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Biomedical subjects

S M Walker

Publications and source records attributed to S M Walker.

At least 19 recordsLinked to original sources
PubMed1995

Grass pollen immunotherapy: efficacy and safety during a 4-year follow-up study.

Grass pollen immunotherapy is effective, although efficacy must be balanced against side-effects. In a double-blind, placebo-controlled trial of 40 adult patients with summer hay fever, immunotherapy with a depot grass pollen extract (Phleum pratense, Alutard SQ) reduced symptoms and medication requirements with an acceptable minimal level of side-effects (31). The original placebo group, as well as the actively treated group, have now received active immunotherapy in an open fashion for a further 3 years. An important question was whether continued injection treatment was accompanied by maintained clinical improvement. By analysis of diary symptoms, rescue medication, and visual analogue scores during the pollen season, we show that efficacy was maintained throughout the 3-4-year study period. Clinical improvement was accompanied by a sustained and marked decrease in immediate conjunctival allergen sensitivity and a further significant decrease in the size of the allergen-induced late cutaneous response. In contrast, an initial decrease in the allergen-induced immediate cutaneous response was not maintained at 3-4 years. Of the patients, 37/40 completed the first year, 33/40 the second year, and 32/40 the third year of treatment. Patients dropped out for reasons other than the outcome of immunotherapy. During a total of 2598 injections, five immediate systemic reactions were observed, all during the induction (not maintenance) phase, and all occurred within 10 min of injection and responded promptly to adrenaline. Grass pollen immunotherapy is effective and safe, provided it is performed on carefully selected patients by trained physicians with immediate access to resuscitative measures.

Adult↗
PubMed1995

CCAAT box-dependent activation of the TATA-less human DNA polymerase alpha promoter by the human cytomegalovirus 72-kilodalton major immediate-early protein.

Human cytomegalovirus (HCMV) immediate-early (IE) proteins are known potent transregulators of viral and cellular gene expression upon HCMV infection. HCMV is known to activate a number of cellular genes intimately associated with the cell cycle and DNA replication by mechanisms involving the viral major IE 86-kDa protein (IE2). We have recently shown that IE2 mediates this activation in a TATA-dependent manner and interacts directly with the TATA-binding protein. However, a number of TATA-less cellular promoters, e.g., DNA polymerase alpha and dihydrofolate reductase, are also activated by HCMV infection. Consequently, we have asked how HCMV mediates this activation. We show that, consistent with its known TATA dependency, IE2 does not activate the DNA polymerase alpha promoter. In contrast, this promoter is strongly activated by the major IE 72-kDa protein (IE1). Whilst deletion of ATF or E2F sites within the DNA polymerase alpha promoter had little effect on IE1-mediated activation, removal of the CCAAT box appeared to abolish high levels of activation by IE1. Consistent with this observation, we also find that IE1 interacts directly with the CCAAT box binding factor CTF1 in vitro and massively augments CTF1-mediated activation of the DNA polymerase alpha promoter in transient transfection assays.

Base Sequence↗
PubMed1995

SV40-immortalized and primary cultured human retinal pigment epithelial cells share similar patterns of cytokine-receptor expression and cytokine responsiveness.

Retinal pigment epithelial (RPE) cells produce and respond to a variety of cytokines; however, molecular and biochemical studies are restricted by the limited access to large numbers of pure cells and the variability associated with different donor sources. Despite success in establishing primary human RPE (HRPE) cell cultures, the inability to sustain consistent proliferation rates and morphology over several passages remains a concern. This problem was approached by using an immortalized line of simian virus (SV)40 transformed fetal HRPE cells (SVRPE). Cytokine production, receptor expression and responsiveness in the SVRPE cell line was analyzed to determine the usefulness of this model for studying HRPE-cytokine interactions. Using reverse transcriptase polymerase chain reaction (RT-PCR), HRPE and SVRPE cells demonstrated an identical pattern of interleukin-1 receptor (IL-1R), IL-2R (alpha sub-unit), IL-6R, interferon (IFN)-gamma R and tumor necrosis factor-alpha (TNF)R p55 expression. No amplification products for TNFR p75 or granulocyte/macrophage colony stimulating factor (GM-CSF)R were demonstrated in either population. IFN-gamma stimulation induced surface human leukocyte antigen (HLA)-DR in both SVRPE and HRPE, while TNF treatment induced surface expression of intercellular adhesion molecule (ICAM)-1 on SVRPE and upregulated ICAM from basal levels on HRPE. Both cell types showed amplification products for interleukin (IL)-1 beta, IL-6 and transforming growth factor (TGF)-beta 1 using RT-PCR. The bioassays demonstrated that both populations of unstimulated cells constitutively secrete very low levels of TGF-beta and no IL-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Ovarian 11 beta-hydroxysteroid dehydrogenase activity is inversely related to the outcome of in vitro fertilization-embryo transfer treatment cycles.

OBJECTIVES: To determine the relationship of ovarian 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity to the outcome of IVF-ET and to establish whether 11 beta-HSD activities vary for a given patient between consecutive treatment cycles. DESIGN: Retrospective correlation analysis. SETTING: Patients were treated and ovarian 11 beta-HSD activities were measured at independent fertility and biochemistry departments, respectively. PATIENTS: Random series of 137 women undergoing a total of 172 treatment cycles for IVF-ET. INTERVENTIONS: Subcutaneous buserelin acetate plus IM hMG and hCG for controlled ovarian hyperstimulation; blood samples were collected for plasma LH and steroid determinations. MAIN OUTCOME MEASURES: Presence or absence of detectable ovarian 11 beta-HSD activity, oocyte fertilization rates, and the identification of clinical pregnancies. RESULTS: None of the 101 cycles associated with 11 beta-HSD positive granulosa-lutein cells resulted in clinical pregnancies, whereas the pregnancy rate for the 71 patients with undetectable ovarian 11 beta-HSD activity was 63.4% per cycle. The incidence of total fertilization failure was lower and the median oocyte fertilization rate was higher in cycles characterized by 11 beta-HSD-negative cells. Plasma concentrations of LH and E2 were higher in cycles yielding 11 beta-HSD-negative cells, whereas plasma P, patient age, and the number of oocytes retrieved did not relate to ovarian 11 beta-HSD activity. For the 35 patients studied in repeat cycles, ovarian 11 beta-HSD activities did not relate to those in the initial cycles. CONCLUSIONS: Ovarian 11 beta-HSD activity is associated with failure to conceive by IVF-ET. For a given patient, ovarian 11 beta-HSD activity varies between consecutive treatment cycles. Hence, ovarian 11 beta-HSD activities may predict the outcome of this assisted reproduction protocol independently in each treatment cycle.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Exogenous tat protein activates central nervous system-derived endothelial cells.

Tat protein, an HIV gene product known to be secreted extracellularly, was tested to determine its role in the dissemination of HIV into the central nervous system (CNS). Tat was shown to activate human CNS-derived endothelial cells (CNS-EC) by the increase in the expression of E-selectin, the synthesis of IL-6, and the secretion of plasminogen activator inhibitor-1 (PAI-1). Tat also functioned synergistically with tumor necrosis factor alpha (TNF). AIDS brains stained for tat in situ, demonstrated positive cells. These data suggest that secreted tat protein may increase leukocyte binding, and alter the blood-brain barrier permeability to enhance dissemination of HIV-infected cells into the CNS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Quantitation of intrathecal measles virus IgG antibody synthesis rate: subacute sclerosing panencephalitis and multiple sclerosis.

A method for quantitating specific anti-viral antibodies in serum and cerebrospinal fluid (CSF) is established using enzyme-linked immunosorbent assay (ELISA). Quantitated antibody levels are used to determine intrathecal specific IgG synthesis rate for the particular antibody. Measles virus was used as a model for validating this quantitative technique: a mutated form of measles virus is a cause of subacute sclerosing panencephalitis (SSPE) and there is a possibility that measles virus is related to the cause of multiple sclerosis (MS). Matched serum and CSF samples were assayed. Concentration of anti-measles IgG was determined and intrathecal measles-specific IgG synthesis rate was calculated. For the SSPE samples, measles-specific IgG synthesis rate was elevated and comprised > 20% of the total intrathecal IgG synthesis rate; these results are consistent with the literature. The ELISA method can be performed routinely, providing a quick, simple, reproducible means of quantitating specific antibody concentrations, with sensitivity greater than 1 nanogram per milliliter. With this method, quantitation of IgG antibodies to any other viral antigen can be reliably and precisely determined.

Antibodies, Viral↗
PubMed1994

Experience with transcervical fallopian tube catheterization.

Transcervical fallopian tube catheterization has been evaluated on a group of patent tubes in both a model of the human uterotubal complex and during hysterosalpingography. The technique appears to be unreliable and tubal catheterization occurs infrequently.

Adult↗
PubMed1994

A study of the cumulus-corona cell complex in in-vitro fertilization and embryo transfer; a prognostic indicator of the failure of implantation.

In-vitro morphological changes and proliferation of cells of the cumulus oophorus, in particular cells of the corona radiata, were seen to differ between individuals and between oocytes of the same cohort in an unselected series of 159 IVF cycles. Cell proliferation did not relate to indications for treatment, type and length of ovarian stimulation, age of patient, ovarian response and quality of oocyte, fertilization rate or embryo morphology. A direct relationship, however, was demonstrated between the proliferative capacity of these cells and the incidence of clinical pregnancy. No pregnancies resulted when there was an absence of morphological change or proliferation of these cells. In cycles where the proliferative capacity of these cells varied between oocytes of a single cohort the pregnancy rate was 40% per cycle, and in cycles where cells associated with all oocytes underwent extensive proliferation the pregnancy rate was 49% (P < 0.001). Thus, regardless of the apparent quality of gametes or embryo, no pregnancies arose if the cumulus-corona complex was incapable of replication. We have, therefore, identified two populations of oocytes based on the proliferative capacity of cumulus-corona cells in vitro, one being associated with a failure of implantation.

Adult↗
PubMed1994

A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients.

1. The effect of carbamazepine (CBZ), sodium valproate (VPA) and phenytoin (PHT) on the pharmacokinetics of oxcarbazepine (OXC) was explored in three groups of 12 epileptic patients taking one of these drug as monotherapy. 2. Each patient took a single 600 mg dose of OXC followed 7 days later by 3 weeks' treatment with OXC 300 mg thrice daily and matched placebo in random order. 3. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks' active treatment only. 4. In those patients completing the study, the area under the concentration-time curve (AUC) at steady-state for hydroxycarbazepine (OHCZ), the active metabolite of OXC, was significantly lower in the CBZ-treated group than in controls (P < 0.05). 5. No other differences in AUCs or elimination half-lives for OHCZ were found between treated and untreated patients following single or multiple OXC dosing. 6. Median AUCs of CBZ, VPA and PHT during a dosage interval did not differ significantly after treatment with OXC and placebo. 7. Ten patients completing the study complained of side-effects during treatment with OXC compared with one taking placebo (P < 0.01). 8. There were no important changes in cognitive function testing during administration of OXC compared with placebo. 9. Standard doses of OXC can be given as add-on therapy in epileptic patients receiving CBZ, VPA or PHT without producing a clinically relevant pharmacokinetic interaction.

Adult↗
PubMed1993

Exogenous tat protein activates human endothelial cells.

tat protein, a human immunodeficiency virus (HIV) gene product that functions as a transactivator for HIV replication, is known to be secreted extracellularly by infected cells. To determine the potential role of tat in the dissemination of HIV into extravascular tissue, this protein was examined for its ability to activate human endothelial cells. The results show that tat does indeed stimulate endothelial cells. This is evidenced by their expression of the endothelial-leukocyte adhesion molecules, E-selectin, critical for the initial binding of leukocytes to the blood vessel wall, and their increased synthesis of interleukin-6 (IL-6), a cytokine known to enhance endothelial cell permeability. Furthermore, tat acts synergistically with low concentrations of tumor necrosis factor-alpha to enhance IL-6 secretion. These data suggest that extracellular tat protein secreted or released into the microenvironment may contribute significantly to the determination of specific sites of leukocyte binding to blood vessels, to transmigration into tissue, and to eventual dissemination of HIV-infected cells or free virions into tissue.

Cell Adhesion Molecules↗
PubMed1993

Ovarian 11 beta-hydroxysteroid dehydrogenase: potential predictor of conception by in-vitro fertilisation and embryo transfer.

Cortisol is converted to the inactive glucocorticoid, cortisone, in several tissues by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). We have recently measured 11 beta HSD activity in cultured human granulosa-lutein cells recovered from patients undergoing in-vitro fertilisation and embryo transfer (IVF-ET). We now report an association between the outcome of IVF-ET and 11 beta HSD activity in these cells. Of the 64 patients studied, 32 had detectable 11 beta HSD activity and none became pregnant; whereas 76% of the remaining "11 beta HSD-negative" patients achieved pregnancies. Hence 11 beta HSD activity may predict the outcome of IVF-ET.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens [see comment].

Superantigens are products of bacteria with dual affinity for HLA-DR and the variable region of the beta chain of the T cell receptor, leading to the stimulation of large numbers of T cells. Because there is evidence for the involvement of superantigens in various disease conditions in which intravenous IgG (IVIgG) is used as therapy, the purpose of the present study was to determine if IVIgG contains antibodies inhibitory to T cell stimulation by the superantigens. ELISA and Western assays revealed high concentrations of antibodies in the pooled IgG against eight different staphylococcal toxin (Staph-toxin) superantigens. The IVIgG inhibited in vitro stimulation of human peripheral blood T cells by the Staph-toxins, but did not inhibit responses elicited by phytohemagglutinin or anti-CD3. Inhibition was mediated by Staph-toxin-specific antibodies as shown by affinity adsorption depletion studies. The antibodies functioned by inhibiting the binding and/or presentation of Staph-toxins by DR+ accessory cells. In conclusion, this report is the first to show that normal pooled IgG contains antibodies against a major group of the superantigens, the Staph-toxins, and that the antibodies can inhibit Staph-toxin-elicited T cell activation, suggesting a possible immunoregulatory role for the antibodies in vivo.

Antibodies, Bacterial↗
PubMed1992

The 72K IE1 and 80K IE2 proteins of human cytomegalovirus independently trans-activate the c-fos, c-myc and hsp70 promoters via basal promoter elements.

Growth-regulating cellular genes or genes encoding proteins involved in cell cycle control are likely to be major targets of viral gene products in the establishment of a cellular state favourable for a permissive infection. We have examined whether infection of permissive fibroblasts with human cytomegalovirus (HCMV) results in trans-regulation of such cellular genes. Here we have shown that the proto-oncogenes c-fos and c-myc are specifically induced during immediate early (IE) and early times of HCMV infection, as has recently been shown for the heat shock protein 70 gene (hsp70). Deletion analyses and transfection assays of all three promoters showed that previously defined control sequences upstream of the constitutive promoters and downstream of the mRNA cap site are not required for this up-regulation by HCMV, such that the minimal inducible promoters of c-fos, c-myc and the hsp70 gene contained only 50 to 60 bp upstream of the transcription start site. Cotransfection assays with vectors expressing HCMV major IE cDNAs showed that the 72K IE1 and 80K IE2 proteins are involved in the up-regulation of these promoters. IE1 and IE2 products independently were able to up-regulate the minimal constitutive promoters of the constructs tested here, but trans-activation by IE1 and IE2 together was synergistic. In the case of the hsp70 promoter, promoter constructs containing a variety of different TATA elements could be activated by the 72K IE1 and 80K IE2 proteins.

Base Sequence↗
PubMed1991

Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled-release system and as a suspension of 15N-labelled drug to healthy volunteers.

1. Plasma drug concentrations after a single oral administration of a suspension of carbamazepine (CBZ) and a 20/200 CBZ Oros osmotic pump system were measured in eight healthy male volunteers. The oral suspension contained 100 mg CBZ labelled with the stable isotope nitrogen-15, whilst the Oros contained 200 mg unlabelled CBZ. Plasma concentrations of [15N]-CBZ and CBZ were measured simultaneously by gas chromatography-mass spectrometry. 2. The position of the CBZ Oros (labelled with indium-111) in the gastrointestinal tract was followed by gamma scintigraphy. Plasma drug concentrations after the two treatments were used to relate pharmacokinetic with transit data. 3. The Oros was taken after breakfast and gastric emptying occurred between 1.1- greater than h post-dosing (median, 5.3 h). Small intestinal transit times ranged from 1.5- greater than 3.6 h, with a median of 2.2 h. There were wide individual variations in colonic transit, and the total transit time ranged from 10-60 h (median, 22 h). 4. Relative systemic bioavailability of CBZ from the Oros was reduced compared with that from the suspension (mean dose normalised AUC ratio = 0.69 +/- 0.17; mean dose-normalised AUC ratio = 0.85 +/- 0.13, allowing for actual release from the Oros system). 5. The in vivo absorption of drug into the systemic circulation from the Oros was estimated using the Wagner-Nelson method. This showed that absorption of CBZ was rapid when the Oros was present in the stomach and small intestine, the rate being determined by the release of drug from the system.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

High prevalence of IgA rheumatoid factor in severe polyarticular-onset juvenile rheumatoid arthritis, but not in systemic-onset or pauciarticular-onset disease.

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.

Adolescent↗
PubMed1990

Bilateral virilizing sclerosing stromal tumours of the ovary in a pregnant woman with Gorlin's syndrome: implications for pathogenesis of ovarian stromal neoplasms.

A woman with Gorlin's syndrome who had become pregnant following clomiphene therapy presented in early pregnancy with bilateral ovarian sclerosing stromal tumours which were associated with profound virilization. Pre- and post-operative hormone profiles indicated androgen production by the tumours. Ovarian sclerosing stromal tumours have not previously been reported as occurring bilaterally or in association with Gorlin's syndrome. We discuss the questions raised by this unusual case regarding the pathogenesis of ovarian stromal neoplasms.

Adult↗