treatment with recombinant erythropoietin. Extreme prematurity and perinatal asphyxia are common conditions associated with poor neurodevelopmental outcomes including cerebral palsy, mental retardation, hearing or visual impairment, and attention deficit hyperactivity disorder. When high doses of erythropoietin are administered systemically, a small proportion crosses the blood-brain barrier and can protect against hypoxic-ischemic brain injury. In addition to other protective effects, erythropoietin can specifically protect dopaminergic neurons. Since reduced dopamine neurotransmission contributes to attention deficit hyperactivity disorder, this condition may be amenable to erythropoietin treatment. This review focuses on the potential application of erythropoietin as a neuroprotectant with regard to neurologic complications of extreme prematurity, including attention deficit hyperactivity disorder. Recent concerns that early erythropoietin might exacerbate the pathologic neovascularization associated with retinopathy of prematurity are addressed.
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PMID:Recent trends in erythropoietin-mediated neuroprotection. 1793 39

Tumour necrosis factor-alpha (TNF-alpha) is a key mediator of inflammation in host defence against infection and in autoimmune disease. Its production is controlled post-transcriptionally by multiple RNA-binding proteins that interact with the TNF-alpha AU-rich element and regulate its expression; one of these is Fragile X mental retardation-related protein 1 (FXR1). The anti-inflammatory cytokine transforming growth factor-beta1 (TGF-beta1), which is involved in the homeostatic regulation of TNF-alpha, causes post-transcriptional suppression of lipopolysaccharide (LPS)-induced TNF-alpha production. We report here that this depends on FXR1. Using RAW 264.7 cells and bone marrow-derived macrophages (BMDMphi) stimulated with LPS and TGF-beta1, we show that TGF-beta1 inhibits TNF-alpha protein secretion, whereas TNF-alpha mRNA expression remains unchanged. This response is recapitulated by the 3'-UTR of TNF-alpha, which is known to bind FXR1. TGF-beta1 induces FXR1 with a pattern of expression distinct from that of tristetraprolin, T-cell intracellular antigen 1, or human antigen R. When FXR1 is knocked down, TGF-beta1 is no longer able to inhibit LPS-induced TNF-alpha protein production, and overexpression of FXR1 suppresses LPS-induced TNF-alpha protein production. Targeting the p38 mitogen-activated protein kinase pathway of LPS-treated cells with small molecule inhibitors can induce FXR1 protein and mRNA expression. In summary, TGF-beta1 opposes LPS-induced stabilization of TNF-alpha mRNA and reduces the amount of TNF-alpha protein, through induction of expression of the mRNA-binding protein FXR1.
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PMID:Fragile X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-alpha production by transforming growth factor-beta1. 2049 1


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