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Biomedical subjects

K Page

Publications and source records attributed to K Page.

At least 55 records · Page 3Linked to original sources
PubMed1995

CD40 ligand is functionally expressed on human eosinophils.

CD40 ligand (CD40L), a surface molecule which can be expressed by T cells, mast cells and basophils, has been shown to be involved in the control of B cell proliferation, immunoglobulin class switching as well as in the activation of monocytes and T cells. We demonstrate that CD40L can also be expressed constitutively by eosinophils from an hypereosinophilic patient or, upon activation, by the eosinophilic cell line EOL-3 and normal blood eosinophils. Eosinophils were able to induce, in conjunction with IL-4, CD40L-dependent B cell proliferation in vitro. These results suggest that CD40L could play a role in the inflammatory processes during which eosinophil infiltration and activation are observed.

B-Lymphocytes↗
PubMed1995

Anti-inflammatory activity of salmeterol: down-regulation of cytokine production.

Elevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a beta 2-agonist which activates adenylate cyclase, its ability to inhibit cytokine production was evaluated. Though salmeterol, and the related drug albuterol, did not inhibit IL-1 beta production in vitro, both drugs did inhibit tumour necrosis factor-alpha (TNF-alpha) secretion by lipopolysaccharide (LPS)-activated THP-1 cells with similar IC50s of approximately 0.1 microM. This inhibition was effectively reversed by the beta 2-antagonist oxprenolol, indicating that the inhibition was mediated through the beta 2-adrenergic receptor. A strikingly different reactivity profile was seen with T cells. Salmeterol was able to inhibit the activation of both mouse and human T cells, as measured by proliferation and IL-2 secretion in response to anti-CD3 antibody, whereas albuterol was completely inactive in these assays. This T cell inhibition by salmeterol was about 10-fold less potent than that for TNF-alpha production, and was not reversed by a beta 2-antagonist, indicating that a different mechanism was involved in the effect of salmeterol on T cells. Paralleling the TNF-alpha inhibitory activity in vitro, oral dosing of salmeterol and albuterol inhibited LPS-induced increase in murine serum TNF level in vivo, with ED50s of approximately 0.1 mg/kg. This inhibition could be abrogated by dosing orally with the beta-blocker propranolol. The long-acting pharmacological profile of salmeterol was apparent in that it maintained its efficacy for 3 h, while albuterol had a much shorter duration of action. Salmeterol also had some protective effects in the galactosamine/LPS model of endotoxic shock, which is dependent upon TNF-alpha production. Though salmeterol inhibited serum TNF-alpha levels by up to 94% in this assay, it protected less than 50% of the animals from the lethal effects of the LPS/galactosamine mixture. This observation suggests that functional levels of TNF-alpha localized in tissues may not be accurately reflected by serum levels.

Adrenergic beta-Agonists↗
PubMed1995

Generation of recombinant adeno-associated virus (rAAV) from an adenoviral vector and functional reconstitution of the NADPH-oxidase.

The human parvovirus, adeno-associated virus-2 (AAV-2), has many attributes that recommend its use as a gene transfer vehicle, including a broad tissue tropism, the ability to integrate stably into the host genome, and efficient transduction of cells which proliferate slowly. However, application to human gene therapy is currently limited by existing methods for generation of recombinant AAV (rAAV), resulting in relatively low transducing titres. In an attempt to overcome some of these problems, we have developed a defective adenoviral vector which improves the efficiency of rAAV vector delivery to cells in which rAAV is propagated, and from which the rAAV genome can be efficiently rescued. A functional copy of the p47phox gene was successfully transferred to cell lines derived from patients with autosomal recessive chronic granulomatous disease (CGD) by rAAV recovered in this way, and function of the NADPH-oxidase was restored to levels which were stable for at least 8 weeks. This method for generation of rAAV, although still limited by the need for cotransfection of AAV Rep and Cap functions, may permit recovery of higher titre transducing stocks from cell lines in which these genes are stably incorporated, and significantly reduces the risk of contamination with wild-type adenovirus (wtAd).

Adenoviridae↗
PubMed1994

Reversal of diabetes associated with escape of myeloma: evidence for inappropriate IGF-II secretion.

We report the sudden and dramatic reversal of maturity onset diabetes in a 57-year-old woman in association with relapse of IgA myeloma diagnosed 3 years earlier. Prior to the relapse of the myeloma, twice daily insulin had been administered at a dose which had been stable for 3 years. However, the same dose produced hypoglycaemic coma at the time of relapse and, subsequently, blood glucose was controlled by diet alone. There had been no significant change in weight or renal function prior to the hypoglycaemic episode. Investigations showed a suppressed fasting serum insulin level in association with an inappropriately high serum level of IGF-II compared with IGF-I and a 'big' IGF-II concentration at the upper end of the normal range. Pituitary, adrenal and liver disease, as well as the autoimmune insulin syndrome, were excluded. The findings are consistent with the hypothesis that the plasma cell tumour was associated with excessive production of insulin-like peptides with consequent reduction in the blood glucose level.

Diabetes Mellitus, Type 2↗
PubMed1994

HIV infection in homosexual and bisexual men 18 to 29 years of age: the San Francisco Young Men's Health Study.

OBJECTIVES: Recent studies suggest very high human immunodeficiency virus (HIV) infection rates in some populations of younger homosexual men, but these studies may represent only particularly high-risk populations. The current study obtained population-based data on the HIV epidemic in young homosexual/bisexual men. METHODS: A household survey of unmarried men 18 through 29 years of age involved a multistage probability sample of addresses in San Francisco. A follow-up interview and HIV test for men who were HIV negative at baseline were completed; the median follow-up was 8.9 months. RESULTS: Sixty-eight of 380 homosexual/bisexual men (17.9%) tested HIV seropositive. Sixty-three percent of men reported one or more receptive anal intercourse partners in the previous 12 months, and 41% of those men did not use condoms consistently. The HIV seroincidence rate among those seronegative at first study was 2.6% per year. CONCLUSIONS: HIV infection rates in young homosexual men in San Francisco are lower than those in the early 1980s; however, the rate of infection in these men, most of whom became sexually active after awareness of AIDS had become widespread, threatens to continue the epidemic in the younger generation at a level not far below that of a decade ago.

Adolescent↗
PubMed1993

Comparison of risk factors for hepatitis C and hepatitis B virus infection in homosexual men.

Serum samples from 735 homosexual or bisexual men were tested for antibodies to hepatitis C virus (HCV) and serologic markers of hepatitis B virus (HBV), and risk factors for each infection were compared. Thirty-four (4.6%) were confirmed HCV-positive compared with 81% positive for one or more HBV serologic marker(s). History of intravenous drug use (IVDU) and blood transfusion were significantly associated with HCV positivity (odds ratio [OR] = 14.3 and 4.4, respectively), but neither was significantly associated with HBV positivity. Sexual behavior was significantly associated with infection with both viruses. When IVDU and blood transfusion were controlled for, HCV infection was marginally associated with > 50 sex partners/year (OR = 2.1), > 25 oral receptive partners (OR = 2.4), and > 25 anal receptive partners (OR = 1.9). HBV infection was more strongly associated with the same variables. HCV infection is uncommon in homosexual men and IVDU is the primary route of transmission, but sexual transmission also occurs, albeit infrequently.

Adult↗
PubMed1991

In vitro regulation of thyroglobulin (Tg) autoantibody production by Tg-specific T-cell lines and hybridomas.

To define the interactions between self thyroglobulin (Tg)-reactive T and B we co-cultured enriched B cells taken from rat or mouse Tg-primed mice with major histocompatibility complex (MHC) class II-restricted T-cell lines specific for iodinated determinants on self-Tg, or hybridomas derived from those lines. Using two clonally distinct T-cell hybridomas, ADA2 and CH9, in vitro help for Tg autoantibody responses was observed using mouse (M)Tg-primed B cells and a 100 ng/ml MTg challenge. Using rat Tg-primed B cells and the same conditions, only CH9 provided help, indicating that the fine specificity of B cells influences their ability to interact with specific anti-Tg T-cell clones. In contrast to T-cell hybridomas, their parent T-cell lines MTg9B3 and MTg12B suppressed Tg autoantibody responses in vitro, although they augmented bystander proliferation of unprimed B cells. The MTg12B cells also (i) diminished the survival of Tg-primed B cells, and (ii) inhibited the proliferation of an antigen-presenting B-cell hybridoma (LK35.2) in a cytostasis assay. These findings together support the view that their suppressive activity is mediated through cytotoxicity. While the role of class II-restricted cytotoxic cells in thyroid autoimmunity is unknown, the results suggest that such cells may act to suppress autoantibody responses as well as to mediate tissue damage to class II-expressing thyroid cells.

Animals↗
PubMed1991

Secondary immunoglobulin responses of BALB/c mice previously stimulated with goat anti-mouse IgD.

Intravenous injection of goat antibodies to mouse IgD (GAMD) into BALB/c mice has been shown to induce vigorous T-cell dependent immunoglobulin responses, particularly of the IgG1 and IgE isotypes. We have confirmed these findings and show that IgA responses are also triggered in this model. Since the study of IgE regulation in allergic individuals is concerned with secondary and subsequent T- and B-cell responses, we boosted GAMD-primed mice with goat antibodies to IgE or IgA in an attempt to specifically retrigger IgE- and IgA-bearing memory B cells. However, we found that secondary IgG1, IgE and IgA production could be elicited equally well by either antibody preparation or by normal goat IgG (GIg). As with the primary response, GIg primed and boosted mice produced very low or undetectable IgG1, IgE and IgA responses. These data suggest that GAMD is very efficient at priming T cells specific for GIg epitopes and that once primed they can be readily re-triggered by GIg. Spleen cells taken 7 days after boosting GAMD-primed mice were found to spontaneously produce much higher levels of interleukin-6 (IL-6) in culture than cells from unboosted or GIg primed and boosted mice. In contrast to primary responses, where IgE levels return to background (less than 40 ng/ml) very quickly, circulating IgE levels in boosted mice initially declined before reaching a plateau level (approximately 1 microgram/ml) which was maintained for at least 148 days. IgG1 and IgA levels continued to fall over this same time period. Mice which had been primed (but not boosted) 10 months earlier were all found to have detectable IgE in their blood, despite the fact that following priming IgE becomes undetectable within 2-3 weeks. Since only a part of the IgE response was directed towards the antigen (GIg), these observations suggest the possibility that B cells initially primed to make IgE can be non-specifically retriggered in vivo.

Animals↗
PubMed1990

The effects of excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets.

The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain (which included the cholinergic cells of the nucleus basalis of Meynert) were studied on three aspects of visual discrimination; learning, retention and reversal performance, in the marmoset. Neurobiological investigations revealed that the lesion produced large reductions in choline acetyltransferase activity within anterior regions of cortex, particularly prefrontal. In Experiment 1 lesioned animals showed impaired retention, one week after surgery, of a visual discrimination learned immediately prior to surgery and subsequently showed impaired performance over a series of reversals. The reversal deficit could be characterized as a tendency to perseverate on the previously correct stimulus on the first reversal and as a failure to show serial reversal learning on subsequent reversals. Acquisition of a novel discrimination was not impaired five weeks after surgery. As time of testing may have been a confounding factor, in Experiment 2 the effects of the same lesion on new learning were examined immediately following surgery and the effects on retention a month later. The lesion was found to disrupt new learning but did not affect retention. From the two experiments it is clear that, whereas disruption of retention and new learning was relatively transient, the impairments in reversal performance were more long lasting. In addition, lesioned animals exhibited behavioural hyperactivity and elevations in consummatory and schedule-controlled licking. The disinhibitory and preservative effects observed following lesions of the basal forebrain in this study are similar to those following lesions of the orbitofrontal cortex while the disruption of serial reversal learning is commonly seen following damage to the amygdala. Therefore, these results are consistent with the hypothesis that the range of behavioural effects of the lesion result from damage to the cholinergic afferents to orbitofrontal cortex and to the amygdala, two structures intimately connected to one another.

Animals↗
PubMed1990

Interleukin 1 responsiveness and receptor expression by murine TH1 and TH2 clones.

Murine Th1 and Th2 T cell lines differ in their responses to interleukin 1 (IL 1). Therefore, we examined two T-cell lines, D10.G4.1 (Th2) and MTg12B (Th1) in an attempt to correlate IL 1 receptor (IL 1R) expression with their IL 1 responsiveness. D10.G4.1 cells, which respond to IL 1, expressed two forms of the IL 1R, with molecular masses of approximately 80 kDa and approximately 60 kDa. In contrast, MTg12B cells failed to respond to IL 1 and only expressed the approximately 60 kDa receptor form. This suggests that the approximately 80 kDa receptor is essential for signaling. Expression of both IL 1R forms on D10.G4.1 cells could be inhibited by the anti-IL 4 antibody, 11B11. Antigen presentation reversibly upregulated both forms of the IL 1R, whereas stimulation with concanavalin A (ConA) and anti-CD3 only upregulated the approximately 60 kDa moiety. Upregulation of the approximately 80-kDa IL 1R by repeated antigenic stimulation resulted in a marked increase in sensitivity of D10.G4.1 cells to IL 1.

Animals↗
PubMed1987

Recognition of thyroglobulin autoantigenic epitopes by murine T and B cells.

We have used a large panel of thyroglobulins (Tg) prepared from a wide range of mammalian species to study the Tg autoantigenic epitopes recognized by populations of monoclonal and polyclonal murine T and B cells. This approach showed the existence of at least six different epitopes; three recognized by T cells (in association with I-Ak on antigen-presenting cells) and three by B cells (monoclonal antibodies). The majority of serum and monoclonal autoantibodies were found to be highly specific for mouse Tg, with some cross-reactive binding to rat Tg. In contrast, T-cell lines/clones and hybridomas recognized cross-reactive epitopes on Tg that were highly conserved throughout most of the mammalian orders. Moreover, two hybrid clones, which showed similar patterns of cross-reactivity, differed in their responsiveness to tryptic digests of human Tg. Thus, autoreactive T and B cells recognize distinct areas of the Tg molecule.

Animals↗
PubMed1986

Partial sequence analysis of cloned dengue virus type 2 genome.

Dengue virus (DEN) is a member of flaviviruses and contains a single, (+)-strand RNA of approx. 11 kb. Complementary DNA copy of the RNA was synthesized using reverse transcriptase and oligo(dT) as primer. The double-stranded DNA copy was cloned at the PstI site of pUC13'-1 vector and was used to transform Escherichia coli JM83. Eleven transfomants were found to contain DEN insert as screened by colony hybridization. Three clones were chosen for further characterization by nucleotide (nt), sequence analysis. Two of these clones overlapped by 470 bp. Sequences of these three clones totalling about 4.6 kb were obtained. Translation of this DNA in all possible reading frames revealed the presence of long open reading frames spanning the entire length of the cDNA clones. The putative polypeptides derived from the nt sequence are 885 and 643 amino acids in length and show homology to the region of polyprotein coded by the yellow fever virus genome corresponding to the non-structural proteins [Rice et al., Science 229 (1985) 726-733]. The significant homology between these two viruses in the regions coding for the non-structural proteins NS3 and NS5 suggests an important role for these two proteins in the life cycle of these viruses.

Amino Acid Sequence↗
PubMed1986

An effect of CO2 on the maximum safe direct decompression to 1 bar from oxygen-nitrogen saturation.

An investigation into the maximum safe decompression step from oxygen nitrogen saturation to 1 bar was carried out with and without the presence of 0.02 bar carbon dioxide. The series, Islander 1, involved 13 teams of 5, fully informed, male volunteers carrying out simulated dives. One group of 6 teams carried out dives in an atmosphere of 0.4 bar oxygen, balance nitrogen (O2-N2); another group of 7 teams used an atmosphere of 0.38 bar oxygen, 0.02 bar carbon dioxide, balance nitrogen (O2-N2-CO2). The dives consisted of a 48-h stay at 1.7 or 1.8 bar to saturate the tissues, followed by decompression to 1 bar air at 0.5 bar/min. Two decompression parameters were studied; the incidence of decompression sickness (DCS) in the 24 h postdecompression, and the incidence and grade of venous gas emboli (VGE) in the first 6 h postdecompression. The grade of VGE was assessed using the Kisman-Masurel scoring system which produces a bubble grade with the subject at rest and after movement. No significant difference was found in the incidence of DCS between the two groups. Twenty subjects were decompressed from 1.7 bar using each mixture, without signs or symptoms of DCS. However, after decompression from 1.8 bar there were 2 cases of DCS in 10 subjects in the O2-N2 group and 2 cases in 15 subjects in the O2-N2-CO2 group. The incidence of detectable VGE was always lower in the O2-N2-CO2 group at both saturation pressures; at 1.7 bar the VGE incidence was lower by 40% (P less than 0.05) at rest and by 55% (P less than 0.001) after movement. At 1.8 bar the reduction was 3% (NS) at rest and 30% (NS) after movement. The results indicate that decompression from 1.8 bar to 1 bar, with or without the presence of 0.02 bar carbon dioxide, is likely to produce more than 5% DCS.

Adult↗