Immunochemical studies of human red cell membrane proteins excreted in normal urine.
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Animals↗
Biomedical subjects
G Gallagher
Publications and source records attributed to G Gallagher.
Metabolites of methyl 5(6)-butyl-2-benzimidazolecarbamate (parbendazole). Structure and synthesis.
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Animals↗
Family association studies of markers on chromosome 2q and Type 1 diabetes in subjects from South India.
BACKGROUND: Several Type 1 diabetes susceptibility loci have been located to chromosome 2q12-21. However, results have not always been consistent and this may reflect study design and the population analysed. We have used a family-based design to look for an association between Type 1 diabetes and markers located to 2q12-21. METHODS: Ninety-one South Indian families consisting of subjects with Type 1 diabetes and their parents were genotyped for eight polymorphic markers localised to 2q12-21, which includes the interleukin-1 gene cluster. Radiation hybrid mapping was used to localise the map position of D2S308 and D2S363 on 2q12-21. The extended transmission disequilibrium test was used for statistical analysis. RESULTS: No associations were found between Type 1 diabetes and markers located in and around the interleukin-1 gene cluster or the interleukin-1 Type 1 receptor. In contrast, a suggestive association was found between Type 1 diabetes and two closely-linked markers telomeric of the interleukin-1 gene cluster (D2S308 and D2S363, separated by 3.3 cR) (p=0.004 and p=0.002, respectively). CONCLUSION: This preliminary study suggests that a locus close to D2S308 and D2S363 is involved in the aetiology of Type 1 diabetes in the South Indian population.
Adolescent↗
Oral involvement in mucous membrane pemphigoid.
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Adult↗
Pyrrolo[1,4]benzodiazepine antitumor antibiotics: relationship of DNA alkylation and sequence specificity to the biological activity of natural and synthetic compounds.
The DNA alkylation and sequence specificity of a group of natural and synthetic pyrrolo-[1,4]benzodiazepines [P(1,4)Bs] were evaluated by using an exonuclease III stop assay, and the results were compared with in vitro and in vivo biological potency and antitumor activity. The P(1,4)B antibiotics are potent antitumor agents produced by various Actinomycetes, which are believed to mediate their cytotoxic effects by covalent bonding through N-2 of guanine in the minor groove of DNA. In this article we describe the results of a sensitive DNA alkylation assay using exonuclease III which permits both estimation of the extent of DNA modification as well as location of the precise guanines to which the drugs are covalently bound. Using this assay, we have evaluated a series of natural and synthetic compounds of the P(1,4)B class for their ability to bind to DNA and also determined their DNA sequence preference. The compounds included in this study are P(1,4)Bs carrying different substituents in the aromatic ring, having varying degrees of saturation in the five-membered ring, or differing in the stereochemistry at C-11a. These same compounds were evaluated for in vitro cytotoxic activity against B16 melanoma cells, for potency in vivo in B6D2F1 mice (LD50), and for antitumor activity (ILSmax) against P388 leukemia cells. A good correlation was found between extent of DNA alkylation and in vitro and in vivo potency. Furthermore, on the basis of electronic and steric considerations, it was possible to rationalize why those compounds that showed negligible biological activity were unable to bond covalently to DNA. Last, we have determined that the degree of saturation in the five-membered ring of the P(1,4)Bs has a significant effect on the DNA bonding reactivity and biological activity of this class of compounds.
Alkylation↗
CD4+, CD8+ and CD4- CD8- T cell-subsets can confer protection against Leishmania m. mexicana infection.
We studied the role of CD4+, CD8+, CD4- CD8- T cells and IgG anti-Leishmania after infection or vaccination in the CBA/ca mouse. Mice were either infected with L. m. mexicana promastigotes or vaccinated with parasite-membrane antigens incorporated into liposomes. Successfully vaccinated mice were used as cell-donors in adoptive transfer experiments. Naive, syngeneic recipients received highly-enriched CD4+, CD8+ or CD4- CD8- T cells from those two set of donors and challenged with live parasites. Our results showed that, both CD4+ and CD8+ T cells from infected or vaccinated donors conferred significant disease-resistance to naive recipients. In addition, adoptive transfer of CD4- CD8- T cells from vaccinated donors significantly delayed lesion growth in recipient mice. We concluded that vaccination of CBA mice correlates with the induction of protective CD4+, CD8+ and CD4- CD8- T cells and the synthesis of IgG anti-Leishmania.
Animals↗
Treatment of pain in severe burns.
Burn pain can cause psychologic and functional difficulties, and is difficult to predict from wound depth. The initial painful stimulation of nerve endings by the burn with continued painful stimuli result in peripheral and central mechanisms causing amplification of painful stimuli, and the development of chronic pain syndromes that can be difficult to treat. In order to assess the effect of analgesic interventions it is essential to measure the patient's pain in a simple and reproducible manner. A number of tools exist for this measurement, ranging from longer and more detailed techniques such as the McGill pain questionnaire most suited to relatively stable pain, to visual analogue scores and picture-based scores for children. Pain management begins with the acute injury, with initial measures such as cooling of the burn and use of inhalational agents such as oxygen/nitrous oxide mixtures. On arrival in hospital, for any but trivial burns, intravenous opioids are appropriate and should be administered as small intravenous boluses titrated against effect. Following the initial resuscitation, pain may be divided into background pain and that associated with procedures. These often require different analgesic interventions. Background pain may be treated with potent intravenous opioids by infusion or patient controlled analgesia and then on to oral, less potent opioids, followed by other oral analgesics. Often drug combinations work best. More severe procedural pain may be treated with a variety of interventions from a slight increase in therapy for the background pain to more potent drugs, local blocks, or general anaesthesia. In addition to drug-based methods of managing burn pain, a number of nonpharmacologic approaches have been successfully employed including hypnosis, auricular electrical stimulation, massage, and a number of cognitive and behavioural techniques.
Analgesics, Opioid↗
Transforming growth factor-beta is not the major soluble immunosuppressor in the microenvironments of human breast tumours.
The immunosuppressive nature of the human breast cancer microenvironment was investigated. The soluble fraction of individual tumours was tested for its ability to influence the activation of peripheral blood lymphocytes (PBL) by interleukin-2 (IL-2) and to effect the continued proliferation of cells which had been pre-activated with IL-2. In all cases, both assays were profoundly inhibited (90-100%). None of this inhibition was due to cell killing by the tumour-derived soluble material (TDS). Sixty-two percent of TDS tested contained measurable transforming-growth factor-beta (TGF-beta) activity; following acidification TGF-beta was present in all TDS. However, in neither case was this material present in sufficient amounts to account for the degree of inhibition observed. In addition, neutralisation experiments failed to demonstrate consistent relief of inhibition in the presence of excess anti-TGF-beta antisera. These results demonstrate that TGF-beta s are not the major soluble immunosuppressive materials within human breast tumours.
Breast Neoplasms↗
Peritumoural IL-4 treatment induces systemic inhibition of tumour growth in experimental melanoma.
We have examined the ability of interleukin-4 (IL-4) to inhibit the growth of the B.16 melanoma in C57BL/6 mice. Tumours were allowed to become established and then treated locally with 50 ng/day IL-4. Treatment was continued for 7 days and then the tumours were removed and weighed. The results showed that recombinant murine IL-4 (rmIL-4) strongly inhibited tumour growth, with some complete resolutions. In addition, the effect of IL-4 treatment was seen to be systemic; in mice bearing two tumours (neck and thigh), which had been innoculated simultaneously, treatment at the neck site resulted in reduced tumour growth at both sites. This effect was accompanied by an increase in the proportion of lymphocytes in the spleen, particularly T-cells, although tumours at neither site showed much evidence of leucocytic infiltration. These results suggest that local treatment with IL-4 is able to profoundly reduce the rate of tumour growth, even of nodules not receiving treatment directly.
Animals↗
The ability of transforming growth factor-beta 1 to preferentially inhibit the induction of cytotoxicity in human T cells is determined by the nature of the activating signals.
TGF-beta is held to be a general inhibitor of the immune system, able to prevent the development of certain differentiated functions, such as the induction of LAK activity by IL-2. In the present study, the potential of TGF-beta 1 to inhibit anti-tumour responses was assessed by determining its relative effect on the proliferation and cytotoxicity of human T-cells, following activation by anti-CD3, anti-CD3 plus anti-CD28 or anti-CD3 plus IL-2. The results demonstrated that TGF-beta 1 inhibits the induction of cytotoxicity in human T-cells stimulated via CD3 or CD3 and CD28 (P < 0.01), without significantly altering their proliferative responses. The cytotoxic response following costimulation with IL-2 was hardly altered, while costimulation via CD28 was susceptible to suppression, suggesting that TGF-beta 1 action is affected by the nature of the costimulatory signals.
Antibodies↗
IL-2 inhibits the induction of systemic antitumour immunity by IL-4 in the peritumoural treatment of experimental melanoma.
We have examined the relative abilities of interleukin-4 (IL-4) and interleukin-2 (IL-2) to inhibit the growth of the B.16 melanoma in C57BL/6 mice. Tumours were allowed to become established and then treated peritumourally with either IL-4 or IL-2, or a combination of IL-4 plus IL-2. Treatment was continued for 7 days and then the tumours were removed and weighed. The results showed that IL-4 strongly inhibited tumour growth in 83% of individuals, but complete resolution was observed in only 18%. In the IL-2 treated groups, the percentage of growth-inhibited tumours was markedly less (50%), with 14% complete resolutions. In the IL-4+IL-2 treated tumours resolution was again different, such that only 57% of tumours were smaller than those seen in the controls but there was a high number bearing no measurable tumour (25%). In addition, of the three treatments described, only peritumoural administration of IL-4 alone could mediate the induction of systemic protection from tumour growth. These results suggest that IL-4 and IL-2 have different mechanisms of action and that IL-2 may antagonise the effect of IL-4 such that the action of the two materials when combined is highly unpredictable.
Animals↗
Vaccination of C57BL/6 mice against cutaneous leishmaniosis. Kinetics of antibody synthesis and induction of cellular responses.
In this report, the effectiveness of vaccination of C57BL/6 mice and its association to long term production of IgG anti-Leishmania, delayed type hypersensitivity response (DTH) and the enlargement of the spleen associated to hyperplasia or parasite visceralization were studied. Mice were vaccinated with Leishmania-membrane antigens incorporated into liposomes, and two weeks later, animals received a homologous challenge with living amastigotes. Antibody levels were weekly recorded during 18 weeks after immunization. It was concluded that this vaccine induces disease-resistance in C57BL/6 mice and this effect correlates with the production of IgG anti-Leishmania, but not with the induction of a DTH or lymphoid hyperplasia.
Animals↗