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Biomedical subjects

Emma Jones

Publications and source records attributed to Emma Jones.

At least 19 recordsLinked to original sources
PubMed2007

Safety and efficacy of a continuous infusion, patient-controlled antiemetic pump for children receiving emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects of moderately or highly emetogenic chemotherapy. Diphenhydramine, lorazepam, and dexamethasone have been used individually to treat CINV. The objective of this study was to evaluate the safety and potential efficacy of those drugs administered via a patient controlled pump (BAD pump) to control CINV. PROCEDURE: A retrospective chart review was conducted of all pediatric oncology patients who received the BAD pump. Emetic episodes, doses of rescue medications to treat breakthrough nausea or vomiting, and occurrence of adverse events were recorded. Complete response (CR) was defined as no emesis or rescue medications, partial response (PR) as emesis but no rescue medications, and failure (F) as rescue medications required. RESULTS: Thirty patients received a total of 141 courses. Adverse events occurred in 4.2% of the courses; confusion (n = 2), depressed mood (n = 1), dysphoria (n = 1), agitation (n = 1), and restlessness (n = 1). All side effects resolved after decreasing the infusion rate, and the pump was not discontinued in any patients. Eighteen patients failed conventional prophylaxis and received BAD pump for identical subsequent chemotherapy cycles; they spent more days in CR with BAD pump than without it, 21 versus 45 days (P = .003) respectively. Patients receiving BAD pump had significantly shorter hospital stay with BAD pump than those not receiving it, 68 days versus 76 (P = .046). CONCLUSIONS: BAD pump is well tolerated in pediatric patients receiving chemotherapy and may be more effective than conventional prophylaxis in controlling CINV in some patients.

Adolescent↗
PubMed2006

Effect of dietary supplementation with beta-casein A1 or A2 on markers of disease development in individuals at high risk of cardiovascular disease.

The present study is the first to examine the hypothesis that dietary supplementation with beta-casein A1 promotes an increased risk relative to supplementation with beta-casein A2 in patients traditionally at high risk of developing CVD. The study was conducted in fifteen asymptomatic participants (six male; nine female) at high risk of developing CVD. A double-blind cross-over study design was used with a total duration of 24 weeks. Dietary intervention was a daily supplementation (25 g) of either casein A1 or A2 (for 12 weeks each). Surrogate measures of cardioprotection studied included the examination of vascular (endothelium and arterial) function, resting blood pressure, plasma lipids and biochemical markers of inflammation. Total plasma cholesterol levels were significantly lower following 12 weeks of both casein A1 and A2 interventions but the decrease was not different between intervention. Plasma insulin, homocysteine, C-reactive protein, fibrinogen, protein C and S and von Willebrand factor levels were not different between the two casein supplements. Endothelium function, measured as a vascular response using venous occlusion plethysmography to intra-arterial infusions of the endothelium-dependent agonist acetylcholine, were not different between the two casein interventions. Similarly, neither blood pressure nor measures of large artery stiffness were affected by differing the casein variant. We therefore conclude that there is no evidence from the present study that supplementation with casein A1 has any cardiovascular health disadvantage over consumption of casein A2.

Adult↗
PubMed2005

The generation of CD25+ CD4+ regulatory T cells that prevent allograft rejection does not compromise immunity to a viral pathogen.

In all but a small minority of cases, continued survival of solid organ grafts after transplantation depends on lifelong, nonselective immunosuppression that, although effective, results in increased rates of infection, cancer, and vascular disease. Therapeutic strategies that engage or mimic self-tolerance may allow prolonged allograft survival without the disadvantages of nonspecific immunotherapy. Pretreatment of recipient mice with donor alloantigen combined with transient modulation of the peripheral T cell pool with anti-CD4 Ab leads to the indefinite survival of MHC-incompatible cardiac allografts without further therapy. Tolerance is dependent on CD25+ CD4+ regulatory T cells that arise from naive CD25- precursors and regulate rejection via both IL-10 and CTLA-4. Although these cells are clearly effective at controlling rejection, the proven ability of recently activated CD25+ cells to mediate bystander regulation raises the possibility that tolerized individuals might also have a reduced capacity to respond to environmental pathogens. We have examined anti-influenza responses in tolerized primary heart recipients, secondary recipients following adoptive transfer of regulatory populations, and tolerized mice in which bystander regulation has been deliberately induced. Neither virus-specific CTL activity in vitro nor the clearance of virus in vivo was significantly diminished in any of these treatment groups compared with infected unmanipulated controls. The data suggest that the induction of dominant allograft tolerance dependent on regulatory T cells does not necessarily result in attenuated responses to pathogens providing further support for the development of tolerance induction protocols in clinical transplantation.

Adoptive Transfer↗
PubMed2005

Incorporation of cis-9, trans-11 conjugated linoleic acid and vaccenic acid (trans-11 18 : 1) into plasma and leucocyte lipids in healthy men consuming dairy products naturally enriched in these fatty acids.

The present study investigated whether consuming dairy products naturally enriched in cis-9, trans-11 (c9,t11) conjugated linoleic acid (CLA) by modification of cattle feed increases the concentration of this isomer in plasma and cellular lipids in healthy men. The study had a double-blind cross-over design. Subjects aged 34-60 years consumed dairy products available from food retailers for 1 week and then either control (0.17 g c9,t11 CLA/d; 0.31 g trans-vaccenic acid (tVA)/d) or CLA-enriched (1.43 g c9,t11 CLA/d; 4.71 g tVA/d) dairy products for 6 weeks. After 7 weeks washout, this was repeated with the alternate products. c9,t11 CLA concentration in plasma lipids was lower after consuming the control products, which may reflect the two-fold greater c9,t11 CLA content of the commercial products. Consuming the CLA-enriched dairy products increased the c9,t11 CLA concentration in plasma phosphatidylcholine (PC) (38 %; P = 0.035), triacylglycerol (TAG) (22 %; P < 0.0001) and cholesteryl esters (205 %; P < 0.0001), and in peripheral blood mononuclear cells (PBMC) (238 %; P < 0.0001), while tVA concentration was greater in plasma PC (65 %; P = 0.035), TAG (98 %; P = 0.001) and PBMC (84 %; P = 0.004). Overall, the present study shows that consumption of naturally enriched dairy products in amounts similar to habitual intakes of these foods increased the c9,t11 CLA content of plasma and cellular lipids.

Adult↗
PubMed2005

Recent advances in trabeculectomy technique.

PURPOSE OF REVIEW: Trabeculectomy is an effective operation for lowering intraocular pressure. However, success is limited by complications such as infection, hypotony, and scarring. RECENT FINDINGS: These complications, which are increased by antifibrotic use, can be reduced with attention to surgical technique. We highlight the benefit of sub-Tenon anaesthesia, careful choice of the surgical site, fashioning of the scleral flap to produce diffuse aqueous flow, and better intraocular pressure control, maintenance of intraocular pressure, a formed anterior chamber, with outflow control during surgery using an infusion, optimal method of antimetabolites application, new adjustable sutures, and corneal-conjunctival closure techniques. SUMMARY: These techniques reduce hypotony, producing a diffuse noncystic bleb with long-term pressure control.

Glaucoma↗
PubMed2004

Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.

Dendrimers are hyperbranched macromolecules that can be chemically synthesized to have precise structural characteristics. We used anionic, polyamidoamine, generation 3.5 dendrimers to make novel water-soluble conjugates of D(+)-glucosamine and D(+)-glucosamine 6-sulfate with immuno-modulatory and antiangiogenic properties respectively. Dendrimer glucosamine inhibited Toll-like receptor 4-mediated lipopolysaccharide induced synthesis of pro-inflammatory chemokines (MIP-1 alpha, MIP-1 beta, IL-8) and cytokines (TNF-alpha, IL-1 beta, IL-6) from human dendritic cells and macrophages but allowed upregulation of the costimulatory molecules CD25, CD80, CD83 and CD86. Dendrimer glucosamine 6-sulfate blocked fibroblast growth factor-2 mediated endothelial cell proliferation and neoangiogenesis in human Matrigel and placental angiogenesis assays. When dendrimer glucosamine and dendrimer glucosamine 6-sulfate were used together in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery, they increased the long-term success of the surgery from 30% to 80% (P = 0.029). We conclude that synthetically engineered macromolecules such as the dendrimers described here can be tailored to have defined immuno-modulatory and antiangiogenic properties, and they can be used synergistically to prevent scar tissue formation.

Animals↗
PubMed2004

Nociception in vertebrates: key receptors participating in spinal mechanisms of chronic pain in animals.

Our view of vertebrate nociceptive processing is ever changing with the discovery of novel molecules that differentially affect sensory responses to noxious and innocuous stimulation and might be involved specifically in chronic pain states. In order to understand the physiology of nociception and design novel analgesics for intractable chronic pain, it is essential to uncover precisely what changes occur between a normal nociceptive processing state and hypersensitive chronic pain states in the spinal cord following different types of injury. An important area of focus for future work in this area will be the cellular and molecular mechanisms of neuronal plasticity that occur.

Analgesics↗
PubMed2004

The influence of CD25+ cells on the generation of immunity to tumour cell lines in mice.

CD25+ regulatory T cells comprise 5-10% of CD4+ T cells in naïve mice and have been shown in several in vivo murine models to prevent the induction of autoimmune disease and inflammatory disease. Since T cells, which mediate autoimmunity, can through recognition of self-antigens also target tumour cells, it was postulated that CD25+ regulatory cells would also inhibit the generation of immune responses to rumours. Depletion of these cells using CD25-specific monoclonal antibodies has indeed been shown to promote rejection of several transplantable murine tumour cell lines including melanoma, leukaemia and colorectal carcinoma. Results obtained using these models indicate that in the absence of regulatory cells, CD4+ T cells mediate tumour immunity, although the precise mechanisms through which these cells result in tumour rejection have not yet been elucidated. The target antigens recognized by these CD4+ T cells have also not yet been identified. Immunization of mice with tumour cells in the absence of CD25+ regulatory cells does, however, induce immunity against a variety of different tumour cell lines indicating that the target antigen(s) are shared amongst tumours of distinct histological origins. Since CD25+ regulatory cells have been identified in humans, the possibility that the cells inhibit immune responses to shared rejection antigens expressed by human tumours is worthy of investigation.

Animals↗
PubMed2003

Anti-CD8 antibodies can inhibit or enhance peptide-MHC class I (pMHCI) multimer binding: this is paralleled by their effects on CTL activation and occurs in the absence of an interaction between pMHCI and CD8 on the cell surface.

Cytotoxic T lymphocytes recognize short peptides presented in association with MHC class I (MHCI) molecules on the surface of target cells. The Ag specificity of T lymphocytes is conferred by the TCR, but invariable regions of the peptide-MHCI (pMHCI) molecule also interact with the cell surface glycoprotein CD8. The distinct binding sites for CD8 and the TCR allow pMHCI to be bound simultaneously by both molecules. Even before it was established that the TCR recognized pMHCI, it was shown that CTL exhibit clonal heterogeneity in their ability to activate in the presence of anti-CD8 Abs. These Ab-based studies have since been interpreted in the context of the interaction between pMHCI and CD8 and have recently been extended to show that anti-CD8 Ab can affect the cell surface binding of multimerized pMHCI Ags. In this study, we examine the role of CD8 further using point-mutated pMHCI Ag and show that anti-CD8 Abs can either enhance or inhibit the activation of CTL and the stable cell surface binding of multimerized pMHCI, regardless of whether there is a pMHCI/CD8 interaction. We further demonstrate that multimerized pMHCI Ag can recruit CD8 in the absence of a pMHCI/CD8 interaction and that anti-CD8 Abs can generate an intracellular activation signal resulting in CTL effector function. These results question many previous assumptions as to how anti-CD8 Abs must function and indicate that CD8 has multiple roles in CTL activation that are not necessarily dependent on an interaction with pMHCI.

Adjuvants, Immunologic↗
PubMed2003

Immunodominance of an antiviral cytotoxic T cell response is shaped by the kinetics of viral protein expression.

Lymphocytic choriomeningitis virus (LCMV) infection induces a protective CTL response consisting of gp- and nucleoprotein (NP)-specific CTL. We find that a small load of LCMV led to immunodominance of NP-CTL, whereas a large viral load resulted in dominance of gp-CTL. This is the first study describing that immunodominance is not fixed after infection with a given pathogen, but varies with the viral load instead. We assumed higher Ag sensitivity for NP-CTL, which would explain their preferential priming at low viral load, as well as their overstimulation resulting in selective exhaustion at high viral load. The higher Ag sensitivity of NP-CTL was due to faster kinetics of NP-epitope presentation. Thus, we uncover a novel factor that impinges upon immunodominance and is related to the kinetics of virus protein expression. We propose that CTL against early viral proteins swiftly interfere with virus replication, resulting in efficient protection. If these "early" CTL fail in immediate virus control, they are activated in the face of higher viral load compared with "late" CTL and are therefore prone to be exhausted. Thus, the observed absence of early CTL in persistent infections might not be the cause, but rather the consequence of viral persistence.

Animals↗
PubMed2003

CD25+ regulatory T cells and tumor immunity.

Tumor cells express a range of antigens including self-antigens (those whose expression is shared by normal host tissue) and non-self antigens (such as those that arise as a result of mutations in normal cellular genes or in the case of some tumors, viral antigens). Immune responses to both types of antigen have been identified in human patients with cancer and in murine tumor models. In both cases, these responses are typically weak and generally fail to result in tumor rejection. Accumulating evidence indicates that a population of T cells, namely CD25(+) regulatory cells, is at least partly responsible for the poor immunogenicity of tumor cells. This evidence is discussed in the context of a murine model of melanoma.

Animals↗
PubMed2003

The influence of macrophage inflammatory protein-1alpha on protective immunity mediated by antiviral cytotoxic T cells.

Macrophage inflammatory protein 1alpha (MIP-1alpha), a member of the CC-chemokine subfamily, is known to induce chemotaxis of a variety of cell types in vivo. Although the role of MIP-1alpha in inflammatory responses generated following primary infection of mice with many different pathogens has been characterized, the influence of this chemokine on the generation of antigen-specific T-cell responses in vivo is less well understood. This is important, as virus-specific CD8+ T lymphocytes (CTL) play a crucial role in defence against viral infections, both acutely and in the long term. In this study, we compared the ability of wild-type and MIP-1alpha-deficient (MIP-1alpha-/-) mice to mount CTL responses specific for the immunodominant epitope derived from influenza nucleoprotein (NP366-374). Influenza-specific CTL responses were compared with respect to frequency, cytotoxic activity and ability to clear subsequent infections with recombinant vaccinia viruses expressing the influenza NP. The results indicate that antiviral CTL generated in MIP-1alpha-/- mice are slightly impaired in their ability to protect against a subsequent infection. However, impaired in vivo CTL-mediated antiviral protection was found to be associated with reduced cytotoxicity rather than with a failure of the CTL to migrate to peripheral sites of infection.

Animals↗
PubMed2002

Exogenous peptides delivered by ricin require processing by signal peptidase for transporter associated with antigen processing-independent MHC class I-restricted presentation.

In this study we demonstrate that a disarmed version of the cytotoxin ricin can deliver exogenous CD8(+) T cell epitopes into the MHC class I-restricted pathway by a TAP-independent, signal peptidase-dependent pathway. Defined viral peptide epitopes genetically fused to the N terminus of an attenuated ricin A subunit (RTA) that was reassociated with its partner B subunit were able to reach the early secretory pathway of sensitive cells, including TAP-deficient cells. Successful processing and presentation by MHC class I proteins was not dependent on proteasome activity or on recycling of MHC class I proteins, but rather on a functional secretory pathway. Our results demonstrated a role for signal peptidase in the generation of peptide epitopes associated at the amino terminus of RTA. We showed, first, that potential signal peptide cleavage sites located toward the N terminus of RTA can be posttranslationally cleaved by signal peptidase and, second, that mutation of one of these sites led to a loss of peptide presentation. These results identify a novel MHC class I presentation pathway that exploits the ability of toxins to reach the lumen of the endoplasmic reticulum by retrograde transport, and suggest a role for endoplasmic reticulum signal peptidase in the processing and presentation of MHC class I peptides. Because TAP-negative cells can be sensitized for CTL killing following retrograde transport of toxin-linked peptides, application of these results has direct implications for the development of novel vaccination strategies.

Animals↗
PubMed2002

Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice.

Treatment with monoclonal antibodies (mAbs) specific for CD25 (anti-CD25 mAb) has been shown to suppress growth of a variety of different tumours in mice. These studies did not however determine whether or not anti-CD25 mAbs facilitate tumour rejection by depletion of regulatory T cells or by binding to tumour-specific effector cells. Using a murine model of melanoma we have found that treatment of mice with anti-CD25 mAb facilitates long-term CD4+ T cell-mediated tumour immunity through depletion of CD25+ regulatory cells. We further show that the effector CD4+ T cells confer long-term tumour immunity even in the presence of CD25+ regulatory cells and do not require CD8+ T cells for tumour rejection. The inhibitory impact of anti-CD25 mAb treatment on tumour growth may be the result of depleting CD25+ regulatory cells that normally inhibit the generation of immune responses to self-antigens that are shared by the tumour. We have performed experiments to determine whether or not immune responses to melanocyte antigens are generated in anti-CD25 mAb-treated, melanoma-immune mice. The results of the experiments indicate that a T cell response to the melanocyte antigen tyrosinase accompanies suppression of tumour growth in mice lacking CD25+ regulatory cells.

Animals↗
PubMed2002

Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.

Although it is known that the immune system can mount responses to a variety of tumors it is clear that most tumors exhibit weak or even undetectable immunogenicity. Recent findings suggest that the lack of tumor immunogenicity is partly due to a population of cells called CD4+ CD25+ regulatory T cells since depletion of these cells in mice can result in tumor rejection. These cells have also been shown to inhibit the development of organ-specific autoimmune diseases suggesting that they inhibit immune responses to tissue-specific self-antigens. Such immune responses may also mediate tumor rejection. Alternatively, immune responses in mice depleted of regulatory cells may target tumor antigens that are not tissue-specific, but which are shared by tumors of diverse origins. In experiments performed to discriminate between these possibilities we found, using the murine colorectal tumor CT26, that tumor immunity stimulated in the absence of regulatory cells is not restricted to tumors of colorectal origin, but is effective against tumors of different histological types such as B cell lymphomas and a renal cell carcinoma. By comparing this to CT26-induced immunity through the use of adjuvant we show that the generation of cross-reactive tumor immunity is a specific manifestation of CD25+ regulatory cell depletion. The generation of CD4+ T cells capable of mediating tumor rejection is another important feature of tumor immunity induced in the absence of CD25+ cells.

Animals↗
PubMed2002

Fas ligand breaks tolerance to self-antigens and induces tumor immunity mediated by antibodies.

The role of Fas ligand (FasL) in programmed cell death via interaction with its receptor Fas is well characterized. It has been proposed that expression of FasL can confer immune privilege to some organs, allowing them to kill infiltrating lymphocytes and inflammatory cells. However, a number of studies have shown that when tumors or transplants express FasL, rejection often occurs as a consequence of proinflammatory functions of FasL. Here we demonstrate that FasL elicits tumor immunity in a murine melanoma model with weak immunogenicity and low expression of major histocompatibility complex (MHC) class I. We show that protected mice recognize melanocyte differentiation self-antigens. Importantly, tumor immunity is mediated by antibodies, as it can be transferred by serum from protected mice.

Animals↗