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Biomedical subjects

Z Ying

Publications and source records attributed to Z Ying.

At least 19 recordsLinked to original sources
PubMed2003

A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor.

We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.

Animals↗
PubMed2002

A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning.

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family. Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.

Animals↗
PubMed2002

Model-checking techniques based on cumulative residuals.

Residuals have long been used for graphical and numerical examinations of the adequacy of regression models. Conventional residual analysis based on the plots of raw residuals or their smoothed curves is highly subjective, whereas most numerical goodness-of-fit tests provide little information about the nature of model misspecification. In this paper, we develop objective and informative model-checking techniques by taking the cumulative sums of residuals over certain coordinates (e.g., covariates or fitted values) or by considering some related aggregates of residuals, such as moving sums and moving averages. For a variety of statistical models and data structures, including generalized linear models with independent or dependent observations, the distributions of these stochastic processes tinder the assumed model can be approximated by the distributions of certain zero-mean Gaussian processes whose realizations can be easily generated by computer simulation. Each observed process can then be compared, both graphically and numerically, with a number of realizations from the Gaussian process. Such comparisons enable one to assess objectively whether a trend seen in a residual plot reflects model misspecification or natural variation. The proposed techniques are particularly useful in checking the functional form of a covariate and the link function. Illustrations with several medical studies are provided.

Adolescent↗
PubMed2001

Fluid-attenuated inversion recovery: correlations of hippocampal cell densities with signal abnormalities.

BACKGROUND: Hippocampal sclerosis (HS) is characterized by hippocampal atrophy and increased signal on T2-weighted images and on fluid-attenuated inversion recovery (FLAIR) images. OBJECTIVE: To quantitate cell loss and compare it with signal abnormalities on FLAIR images. METHODS: Thirty-one patients with temporal lobe resection, pathologically proven HS, and Engel class I and II outcome were included: 20 with HS only and 11 with HS associated with pathologically proven cortical dysplasia (dual pathology). The signal intensity on FLAIR was rated as present or absent in the hippocampus and correlated with the neuronal losses in the hippocampus. RESULTS: FLAIR signal increases were present in 77% (24/31) of all patients studied. In patients with isolated HS, 90% (18/20) had ipsilateral signal increases, but in patients with dual pathology, only 55% (6/11; p < 0.02) showed FLAIR signal increase. Hippocampal cell losses were significantly higher in the isolated HS group. The average cell loss in patients with FLAIR signal abnormalities was 64.8 +/- 8.0% as compared with only 32.7 +/- 5.1% in patients with no FLAIR signal abnormalities. There was a significant positive correlation between the presence of signal abnormality and average hippocampal cell loss in both pathologic groups. CONCLUSIONS: Ipsilateral FLAIR signal abnormalities occur in the majority of patients with isolated HS but are less frequent in those with dual pathology. The presence of increased FLAIR signal is correlated with higher hippocampal cell loss.

Adult↗
PubMed2001

Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery.

OBJECTIVE: To characterize the clinical, EEG, MRI, and histopathologic features and explore seizure outcome in pediatric candidates for epilepsy surgery who have temporal lobe epilepsy (TLE) caused by hippocampal sclerosis (HS). METHODS: The authors studied 17 children (4 to 12 years of age) and 17 adolescents (13 to 20 years of age) who had anteromesial temporal resection between 1990 and 1998. RESULTS: All patients had seizures characterized by decreased awareness and responsiveness. Automatisms were typically mild to moderate in children and moderate to marked in adolescents. Among adolescents, interictal spikes were almost exclusively unilateral anterior temporal, as opposed to children in whom anterior temporal spikes were associated with mid/posterior temporal, bilateral temporal, extratemporal, or generalized spikes in 60% of cases. MRI showed hippocampal sclerosis on the side of EEG seizure onset in all patients. Fifty-four percent of children and 56% of adolescents had significant asymmetry of total hippocampal volumes, whereas the remaining patients had only focal atrophy of the hippocampal head or body. Subtle MRI abnormalities of ipsilateral temporal neocortex were seen in all children and 60% of adolescents studied with FLAIR images. On histopathology, there was an unexpectedly high frequency of dual pathology with mild to moderate cortical dysplasia as well as HS, seen in 79% of children and adolescents. Seventy-eight percent of patients were free of seizures at follow-up (mean, 2.6 years). A tendency for lower seizure-free outcome was observed in patients with bilateral temporal interictal sharp waves or bilateral HS on MRI. The presence of dual pathology did not portend poor postsurgical outcome. CONCLUSIONS: TLE caused by HS similar to those in adults were seen in children as young as 4 years of age. Focal hippocampal atrophy seen on MRI often was not reflected in total hippocampal volumetry. Children may have an especially high frequency of dual pathology, with mild to moderate cortical dysplasia as well as HS, and MRI usually, but not always, predicts this finding. Postsurgical seizure outcome is similar to that in adult series.

Adolescent↗
PubMed2001

Mechanisms of epileptogenesis.

The cellular mechanisms of epileptogenesis are reviewed as related to their role(s) in the expression of hyperexcitability and hypersynchrony. The data on the roles of the glutamate, GABA, acetylcholine, and adenosine receptors is discussed. The recent information on the role of glial cells in the expression of epileptogenicity is reviewed.

Brain↗
PubMed2001

Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle.

We have investigated the impact of neuromuscular activity on the expression of neurotrophins in the lumbar spinal cord region and innervating skeletal muscle of adult rats. Rats were exercised on a treadmill for 1 day or 5 consecutive days and euthanized at 0, 2 or 6 h after the last bout of exercise. By Day 1, there was no clear evidence of an increase in brain-derived neurotrophic factor (BDNF) mRNA in the spinal cord or the soleus muscle. By Day 5, there was a significant increase in BDNF mRNA in the spinal cord at 2 h post-training, and the soleus muscle showed a robust increase between 0 and 6 h post-training. Immunoassays showed significant increases in BDNF protein in the soleus muscle by training Day 5. Immunohistochemical analyses showed elevated BDNF levels in motoneuron cell bodies and axons in the ventral horn. Neurotrophin-3 (NT-3) mRNA was measured to determine whether selected neurotrophins respond with a selective pattern of induction to neuromuscular activity. In the spinal cord, there was a progressive post-training decrease in NT-3 mRNA following a single bout of training, while there was a significant increase in NT-3 mRNA at 2 h post-training by Day 5. The soleus muscle showed a progressive increase in NT-3 mRNA by Days 1 and 5 following training. These results show that neuromuscular activity has specific effects on the BDNF and NT-3 systems, and that repetitive exercise affects the magnitude and stability of these responses.

Animals↗
PubMed2001

Nonparametric tests for the gap time distributions of serial events based on censored data.

This article deals with the problem of comparing two populations with respect to the distribution of the gap time between two successive events when each subject can experience a series of events and when the event times are potentially right censored. Several families of nonparametric tests are developed, all of which allow arbitrary distributions and dependence structures for the serial events. The asymptotic and small-sample properties of the proposed tests are investigated. An illustration with data taken from a colon cancer study is provided. The related problem of testing the independence of two successive gap times is also studied.

Chemotherapy, Adjuvant↗
PubMed2001

Therapeutic advantage of (90)yttrium- versus (131)iodine-labeled PAM4 antibody in experimental pancreatic cancer.

OBJECTIVES: Radioimmunotherapy studies using (131)I-PAM4 have demonstrated significant antitumor effects in mice bearing human pancreatic cancer xenografts. For several reasons (90)Y has been proposed as a more effective radionuclide for radioimmunotherapy of pancreatic cancer. The present study examined whether one radionuclide was more efficacious than the other in tumor-bearing mice. METHODS: Athymic nude mice bearing CaPan1 xenograft tumors ( approximately 1.0 cm(3)) were given increasing doses of either (90)Y-PAM4 or (131)I-PAM4 up to their respective maximal tolerated doses [MTDs (260 and 700 microCi, respectively)]. RESULTS: (90)Y-PAM4 provided significantly greater growth inhibition than the (131)I-PAM4 (P < 0.035). Median survival time for the untreated mice was 6 weeks, whereas median survival times for the (131)I-treated mice and (90)Y-treated mice at their respective MTDs were 17.5 weeks and >26 weeks (the end of the study period), respectively. Within the (131)I-PAM4-treated group, two of eight mice were responders (>50% decrease in tumor size) for a median of 14 weeks. At the end of the study (26 weeks), 1 mouse was alive with no sign of tumor. All of the (90)Y-PAM4-treated mice were responders with a median duration of response of 20 weeks. Six of the seven mice were alive at week 26, with four mice having no evidence of disease. CONCLUSIONS: These data demonstrate the advantage of (90)Y over (131)I as the radionuclide for PAM4-targeted radioimmunotherapy of xenografted pancreatic cancer. Furthermore, the duration and extent of the antitumor response suggests that multiple treatment cycles of (90)Y-PAM4 may provide an effective therapeutic for the control of pancreatic cancer.

Animals↗
PubMed2000

Anti-oxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy.

Our purpose was to determine whether the administration of anti-oxidant vitamins could reduce dose-limiting toxicity from radio-immunotherapy (RAIT) and thereby allow higher escalation of RAIT doses. Lipophilic vitamins A and E were administered i.p. and hydrophilic vitamin C was administered i.m. for 14 days (3 days pre-RAIT through 11 days post-RAIT) alone or with bone marrow transplantation (BMT) to either BALB/c mice for toxicity studies or to nude mice bearing s.c. GW-39 human colonic cancer xenografts for therapy studies. The maximal tolerated dose (MTD) of RAIT ((131)I-MN14 anti-CEA IgG) that results in no lethality was determined for mice that did not receive vitamins or BMT and those that did receive one or both interventions. Body weight, peripheral white blood cell (pWBC) and platelet (PLT) counts and tumor growth were also measured. Administration of vitamins (equivalent of 3.5 IU/day vitamin A, 0.107 IU/day vitamin E and 4.0 mg/day ascorbic acid) to mice along with BMT increased the MTD by 42% and reduced body weight loss associated with RAIT. Vitamins also reduced the magnitude of RAIT-induced myelosuppression. As early as day 7 after RAIT, vitamins increased WBC counts following both a 400 microCi and a 500 microCi dose. On day 14 after the 400 microCi dose of RAIT (day 7 post-BMT), the additive effect of BMT and vitamin could be detected. Tumor growth was not adversely affected by vitamin administration.

Animals↗
PubMed2000

Comparison of diagnostic markers with repeated measurements: a non-parametric ROC curve approach.

In this paper we study a class of non-parametric statistics for comparing diagnostic markers with repeated measurements. Using adapted definitions of specificity and sensitivity, we suggest methods to compare the average of sensitivities across all specificities or a range of specificities. The theory allows for correlations introduced by the fact that markers may be obtained from the same patient at multiple visits and that both markers being compared may be obtained from the same patient. Results of the Monte Carlo simulations and an example from a breast cancer setting are provided.

Biomarkers, Tumor↗
PubMed2000

Plasma FLT3-L levels predict bone marrow recovery from myelosuppressive therapy.

BACKGROUND: During the recovery period after anticancer myelosuppressive therapy, hematopoietic progenitor cells become mitotically active in order to replenish the bone marrow compartment and remain hyperproliferative even after normalization of peripheral white blood cells and platelets. At this stage, the progenitors are more radiosensitive and chemosensitive. Dosing patients with additional cytotoxic therapy during this phase will likely result in more severe toxicity. For example, the authors have noted that the red bone marrow (RM) dose resulting from radioantibody therapy does not correlate with observed bone marrow toxicity. Several patients given similar RM doses had Grade 3 or 4 toxicity, whereas others had Grade 0-2 toxicity even though their white blood cell (WBC) and (PLT) counts were normal at the time of dosing. The goal of these studies was to establish a noninvasive predictive marker of bone marrow activity that could determine stem cell and progenitor cell recovery from previous myelosuppressive therapy. METHODS: A retrospective study was conducted to quantitate plasma levels of 5 cytokines regulating hematopoiesis, namely, 2 stimulatory fms-like tyrosine kinase (FLT3-L) and stem cell factor (SCF) and 3 inhibitory growth factors tumor necrosis factor-alpha (TNFalpha), tumor growth factor-beta, and macrophage inflammatory protein (MIP-1alpha), by immunoassay in 43 patients enrolled in clinical trials at Garden State Cancer Center in Belleville, New Jersey. All patients had had previous chemotherapy with a duration of 1-24 months. The serum cytokine values were correlated with the magnitude of leukopenia or thrombocytopenia following a single dose of radioantibody as the cytotoxic therapy. RESULTS: Plasma FLT3-L levels predicted excess platelet toxicity in 13 of 16 patients (mean = 225 +/- 106 pg/mL) and resulted in a false-positive in only 3 of 27 other patients (mean = 80 +/- 41 pg/mL). Plasma FLT3-L > 135 pg/mL resulted in 81% sensitivity and 89% and 86% specificity and accuracy, respectively, for predicting excess toxicity caused by additional cytotoxic therapy. The positive likelihood ratio was 7.5 (95% confidence interval, 2.5-22.5) and the negative likelihood ratio was 0.19 (95% confidence interval, 0.05-0.67). CONCLUSIONS: Elevated plasma FLT3-L in patients who previously received chemotherapy is a predictive measure of the stage of recovery of the bone marrow compartment. FLT3-L seems to identify the likelihood that the patient will experience Grade > or = 3 thrombocytopenia if additional cytotoxic therapy is administered. Knowledge of bone marrow activity should permit therapy that is more aggressive by establishing the earliest possible time for dosing with any cytotoxic agent for which myelosuppression is the dose-limiting toxicity.

Antineoplastic Agents↗
PubMed2000

NMDAR1 receptor proteins and mossy fibers in the fascia dentata during rat kainate hippocampal epileptogenesis.

We examined the time course of NMDAR1 (NR1) immunoreactivity (IR) in the rat inner molecular layer of the dentate gyrus following unilateral intrahippocampal (hilar) kainic acid (KA) lesions and compared them to progressive aberrant mossy fiber (MF) sprouting into the inner molecular layer (IML). The results demonstrated that NR1 receptors in the IML of the KA side were decreased as early as 3 days after KA-induced denervation, then significantly increased at postinjection day (PID) 7. The densities of NR1 IR in the IML continued to increase up to 5 months. By comparison, MF sprouting did not occur significantly in the IML until PID 17, 10 days after NR1 IR was significantly increased. Recurrent MF-IML neoinnervation significantly increased on days 17, 60, and 150. This progressive MF innervation was significantly correlated with NR1 increases. These results suggest that NR1 receptors were decreased soon after KA-induced deafferentation of granule cell dendrites in the IML; however, they were replaced by new NR1 receptors at increased densities in the granule cell dendrites, which may have released neurotrophic factors to stimulate growth cones of MFs to reinnervate the IML. The progressive increases of NR1 and MFs in the IML suggest that such neosynaptogenesis would contribute monosynaptic recurrent excitatory mechanisms for focal hippocampal hyperexcitability and seizure onsets.

Animals↗
PubMed2000

Regulation of tumour drug delivery by blood flow chronobiology.

The chronobiology of various physiological phenomena that impact tumour drug delivery has not been established. Since the delivery of therapeutic agents is directly influenced in part by tumour vascular volume (VV), vascular permeability (VP) and local blood flow (BF), we have performed a series of studies to assess the natural rhythms of these functions in tumour and normal tissues. Preliminary results by Hori et al. Cancer Res 1992, 52, 912-916, have demonstrated fluctuations in tumour blood flow in subcutaneous (s.c.) rat tumours with a higher rate at 15-21 h after light onset (HALO) compared with 3-9 HALO. We used the GW-39 and LS174T human colon carcinoma xenografts grown s.c. in nude mice for these studies. VV, VP and BF were determined at 3, 7, 10, 13, 17, 20 and 23 HALO. In separate studies, dosing with a small therapeutic agent ([3H]-5-fluorouracil (5-FU)) or a macromolecule ([131I]-131-MN-14-anti carcinoembryonic antigen (CEA) immunoglobulin G (IgG)) was done at 10 and 17 HALO and 3, 10 and 17 HALO, respectively, and tissue and tumour uptake was determined in each group. Well-defined peaks and nadirs were observed for all three vascular functions. The peaks for VV and VP were similar in tumour and normal tissue whereas BF rate had a unique rhythm in tumour. Using cosinor analysis of the BF rate, we have found that the acrophase (peak) for tumour BF occurs at approximately 17 HALO in both tumour xenografts, while maximal liver, lung and kidney BF occurred at 10-13 HALO. Tumour BF rate ranged from the lowest value of 1.34+/-0.54 microliter/g/min at 20 HALO to the highest value of 2.79+/-0.57 microliter/g/min at 17 HALO. Liver BF rate ranged from 4.1+/-1.1 microliter/g/min at 3 HALO to 10.22+/-1.31 microliter/g/min at 10 HALO, and was 5.83+/-1.37 microliter/g/min at 17 HALO. Thus, the rhythm of tumour and normal tissue BF are different, creating a window of opportunity when tumours can be targeted with a therapeutic agent. At 3 h postinjection, the %ID/g of 5-FU in tumour at 10 HALO was 0.14+/-0.09 and at 17 HALO was 0.32+/-0.12 (P<0.02). In liver at 10 HALO, uptake was 0.13+/-0.06 and at 17 HALO was 0. 07+/-0.03 (P<0.05). At 24 h postinjection, the %ID/g of [131I]-MN-14 IgG in tumour at 10 HALO was 11.50+/-1.58 and at 17 HALO was 1. 5-fold higher at 16.96+/-2.35 (P<0.001). In liver at 10 HALO, uptake was 6.47+/-0.49 and at 17 HALO was 30% lower at 4.48+/-0.81 (P<0.01). These results suggest that small shifts in the chronobiology of BF in tumour and in normal tissue can have a sizeable impact on the distribution of chemotherapeutics and antibody-based drugs.

Animals↗
PubMed2000

Multiple paths of sugar-sensing and a sugar/oxygen overlap for genes of sucrose and ethanol metabolism.

The two-fold purpose of this work is, first, to review current hypotheses for multiple paths of sugar-sensing in an oxygen-responsive context, and second, to present evidence for the extent of sugar/oxygen overlap regulating genes for sucrose and ethanol metabolism. Current data indicate that sugar signals in plants may be initiated by (a) hexokinases, (b) membrane sensors, (c) acetate and/or respiratory metabolites, and (d) other signals and/or crosstalk. Responses may also involve concurrent input along transduction paths by effectors such as energy charge, P status, and phytohormones. Prime candidates for initiation and/or integration of such signal integration include SNF1- and SCF-like, multi-enzyme complexes. In addition, different paths of sugar signal transduction may be linked to contrasting roles of responsive genes during feast, famine or pathogen attack. Oxygen can potentially alter sugar signals at several points, so its influence on feast and famine responses was initially tested with genes for sucrose metabolism in maize root tips. The Sus1 and Sh1 sucrose synthases in maize (typically up-regulated by carbohydrate abundance and deprivation, respectively) showed parallel responses to hypoxia (3% O2 [0.03l l-1 O2]) and anoxia (0% O2 [0l l-1 O2]) that were consistent with involvement of similar signals. In contrast, the differential sugar-responses of the lvr1 and lvr2 invertases were not evident under low oxygen, and both genes were rapidly repressed. A third response was evident in the marked, sugar-regulation of an oxygen-responsive Adh1 gene for alcohol dehydrogenase, which was sensitive to sugar availability from deficit to abundance, regardless of oxygen status (anaerobic to fully aerobic [40% O2 (0.04l l-1 O2)]. A clear interface is thus evident between sugar and oxygen signals, but this varies markedly with the genes involved and probable differences in respective transduction paths.

Carbohydrate Metabolism↗
PubMed2000

Epileptogenicity correlated with increased N-methyl-D-aspartate receptor subunit NR2A/B in human focal cortical dysplasia.

PURPOSE: Human cortical dysplasia (CD) is a frequent cause of medically intractable focal epilepsy. The neurotransmitter mechanisms of epileptogenicity in these lesions have been attributed to changes in various glutamate receptor subtypes. Increased N-methyl-D-aspartate (NMDA) receptor (NR) 2A/B coassembled with NR1 subunits has been shown in focal epileptic CD. The purpose of this study is to correlate in situ CD epileptogenicity and the expression of various glutamate receptor subtypes. METHODS: The histopathological, morphological, and immunocytochemical findings in cortical tissue resected from five patients with medically intractable epilepsy and CD were correlated with electroencephalographic data recorded from subdural grids. The NMDA antibodies identified subunits NR1 (splicing variants 1a, 1b, 2a, and 2b) and NR2A/B. RESULTS: Epileptogenic specimens displayed the following common features: (a) widespread histological abnormalities of horizontal and columnar dyslamination, neurons with inverted polarity, and more extensive dendritic changes; (b) significantly higher NR2A/B immunoreactivity in both the dysplastic somata and all their dendritic processes; and (c) no statistically significant change in NR1 subunit expression but a more pronounced staining of the apical dendrites in highly epileptogenic cortex. These abnormalities were either absent or minimal in resected specimens that did not show evidence of severe in vivo epileptogenicity. CONCLUSION: These studies provide direct evidence for a major contribution of the NR2A/B subunit in CD-induced epileptogenicity.

Adolescent↗
PubMed2000

Brain plasticity and cellular mechanisms of epileptogenesis in human and experimental cortical dysplasia.

PURPOSE: The cellular mechanisms that may contribute to epilepsy in resected human cortical dysplasia (CD) were compared with the in utero radiated rat CD model. In human and rat focal hippocampal epilepsy, postsynaptic N-methyl-D-aspartate receptors are up-regulated and presynaptic axon collaterals hyperinnervate them. We hypothesized that in both human and rat CD: (a) the N-methyl-D-aspartate receptor subunits NR1 and NR2A/B would be increased and coassembled, and (b) aberrant axons would be in regions of CD. METHODS: Tests for presynaptic and postsynaptic changes in human and rat CD included the following: (a) cytology, (b) immunocytochemistry, (c) coimmunoprecipitation, (d) double-labeled immunofluorescence, and (e) Timm histochemistry of hippocampal mossy fibers. Within-patient comparisons were made between epileptic tissue, identified by subdural electro-encephalographic seizure onsets, and nonepileptic tissue remote from the focus but within the therapeutic resection. Rats were radiated at embryonic day 17, and offspring were studied postnatally. Statistical comparisons were made against normal rats matched for age and tissue processing. RESULTS: In focal CD patients, NR2A/B subunits and their coassemblies with NR1 were increased significantly more than for the remote nonepileptic cortex. Confocal microscopy showed that NR1-NR2A/B colabeled single dysplastic neurons in both human and rat. In CD rats, mossy fibers innervated the anomalously oriented hippocampal neurons. CONCLUSIONS: Human epileptic CD exhibits a spectrum of abnormal cell orientations and laminations that must require plastic axodendritic changes during development. These altered circuits and receptors could account for the seizures and cognitive deficits found in patients with CD. The radiated rat CD model with cortical dyslaminations and NR2A/B subunit increases would allow the development and testing of drugs targeted at only the NR2A/B subunit or at decoupling the NR1-NR2 coassembly, which could provide a specific antiepileptic drug for dysplastic circuits without inducing general depression of all brain neurons.

Abnormalities, Radiation-Induced↗