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Biomedical subjects

A K Percy

Publications and source records attributed to A K Percy.

At least 37 records · Page 2Linked to original sources
PubMed1998

C-fos mediates cocaine inhibition of NGF-induced PC12 cell differentiation.

In utero cocaine exposure can affect CNS development. Previous studies showed that cocaine inhibits neuronal differentiation in a dose-dependent fashion, in nerve growth factor (NGF)-stimulated PC12 cells, without affecting cell viability. NGF activates intracellular signaling proteins, specific immediate-early genes (IEG) including a transient peak of c-fos expression, and induction of late genes expression, leading to the neuronal phenotype. We hypothesized that cocaine interferes with NGF signaling. Therefore, we examined the pattern of c-fos expression in our cellular model. Time course of c-fos expression up to 72 h was determined in cells treated with NGF 20 ng/ml and cocaine 10 microgram/ml (a moderately toxic level) by RT-PCR analysis. Total RNA was isolated from cells, and levels of c-fos mRNA were estimated using gene-specific primers. In both control and experimental conditions, c-fos level was maximal at 0.5 h. In the control cells, c-fos expression declined rapidly to less than 5% of the 0.5h value, while in the cocaine-treated cells, c-fos level persisted through the 72-h exposure. Adding c-fos antisense to cells treated with NGF and cocaine resulted in significant improvement of neurite out-growth, from 28% (NGF + cocaine) to 89% (NGF + cocaine + c-fos antisense) of control differentiation after 72 h of exposure (Dunnet's T < 3.24). Inhibitory effects of cocaine on NGF-induced PC12 differentiation may be attributed to alteration of c-fos expression. Further studies will be required to examine the role of D1 receptor activation in mediating c-fos expression and to explore the effects of cocaine on other IEGs.

Animals↗
PubMed1998

Neonatal encephalopathy in two boys in families with recurrent Rett syndrome.

Rett syndrome (RTT) has been described in its classic form only in females. Although the majority of cases are sporadic, familial cases give valuable insight into the genetic basis and phenotypic variability of the disorder. The exclusive occurrence of classic Rett syndrome in females led to the hypothesis that the Rett syndrome locus is likely to be X-linked and mutations are lethal in hemizygous males. We identified two boys in families with recurrent Rett syndrome who had encephalopathies with neonatal onset and who may represent the phenotype of males harboring Rett syndrome mutations. The difference in severity of disease in these males and their female relatives supports the location of Rett syndrome locus on the X-chromosome.

Brain Diseases↗
PubMed1998

Age-related changes in the level of urinary myelin basic protein-like material during childhood.

OBJECTIVE: To examine the developmental profile of myelin basic protein-like material (MBPLM) in urine. If urinary MBPLM exhibits a developmental profile corresponding to that of forebrain myelination, certain inferences should follow deviations from normal. Thus, MBPLM might provide a marker for monitoring the neurodevelopmental status in infants at risk for adverse outcomes. BACKGROUND: MBPLM in different immunochemical forms is detectable in human CSF and urine, presumably a result of myelin basic protein (MBP) catabolism. Urinary MBPLM has been used successfully as a marker of disease status in adults with MS. Urinary MBPLM increases in MS patients changing from a relapsing-remitting to a progressive course, possibly reflecting attempted or failed remyelination. Scant information exists concerning the presence or specific levels of urinary MBPLM during infancy and childhood when myelination is most active. METHODS: MBPLM was assayed in 402 urine specimens from 398 infants and children ranging in age from birth to 17 years according to previously described methods. RESULTS: MBPLM is detectable in urine from newborns, although at substantially lower levels than in adults (157.3 +/- 83.9 ng/mg creatinine). Whether expressed as nanograms per milliliter urine or nanograms per milligram creatinine, MBPLM levels are lower (p < 0.05) from birth through 12 months and greater (p < 0.05) between ages 2 to 8 years than in adults. CONCLUSION: Human urinary MBPLM exhibits a developmental profile that parallels the onset of normal myelination and exceeds normal adult values through early childhood. Thus, urinary MBPLM could serve as a useful marker of myelination in the developing child.

Adolescent↗
PubMed1997

Decreased cerebrospinal fluid levels of substance P in patients with Rett syndrome.

To clarify the mechanism of brain and spinal cord impairment in Rett syndrome (RS), we measured the cerebrospinal fluid (CSF) levels of substance P in 20 patients with RS including 16 childhood patients and 4 adult patients. Findings were compared with those obtained in age-matched controls and diseased controls. The CSF level of substance P was significantly lower in patients with RS compared with controls. The alteration in the CSF level of substance P may be related to the neurological impairment, especially autonomic dysfunction, and neuropathological involvement of dorsal root ganglia and peripheral nerve observed in RS.

Adult↗
PubMed1997

In vitro copper stimulation of plasma peptidylglycine alpha-amidating monooxygenase in Menkes disease variant with occipital horns.

We determined the concentrations of copper, the activities of ceruloplasmin and peptidylglycine alpha-amidating monooxygenase (PAM), and the stimulation index of PAM by the in vitro addition of copper in plasma samples obtained from three male patients with occipital horns and a milder Menkes disease phenotype, having severe copper deficiency due to the defect in copper transport. We found a decreased plasma ceruloplasmin activity and an increased copper stimulation index of plasma PAM in these patients compared with healthy control subjects. The combination of these two determinations may provide a means for the assessment of copper nutriture in humans using blood samples obtained in a single microhematocrit tube. Further investigation is warranted to evaluate whether these noninvasive measurements can be used for the diagnosis of mild copper deficiency in humans with sufficient specificity and sensitivity.

Adult↗
PubMed1997

Neurobiology and neurochemistry of Rett syndrome.

Rett syndrome (RS) represents a neurodevelopmental disorder of uncertain pathogenesis, featuring an apparent arrest in neural maturation during the perinatal period. Recent findings highlight the intensive ongoing research activities surrounding the neurobiology and neurochemistry of this unique disorder. Abnormalities in multiple neurotransmitter/receptor systems (dopaminergic, glutamatergic, and cholinergic), whether primary or secondary, underscore the pervasive effects of this maturational arrest. The possible role of neurotrophic factors is supported by significantly reduced nerve growth factor levels in cerebrospinal fluid. Similarly, gangliosides and other neuronal markers are perturbed in RS and may represent another critical area of study. The availability of a suitable animal model would accelerate the pace of these important investigations.

Biomarkers↗
PubMed1996

Distinctive Menkes disease variant with occipital horns: delineation of natural history and clinical phenotype.

To delineate further the clinical spectrum of Menkes disease, an X-linked recessive disorder of copper transport, we studied 4 related males, ranging in age from 4-38 years, with a unique phenotype that combines manifestations of classical and mild Menkes disease and occipital horn syndrome (OHS). The propositus, and 18-year-old man, was evaluated following an intracerebral hemorrhage at age 15 years and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, failure to thrive, and diarrhea from infancy; seizures from age 3 years; and abnormal hair (pili torti) and face, cutis laxa, and multiple joint dislocations. Radiographic abnormalities included occipital exostoses, tortuous cerebral blood vessels with multiple branch occlusions, and hammer-shaped clavicles. Biochemical studies demonstrated reduced copper and ceruloplasmin levels in serum, and abnormal plasma catecholamine ratios. We reported previously the molecular defect in this family, a splice-site mutation that predicts formation of approximately 20% of the normal Menkes gene product [Kaler et al., 1994: Nat Genet 18:195-202]. Here, we detail the clinical course and physical features and radiographic findings in these 4 individuals, and compare their phenotype with classical and mild Menkes and OHS. Unusual Menkes disease variants such as this may escape recognition due to anomalies that appear inconsistent with the diagnosis, particularly prolonged survival and later onset of seizures. Males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport.

Adolescent↗
PubMed1996

Inhibitory effects of cocaine on NGF-induced neuronal differentiation: incomplete reversibility after a critical time period.

We extend our findings showing dose-dependent cocaine inhibition of differentiation in NGF-stimulated PC-12 cells without affecting cell viability by demonstrating that neurite extension is severely limited after 24 h, maximal effect is reached at 36 h and recovery is only partial. Cocaine metabolites lack these effects. A similar process may occur following human prenatal exposure, perhaps through cocaine-induced changes in gene expression or other intracellular signalling events.

Animals↗
PubMed1995

Population-based registries using multidisciplinary reporters: a method for the study of pediatric neurologic disorders.

Few registries are available for evaluating population differences for rare, newly, or ill-defined pediatric neurologic disorders. The purpose of this article is to present standard methodologies for establishing a population-based registry and evaluating the completeness of a registry's case ascertainment. The Texas Rett Syndrome Registry (TRSR) is used as a model. The combination of health care and education resources has identified approx. 89-100% of the Rett syndrome cases in Texas. Cases reported by non-physician sources, although older on average (10.7 vs 7.7 years of age), did not differ by other demographic characteristics from those reported by physicians. Non-physician health and education professionals participated with the TRSR at a significantly higher rate than physicians, 89 and 37% (p < 0.05), respectively. Capture-recapture techniques, both two-sample and log-linear modeling, were used to quantitatively evaluate case ascertainment. Standardized national and international population-based registries could be the basis of an initiative to identify the etiology and perhaps preventive measures for pediatric neurologic disorders.

Child↗
PubMed1995

Rett syndrome.

Rett syndrome is a unique and puzzling disorder noted in females, and is possibly caused by fundamental failures in critical brain connectivity during early infancy. Recent reports expand our understanding of the Rett syndrome phenotype, continue the pattern of inconsistent or inconclusive metabolic and genetic results, and extend observations regarding abnormal brain cytoarchitecture.

Brain↗
PubMed1994

Rett syndrome: controlled study of an oral opiate antagonist, naltrexone.

HYPOTHESIS: The opiate antagonist, naltrexone, will be beneficial in Rett syndrome. SUBJECTS: Twenty-five individuals fulfilling the criteria for Rett syndrome. METHOD: Randomized, double-blind, placebo-controlled crossover trial with two treatment periods, 4 months each, and an intervening 1-month washout period. Clinical stage, motor and cognitive development, motor-behavioral analysis, neurophysiological parameters (computerized electroencephalographic analysis, breathing characteristics, quantification of stereotyped hand movements, and sleep characteristics), and cerebrospinal fluid beta-endorphin measurements were evaluated at baseline and at the end of each treatment period. RESULTS: Only data from the first period of this study were analyzed due to significant sequence effects in the crossover design. This analysis indicated positive effects on certain respiratory characteristics including decreased disorganized breathing during wakefulness. Four (40%) of the individuals receiving naltrexone progressed one or more clinical stages versus none of the individuals receiving placebo. The adjusted (for baseline value and Rett stage) end of treatment psychomotor test age (Bayley Scales) was significantly higher for the placebo group. There was no significant change for the other parameters. CONCLUSION: Naltrexone may modify some of the respiratory disturbance in Rett syndrome. Declines in motor function and more rapid progression of the disorder suggest a deleterious effect.

Adolescent↗
PubMed1994

Choline deficiency in cultured adrenal medullary cells: effect on phosphatidylcholine biosynthesis.

The effect of choline deficiency on the composition and biosynthesis of the major membrane phospholipids was examined in adrenal medullary cells maintained in suspension cultures. The amount and proportions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in these cells were not affected by the removal of choline from the culture media. However, the rate of biosynthesis of choline at the phosphatide level by the stepwise methylation of PE increased twofold within 24 h after choline was removed from the culture media, while ethanolamine incorporation into PE was increased by 50%. In contrast, the rate of incorporation of labeled choline into PC, presumably via CDP-choline, was virtually identical in cells that had been preincubated in the presence or absence of 1 mM choline. These results demonstrate that cultured cells of neural origin are capable of compensating for lack of exogenous choline by forming choline at the phosphatide level through the sequential methylation of PE. The hypolipidemic drug, DH-990, when added to the culture media, inhibited conversion of phosphatidylmonomethylethanolamine (PME) to PC, but had no effect on the N-methylation of PE. This differential effect indicates that the initial N-methylation of PE is catalyzed by an enzyme that is distinguishable from the enzyme(s) catalyzing the conversion of PME to PC.

Adrenal Medulla↗
PubMed1994

Globoid cell leukodystrophy: comparison of neuropathology with magnetic resonance imaging.

Previous imaging studies in infants with globoid cell leukodystrophy (GLD) using computed tomography have demonstrated a reduction in cerebral white matter and increased density symmetrically in the regions of the thalami, periventricular white matter, and the internal capsules. Correlation of these findings with morphologic studies at necropsy has not been made. In particular, deposition of calcium has not been described. We have evaluated two children with GLD confirmed by the absence of leukocyte galactosylceramide beta-galactosidase activity using repeated magnetic resonance (MR) scans in each and correlated the imaging results with post-mortem analyses in one. Neuropathologic examination revealed abnormalities typical for GLD. In addition to the absence of normal myelination throughout cerebral and cerebellar white matter, MR images demonstrated the presence of a paramagnetic effect in the regions of the thalami, corona radiata, and centra semiovale. We have observed in histologic preparations from these areas a dense accumulation of globoid cells and some calcium, which we suggest may be responsible for producing the paramagnetic effect.

Brain↗