Biomedical subjects
G Gallagher
Publications and source records attributed to G Gallagher.
Polymorphism at the tumour necrosis factor locus: a marker of genetic predisposition to colorectal cancer?
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Increased monocyte cytokine production in association with systemic complications in acute pancreatitis.
Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 beta, IL-6 and IL-8 are thought to play a central role in the pathophysiology of sepsis but their role in acute pancreatitis is unknown. In the present study, monocytes were isolated from the peripheral blood of 26 patients with moderate or severe acute pancreatitis without biliary sepsis. Secretion of these cytokines in vitro was measured at intervals during the first week of illness. Sixteen patients developed systemic complications. Peak TNF-alpha secretion was significantly higher in patients who developed systemic complications (median (interquartile range (i.q.r.)) 18.5 (5.5-28.5) ng/ml) than in those with an uncomplicated course (3.7 (2.3-6.4) ng/ml, P < 0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6: complicated median (i.q.r.) 48.9 (12.1-71.0) ng/ml, uncomplicated 16.3 (14.2-37.9) ng/ml, P < 0.05; IL-8: complicated 748 (643-901) ng/ml, uncomplicated 608 (496-749) ng/ml), P < 0.05). No significant difference in peak IL-1 beta secretion was observed between the two groups. Systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNF-alpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease.
A second polymorphic dinucleotide repeat in the 5' flanking region of the human IL10 gene.
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A polymorphic dinucleotide repeat in the human IL-10 promoter.
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The development of a novel immunotherapy model of human ovarian cancer in human PBL-severe combined immunodeficient (SCID) mice.
The reported ability of SCID mice to accept xenografts of both human tumors and peripheral blood lymphocytes (PBL) provides the potential for the development of novel immunotherapy models in these animals. This study describes the development of a novel small animal model of human ovarian cancer. This was achieved by engrafting a human ovarian cancer cell line (Ovan-4) into the peritoneal cavity of immunodeficient SCID and immune reconstituted human PBL-SCID mice. When transplanted to SCID mice this cell line exhibited growth characteristics similar to the clinical disease observed in patients with implantation of metastatic nodules onto the interior surface of the peritoneal wall. Reconstituted human PBL-SCID mice challenged with identical numbers of Ovan-4 cells exhibited a significant increase in survival time, suggesting a role for cells of the human immune system in preventing the development of this type of malignancy in vivo. Furthermore, vaccination of human PBL-SCID mice against Ovan-4 produced tumour-specific human antibodies in the serum of these animals. Animals reconstituted with CD8-depleted PBL exhibited increased serum immunoglobulin levels and produced enhanced anti-Ovan-4 activity after vaccination. Subsequent challenge of these animals with Ovan-4 revealed a further increase in survival time. These results suggest that human antibodies may have a role in immunity against ovarian cancer and could be of therapeutic value in this type of disease.
Polymorphism at the tumour necrosis factor locus: a marker of genetic predisposition to colorectal cancer?
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Diffuse astrocytic swelling and increased second messenger activity following acute Haemophilus influenzae meningitis--evidence from a rat model.
Despite numerous epidemiological analyses of bacterial meningitis there is very little pathological data concerning the acute glial and neuronal responses to the disease. We have developed a safe, easily used rat model for Haemophilus influenzae type b meningitis. We measured cerebral blood flow, glucose utilisation and second messenger activity in this model, and carried out parallel light and ultrastructural analysis of glial and neuronal responses. Only protein kinase C activity was changed from control values. We obtained evidence for massive astrocytic swelling and neuronal degeneration. We posit that cytotoxic mechanisms may contribute to the pathology of meningitis.
TNF Nco-I RFLP is not an independent risk factor in rheumatoid arthritis.
The human TNF genes are located within the MHC class-III region on chromosome 6. The presence or absence of an Nco-I restriction site in the 5' non-coding sequence of the TNF beta gene defines two alleles (TNFB*1 and TNFB*2). The segregation of these alleles has been associated with levels of TNF alpha or TNF beta production in systemic lupus erythematosis (SLE), insulin-dependent diabetes mellitus (IDDM) and in healthy control individuals. Rheumatoid arthritis (RA) is characterized by high levels of TNF alpha within the synovial fluid and to address the question of whether this could be brought about by a genetic predisposition to high TNF production by RA individuals, we examined the distribution of this Nco-I polymorphism in 98 healthy volunteers and 123 patients with active rheumatoid arthritis. No difference was observed between the normal and RA groups with respect to haplotype segregation or allelic frequency. Furthermore, no difference was observed between DR4+ or DR4- individuals in the control or RA groups. These data demonstrate that the high level of TNF alpha seen in the joints of RA patients is unlikely to be due to a genetic predisposition of these patients to high TNF alpha production, as defined by the TNF Nco-I restriction fragment length polymorphism (RFLP).
The in vivo production of specific human antibodies by vaccination of human-PBL-SCID mice.
Human-PBL-SCID animals were created by intraperitoneal (i.p.) transfer of human peripheral blood lymphocytes (PBL) or PBL depleted of CD8-expressing lymphocytes (CD8dL). Analysis of human immunoglobulin levels in these animals revealed that severe combined immunodeficiency (SCID) mice receiving CD8dL produced significantly higher levels of serum human immunoglobulin than those receiving PBL. In an attempt to induce antigen-specific human antibodies these human-PBL-SCID animals were vaccinated with soluble protein antigen [ovalbumin (OVA)] entrapped within liposomes as an immunological adjuvant. Vaccination produced antigen-specific human IgM and IgG in human-PBL-SCID mouse serum. The use of liposomes as adjuvant and the reconstitution of animals with CD8dL together enhanced the OVA-specific immune response as evidenced by the detection of significantly increased serum antibody titres. In the CD8dL reconstituted group, solid tumours of human B-cell origin became detectable in the peritoneal cavity of animals at 8-10 weeks post-reconstitution. These tumours were readily established in vitro and subsequent analysis of culture supernatants showed that these malignant cells continue to secrete human antibodies specific for the original immunizing antigen in vitro. We believe this vaccination of the human-PBL-SCID mouse to produce antigen-specific human antibodies, may find use in the future production of human monoclonal antibodies and in the testing and development of novel vaccine/adjuvant systems.
Soluble interleukin-2 receptors and CA 125 in ovarian cancer, a longitudinal and cross-sectional study.
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Human immunoglobulin production in SCID mice following primary sensitisation of human lymphocytes in situ.
We have grafted human peripheral blood mononuclear cells to the peritoneal cavity of SCID mice, exposed them to soluble antigens in the absence of adjuvant and examined their ability to make specific antibody. The effect of in vitro pre-priming of donor cells on antibody production was determined. Human IgM and IgG antibodies were found in the SCID serum following in situ antigenic challenge and there was good evidence of antigen specificity. The total Ig levels and the relative antigen binding ability were diminished by in vitro pre-priming. The results demonstrate that primary human antibodies against antigens to which the donor is probably naive can be generated by in situ sensitisation in SCID mice, but that optimisation for each antigen may be required.
Co-stimulation with IL-2, but not via CD28, overcomes immunosuppression by breast tumour-derived factors on the in vitro stimulation of human T-cells.
In order to investigate the mode of action of tumour-derived immunosuppressive factor from breast cancer (TDS) we examined its function on human T-cells stimulated via CD3 and co-stimulated via CD28 or the IL-2 receptor. When added at the initiation of culture, TDS inhibited anti-CD3 stimulation and co-stimulation by anti-CD28. In contrast, co-stimulation with IL-2 greatly diminished the TDS inhibition of anti-CD3 stimulated cells. Activation by IL-2 alone was also inhibited at the initiation of culture. When PBMC were activated with IL-2 or anti-CD3 for three days and then exposed to TDS for a further 3 days, only the proliferation of the cells pre-activated with IL-2 was inhibited; the cells pre-activated via CD3 were refractory to TDS inhibition. Pre-activation with anti-CD3 for 48 h was required for this to develop. The cytotoxicity of cells pre-activated with anti-CD3 was lower than that of cells exposed to IL-2, but killing obtained from cultures pre-activated with anti-CD3 plus IL-2 was equivalent to that obtained with IL-2 alone and additionally, these pre-activated cells were not subject to inhibition upon subsequent exposure to TDS.
Patient Self-Determination Act. Implementing an information program in a nursing facility.
1. Several legal landmarks regarding the withdrawal or refusal of life-sustaining treatments led to the development of advance directive documents. Advance directive documents allow an individual to indicate preference for medical treatment while he or she is capable. 2. The Patient Self-Determination Act (1991) was enacted to ensure that patients are advised of their right to accept or refuse medical care, and to promote the right to execute an advance directive. 3. Implementing an information program about advance directives in a nursing facility requires an understanding of the process of change.
Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster.
Transforming growth factor-alpha (TGF-alpha) and TGF-beta 1 have been proposed as important regulators of processes critical to successful wound healing. Although various cells present in wounds represent potential sources of either TGF-alpha and/or TGF-beta, including macrophages, neutrophils, keratinocytes, fibroblasts, and endothelial cells, we recently identified eosinophils as an additional potential source of these cytokines. We therefore used in situ hybridization and immunohistochemistry to determine whether eosinophils represent significant sources of TGF-alpha and/or TGF-beta 1 in skin wounds in the hamster. We found that these wounds developed a prominent infiltration of eosinophils, and that eosinophils were a cellular source of both TGF-alpha and TGF-beta 1 mRNAs. TGF-alpha and TGF-beta 1 proteins were detectable both within eosinophils and extracellularly. Moreover, there was a sequential pattern of TGF-alpha and TGF-beta 1 expression by infiltrating eosinophils, with the onset of eosinophil-associated TGF-alpha expression preceding that of TGF-beta 1. This sequential pattern of TGF expression suggests that eosinophils may help to regulate critical biological processes during wound healing.
Organophosphate pesticide exposure in a group of Washington State orchard applicators.
As part of a study to investigate the potential for organophosphates to cause chronic neurologic sequelae, we assessed the pesticide exposure experience of a group of Washington State apple orchard applicators. Seasonal monitoring of cholinesterase activity for 48 regular organophosphate applicators and a control group of 40 slaughterhouse workers was performed. A subset of the pesticide applicators participated in an in-depth exposure assessment. This involved observation of spraying activities during 1 spray day, as well as cholinesterase monitoring and dermal exposure assessment using a fluorescent tracer in the pesticide formulation. Comparison of seasonal red blood cell cholinesterase change in pesticide workers according to exposure level, characterized by frequency of pesticide spraying and protective equipment use, showed lower cholinesterase levels among higher exposed groups compared to lesser exposed groups. In-depth exposure assessment revealed exposure primarily on the head and hand regions. Subclinical changes (less than 15% inhibition) in red cell cholinesterase correlated well with dermal exposure calculations. This study suggests that cholinesterase monitoring may be a useful biological marker for even subclinical organophosphate pesticide effects.
Cytokine control of Leishmania infection in the BALB/c mouse: enhancement and inhibition of parasite growth by local administration of IL-2 or IL-4 is species and time dependent.
The therapeutic potential of locally injected interleukin-2 (IL-2) or interleukin-4 (IL-4) was studied in the footpads of Leishmania mexicana or Leishmania major infected BALB/c mice. The disease state was measured both pathologically, by measuring lesion size, and parasitologically, by counting total parasite numbers from infected footpads. IL-2 (0.5 microgram/dose) or IL-4 (0.1 microgram/dose) was administered either early, 1 day and/or 15 days after infection, or late, after palpable lesions had developed. Results differed markedly depending on which Leishmania species was used and at what time during the course of disease that therapy commenced. Both L. major and L. mexicana infections, as measured by footpad thickness and parasite number, were exacerbated if IL-4 was injected into the infected footpads early, during the first two weeks of infection. Paradoxically, late intralesional injection (i.e. after measurable lesions had developed) of IL-4 markedly inhibited both lesion size and parasite growth in L. major, though not L. mexicana, infected mice. IL-2 had no measurable effect on the course of L. major infections no matter when or how often, the infected footpads of mice were treated. However, early administration of IL-2 did exacerbate L. mexicana lesion and parasite growth while late treatment had no effect. Generally, but not always, increases in footpad size correlated with increases in parasite number.