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Biomedical subjects

S Hurst

Publications and source records attributed to S Hurst.

18 recordsLinked to original sources
PubMed2001

Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus.

Cytokine networking in the lung in response to inhaled Aspergillus fumigatus was assessed using a murine model of primary pulmonary aspergillosis in immunocompetent Crl:CF-1 mice. Inhalation of virulent A. fumigatus (6 x 10(6) CFU) resulted in the induction of interleukin 18 (IL-18), tumor necrosis factor alpha (TNF-alpha), IL-12, and gamma interferon (IFN-gamma) protein in bronchoalveolar lavage fluid and/or lung tissue. Induction of immunoreactive IL-18 preceded induction of TNF-alpha protein, which preceded induction of immunoreactive IL-12 and IFN-gamma. Real-time reverse transcriptase (RT) PCR analysis of infected lung tissue demonstrated that induction of IL-18 protein also preceded induction of pulmonary TNF-alpha, IL-12, and IFN-gamma mRNAs. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to the IL-18 receptor (anti-IL-18R MAb), TNF-alpha (anti-TNF-alpha MAb), IL-12 (anti-IL-12 MAb), and/or IFN-gamma (anti-IFN-gamma MAb), and effects on intrapulmonary cytokine activity and growth of A. fumigatus were assessed in infected lung homogenates. Simultaneous neutralization of IL-12 and IL-18 resulted in decreased levels of immunoreactive TNF-alpha, while neutralization of IL-18, TNF-alpha, or IL-12 alone or of IL-18 and IL-12 together resulted in decreased levels of immunoreactive IFN-gamma. Simultaneous neutralization of IL-12 and IL-18 or neutralization of TNF-alpha alone or in combination with IL-12, IL-18, or IFN-gamma also resulted in a significant increase in A. fumigatus CFU in lung tissue. Taken together, these results demonstrate that endogenous IL-18, IL-12, and TNF-alpha, through their modulatory effects on both intrapulmonary cytokine activity and growth of A. fumigatus, play key roles in host defense against primary pulmonary aspergillosis.

Adjuvants, Immunologic↗
PubMed2000

Aggravation of licensing procedures by doubtful thermodynamic data.

Environmental prognosis by geochemical modelling is a scientific approach to several open questions of general public interest. Two prominent fields where geochemical modelling holds an important share are the remediation of contaminated former uranium mining areas and safety assessment of radioactive waste repositories in the geosphere. In both fields, application of geochemical modelling is stipulated by public authorities. The enormous complexity of models that can be handled by computers rises the awareness on the meaningfulness of a modelling result and demands for provision of an estimate of the dependability of a calculation output by the computers. It is obvious that bias, over- and underestimation of uncertainty in input data reduces the relevance of the calculation output. Chemistry contributes important data to geochemical modelling, both from field analysis and in the fundamental physico-chemical quantities enclosed into the thermodynamic data base. Some examples will be given where progress in quality assessment of chemical data may further the predictive power of geochemical modelling.

Journal Article↗
PubMed2000

Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection.

The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-gamma)-mediated resolution of replicative Legionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (10(6) L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-gamma mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior to L. pneumophila infection inhibited induction of intrapulmonary IFN-gamma production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-gamma and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-gamma in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

Animals↗
PubMed2000

Modeling therapeutic strategies in rheumatoid arthritis: use of decision analysis and Markov models.

OBJECTIVE: The management of patients with rheumatoid arthritis (RA) is controversial, with a number of different proposed treatment strategies based on different conceptions of the natural history of the disease and different interpretations of the efficacy and effectiveness of the drugs used for treatment. We attempted to develop a theoretical framework to assess the effectiveness of different treatment regimens for RA. METHODS: We used decision analysis to structure the problem of comparing sequential monotherapy to a combination strategy. Subsequently, we used 3 different estimates of drug effectiveness: one from expert rheumatologists; a metaanalysis; and a recent nationwide survey of American rheumatologists, in a Markov model. Last, we utilized published duration of therapy data to model drug treatment over time. RESULTS: Estimates of drug effectiveness differed substantially among rheumatologists, but regardless of the estimates and the treatment strategy used, the model predicted over 90% of patients improved by the 3rd drug trial. Over time, treatment patterns in our model resemble the "sawtooth" pattern previously observed. CONCLUSION: Treatment strategies in RA are difficult to model because of uncertainty in both the structure of the model and the data needed to perform the analysis. These models tend to overestimate the effectiveness of drug sequences because of nonindependence between therapies, probably due to sequence effects, a change in responsiveness over time, or resistant subgroups. Our preliminary analysis suggests that the most effective agent, possibly methotrexate, should be used first if the objective is to get as many patients into remission as quickly as possible.

Arthritis, Rheumatoid↗
PubMed1999

A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells.

IL-10 is a cytokine secreted by a wide variety of cells type that has pleiotropic stimulatory and suppressive activities on both lymphoid and myeloid cells in vitro. To analyze the consequences of high IL-10 secretion by APCs in immune responses, we produced transgenic mice expressing human IL-10 directed by the MHC class II Ea promoter. Despite alterations in the development of T and B cells, no gross abnormalities were detected in peripheral lymphocyte populations or serum Ig levels. However, when immunized using conditions that give either a Th2-type or a Th1-type response, IL-10 transgenic mice failed to mount a significant T or B cell immune response to OVA. IL-10 transgenic mice were also highly susceptible to infection with intracellular pathogens like Listeria monocytogenes or Leishmania major, in contrast to IL-10 transgenic mice, where the transgene was express in T cells. Finally, the recently described stimulatory effect of IL-10 on CD8+ T cells was confirmed by the ability of IL-10 transgenic mice to limit the growth of immunogenic tumors by a CTL-mediated mechanism. These results demonstrate, that, depending on the type of immune response, IL-10 can mediate immunosuppressive or immunostimulatory activities in vivo.

Animals↗
PubMed1999

A staufen-like RNA-binding protein in translocation channels linking nurse cells to oocytes in Notonecta shows nucleotide-dependent attachment to microtubules.

In Drosophila melanogaster the staufen gene encodes an RNA-binding protein that is essential for the correct localization of certain nurse cell-derived transcripts in oocytes. Although the mechanism underlying mRNA localization is unknown, mRNA-staufen complexes have been shown to move in a microtubule-dependent manner, and it has been suggested that staufen associates with a motor protein which generates the movement. We have investigated this possibility using Notonecta glauca in which nurse cells also supply the oocytes with mRNA, but via greatly extended nutritive tubes comprised of large aggregates of parallel microtubules. Using a staufen peptide antibody and RNA probes we have identified a staufen-like protein, which specifically binds double-stranded RNA, in the nutritive tubes of Notonecta. We show that while the staufen-like protein does not co-purify with microtubules from ovaries using standard procedures it does so under conditions of motor-entrapment, specifically in the presence of AMP-PNP. We also show that the staufen-like protein is subsequently removed by ATP and GTP, but not ADP. Nucleotide-dependent binding to microtubules is typical of a motor-mediated interaction and the pattern of attachment and detachment of the staufen-like protein correlates with that of a kinesin protein within the ovaries. Our findings indicate that the staufen-like RNA-binding protein attaches to, and is transported along, Notonecta ovarian microtubules by a kinesin motor.

Adenosine Diphosphate↗
PubMed1998

Expression of a testis-specific putative actin-capping protein associated with the developing acrosome during rat spermiogenesis.

Actin-capping proteins are ubiquitous components of mammalian cells. They are known to regulate the polymerization state of actin and hence indirectly control the activity of the cytoskeleton and cell shape. As part of our investigation into the molecular mechanisms that direct differentiation of a round spermatid into an elongating spermatozoa, we report on a testis-specific 1.7-kb transcript from rat testis with sequence similarities to the alpha subunit of actin-capping proteins (ACPs) from somatic cells. The transcript contains a putative cAMP-responsive motif (CREM) upstream of the initiation codon in the DNA sequence and is expressed postmeiotically, first appearing between 20 and 30 days of postnatal development. The primary amino acid sequence is 90% identical to that of a previously identified testis-specific mouse protein, gsg3, both showing approximately 40% homology to the alpha subunit of somatic ACPs. An affinity-purified polyclonal antibody to a synthetic peptide derived from the rat transcript identified a 32-kDa protein on Western blots of testicular extracts. Indirect immunofluorescent localization of the protein on frozen sections of adult rat testis showed that it is intracellular and accumulates asymmetrically in the cytoplasm of round spermatids coincident with the position of the developing acrosome. This spatial expression parallels the distribution of F-actin during sperm differentiation, supporting the hypothesis that testis-specific ACPs have an important role in determining the final shape of mature sperm heads. A disturbance in the expression of these ACPs may underlie many of the abnormalities in sperm morphology observed in infertile semen.

Acrosome↗
PubMed1998

Cellular distribution and molecular heterogeneity of MAC393 antigen (clusterin, beta-chain) on the surface membrane of bull spermatozoa.

The distribution and size of a surface membrane antigen identified by a monoclonal antibody (MAC9393) have been examined in testicular and epididymal bovine sperm preparations. Western blots indicated a substantial decrease in molecular mass of the antigen during epididymal maturation from approximately 87 kDa in the testis to approximately 35 kDa in the cauda epididymidis. This was accompanied by a change in its cellular localization from the neck and whole head to the acrosomal region. N-terminal microsequencing identified MAC393 antigen as the beta-chain of clusterin. A polyclonal antiserum to the alpha-chain of clusterin recognized both testicular and epididymal forms and revealed that the heterodimer was present on the sperm tail as well as the acrosome. These findings are explained by the co-existence of dimeric and monomeric pools of clusterin on spermatozoa. The polyclonal antiserum recognizes both testicular and epididymal forms of the heterodimer and although the monoclonal antibody binds to the testicular heterodimer, it only recognizes the beta-chain monomer of epididymal clusterin. These findings support previous observations made on human spermatozoa that two forms of clusterin, the beta-chain monomer and the heterodimer, are present on the surface membrane and in seminal plasma.

Amino Acid Sequence↗
PubMed1996

Ethanol ingestion inhibits cell-mediated immune responses of unprimed T-cell receptor transgenic mice.

This paper introduces a transgenic (Tg) mouse in which the majority of the CD4-bearing T cells have T-cell receptors that react with ovalbumin (OVA) as a model for ethanol research. Although these Tg animals were bred onto the BALB/c genetic background, a strain generally considered to be nonpreferring in ethanol consumption, we determined that BALB/c mice would consume an ethanol-containing liquid diet, without significant mortality, and assessed alteration of specific immune responses. BALB/c, C57BL/6 (B6), or (BALB/c x C57BL/6)F-1 hybrid (CB6F1) mice were fed LED containing 35, 30, 25, or 20% ethanol-derived calories. Significant mortality (> 40%) was seen only in BALB/c and pronounced weight loss was seen in BALB/c, B6, CB6F1 mice when they were fed the diet containing the greatest ethanol concentration (LED35). Diets containing lesser amounts of ethanol did not cause mortality. Liquid diets containing > or = 30% ethanol-derived calories significantly impaired the chicken gamma-globulin-specific delayed hypersensitivity responses in BALB/c, B6, and CB6F1mice without significantly affecting the humoral immune response to sheep red blood cells. We show that immunization of the Tg mice is not required for the development of a vigorous "delayed hypersensitivity" response to OVA or the I-Ad-restricted peptide OVA323-339 in mice fed standard solid lab chow or liquid control diet. In marked contrast, OVA Tg mice fed ethanol show a profound inhibition of this immune response, indicating that ethanol-induced inhibition of cell-mediated immunity occurs independently of antigen priming.

Alcoholism↗
PubMed1996

Multidisciplinary discharge planning.

Patients undergoing total hip replacement need careful rehabilitation to avoid complications. Communication is essential for effective discharge planning. The named nurse is ideally placed to co-ordinate the activities of the health-care team.

Hip Prosthesis↗
PubMed1994

Synergism between interleukins 1 beta and 6 on noradrenergic nerves in rat myenteric plexus.

BACKGROUND/AIMS: Because levels of interleukins 1 beta and 6 (IL-1 beta and IL-6) are elevated during intestinal Trichinella spiralis infection, they may mediate the changes in enteric neural function in that model. IL-1 beta suppresses norepinephrine release from the myenteric plexus, but the effect of IL-6 is unknown. Therefore, we investigated the effects of IL-6 alone and in combination with IL-1 beta on norepinephrine release. METHODS: Longitudinal muscle myenteric plexus or myenteric nerve varicosity preparations from jejunum of noninfected rats were loaded with [3H]norepinephrine, and 3H release was measured after a preincubation with or without human recombinant IL-6, alone or in combination with human recombinant IL-1 beta. RESULTS: 1 ng/mL of IL-6 augmented 3H release, 100 ng/mL suppressed 3H release, whereas 10 ng/mL had no effect. However, IL-6 (10 ng/mL) plus a subthreshold concentration of human recombinant IL-1 beta significantly suppressed 3H release, and this was abolished by adding anti-IL-6 antibody or an IL-1 receptor antagonist. CONCLUSIONS: Because 3H release reflects [3H]norepinephrine release, our results show that IL-6 exerts a dual effect on norepinephrine release. Furthermore, there is synergism between IL-1 beta and IL-6 resulting in suppression of norepinephrine release. Therefore, both cytokines may contribute to the suppression of norepinephrine release observed in the inflamed intestine.

Animals↗
PubMed1993

Interleukin-1 beta modulation of norepinephrine release from rat myenteric nerves.

We examined the ability of human recombinant interleukin-1 beta (hrIL-1 beta) to alter the release of [3H]norepinephrine ([3H]NE) by KCl or electrical field stimulation in longitudinal muscle-myenteric plexus of rat intestine. The cytokine had no immediate effect on either the basal or evoked release of [3H]NE. However, hrIL-1 beta caused a biphasic time-dependent suppression of evoked [3H]NE release that was delayed in onset. IL-1 beta also stimulated the cycloheximide-sensitive uptake of [35S] methionine uptake by the tissue. The initial suppression of [3H]NE release was observed after 30 min and could not be inhibited by cycloheximide. A delayed peak was observed after 120 min and was inhibited by cycloheximide. The effect of IL-1 beta was maximal at 10 ng/ml and could be prevented by a neutralizing anti-IL-1 beta antibody or by preincubating the tissue with an IL-1-receptor antagonist. These results indicate that IL-1 beta suppresses [3H]NE release from rat myenteric plexus by two mechanisms, one of which is independent of protein synthesis and the other of which is mediated by endogenous IL-1.

Animals↗
PubMed1980

The effects of misonidazole during continuous low dose rate irradiation.

Hypoxic cell sensitizers have been shown to enhance the radiation effects on tumors for single and multifractionated doses of radiation given in acute exposures. Low dose rate brachytherapy provides an opportunity for short-term high dose drug administration and continuous drug exposure throughout the entire brachytherapy course. To determine the effects of misonidazole during continuous low dose rate irradiation we have exposed the EMT6/SF tumor to continuous irradiation at 4.2 and 1.64 rads/minute with and without misondiazole (at doses of 1 mg/g or 0.2 mg/g), in bilaterally nephrectomized mice, and compared the results to those obtained wih acute exposures. Radiosensitization by misonidazole at a clinically achievable plasma concentration was observed during continuous low dose rate irradiation. The DMF (dose-modifying factor) varied with drug dose and dose rate. At a dose of 1 mg/g the DMF was 2.4 at 221 rads/minute and 1.6 at 4.2 rads/minute; at 0.2 mg/g it was 1.5 at 221 rads/minute and 4.2 rads/minute and 1.4 at 1.64 rads/minute. Cytotoxicity was also observed with drug exposure greater than 6 hours. Our results suggest that it would be advantageous to sue misonidazole during low dose rate brachytherapy.

Animals↗