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Biomedical subjects

K Hyland

Publications and source records attributed to K Hyland.

At least 55 records · Page 3Linked to original sources
PubMed1998

Depression among African American nursing home patients with dementia.

The authors compared 218 black and 68 white nursing home patients with dementia for differences in the prevalence, recognition, and treatment of depression. There were no racial differences in depressive symptoms, but whites were significantly more likely to receive a diagnosis of "possible depression" and there were few racial differences in clinical, social, or demographic factors associated with depression. Depression was often unrecognized and undertreated in both racial groups; several depression instruments developed for use in dementia had good reliability and validity among blacks; and there were no significant differences in depressive symptoms or diagnosis between U.S.-born and Caribbean-born black patients. The absence of any appreciable interracial or intraracial differences in depression symptoms or diagnoses may reflect uniformity in nursing home selection criteria or lessening of mood differences that may have existed before admission.

Activities of Daily Living↗
PubMed1997

Human hair follicles as a peripheral source of tyrosine hydroxylase and aromatic L-amino acid decarboxylase mRNA.

Total RNA from human hair follicles was reverse transcribed and amplified using primers specific for aromatic L-amino acid decarboxylase (AADC) and tyrosine hydroxylase (TH). Agarose electrophoresis of the amplified products showed reverse transcription polymerase chain reaction (RT-PCR) products of the expected size for both TH and AADC. Sequencing showed that the amplified products matched the known sequences of TH and AADC. This study identifies hair follicles as a convenient, uninvasive, source of the mRNA for TH and AADC. Analysis of these mRNA's may be useful in the diagnosis and investigation of conditions resulting from qualitative changes in the genes that code for these enzymes.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1997

Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family.

Aromatic L-amino acid decarboxylase deficiency is an inborn error of metabolism that leads to combined serotonin and catecholamine deficiency, first described by Hyland et al in 1990. The clinical features, biochemical findings, and treatment of the second family with this condition are reported. Our male patient presented with developmental delay, extreme hypotonia, oculogyric crises, and irritability. The diagnosis of this inborn error of biogenic amine metabolism was accomplished by determining low concentrations of homovanillic, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenyl-ethyleneglycol in cerebrospinal fluid with normal biopterin metabolism and increased L-dopa, in plasma, cerebrospinal fluid, and urine. Greatly reduced activity of aromatic L-amino acid decarboxylase in plasma confirmed this diagnosis. Combined treatment with pyridoxine, tranylcypromine, and bromocriptine produced some clinical improvement.

5-Hydroxytryptophan↗
PubMed1997

Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer.

PURPOSE: Folate deficiency, either by diet or drug, increases plasma homocysteine (Hcy). Hcy damages cerebrovascular endothelium, and hyperhomocysteinemia is a risk factor for stroke. Hcy is metabolized to excitatory amino acid (EAA) neurotransmitters, such as homocysteic acid (HCA) and cysteine sulfinic acid (CSA), which may cause seizures and excitotoxic neuronal death. We postulated that excess Hcy and EAA neurotransmitters may partly mediate methotrexate (MTX)-associated neurotoxicity. PATIENTS AND METHODS: In this retrospective analysis, we used high-performance liquid chromatography (HPLC) to measure Hcy, HCA, and CSA in CSF from two groups of children: (1) a control group of patients with no MTX exposure, and (2) a treatment group of patients who had received MTX no more than 7 days before a scheduled lumbar puncture. RESULTS: The treatment group had a significantly (P = .0255) greater concentration of Hcy in CSF (0.814 micromol/L +/- 0.215 [mean +/- SEM], n = 23) than the control group (0.210 micromol/L +/- 0.028, n = 34). HCA and CSA were not detected in CSF from control patients (n = 29); however, MTX caused marked accumulation of CSF HCA (119.1 micromol/L +/- 32.0, n = 16) and CSA (28.4 micromol/L +/- 7.7, n = 16) in the treatment group. Patients with neurologic toxicity at the time of lumbar puncture had many of the highest concentrations of Hcy, HCA, and CSA. CONCLUSION: These data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excitotoxic neurotransmitters.

Antimetabolites, Antineoplastic↗
PubMed1997

Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test.

To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg). Seven adults with DRD, two severely affected children with DRD, and nine adult controls were studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the adult patients, phenylalanine levels were higher than in controls at 2, 4, and 6 hours post-load (p < 0.0005); tyrosine concentrations were lower than control levels at 1, 2, and 4 hours post-load (p < 0.05). Phenylalanine to tyrosine ratios were elevated in patients at all times post-load (p < 0.0005). Biopterin levels in the patients were decreased at baseline and 1, 2, and 4 hours post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized phenylalanine and tyrosine profiles in two adult patients. In the children with DRD, phenylalanine to tyrosine ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients but there was no elevation in plasma tyrosine. Baseline biopterin levels were lower in the children with DRD than in the adult patients or the controls and there was no increase in biopterin post-load. In both the children and adults with DRD, neopterin concentrations did not differ from control values at baseline or after phenylalanine load. The results are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a phenylalanine load may be useful in the diagnosis of this disorder.

Administration, Oral↗
PubMed1997

Aromatic L-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crises.

Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Alternative splicing in the coding region of human aromatic L-amino acid decarboxylase mRNA.

Total RNA from human neuroblastoma cells (SK-N-SH) was reverse transcribed and amplified using primers specific for aromatic L-amino acid decarboxylase (AADC). Two polymerase chain reaction (PCR) products were observed following agarose electrophoresis. Cycle sequencing of the PCR products revealed the larger fragment (414 bp) to be identical to the published human cDNA sequence (Type I). Sequencing of the smaller band (300 bp) demonstrated a form missing exon three (Type II). Both types of the mRNA were colocalized in human brain regions (gray matter and white matter) and other human tissues (liver, kidney, adipose, heart, adrenal gland and keratinocytes). The relative concentrations varied in each tissue studied but specific neuronal or non-neuronal patterns were not apparent. The study demonstrates alternative splicing within the coding region of the human AADC mRNA and the results suggest the possibility that two proteins are derived from the AADC gene in human tissues.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1996

Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse.

The hph-1 mouse which displays tetrahydrobiopterin deficiency and impaired dopamine and serotonin turnover, has been used to study cofactor replacement therapy for disorders causing brain tetrahydrobiopterin deficiency. Subcutaneous administration of 100 mumol/kg (30 mg/kg) of tetrahydrobiopterin resulted in a twofold increase in brain cofactor concentration 1 h after administration. Concentrations remained above the endogenous level for at least 4 h but returned to normal by 24 h. The lipophilic tetrahydrobiopterin analogue 6-methyltetrahydropterin entered the brain five times more efficiently than tetrahydrobiopterin but was cleared at a faster rate. Tetrahydropterins linked to the lipoidal carrier N-benzyl-1, 4-dihydronicotinoyl did not result in a detectable increase in levels of brain pterins over the period of the study (1-4 h). Stimulation of monoamine turnover was not observed at any time point with either natural cofactor or the methyl analogue. Increasing the amount of tetrahydrobiopterin to 1,000 mumol/kg resulted in elevation of cofactor concentrations, a brief increase in the activity of tyrosine and tryptophan hydroxylase 1 h postadministration, and increased turnover of dopamine and serotonin metabolites lasting 24 h. However, 2 of 12 (17%) mice died following administration of this dose of cofactor. Our findings suggest that acute peripheral tetrahydrobiopterin administration is unlikely to stimulate brain monoamine turnover directly unless very large and potentially toxic doses of cofactor are used.

Animals↗
PubMed1996

Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse.

hph-1 mice, which have defective tetrahydrobiopterin biosynthesis due to decreased GTP cyclohydrolase I activity, have been used to investigate the effects of tetrahydrobiopterin deficiency on aromatic L-amino acid monooxygenases and brain monoamine metabolism. Liver tetrahydrobiopterin levels were decreased, and tetrahydrobiopterin deficiency and reduced levels of dopamine, norepinephrine, serotonin, and their metabolites in the brain occurred both pre- and postnatally. Chronic subcutaneous tetrahydrobiopterin elevated brain levels to values higher than those seen in controls but had no effect on monoamine metabolism. In vivo activities of tyrosine hydroxylase and tryptophan hydroxylase were significantly decreased. There was a 30% decrease in the in vitro activity of striatal tyrosine hydroxylase and 50% decrease in liver phenylalanine hydroxylase. Western blotting demonstrated that the lower monooxygenase activities resulted from a reduced absolute amount of tyrosine hydroxylase and phenylalanine hydroxylase protein. The findings suggest involvement of tetrahydrobiopterin in the control of the steady-state concentration of the aromatic L-amino acid monooxygenases. In addition, demonstration of central monoamine changes in the hph-1 mouse make it a possible model system for the investigation of the neuropathological mechanisms in Dopa-responsive dystonia, which has recently been linked with mutations in the gene for GTP cyclohydrolase I.

Animals↗
PubMed1995

Biochemical indices of vitamin B12 nutrition in pregnant patients with subnormal serum vitamin B12 levels.

To determine the significance of the commonly observed fall in serum vitamin B12 levels during pregnancy, serum levels of the B12 metabolites methylmalonic acid (MMA) and homocysteine (Hcy) were measured in a group of 50 pregnant patients with subnormal serum B12 (range 45-199 pg/ml) and the results compared with those of 25 pregnant controls (serum B12(208-580) pg/ml). Mean values for serum MMA and total Hcy in the subnormal B12 group were 445.4 nmol/L and 7.03 mumol/L, respectively, which were not significantly different from the mean MMA of 440.5 nmol/L and Hcy of 6.88 nmol/L in the controls. For the total group of patients, neither serum MMA nor serum Hcy levels correlated with serum B12. One-third of pregnant patients showed elevated serum MMA values, independent of B12 status. Significant elevation of serum Hcy was detected in only two patients, both with subnormal serum B12 and hematological evidence of B12 deficiency. We conclude that the usual fall in serum B12 concentration in pregnancy does not reflect B12 deficiency at the biochemical level. In establishing true B12 deficiency in pregnancy, the serum Hcy level (in the absence of folate deficiency) but not serum MMA, is of value.

Female↗
PubMed1994

S-adenosylmethionine levels in psychiatric and neurological disorders: a review.

INTRODUCTION: S-adenosylmethionine (SAMe) is an important methyl donor in over 35 methylation reactions involving DNA, proteins, phospholipids and catechol- and indole- amines. MATERIAL AND METHODS: This article reviews the studies that have examined brain and blood levels of SAMe in several psychological, neurological and metabolic disorders. RESULTS: Although studies have found no consistent changes in whole blood SAMe levels in psychiatric patients, other investigators have found low cerebrospinal fluid (CSF) SAMe levels in patients with neurological disorders such as Alzheimer's dementia, subacute combined degeneration of the spinal cord (SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders such as 5, 10-CH2-H4 folate reductase deficiency. CONCLUSION: Intravenous or oral administration of SAMe thus represents a possible treatment for these neurological and metabolic disorders.

AIDS Dementia Complex↗
PubMed1994

The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders.

This review focuses on the biochemical and clinical aspects of methylation in neuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems. SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.

AIDS Dementia Complex↗
PubMed1994

Detection of metabolic disorders among selectively screened people with idiopathic mental retardation.

Fifth-eight people receiving residential or other services for idiopathic mental retardation were evaluated for evidence of metabolic disease. Five (8%) demonstrated persistent urinary organic acid abnormalities on at least three occasions, which pointed towards specific genetic metabolic defects. Instigation of specific treatment programs may have improved the quality of life for one of these participants. Appropriate genetic counseling was provided but could have been instigated much earlier had these investigations been performed as part of a routine workup for idiopathic mental retardation. This pilot study suggests a need for evaluation of other similar populations with idiopathic mental retardation.

Adolescent↗
PubMed1993

Quinolinic acid in children with congenital hyperammonemia.

Levels of the excitotoxin quinolinic acid (QUIN) were measured in the cerebrospinal fluid of infants and children with congenital hyperammonemia. Twofold to tenfold elevations of QUIN were found in 4 neonates in hyperammonemic coma (QUIN range, 250-990 nM; control mean, 110 +/- 90 nM; p < 0.005). Similar elevations of neopterin were found (range, 24-75 nM; control mean, 9.0 +/- 4.9 nM; p < 0.005). In addition, significant elevations of QUIN were found in 14 older children with congenital hyperammonemia (mean, 50 +/- 20 vs 17 +/- 6 nM; p < 0.05). Neopterin levels were not elevated in these children. The QUIN may originate from an increase in tryptophan transport across the blood-brain barrier or from induction of indolamine-2,3-dioxygenase activity. These findings support a role for QUIN in the neuropathology of congenital hyperammonemia. They also suggest the potential utility of N-methyl-D-aspartate receptor-blocking agents or inhibitors of QUIN synthesis in the treatment of hyperammonemic coma.

Ammonia↗