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Biomedical subjects

J Gordon

Publications and source records attributed to J Gordon.

At least 109 records · Page 6Linked to original sources
PubMed1997

A murine model for human cord blood transplantation: near-term fetal and neonatal peripheral blood cells can achieve long-term bone marrow engraftment in sublethally irradiated adult recipients.

The purposes of the research reported here were first to explore a murine model for human placental and umbilical cord blood transplantation and second to evaluate the engraftment ability of ex vivo cultured hematopoietic cells. Murine near-term fetal and neonatal peripheral blood (FNPB) cells, genetically marked with the human multiple drug resistance transgene (MDR1) were used for syngeneic transplants into sublethally irradiated adult mice. Donor cells were transplanted either fresh and untreated, or after ex vivo culture in the presence of the hematopoietic growth factors recombinant murine stem cell factor, recombinant human interleukin-3 (rHu IL-3), and rHu IL-6, in a liquid culture system. To evaluate, count, and characterize FNPB progenitor cell-derived colonies, neonatal mouse mononuclear cells were cultured directly in methylcellulose with growth factors. To assess their ex vivo expansion ability, FNPB mononuclear cells were first cultured in liquid medium for 3 to 8 days and then transferred to semisolid assay plates. Evaluation of the cell counts after liquid culture showed a 1.4- to 11.6-fold increase, and the numbers of colonies observed in methylcellulose were similar to those produced by fresh FNPB cells. Donor-type engraftment was demonstrated by polymerase chain reaction (PCR) amplification of the human MDR1 transgene in the peripheral blood of all surviving animals (5 of 7 recipients of the fresh, and 3 of 8 recipients of the ex vivo-cultured cells) 2 to 4 months after transplantation. The proportion of donor leukocytes in the peripheral blood of the recipients (chimerism) was evaluated using fluorescence in situ hybridization (FISH) analysis 4 to 6 months after transplantation and ranged from 2% to 26%. In addition, bone marrow cultures were obtained from two recipient animals: one had received fresh-untreated cells and was evaluated 8 months after transplant, the other had received ex vivo cultured cells and was tested 14 months after grafting. The derived hematopoietic colonies were tested by PCR and the transgene was detected, conclusively proving long-term engraftment of donor cells. These results indicate that FNPB transplants can be successfully performed in sublethally irradiated mice with and without ex vivo culture. Long-term donor-type engraftment with sustained chimerism has been demonstrated. Thus, murine neonatal blood grafts can be used as an animal model for cord blood transplantation for gene therapy studies where complete myeloablation is not desirable and partial replacement of defective marrow may be sufficient. Furthermore, the possibility of numerically expanding hematopoietic progenitor cells contained in neonatal blood without affecting their engraftment ability could facilitate use of cord blood grafts in adult recipients.

Animals↗
PubMed1997

Use of aspirin to facilitate vomiting in a young woman with bulimia nervosa: a case report.

A 25-year-old female patient with a 9-year history of bulimia nervosa gave a 2-year history of regularly ingesting up to 24 x 300 mg aspirin tablets to facilitate vomiting after a binge. Awareness of this dangerous practice is important when asking for an eating disorder history. Assessing for the possible physical sequelae of aspirin misuse and educating the patient about the risks would be an important part of the overall treatment.

Adult↗
PubMed1997

Memory B-cell clones and the diversity of their members.

Memory B-cell clones develop from virgin B cells that take up processed antigen, make cognate interaction with primed T cells and then grow in germinal centres. Within the germinal centre the proliferating B cells undergo Ig variable-region mutation and are subsequently selected on their ability to bind antigen held on follicular dendritic cells and then to make cognate interaction with germinal centre T cells. The selected cells emerge as memory B cells or plasmablasts. Although many of the memory B cells and most of the plasma cells emerging from follicles have undergone Ig class switch recombination a substantial minority of the memory B cells have not switched. These non-switched memory cells can be induced to switch on re-exposure to antigen. Affinity maturation following a single immunization ceases as germinal centres wane some 3-4 weeks after immunization - memory cells and antibody production, on the other hand, persist for months and even years.

Animals↗
PubMed1997

Discrete and continuous planning of hand movements and isometric force trajectories.

We have previously demonstrated that, in preparing themselves to aim voluntary impulses of isometric elbow force to unpredictable targets, subjects selected default values for amplitude and direction according the range of targets that they expected. Once a specific target appeared, subjects specified amplitude and direction through parallel processes. Amplitude was specified continuously from an average or central default; direction was specified stochastically from one of the target directions. Using the same timed response paradigm, we now report three experiments to examine how the time available for processing target information influences trajectory characteristics in two-degree-of-freedom forces and multijoint movements. We first sought to determine whether the specification of force direction could also take the form of a discrete stochastic process in pulses of wrist muscle force, where direction can vary continuously. With four equiprobable targets (two force amplitudes in each of two directions separated by 22 degrees or 90 degrees), amplitude was specified from a central default value for both narrow and wide target separations as a continuous variable. Direction, however, remained specified as a discrete variable for wide target separations. For narrow target separations, the directional distribution of default responses suggested the presence of both discrete and central values. We next examined point-to-point movements in a multijoint planar hand movement task with targets at two distances and two directions but at five directional separations (from 30 degrees to 150 degrees separation). We found that extent was again specified continuously from a central default. Direction was specified discretely from alternative default directions when target separation was wide and continuously from a central default when separation was narrow. The specification of both extent and direction evolved over a 200-ms time period beginning about 100 ms after target presentation. As in elbow force pulses, extent was specified progressively in both correct and wrong direction responses through a progressive improvement in the scaling of acceleration and velocity peaks to the target. On the other hand, movement time and hand path straightness did not change significantly in the course of specification. Thus, the specification of movement time and linearity, global features of the trajectories, are given priority over the specific values of extent and direction. In a third experiment, we varied the distances between unidirectional target pairs and found that movement extent is specified discretely, like direction, when the disparity in distances is large. The implications of these findings for contextual effects on trajectory planning are discussed. The independence of extent and direction specification and the prior setting of response duration and straightness provide critical support for the hypothesis that point-to-point movements are planned vectorially.

Adult↗
PubMed1997

Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS.

PURPOSE: To report the observation that anti-retroviral therapy that includes a protease inhibitor can induce the regression of cytomegalovirus retinitis without requiring specific anticytomegalovirus drug therapy. METHODS: We examined the fundi of four patients with advanced acquired immunodeficiency syndrome (AIDS) who were placed on highly active antiretroviral therapy consisting of two nucleoside analogs and a protease inhibitor. The combined medications resulted in increased CD4+ T-lymphocyte counts and decreased load of human immunodeficiency virus (HIV-1). A prospective evaluation of the effect of these medications on an active cytomegalovirus retinitis lesion was conducted in one patient. Retinal lesions were documented with fundus photography. RESULTS: None of these patients received specific anticytomegalovirus medications. The average baseline CD4+ T-lymphocyte count was 33 cells per microliter (range, 4 to 88 cells per microliter) and increased an average of 118.5 cells per microliter (range, 66 to 185 cells per microliter). Average baseline plasma HIV-1 viral loads (HIV-1-RNA copies per ml) decreased 1.46 log units (range, 0.65 to 2.93 log units). In one patient, posterior progression (border advancement toward the posterior pole) of a cytomegalovirus retinitis lesion decelerated over time and stopped. Three other patients on initial examination had areas of retinal scarring consistent with healed cytomegalovirus retinitis. CONCLUSIONS: The addition of an HIV-1 protease inhibitor in the treatment of AIDS may lead to complete regression of cytomegalovirus retinitis without specific anticytomegalovirus medications. This effect may be related to reduced HIV-1 loads, a possible direct drug effect, an increase in CD4+ T-lymphocyte counts, or other associated changes in immune status.

Acquired Immunodeficiency Syndrome↗
PubMed1997

An electrophysiological technique for assessment of the development of spatial vision.

An objective visual evoked potential (VEP) technique was developed to evaluate spatial processing in humans over a wide range of ages. The constellation of stimulus conditions and analysis methods constitute a novel tool for the assessment of neural development. The key points that delineate this VEP technique are: (1) A brief, 6-s, swept-parameter stimulus with spatial frequency of square-wave grating patterns varied in octave steps, which facilitates correct accommodation and increases the likelihood of collecting uninterrupted, useable data; (2) data collection synchronous with stimulus presentation, which prevents contamination of the relevant frequency component from other frequency components in the response, thereby increasing the signal-to-noise ratio; (3) noise estimation at the response frequency of interest (second harmonic), based on a multivariate statistic (Tcirc2), which yields a realistic measure of signal-to-noise; (4) estimation of grating acuity from linear interpolation of the signal-to-noise measure; (5) monocular testing followed by multivariate statistical comparison of fellow eye data for each spatial frequency condition, which enables the determination of asymmetries within monocular neural pathways; (6) evaluation of maturation of the visual system based on vector-averaged amplitude and phase measures. Preliminary results indicate that reliable response functions are obtained from infants, children, and adults. Acuity estimates increased as a function of age. Phase values decreased consistently with increases in spatial frequency greater than 4 c/deg. Infants produced larger peak amplitude responses than did older observers, consistent with known developmental changes in cortical synaptic density. Phase data for the 2 c/deg condition provided additional evidence for the lack of maturity in the infant visual system as compared with that of older observers.

Adolescent↗
PubMed1997

Influence of topical human epidermal growth factor on postkeratoplasty re-epithelialisation.

AIM: To test the efficacy and safety of recombinant human epidermal growth factor (hEGF) on corneal re-epithelialisation following penetrating keratoplasty. METHODS: A prospective, randomised, placebo controlled study was carried out in which patients were matched for diagnosis and received either hEGF ophthalmic solution (30 micrograms/ml or 100 micrograms/ml) or placebo in a double masked fashion. Matched pairs of patients received donor corneas from the same donor and were operated by the same surgeon on the same day. At the end of surgery all donor epithelium was removed mechanically. Patients were examined twice daily and fluorescein stained photographs were taken until the epithelium had closed. The area of the defect was measured by planimetry of the fluorescein stained defect on the photographs. RESULTS: There were no significant differences in re-epithelialisation of the donor cornea between the placebo group and the group treated with 30 micrograms/ml hEGF. Time until complete closure was slightly longer with 100 micrograms/ml hEGF compared with 30 micrograms/ml hEGF and with placebo. Mean healing rate of the epithelial defect with 100 micrograms/ml hEGF was significantly slower than in the other groups. CONCLUSION: No significant acceleration of corneal re-epithelialisation was demonstrated with the use of recombinant hEGF after penetrating keratoplasty in humans.

Administration, Topical↗
PubMed1996

Bacteriophage T4 regA protein binds RNA as a monomer, overcoming dimer interactions.

The stoichiometry of the complex formed between the T4 translational repressor protein regA and the 16 nt gene 44 recognition element (gene 44RE) RNA has been determined. Under quantitative binding conditions, the association of wild-type regA protein with gene 44RE RNA exhibits saturation at a 1:1 ratio of protein to RNA. It is known that regA protein exists as a dimer in protein crystals. Thus, the stoichiometry may be indicative of a regA dimer bound to two RNAs or a regA monomer bound to one RNA. Gel filtration through Sephadex G-75 revealed that wild-type and R91L regA proteins (14.6 kDa) elute at a mass of 29 kDa, consistent with the mass of a dimer. However, wild-type regA preincubated with gene 44RE (1:1) resulted in a complex that eluted at approximately 20 kDa, consistent with a regA monomer-RNA complex. Covalent crosslinking of surface lysines with glutaraldehyde confirmed that wild-type and R91L proteins exist as dimers and higher oligomers in solution. However, the addition of RNA to wild-type regA protein prior to crosslinking inhibited the formation of crosslinked dimers. Thus, the regA protein-protein interactions observed in solution are disrupted or blocked in the presence of gene 44RE RNA. Together, these studies demonstrate that regA protein binds RNA as a monomer, although free protein exists predominantly as a dimer.

Chromatography, Gel↗
PubMed1996

Learning of scaling factors and reference axes for reaching movements.

TO further understand visuomotor transformations in reaching, we compared adaptation to display rotation and altered gain in planar movements. Healthy subjects moved a cursor on a screen by moving an indicator on a horizontal digitizing tablet with their unseen hand. Adaptation to rotation was less complete and was accompanied by markedly increased directional variability. Adaptation training on a single target generalized broadly for gain change, but poorly for rotation. We propose that the difficulty in adapting to rotation arises from the substantial demands on short-term working memory imposed by the need to determine the new reference direction. Adaptation to gain change makes more modest demands on short-term memory to recalibrate the visuomotor scaling factor.

Adaptation, Physiological↗
PubMed1996

Repression of apoptosis in human B-lymphoma cells by CD40-ligand and Bcl-2: relationship to the cell-cycle and role of the retinoblastoma protein.

Using a Burkitt lymphoma cell line to model human B-cell apoptosis in vitro, we observed that crosslinking, by antibody, of cell surface immunoglobulin induced G1 growth-arrest followed by apoptosis. By contrast, cells treated with the Ca(2+)-ionophore, ionomycin, generated apoptotic signals in G2/M as well as in G1. Both ionomycin and anti-immunoglobulin treatment induced rapid dephosphorylation of Rb prior to apoptosis. Apoptosis was repressed following exposure to CD40-ligand and was accompanied by hyperphosphorylation of Rb and cell-cycle progression but not Bcl-2 expression. Expression of Bcl-2 protein in stable bcl-2-transfectants, also resulted in repression of apoptosis and anti-immunoglobulin-treated cells no longer underwent growth-arrest. In Bcl-2-expressing cells in which apoptosis was repressed, Rb remained hyperphosphorylated, even during G1-arrest induced by ionomycin. TGF beta treatment of Bcl-2-expressing cells induced G1-arrest, de-phosphorylation of Rb and apoptosis. These results suggest that the functional activity of Bcl-2 in B-lymphoma cells is dependent upon, or leads to, sustained hyperphosphorylation of Rb and that Rb hyperphosphorylation can be uncoupled from cell-cycle progression.

Antibodies, Anti-Idiotypic↗
PubMed1996

Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma.

We describe molecular and clinical findings in an immunocompetent patient with an oligoastrocytoma and the concomitant presence of the human papovavirus, JC virus (JCV), which is the etiologic agent of the subacute, debilitating demyelinating disease, progressive multifocal leukoencephalopathy. Histologic review revealed a glial neoplasm consisting primarily of a moderately cellular oligodendroglioma with distinct areas of a fibrillary astrocytoma. Immunohistochemical analysis revealed nuclear staining of tumor cells with antibodies against the viral oncoprotein [tumor antigen (T antigen)], the proliferation marker (Ki67), and the cellular proliferation regulator (p53). Using primers specific to the JCV control region, PCR yielded amplified DNA that was identical to the control region of the Mad-4 strain of the virus. PCR analysis demonstrated the presence of the genome for the viral oncoprotein, T antigen, and results from primer extension studies revealed synthesis of the viral early RNA for T antigen in the tumor tissues. The presence of viral T antigen in the tumor tissue was further demonstrated by immunoblot assay. To our knowledge, this is the first report of the presence of JCV DNA, RNA, and T antigen in tissue in which viral T antigen is localized to tumor cell nuclei and suggests the possible association of JCV with some glial neoplasms.

Antigens, Neoplasm↗
PubMed1996

Formation of undifferentiated mesenteric tumors in transgenic mice expressing human neurotropic polymavirus early protein.

The human polyomavirus, JCV, is the established etiologic agent of the human demyelinating disease, progressive multifocal leukoencephalopathy (PML) seen in immunosuppressed individuals. In PML patients, the viral early protein, which is produced exclusively in glial cells is responsible for initiation of the viral lytic cycle. The JCV early protein, T-antigen, has greater than 70% homology to the well characterized SV40 early protein which has established oncogenic properties. To investigate the role of JCV T-antigen in tumorigenesis, transgenic mice containing the viral early genome were produced. Of the four positive transgenic animals, one developed severe neurological abnormalities and succumbed to death at 3 weeks of age. Another animal died with no visible gross pathology and the cause of death was not determined. The remaining two founders developed massive, undifferentiated, solid mesenteric tumors with no obvious neurological symptoms. Results from histologic analysis demonstrated the presence of highly cellular, poorly differentiated neoplastic cells in the tumor tissue. Electron microscopic evaluation of the tumor revealed the presence of a small blue cell-like tumor of epithelial/neuroectodermal origin. Results from RNA analysis by non-quantitative and highly sensitive RT-PCR indicated the presence of the JCV early transcript in various tissues, including kidney, liver, spleen, heart, lung, and brain, as well as in the tumors. However, analysis of the viral early protein by Western blot and immunohistochemistry indicated high level production of JCV early protein in the tumor tissue, but not in any other tissues. These observations present the first evidence for the development of inheritable neuroectodermal tumors induced by the human polyomavirus, JCV, early protein in a whole animal system.

Abdominal Neoplasms↗
PubMed1996

Human immunodeficiency virus tat gene transfer to the murine central nervous system using a replication-defective herpes simplex virus vector stimulates transforming growth factor beta 1 gene expression.

The high incidence of neurological disorders in patients afflicted with acquired immunodeficiency syndrome (AIDS) may result from human immunodeficiency virus type 1 (HIV-1) induction of chemotactic signals and cytokines within the brain by virus-encoded gene products. Transforming growth factor beta1 (TGF-beta1) is an immunomodulator and potent chemotactic molecule present at elevated levels in HIV-1-infected patients, and its expression may thus be induced by viral trans-activating proteins such as Tat. In this report, a replication-defective herpes simplex virus (HSV)-1 tat gene transfer vector, dSTat, was used to transiently express HIV-1 Tat in glial cells in culture and following intracerebral inoculation in mouse brain in order to directly determine whether Tat can increase TGF-beta1 mRNA expression. dSTat infection of Vero cells transiently transfected by a panel of HIV-1 long terminal repeat deletion mutants linked to the bacterial chloramphenicol acetyltransferase reporter gene demonstrated that vector-expressed Tat activated the long terminal repeat in a trans-activation response element-dependent fashion independent of the HSV-mediated induction of the HIV-1 enhancer, or NF-kappaB domain. Northern blot analysis of human astrocytic glial U87-MG cells transfected by dSTat vector DNA resulted in a substantial increase in steady-state levels of TGF-beta1 mRNA. Furthermore, intracerebral inoculation of dSTat followed by Northern blot analysis of whole mouse brain RNA revealed an increase in levels of TGF-beta1 mRNA similar to that observed in cultured glial cells transfected by dSTat DNA. These results provided direct in vivo evidence for the involvement of HIV-1 Tat in activation of TGF-beta1 gene expression in brain. Tat-mediated stimulation of TGF-beta1 expression suggests a novel pathway by which HIV-1 may alter the expression of cytokines in the central nervous system, potentially contributing to the development of AIDS-associated neurological disease.

Animals↗
PubMed1996

Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines.

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.

Animals↗
PubMed1996

Cerebral demyelination syndrome in a patient treated with 5-fluorouracil and levamisole. The use of thallium SPECT imaging to assist in noninvasive diagnosis--a case report.

BACKGROUND: The use of 5-fluorouracil (5-FU) and levamisole in patients with Stage III adenocarcinoma of the colon has now become standard. There have been several reports of a multifocal cerebral demyelination syndrome following 5-FU and levamisole administration. METHODS: We describe a patient who developed focal neurologic symptoms while being treated with levamisole and 5-FU in whom the diagnosis of central nervous system (CNS) metastases was considered. RESULTS: A magnetic resonance imaging (MRI) scan showed a diffuse, multifocal white matter process. Diagnostic evaluation did not support a diagnosis of CNS metastasis. 201Thallium chloride single photon emission computed tomography (SPECT) study was cold. A stereotactic brain biopsy disclosed demyelination but not tumor. The patient had complete functional resolution of symptoms with 1 month of dexamethasone therapy, although follow-up MRI scans have shown persistent abnormality on T2-weighted images. CONCLUSIONS: In patients receiving 5-FU and levamisole who develop focal neurologic symptoms with an abnormal MRI scan, the diagnosis of CNS metastasis should not be made without a thorough diagnostic evaluation. We suggest the use of 201thallium chloride SPECT imaging to support the diagnosis of multifocal leukoencephalopathy related to 5-FU and levamisole. In atypical cases, a stereotactic brain biopsy may be required for confirmation.

Adenocarcinoma↗