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Query: UMLS:C0013080 (Down syndrome)
 14,180 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular basis of the antimyoclonic and antiepileptic properties of ACTH is unknown. Direct actions at neurotransmitter receptors have been hypothesized. Abnormalities of serotonergic neurotransmission have been suggested in the ACTH-responsive disorder infantile spasms based on elevated blood or platelet serotonin (5-HT) levels and induction of infantile spasms in Down's syndrome by the 5-HT precursor 5-hydroxytryptophan. To pursue these and other clinical and basic links between ACTH and 5-HT, the activity of ACTH at 5-HT receptors was determined n vitro and in vivo. Neonatal rats were treated for 30 consecutive days with a pharmacologic dose (40 IU/kg) of lyophilized porcine ACTH1-39 reconstituted in normal saline or with saline alone. ACTH administration impaired the weight gain of rat pups. In saturation receptor binding studies of rats treated as neonates (n = 7/group), ACTH significantly reduced receptor density (Bmax) of 5-HT2 sites in the cortex (-13%) compared to controls without a change in receptor affinity. Regional 5-HT1 receptor sites and 5-HT and 5-HIAA levels were not altered. Cortical tryptophan concentrations were significantly decreased (-29%) in rats treated neonatally with ACTH. In competition experiments in vitro using naive 7- to 10-day-old neonatal rat forebrain, ACTH1-39 displaced 5-HT1 and 5-HT2 sites only with 100 micromolar IC50 values. The small effects of ACTH at 5-HT receptors even at a supraclinical dose may not explain its potent clinical antimyoclonic properties.
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PMID:In vivo and in vitro effects of adrenocorticotrophic hormone on serotonin receptors in neonatal rat brain. 247 May 62

Plasma concentration of tryptophan, tyrosine, leucine and thiamine were reduced in senile dementia of Alzheimer type. In Down's syndrome, where Alzheimer-type histology appears consistently at an early age, there was a definite type of abnormality, raised concentrations of isoleucine, leucine, phenylalanine and cystine. Because of the competition between amino acids for transfer into the brain, either or both of these types of change could lie in the aetiological chain underlying the development of Alzheimer pathology. Alternatively, these patterns could reflect the requirements of aberrant central/peripheral protein turnover.
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PMID:Plasma amino acids in patients with senile dementia and in subjects with Down's syndrome at an age vulnerable to Alzheimer changes. 252 95

In 25 children with Down's syndrome, the content of free amino acids in the blood plasma, was examined chromatographically. The content of free phenylalanine, thyrosine, lysine, histidine, tryptophan, leucine and isoleucine was found to be lowered. In the brain cortex of newborn infants with Down's syndrome and increased content of cystine, alanine, phenylalanine, threonine, leucine, isoleucine, as well as double excess of gamma-aminobutyric acid were revealed.
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PMID:[Free plasma and cerebral amino acids in children with Down's syndrome]. 645 78

In a follow-up survey to a 1984 study, 339 paediatricians in Australia were invited to complete a brief questionnaire in 1990, in which they indicated their usual recommendations, practices and advice when managing children with Down syndrome. The response rate was 67%. The results indicated that the most frequent paediatrician-initiated referrals were for early intervention and for discussion with other parents; these options were selected more frequently in 1990 than in 1984. While referral to a social worker was the next most frequent choice, it occurred less in 1990 than in 1984. Other increases in referrals were for physiotherapy and speech therapy. Paediatricians were more likely to support referral to a geneticist, speech therapist or cosmetic surgeon in response to a specific parental enquiry, and less likely to support referral to a social worker or to full-time care. There had been significant increases since 1984 in the likelihood that paediatricians would order audiology and investigation of thyroid and cardiac function. There was less opposition to the use of sedatives, and virtual cessation of the use of tryptophan. Paediatricians were more optimistic about the likelihood of persons with Down syndrome living independently, caring for their own finances, and marrying, but not about other developmental areas.
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PMID:Paediatric management practices in Down syndrome: a follow-up survey. 846 Nov 75

Excitatory amino acid (EAA) receptors are central to brain physiology and play important roles in learning and memory processes. Kynurenic acid (KYNA), a metabolite of tryptophan in the brain blocks all three classical ionotropic EAA receptors and also serves as an antagonist at the glycine site associated with the N-methyl-D-aspartate receptor (NMDA) complex. We measured the endogenous levels of KYNA and activities of KYNA synthesizing enzymes kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal and temporal cortex of elderly Down syndrome (DS) patients (aged 46-69 years). Compared with control specimens (0.21 +/- 0.06 pmol/mg tissue), the measurement of KYNA content revealed a significant 3-fold increase in frontal cortex of DS patients (0.67 +/- 0.13 pmol/mg tissue; p < or = 0.01). In temporal cortex KYNA levels were increased by 151% (p < or = 0.05) of control (0.41 +/- 0.09 pmol/mg tissue) Using crude cell free homogenate KAT's activities were determined in the presence of the 1 mM 2-oxoacid as a co-substrate at their pH optima of 10.0 for KAT I and 7.4 for KAT II. KATs activities in the presence of 1 mM pyruvate were 2.79 +/- 0.52 and 4.55 +/- 1.98 pmol/mg protein/h for KAT I and 0.98 +/- 0.07 and 1.09 +/- 0.14 pmol/mg protein/h for KAT II in frontal cortex and temporal cortex, respectively. When compared with the brain samples of controls the activity of KAT I was reduced in frontal cortex (9.8 +/- 2.4%; p < or = 0.01) and temporal cortex (25.8 +/- 6.4 %) of DS patients, while KAT II levels were within the normal range. Measurement of the neuronal, cholinergic marker choline acetyltransferase (ChAT) in the frontal cortex, revealed a significant reduction (36.6 +/- 4.3% of control; p < or = 0.01) in DS. Our data demonstrate the involvement of KYNA-metabolism in the cellular mechanisms underlying altered cognitive function in patients with DS. Although the localisation of both, KAT I and KAT II is not stated yet the reduction of KAT I may suggest impairment of KYNA metabolism in neuronal and/or nonneuronal compartments.
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PMID:Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with Down syndrome. 863 15

Cysteine conjugate beta-lyase/glutamine transaminase K/kynurenine aminotransferase (CS-lyase/GTK/KAT) is a tri-functional enzyme found in several organs, including the brain. Kynurenine aminotransferase is important in tryptophan metabolism in the CNS, producing kynurenic acid, a NMDA receptor antagonist and neuroprotective. Tryptophan not metabolised via kynurenine aminotransferase may form quinolinic acid, a NMDA receptor agonist and neurotoxin. Kynurenic acid co-treatment blocks quinolinic acid induced lesions in the CNS in rat. In many conditions exhibiting neurodegeneration (i.e. Huntington's, Parkinsonism, Down's syndrome) quinolinic acid and/or kynurenic acid concentrations are altered, suggesting the ratio of these chemicals may be important in neurodegeneration. We have investigated the developmental modulation of CS-lyase/GTK/KAT mRNA in rat brain. CS-lyase/GTK/KAT mRNA was measured in 14, 21, 28, 35, 42 day post-natal and adult rats. While many regions demonstrated a steady increase to adult levels, two other profiles were seen. Five regions rapidly reached adult levels of the mRNA, while two peaked above the adult level before falling back. This provides evidence that expression of the CS-lyase/GTK/KAT gene is physiologically modulated, and provides the basis for further investigation into the mechanism of control. Artificial modulation could possibly be used to alter levels of the neuroprotectant kynurenic acid in neurodegeneration.
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PMID:Developmental modulation of cysteine conjugate beta-lyase/glutamine transaminase K/kynurenine aminotransferase mRNA in rat brain. 951 31

Congenital heart disease (CHD) affects over 40% of Down syndrome (DS) patients. The region proposed to contain the gene(s) for DS CHD has been restricted to 21q22.2-22.3, from D21S55 to MX1. The identification and functional characterization of the genes mapping to this region is a necessary step to understand the pathogenesis of CHD in DS. In an effort to contribute to the construction of a transcriptional map of the DS CHD region we have performed direct cDNA selection using a YAC contig that maps between ETS2 and D21S15 and cDNAs synthesised from fetal heart structures. Here we describe the identification and characterization of a new gene, WRB, that maps to 21q22.3 between ACTL5 and HMG 14 and appears to be widely expressed in adult and fetal tissues. The new gene encodes a basic protein of unknown function containing a tryptophan-rich carboxyl-terminal region and a potential nuclear localization signal. Immunofluorescence analysis shows a predominant localization in the cell nucleus. The understanding of the biological function of the protein product should clarify the potential role of WRB in the pathogenesis of DS CHD.
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PMID:Identification and characterization of a new human cDNA from chromosome 21q22.3 encoding a basic nuclear protein. 954 40

The isoprenoid pathway related cascade was assessed in trisomy 21 and Huntington's disease. Membrane Na+-K+ ATPase activity, serum magnesium and ubiquinone were decreased while HMG CoA reductase activity, serum digoxin and dolichol levels were increased in both the disorders. There were increased levels of tryptophan catabolites (nicotine, strychnine, quinolinic acid and serotonin) and decreased levels of tyrosine catabolites (dopamine, noradrenaline and morphine) in both trisomy 21 and Huntington's disease. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual GAG fractions and lysosomal enzymes in both disorders. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in both the disorders. The role of hypothalamic digoxin and a disordered isoprenoid pathway in the pathogenesis of trisomy 21 and Huntington's disease is discussed.
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PMID:Endogenous sodium-potassium ATPase inhibition related biochemical cascade in trisomy 21 and Huntington's disease: neural regulation of genomic function. 1213 82

The study assessed the isoprenoid pathway, digoxin synthesis, and neurotransmitter patterns in individuals of differing hemispheric dominance, neurogenetic disorders, and neoplasms. The HMG CoA reductase activity, serum digoxin, magnesium, tryptophan catabolites, tyrosine catabolites, and RBC membrane Na+-K+ ATPase activity were measured in individuals of differing hemispheric dominance. The digoxin status, membrane Na+-K+ ATPase activity, and serum magnesium were assessed in Huntington's disease, trisomy 21, glioblastoma multiforme, and non-Hodgkin's lymphoma (high grade lymphoma). The results showed that right hemispheric, chemically dominant individuals had elevated digoxin synthesis, increased tryptophan catabolites, and reduced tyrosine catabolites, and membrane Na+-K+ ATPase with hypomagnesemia. Left hemispheric, chemically dominant individuals had the opposite patterns. In neurogenetic disorders and neo plasms also hyperdigoxinemia induced membrane Na+-K+ ATPase inhibition, and hypomagnesemia similar to right hemispheric chemical dominance could be demonstrated. The role of hemispheric chemical dominance and hypothalamic digoxin secretion play a key role in the regulation of cell differentiation/proliferation and genomic function. Ninety-five percent of the patients with neurogenetic disorders and neoplasms were right-handed/left hemispheric dominant by dichotic listening test. However, all of them had biochemical patterns similar to right hemispheric chemical dominance. Hemispheric chemical dominance has no correlation to cerebral dominance detected by handness/dichotic listening test.
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PMID:Cerebral chemical dominance and neural regulation of cell division, cell proliferation, neoplastic transformation, and genomic function. 1274 28

The isoprenoid pathway related cascade was assessed in trisomy 21. Membrane Na+, K(+)-ATPase activity, serum magnesium, and ubiquinone were decreased while hydroxy methyl glutaryl CoA (HMG) coenzyme A (CoA) reductase activity, serum digoxin, and dolichol levels were increased in trisomy 21. There were increased levels of tryptophan catabolites--nicotine, strychnine, quinolinic acid, and serotonin--and decreased levels of tyrosine catabolites--dopamine, noradrenaline, and morphine in trisomy 21. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycan (GAG) fractions, and lysosomal enzymes in trisomy 21. Reduced levels of ubiquinone, reduced glutathione, and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in trisomy 21. Hypothalamic digoxin and a disordered isoprenoid pathway are important in the pathogenesis of trisomy 21.
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PMID:Hypothalamic digoxin-mediated model for trisomy 21. 1469 93


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