Biomedical subjects
Publications and source records attributed to N L Paul.
A pilot telepsychiatry session was conducted with the US Department of Defense Satellite Communication System. The subjects were a family incompletely divorced many years before. There were two satellite interviews with this family. Bringing together all members of the original family so that questions could be addressed as to what happened when the children were very young unblocked a 13-year-old communication problem.
The HTLV-I transcriptional activator tax was used to gain insight into the mechanism of lymphotoxin (LT; TNF-beta) gene induction. Tax-expressing cell lines produce LT biologic activity. An LT promoter (LT-293) CAT construct that contained an NF-kappa B site was active in the LT-producing C81-66-45 cell line, which contains defective HTLV-I but expresses tax. The observation that a mutated LT-kappa B construct (M1-CAT) was inactive in C81-66-45, confirmed the importance of NF-kappa B in LT gene expression. Tax was transfected into HTLV-I-negative human T-cell lines. Jurkat T cells stably expressing tax contained elevated levels of NF-kappa B that directly bound to the LT-kappa B site. Tax co-transfected with reporter constructs into Jurkat cells maximally activated HTLV-I-LTR-CAT and kappa B-fos-CAT and also activated LT-293 to a lesser extent. In JM T cells, tax induced LT-293 activity by two- to four-fold, though there was no induction of M1-CAT. The increase in LT-293 CAT activity mirrored the increase in LT biologic activity seen under these conditions. These studies, the first to demonstrate induction of LT promoter activity over basal levels, indicate that HTLV-I tax causes low-level activation of both endogenous LT and the LT promoter, at least in part through activation of NF-kappa B.
We have used Semliki Forest virus (SFV) vectors to express both the human immunodeficiency virus type 1 (HIV-1) envelope precursor gp160 and the cleaved external portion gp120. Expression of the foreign gene in this system is by transfection of recombinant SFV RNA, or by infection with a recombinant SFV virus that has a wide host range. pSFV1-gp120 or pSFV1-gp160 were expressed in baby hamster kidney (BHK) cells and two human cell lines: HeLa cervical carcinoma and MOLT-4 CD4+ T cells. After SFV1-gp120 infection of HeLa cells, 3.3 micrograms of gp120 was secreted into the media by 1 million cells in a 24-hr period. The secreted envelope glycoprotein was recognized by anti-gp120 monoclonal antibodies directed against both linear and conformation-dependent epitopes in different regions of the molecule. The recombinant gp120 also bound to a soluble form of the CD4 receptor. Syncytium formation was observed when MOLT-4 cells were infected with SFV1-gp160. The gp160 expressed by BHK cells induced syncytia during cocultivation with C8166 CD4+ T cells. These data indicate that SFV vectors can be used to produce the HIV-1 envelope glycoproteins to high levels, and that these proteins are correctly processed, folded, and transported to the cell surface. Furthermore, they exhibit functional activity as indicated by their ability to bind to soluble receptor and induce cell-to-cell fusion.
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Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of biologically active lymphotoxin (LT; tumor necrosis factor-beta) protein and LT mRNA. To understand the regulation of LT transcription by HTLV-I, we analyzed the ability of a series of deletions of the LT promoter to drive the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells. The smallest LT promoter fragment (-140 to +77) that was able to drive CAT activity contained a site that was similar to the immunoglobulin kappa-chain NF-kappa B-binding site. Since the HTLV-I tax gene activates the nuclear form of NF-kappa B, this finding suggested a possible means of HTLV-I activation of LT production. We found that the LT kappa B-like site specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2, C81-66-45, and other activated T cells. Mutation of the LT kappa B site in the context of the LT promoter (-293 to +77) (mutant M1) reduced the ability of the promoter to drive the CAT gene in HTLV-I-infected and noninfected human T-cell lines. These data suggest a general role for NF-kappa B activation in the induction of LT gene transcription. Activation of LT in HTLV-I-infected cells may explain the pathology associated with HTLV-I infection, including the hypercalcemia that is prevalent in adult T-cell leukemia.
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LT was one of the first lymphokines to be described and has been one of the most difficult to fit into a conceptual framework. Now, 20 years after its discovery, its structure, genetic organization, and linkage are well understood in mouse and human, and insight has been gained into its biological role. It is a T cell-derived glycoprotein of 25 kd coded by a gene within the MHC. It is somewhat (35%) structurally homologous to the macrophage product TNF. The genes for LT and TNF are tightly linked, and the proteins share most biological activities and compete for the same cell surface receptor. LT is induced in an antigen-specific MHC restricted fashion from class I and class II restricted T cells. Viral infection is also associated with LT production by lymphoid cells. LT has several effects on target cells including killing, growth stimulation, and induction of differentiation. The mechanism of LT's effects involves receptor binding and internalization and several sequelae including changes in prostaglandins and chromosome integrity. LT probably plays several biological roles. It can contribute to immunoregulation, defense against viruses, parasitic infections, and rejection of tumors. Understanding LT's role in the pathogenesis of diseases of autoimmunity and immune dysregulation will be the key to devising effective regimens for prophylaxis and treatment.
This communication describes a technique of stimulated recall and video replay which has reduced the frequency of seizures in five epileptic patients. Each of the patients had long standing partial epilepsy with complex symptomatology of the psychomotor type. It was generally acknowledged that emotional factors played an important role in their poor seizure control. Previous psychotherapeutic efforts had been without benefit because ictal amnesia had erased the memory of the stressful antecedent message-input which had triggered the seizures. Creation of empathetically stressful responses to presentation of audio and video tape recordings of specific problematic social interactions was sufficient to induce seizures in these patients. Video tape recording of the seizure and the antecedant events provided by means by which the patients could acquire otherwise unrecognized or forgotten information. Once equipped with the identity of the specific emotional trigger, the patient could avoid the kinds of events which might be expected to induce a seizure and be better able to cope with threatening environmental cues when encountered in the future.
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