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Biomedical subjects

P S Mischel

Publications and source records attributed to P S Mischel.

13 recordsLinked to original sources
PubMed2001

The extracellular domain of p75NTR is necessary to inhibit neurotrophin-3 signaling through TrkA.

The TrkA receptor is activated primarily by nerve growth factor (NGF), but it can also be activated by high concentrations of neurotrophin 3 (NT-3). The pan-neurotrophin receptor p75(NTR) strongly inhibits activation of TrkA by NT-3 but not by NGF. To examine the role of p75(NTR) in regulating the specificity of TrkA signaling, we expressed both receptors in Xenopus oocytes. Application of NGF or NT-3 to oocytes expressing TrkA alone resulted in efflux of (45)Ca(2+) by a phospholipase C-gamma-dependent pathway. Coexpression of p75(NTR) with TrkA inhibited (45)Ca(2+) efflux in response to NT-3 but not NGF. The inhibitory effect on NT-3 activation of TrkA increased with increasing expression of p75(NTR). Coexpression of a truncated p75(NTR) receptor lacking all but the first 9 amino acids of the cytoplasmic domain inhibited NT-3 stimulation of (45)Ca(2+) efflux, whereas coexpression of an epidermal growth factor receptor/p75(NTR) chimera (extracellular domain of epidermal growth factor receptor with transmembrane and cytoplasmic domains of p75(NTR)) did not inhibit NT-3 signaling through TrkA. These studies demonstrated that the extracellular domain of p75(NTR) was necessary to inhibit NT-3 signaling through TrkA. Remarkably, p75(NTR) binding to NT-3 was not required to prevent signaling through TrkA, since occupying p75(NTR) with brain-derived neurotrophic factor or anti-p75 antibody (REX) did not rescue the ability of NT-3 to activate (45)Ca(2+) efflux. These data suggested a physical association between TrkA and p75(NTR). Documenting this physical interaction, we showed that p75(NTR) and TrkA could be coimmunoprecipitated from Xenopus oocytes. Our results suggest that the interaction of these two receptors on the cell surface mediated the inhibition of NT-3-activated signaling through TrkA.

Animals↗
PubMed2001

Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B.

Tuberous sclerosis (TSC) is a multi-system disorder characterized by hamartomatous tumors and abnormal brain development, with multiple foci of disrupted neuronal migration and giant dysmorphic neurons within cortical tubers. TSC is associated with mutations in 2 genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively. The functions of these proteins have yet to be determined. Recently, the Drosophila homologue of TSC2, gigas, has been shown to be required for the G2/M transition of the cell cycle. However, the mechanism of this action remains unknown. Because the cyclin-dependent kinase CDK1 forms a complex with cyclin B1 to trigger the G2/M transition, we hypothesized that tuberin interacts with CDK1 to regulate its activity. In the study reported in this paper, we have used co-immunoprecipitation and confocal microscopy to demonstrate that tuberin interacts with and co-localizes with CDK1 and its binding partner cyclin B1 in multiple cell types. We also demonstrate that hamartin interacts with CDK1 and cyclin B1. We further present evidence that tuberin interacts with the other regulatory subunit of CDK1, cyclin A. These findings suggest a direct role for tuberin and hamartin in modulating the activity of CDK1 during G2 and the G2/M transition. This is the first description of a role for both tuberin and hamartin in a common cellular function, providing a potential mechanism for the identical clinicopathologic manifestations that result when either of these proteins are inactivated.

Antibody Specificity↗
PubMed1999

Cortical dysplasia, genetic abnormalities and neurocutaneous syndromes.

Cortical dysplasia (CD) represents a common neuropathologic substrate of pediatric epilepsy, one frequently encountered in surgical resection specimens from infants and children with intractable seizure disorders, including infantile spasms. Severe CD shows similarities to structural features noted in tubers from individuals with tuberous sclerosis (TSC). The latter disorder, one with neurocutaneous and visceral manifestations, results from mutations in one of two recently cloned genes, TSC1 or TSC2, which encode (respectively) the proteins hamartin and tuberin. There is circumstantial evidence that both proteins may influence cell growth and differentiation, specifically that they may represent growth suppressors. Neither protein has a defined role in brain development. We discuss and illustrate neuropathologic features of both CD and TSC, and discuss the patterns and time course of hamartin/tuberin expression in normal brain, CD and TSC. Other recently cloned genes associated with cortical malformations encompassed by the term CD are briefly described.

Cerebral Cortex↗
PubMed1997

Bilateral neuropathologic changes in a child with hemimegalencephaly.

Evaluation of a 7-month-old girl with developmental delay and intractable seizures revealed hemispheric asymmetry and an enlarged right cerebral hemisphere. Because of a history of seizures refractory to medical therapy, she was admitted for right hemispherectomy, but died of complications of surgery. Postmortem brain examination revealed asymmetric enlargement of the right cerebral hemisphere but no gross abnormalities in the left hemisphere. Microscopic examination demonstrated bilateral neuropathologic changes consistent with severe cortical dysplasia in the right cerebral hemisphere and mild cortical dysplasia in the left. Although white matter abnormalities in the unaffected hemisphere have been reported in hemimegalencephaly, bilateral cortical abnormalities, not reported previously in patients with hemimegalencephaly, may account for the varied clinical outcome with medical therapy or after hemispherectomy.

Autopsy↗
PubMed1996

Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fibre synaptic reorganization.

In this study, we determined whether childhood seizures were associated with hippocampal neuron loss and mossy fibre synaptic reorganization and if hippocampal sclerosis evolved from longer seizure histories. Children undergoing surgical treatment for catastrophic epilepsy were grouped into the following pathology categories: (i) those with generalized seizures and extra-hippocampal congenital pathologies (i.e. prenatal cortical dysplasia; n = 17); (ii) cases of generalized seizures and extra-hippocampal acquired lesions. (i.e. postnatal ischaemic injuries and encephalitis; n = 7); (iii) children with complex partial hippocampal epilepsy (n = 4). Further, to determine whether the epileptogenic location influenced hippocampal pathology, the seizure focus was classified as (i) hippocampal, (ii) temporal (n = 13) or (iii) extra-temporal (n = 11). Surgical and autopsy (n = 23) hippocampi were studied for (i) fascia-dentata (FD) and Ammon's horn (AH) neuron densities; (ii) thickness; height or length of the FD molecular layer, stratum granulosum (SG) and stratum pyramidale; and (iii) grey value (GV) densities of supragranular neo-Timm's staining. Statistically significant results (P < 0.05) showed the following. (i) Autopsy hippocampal neuron densities for the hilus (H), AH and prosubiculum (Pro) decreased logarithmically at the same time as the thickness of the stratum pyramidale and Pro increased. By contrast, autopsy granule cell densities and thickness did not significantly change with age; however, the SG lengthened-expanding around the enlarging H. Further, the supragranular molecular layer height increased logarithmically, and took longer than the increase in stratum pyramidale thickness. (ii) Compared with age-matched autopsies, young children with a history of hippocampal seizures showed decreased granule cell, hilar and regio superior neuron densities similar to adults with hippocampal sclerosis (average loss 70%). By contrast, children with extra-hippocampal congenital or acquired pathologies showed only decreased granule cell densities, along with a thinner and shorter SG. Compared with extra-temporal locations, those with temporal lobe lesions showed decreased hilar and AH neuron densities, but averaged 20-30% less than autopsies and not in the pattern typical of hippocampal sclerosis. (iii) The neo-Timm's GV densities, when compared with autopsies, showed supragranular mossy fibre sprouting in children with congenital pathologies and temporal lobe lesions; however, the greatest GVs were in children with hippocampal seizures. (iv) Of the children with extra-hippocampal congenital or acquired pathologies there were no statistical correlations between longer duration of seizures with changes in neuron densities, hippocampal heights, or mossy fibre sprouting. These results indicate the following. (i) In the human there is anatomical evidence for postnatal maturation of the hippocampus and our results are consistent with the notion that AH pyramids are a stable population; however, there are probably increases in granule cell numbers. Further, compared with the AH, dendritic maturation of the FD granule cells appears to take longer. (ii) Extra-hippocampal childhood seizures whether from prenatal or postnatal aetiologies are associated with moderate FD and minimal AH neuron losses and signs of aberrant mossy fibre sprouting. (iii) By contrast, young children with the syndrome of mesial temporal epilepsy show patterns of neuron loss and mossy fibre sprouting, typical of hippocampal sclerosis. (iv) Repeated extra-hippocampal childhood seizures are not associated with progressive evolution of hippocampal damage or mossy fibre sprouting. These findings support the hypothesis that childhood seizures can damage or alter the postnatally developing granule cells of the human hippocampus, and that early neuron loss and aberrant axon circuits may contribute to chronic hippocampal seizures. However, repeated childhood generalized seiz

Adolescent↗
PubMed1996

Tissue and cell-type specific expression of the tuberous sclerosis gene, TSC2, in human tissues.

TSC2 is a gene on chromosome 16p13.3 associated with the autosomal dominant neurocutaneous disorder, tuberous sclerosis complex (TSC). By using a partial nucleotide sequence from the cloned TSC2 and polymerase chain reaction methodology, we constructed a digoxigenin-labeled complementary DNA probe to examine TSC2 gene expression in autopsy- or biopsy-derived human tissues by in situ hybridization. TSC2 messenger RNA was widely expressed in various cell types throughout the body, including epithelia, lymphocytes, and cells with endocrine functions, e.g., adrenal cortex and anterior pituitary. It was prominently and selectively (within the central nervous system) expressed in pyramidal cells of the cerebral cortex and other motor neurons, e.g., in spinal cord and brainstem nuclei. Visceral TSC2 expression was comparable in autopsy tissues from patients with and without TSC; TSC2 messenger RNA expression was most prominent in cells with a rapid mitotic rate and turnover, e.g., epithelia and lymphocytes, with central nervous system pyramidal cells and other neurons being an obvious exception, and/or in cells with important secretory/transport functions. This widespread expression of the TSC2 gene supports the view that it encodes a protein vital to cell growth and metabolism or one that functions as a tumor/growth suppressor.

Adult↗
PubMed1995

Coccidioidomycosis of the central nervous system: neuropathological and vasculopathic manifestations and clinical correlates.

Infection due to the fungus Coccidioides immitis, which is endemic to the southwestern United States, is currently occurring in epidemic proportions. Although it usually presents as a subclinical infection or a mild, self-limited pulmonary infection, disseminated infection can occur, especially in immunosuppressed patients. In patients with disseminated coccidioidomycosis, CNS spread is commonly responsible for significant morbidity and mortality. The neurological presentations of C. immitis infection of the CNS are variable. The spectrum of neuropathological change ranges from meningitis to meningoencephalitis and meningomyelitis with extensive parenchymal destruction, sometimes as a result of an associated endarteritis obliterans. We describe a patient with AIDS who developed CNS coccidioidomycosis, and we report the findings of a clinicopathological analysis of eight patients with fatal CNS coccidioidomycosis who were autopsied at UCLA Medical Center. CNS coccidioidomycosis should be considered in the differential diagnosis of patients with neurological symptoms, especially when they are immunosuppressed and live in regions where the disease is endemic.

AIDS-Related Opportunistic Infections↗
PubMed1995

Hyperacute thermal lesions: MR imaging evaluation of development in the brain.

PURPOSE: To determine the natural time course of development of hyperacute thermal lesions in the brain. MATERIALS AND METHODS: Ten interstitial lesions were created in five rabbit brains with a radio-frequency probe; an electrode-tip temperature of 80 degrees C was maintained for 60 seconds. Continuous fast spin-echo magnetic resonance (MR) imaging was used to follow lesion development for a minimum of 30 minutes. Temporal variations in lesion size and signal intensity were examined. Findings in final images were correlated with histologic findings. RESULTS: Images demonstrated a focal hyperintense zone, which developed into an expanding ring of edema surrounding a necrotic center in about 10 minutes. Quantitative analysis revealed a 23% +/- 6 (standard deviation) increase in average signal intensity of the edema layer and a 152% +/- 41 increase in overall lesion size. CONCLUSION: Full development of a thermal lesion is delayed for a period of minutes. Clinical implications of this effect should be considered when MR imaging-guided thermal ablation is performed.

Animals↗
PubMed1995

Sneddon's syndrome is a thrombotic vasculopathy: neuropathologic and neuroradiologic evidence.

We report the first case of pathologic findings from brain biopsy in a patient with Sneddon's syndrome. The observations suggest that Sneddon's syndrome is not a vasculitis but is more comparable to the autoimmune vasculopathies such as the antiphospholipid antibody syndrome. Vascular thrombosis and emboli from cardiac sources are the likely causes of stroke in most cases. The success of warfarin in the treatment of antiphospholipid syndromes and the failure of immunosuppression and aspirin in the treatment of Sneddon's syndrome argue that warfarin anticoagulation may be the most appropriate intervention currently available.

Cerebrovascular Disorders↗
PubMed1995

Neuropathology.

The surgical neuropathologist who examines corticectomy specimens from infants and children with epilepsy is in a unique position to make observations of fundamental importance in understanding the pathogenesis of seizures as well as the basic neurobiology of brain lesions that are associated with epilepsy. Findings on the resected human tissue using novel immunocytochemical and molecular probes can supplement and even build on relevant findings in experimental models, the goal of which is an understanding of epilepsy at cellular and subcellular levels.

Brain↗
PubMedDate not supplied

Lymphomatosis cerebri presenting as a rapidly progressive dementia: clinical, neuroimaging and pathologic findings.

Primary central nervous system lymphoma (PCNSL) usually presents with clinical and neuroimaging findings consistent with single or multiple intracranial mass lesions. On cranial magnetic resonance imaging (MRI), such lesions are nearly always contrast enhancing, reflecting disruption of the blood-brain barrier at the site of tumor nodules. We describe 2 cases from the UCLA Medical Center who developed a rapidly progressive dementia due to extensive gray and white matter cerebral lesions involving much of the brain. In the patient who came to autopsy, widely infiltrating, focally necrotic B-cell plasmacytoid lymphoma was noted throughout the cerebral neuraxis. MRI findings in case 2 were consistent with diffuse lymphomatous brain infiltration without mass lesions, which was biopsy proven. We conclude that PCNSL may occur in a diffusely infiltrating form which may occur without MRI evidence of mass lesions or blood-brain barrier compromise. We refer to this entity as 'lymphomatosis cerebri' and add it to the differential diagnosis of a rapidly progressive dementia.

Adult↗