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Biomedical subjects

N C Moore

Publications and source records attributed to N C Moore.

At least 19 recordsLinked to original sources
PubMed1998

P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication.

BACKGROUND: P300 amplitude reduction in schizophrenia has been found by many investigators, but P300 latency generally has been reported to be normal; however, conflicting findings are present in the literature, and interpretation has been confounded by medication effects and methodological differences. METHODS: This study used a standard auditory oddball paradigm to compare the latency, amplitude, and topographic distribution of P300s in neuroleptic-free schizophrenic patients with those of healthy controls. The patients then were treated for 6 weeks with either remoxipride or haloperidol, and their P300s were reassessed. RESULTS: P300s were attenuated and delayed among neuroleptic-free patients. There was no evidence of peak lateralization or amplitude asymmetry over temporal areas. Subsequent neuroleptic medication normalized P300 latencies and increased P300 amplitudes, but the latter remained below normal limits over all except frontal areas. There were no correlations between P300 latency or amplitude and clinical symptomatology either before or after treatment. CONCLUSIONS: The finding of a P300 delay in neuroleptic-free schizophrenics that is normalized by neuroleptic medication has not been reported previously. Neuroleptic effects on P300 amplitude and latency appear to be independent of effects on clinical symptoms, and cannot be attributed to anticholinergic activity.

Adult↗
PubMed1998

Intrathymic expression of genes involved in organ specific autoimmune disease.

Insulin, thyroglobulin and myelin basic protein (MBP) are implicated as autoantigens in the autoimmune diseases, insulin-dependent diabetes mellitus (IDDM), autoimmune thyroid-disease and multiple sclerosis. Self tolerance to these antigens, until recently only thought to be present extrathymically, is generally considered to be maintained by 'peripheral' mechanisms, such as clonal anergy or clonal ignorance. The techniques of reverse transcription and polymerase chain reaction (RT-PCR) were used to investigate the intrathymic expression of these genes. Expression was examined in mRNA isolated from complete adult rat thymus, various mouse thymic cell-types isolated from fetal thymic-organ cultures and from neonatal-mouse thymocyte subsets. mRNA for insulin, thyroglobulin and MBP were detected in unfractionated adult rat and embryonic mouse thymus. Rat thymus expressed both insulin I and II, while mouse thymus only expressed insulin II. Thyroglobulin and MBP, but not insulin mRNA were detected in mouse MHC class II+ thymic epthelial cells and class II+ dendritic cells and in certain thymocyte subsets. The presence of insulin, thyroglobubin and MBP mRNA in the thymus has important implications for the development of the T-cell repertoire, particularly for the mechanisms of tolerance that prevent autoreactivity to these antigens in healthy individuals.

Animals↗
PubMed1998

Induction of apoptosis in thecal/interstitial cells: action of transforming growth factor (TGF) alpha plus TGF beta on bcl-2 and interleukin-1 beta-converting enzyme.

Follicular atresia is characterized by the initial rapid loss of granulosa cells by apoptosis, followed by the loss of thecal cells at a slower rate. We have previously shown that treatment of subconfluent cultures of thecal/interstitial cells (T/I) with transforming growth factor (TGF) alpha plus TGF beta caused chromatin condensation and internucleosomal fragmentation characteristic of apoptosis, whereas in the presence of either TGF alpha or TGF beta alone the cells remained healthy. In this study we have examined the effect of TGF alpha and TGF beta alone and in combination on the levels of mRNA encoding bcl-2 and interleukin-1 beta-converting enzyme (ICE) in T/I cells using a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. Bcl-2, a cell survival gene, has been implicated in regulating the balance between cell proliferation and cell death in physiological processes. ICE, the homolog of the C. elegans cell death gene, ced-3, is also involved in apoptotic signal transduction. The levels of mRNA encoding specific PCR products for bcl-2 (430 bp) and ICE (453 bp) were amplified from T/I cell cDNA. Untreated T/I cells and TGF alpha- or TGF beta-treated cells contained comparable levels of bcl-2 mRNA. Treatment of T/I cells with TGF alpha plus TGF beta significantly decreased the levels of bcl-2 mRNA expression. TGF alpha plus TGF beta caused a significant decrease in bcl-2 mRNA levels within 3 h of treatment of T/I cells, followed by a progressive decline to 10% of control levels after 24 h of treatment. In contrast, in control T/I cells, the levels of ICE mRNA were low. TGF alpha plus TGF beta caused a progressive increase in ICE mRNA, reaching levels 2- and 3-fold higher than control cells after 5 and 7 h respectively. DNA analysis showed that DNA fragmentation, indicative of apoptosis, occurred after 10 h of treatment with TGF alpha plus TGF beta. These studies demonstrated that treatment of T/I cells with TGF alpha plus TGF beta influenced gene expression of bcl-2 and ICE prior to the time at which DNA fragmentation was observed. We propose that the gene products of bcl-2 and ICE are involved in the apoptotic signal transduction pathway induced by TGF alpha plus TGF beta in T/I cells.

Animals↗
PubMed1997

Visual evoked responses in Alzheimer's disease: a review.

This review of the literature has shown that a delayed flash P2, in the presence of a normal flash P1 and pattern-reversal P100, can distinguish groups of Alzheimer's patients from groups who are healthy, psychiatrically ill, or suffering from other types of dementia. The VER's usefulness in the individual patient remains undetermined. With today's techniques, too many patients are misclassified. False negatives may result if Alzheimer's patients with visual symptoms are a distinct subgroup. Those with a normal flash VER may have cortical dysfunction outside the visual association areas. This would most likely be in the earliest stages of the disease before the atrophy becomes widespread. It may be that a VER test would only be valid in established disease. Future research should use adequate numbers of patients who are in a single category of mild, moderate or severe, so that the applicability of a VER test in the early stages of the disease can be determined. Strict diagnostic criteria such as the NINCDS-ADRDA guidelines should be used. Patients should be drug free, or at least not taking medications with anticholinergic properties. Flash VER should be obtained using a strobe light with eyes closed, and the pattern VER using a black and white television with a large pattern and high contrast.

Aged↗
PubMed1996

The role of the thymus in the control of autoimmunity.

Self tolerance among T cells is believed to be maintained by two principal mechanisms: clonal deletion for self antigens expressed in the thymus and T cell anergy or T cell indifference for those whose expression is solely extrathymic. These mechanisms are passive in that they depend on autoreactive T cells being either eliminated during their maturation or rendered intrinsically non-responsive after they have matured. The data presented in this paper indicate that this scheme requires modification. First, it is evident that self antigens that are commonly regarded as being tissue-specific may also be expressed in the thymus where they influence the developing T cell repertoire. Second, it appears that there is some T cell-mediated regulatory mechanism that actively prevents potentially autoreactive T cells from expressing their disease-inducing potential. Our data indicate that this regulatory mechanism is established intrathymically and is an innate property of the naive T cell repertoire. The mechanism is discussed in terms of what is currently known of the ways that an individual T cell responds when interacting with agonist and antagonist peptides and possible therapeutic implications are considered.

Animals↗
PubMed1996

Nitric oxide synthase (NOS) in schizophrenia: increases in cerebellar vermis.

A high proportion of neurons in the cerebellum and in cholinergic brainstem nuclei stain positive for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd), which is a nitric oxide synthase (NOS). Recent evidence suggests that schizophrenia may involve increased numbers of NADPHd-stained neurons in different areas of the subcortex. This led us to examine the actual concentration of NOS in postmortem brain specimens of cerebellum, and the relevant regions of brainstem tegmentum, to see if NOS concentrations were also increased in schizophrenia. Postmortem brain tissue was obtained at autopsy from schizophrenics and controls who did not have other brain disease. In patients with schizophrenia, NOS concentration was higher.

Aged↗
PubMed1996

P2 flash visual evoked response delay may be a marker of cognitive dysfunction in healthy elderly volunteers.

In an earlier study, 31 healthy elderly volunteers had normal cognitive function as measured by the Mini-Mental State Examination. Twenty-seven returned for further memory testing using the Wechsler Memory Scale-Revised (WMS-R). The P2 latency of the flash visual evoked response was positively correlated with age (p = .0008), but was not significantly related to gender. Nine of these 27 putatively healthy subjects had a delayed P2, suggestive of dementia. Although unaware of any memory deficits, 5 of the 27 had WMS-R Visual Memory Span percentile scores 1 or more standard deviations less than age-matched controls. Four of the five also had a significantly delayed P2 component. This positive correlation, adjusted for age, between poor Visual Memory Span performance and a delayed P2 was statistically significant (p < .025). These findings suggest that a delayed P2 in putatively healthy subjects is indicative of a visuospatial deficit which might be a precursor of dementia later.

Aged↗
PubMed1996

Involvement of LFA-1/ICAM-2 adhesive interactions and PKC in activation-induced cell death following SEB rechallenge.

Ligation of T-cell receptor (TCR) causes mature T cells to proliferate or, on re-exposure to antigen, can cause them to die by activation-induced cell death (AICD). In proliferative responses, costimulatory and adhesive interactions are required and activation of protein kinase C (PKC) has been shown to be essential. Whether or not interactions involving costimulatory signals and PKC have a role in facilitating AICD remains unclear. Here we have examined the role of CD28/B7 and leucocyte function associated antigen-1 (LFA-1)/intracellular adhesion molecule (ICAM) mediated interactions in AICD triggered by staphylococcal enterotoxin B (SEB) in murine lymph node T cells. We show that, after a primary proliferative response to SEB, LFA-1/ICAM-2 adhesive interactions can play a part in AICD following SEB rechallenge, while B7 and ICAM-1 mediated interactions are not essential for this process. In addition, using a highly selective PKC inhibitor, Ro31.8425, we show that PKC activation is essential for the regulation of AICD by SEB rechallenge.

Animals↗
PubMed1996

Cellular interactions in thymocyte development.

Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4-8- stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4+8+ stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity. Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge. Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.

Animals↗
PubMed1995

Stimulation of thymocytes before and after positive selection results in the induction of different NF-kappa B/Rel protein complexes.

Positive selection triggers the differentiation of immature CD4+8+TCRlow thymocytes into TCRhigh single-positive CD4+ or CD8+ cells and is associated with major changes in gene expression. However, little is known about the DNA binding factors controlling these fundamental changes. Here we have examined NF-kappa B/Rel subunit expression and DNA-binding activity in developing thymocytes before and after the induction of positive selection. We show that positive selection is accompanied by the strong up-regulation of c-rel mRNA expression and the constitutive activation of p50/p65 and p50/c-Rel NF-kappa B/Rel complexes, confirming the activation-like status of cells undergoing positive selection. Moreover, CD69+ cells that have initiated positive selection (but not their preselection CD4+8+TCR- precursors) respond to stimulation by the preferential activation of c-Rel-containing DNA-binding complexes. Because the different NF-kappa B/Rel dimers have distinct transcriptional activities and binding site preferences, this preferential activation of c-Rel-containing DNA-binding complexes may well have implications for the changes in gene expression and functional response associated with positive selection.

Amino Acid Sequence↗
PubMed1995

Intracellular signaling events during positive and negative selection of CD4+CD8+ thymocytes in vitro.

We have used in vitro models of thymocyte positive and negative selection in conjunction with selective inhibitors of the TCR-mediated signaling cascade to investigate the intracellular signaling events that mediate these processes. We report that Ro 31.8425, a potent and selective inhibitor of protein kinase C, which blocks the activation of mature T cells in a dose-dependent fashion, has no effect on either positive or negative selection of CD4+8+ thymocytes. In contrast, cyclosporin A fails to prevent negative selection, but inhibits positive selection through a direct effect on developing thymocytes, rather than through the perturbation of stromal cell support. Thus, our data suggest that positive and negative selection may operate via distinct intracellular signaling pathways.

Animals↗
PubMed1995

Thymocyte-stromal-cell interactions and T-cell selection.

Several key advances have been made since 1992, notably in teh area of signalling in early T-cell development and in the regulation of T-cell selection. Future goals include a fuller understanding of the roles of stromal cells and matrix molecules in T-cell development and further elucidation of the diverse signalling pathways involved. The ultimate challenge will be to generate T cells from stem cells under conditions where all of the developmental cues that earmark thymopoiesis are defined.

Animals↗
PubMed1995

Flash P2 delay in primary degenerative dementia of the Alzheimer type.

1. Flash visual evoked responses of 31 patients meeting DSM-III-R criteria for primary degenerative dementia of the Alzheimer type were compared with 31 healthy controls. 2. P1 latency was normal (75 +/- 6 msec Alzheimer's; 75 +/- 6 msec controls). 3. P2 was significantly delayed (162 +/- 32 msec, 147 +/- 20 msec, p < 0.03) among patients. 4. P1-P2 interpeak latency was significantly increased (87 +/- 32 msec, 71 +/- 21 msec, p < 0.03) among patients.

Aged↗
PubMed1994

Characteristics of an in vitro system of thymocyte positive selection.

We investigated the phenotypic changes accompanying maturation of CD4+CD8+ thymocytes in the presence of thymic stomal cells in vitro. Many of the features that are characteristic of positive selection in vivo, such as an ordered down-regulation of CD4 or CD8 together with up-regulation of the TCR-alpha beta complex, also occurred in vitro. Transient expression of CD69 was also observed, together with activation of IL-2 and IL-4 cytokine genes, providing further evidence that positive selection in vitro involves a pattern of gene regulation comparable to that seen in vivo.

Animals↗
PubMed1994

Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro.

Using a novel system that supports positive selection in vitro, we have investigated the cellular requirements for this process by testing the ability of individual thymic and nonthymic stromal cell types to support the maturation of CD4+CD8+ thymocytes into CD4+ or CD8+ T cells. We show that thymic cortical epithelial cells are unique in their ability to mediate this maturation, and suggest that in addition to TCR ligation, these cells supply specific signals for positive selection. Moreover, by demonstrating positive selection on ECDI (1-ethyl-3-[3'dimethyl-aminopropyl]-carbodiimide)-fixed epithelial cells in this system, we provide direct evidence that the provision of these signals involves interactions with epithelial cell surface molecules rather than the release of soluble factors.

Animals↗
PubMed1994

Differential expression of Mtv loci in MHC class II-positive thymic stromal cells.

Despite the important role played by endogenous superantigen in shaping the T cell repertoire, little is known concerning the expression of the different Mtv loci in cells of the thymic microenvironment involved in repertoire selection. Here we have examined the expression of a panel of Mtv Ags by different MHC class II+ stromal cel types using reverse transcriptase-PCR and monitored the effects of these stromal cells on the development of cells expressing Mtv-reactive TCR V beta elements in closed thymic organ culture systems. Although Mtv-6 and Mtv-8/9 mRNAs are expressed in normal thymus lobe organ cultures, no Mtv expression was detected in MHC class II+ thymic epithelial cells. In contrast a striking pattern of differential expression was observed in dendritic cells of thymic origin that were devoid of Mtv-8/9 but expressed readily detectable levels of Mtv-6. This pattern of Mtv gene expression correlated well with TCR V beta repertoire development. TCRV beta 3+ T cells, normally deleted in response to Mtv-6, were virtually absent from the single positive thymocyte compartment in thymic organ cultures where dendritic cells are present but were present in reaggregate cultures where the only MHC class II-positive cells were thymic epithelial cells. On the other hand, V beta 11+ T-cells were not deleted in organ cultures, possibly reflecting the absence of Mtv-8/9 expression in dendritic cells. Our studies suggest that the influence Mtvs have on shaping the T cell repertoire not only depends on their expression within a particular strain but also on their tissue specific expression in relation to MHC class II, which is necessary for their presentation.

Animals↗