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Biomedical subjects

E J Hall

Publications and source records attributed to E J Hall.

At least 325 records · Page 18Linked to original sources
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The enhanced sensitivity of mammalian cells to killing by X rays after prolonged exposure to several nitroimidazoles.

Electron affinic compounds, such as misonidazole, preferentially sensitize hypoxic cells to killing by X rays, and are also preferentially cytotoxic to cells deficient in oxygen. Prolonged exposure of cells to misonidazole prior to irradiation results in an increased radiosensitization. This is expressed as the Extra Enhancement Ratio (EER), defined as the ratio of the doses delivered immediately after the addition of the sensitizer or after prolonged incubation, that produce a given biological effect. Chinese hamster V79 cells have been used to investigate this prolonged incubation effect for a variety of 2-nitroimidazoles including misonidazole, desmethylmisonidazole and SR-2508 and as well as two ortho-substituted-4-nitroimidazoles with a bromine or sulfonamide group substituted in the 5-position. A considerable variation was observed in the magnitude of the Extra Enhancement Ratio (EER) produced by pre-incubation with different compounds at concentrations that produce the same sensitizing effect. There is a good correlation between the EER and the measured rate at which the various sensitizers deplete cells of non-protein sulfhydryl compounds. There is also a good correlation between the EER and the fraction of cells killed by the pre-incubation period in the drug.

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Enhanced cytotoxicity of melphalan by prolonged exposure to nitroimidazoles: the role of endogenous thiols.

It was first demonstrated that prolonged exposure of hypoxic V-79 cells to misonidazole prior to irradiation produced an increased radiosensitization in 1977; it was postulated that the reduction of misonidazole resulted in intermediates capable of depleting cells of endogenous thiols, substances known to play a role in the hydrogen repair of target radicals produced by ionizing radiation. The present study shows that a prolonged exposure of V-79 cells to a variety of nitroimidazoles (misonidazole, Ro-05-9963, SR-2508, and MTR1-80) results in an enhanced cytotoxicity when these cells are subsequently exposed to melphalan. This process of enhanced melphalan toxicity occurred only when cells were pretreated with misonidazole under hypoxic conditions, suggesting that nitroreduction is necessary for chemosensitization as it is for increased radiosensitization. Different nitroimidazoles tested vary in the extent to which they sensitize cells to the subsequent action of melphalan. Repair from a misonidazole pretreatment is essentially complete by six hours. This study demonstrated that cysteamine could reduce the cytotoxicity of misonidazole and the enhancement of melphalan toxicity. This was an effect reversible with time and one implying similar mechanisms for the preincubation effect observed in vitro for radiation and chemotherapy agents.

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Assessment of a breath collection technique and portable breath hydrogen monitor for use in cats and dogs.

Until now the use of breath hydrogen testing in companion animal gastroenterology has been limited to academic institutions because of the expense of the equipment. Recently portable breath hydrogen monitors, designed for use in paediatric gastroenterology, have been developed. They may be suitable for use in veterinary medicine as an ancillary diagnostic aid but, before widespread use can be recommended, thorough validation is required. Hydrogen breath tests were conducted in five dogs and four cats, undergoing investigations for small intestinal disease. Breath samples were taken using a closed-flow collection system and concurrently analysed with a commercially available portable breath hydrogen monitor and a previously validated breath hydrogen monitor. In cats, sample collection was troublesome and complete studies could only be performed in two individuals. Good correlation was demonstrated between the readings of both monitors (rs=0.902 and 0.935 for dogs and cats respectively; P<0.002) but agreement was poor with significant under-read from the portable monitor. Our results demonstrate that more studies on validation and the generation of a reference range would be required before the use of this portable hydrogen monitor could be recommended.

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Radiobiological principles in intravascular irradiation.

BACKGROUND: There is wide interest in the use of intravascular irradiation to control restenosis following balloon angioplasty. Part of the mechanism of restenosis appears to be the proliferation of smooth muscle cells (SMCs), triggered to divide by the damage caused by the angioplasty, and this proliferation can be inhibited by irradiation with y-rays or beta-rays. METHODS: In vitro data for the survival of smooth muscle cells exposed to radiation was used to model the likely control of restenosis by radiation. Physical and biological data were used to estimate differences in biological effectiveness of gamma-rays and beta3-rays, as well as the effect on cell killing of extending the exposure time. RESULTS: Based on the radiosensitivity of SMCs, measured in vitro, and the limited proliferative potential of these normal somatic cells, it is possible to understand and to model quantitatively how a single acute gamma-ray dose in the range of 15-20 Gy can inhibit restenosis. The few successful trials carried out to date where radiation has been shown to inhibit restenosis have all involved the gamma-emitter Iridium-192. The use of this radionuclide involves radiation safety problems and an inconveniently long treatment time. Consequently, there is much interest in developing a beta-emitting source that would solve both problems, and a number of different possibilities are being pursued. This development introduces two new problems discussed in this paper. First, beta-rays in the megavoltage range are less effective biologically than gamma-rays in the kilovoltage range, but the magnitude of the difference is not well known. Second, in the case of a single large dose, such as that proposed to inhibit restenosis, the biological effect will vary substantially as the exposure time varies from 1 to 20 min. If the clinical data are to be compared between centers using a variety of beta and y-emitting radionuclides, these factors will need to be taken into account. CONCLUSIONS: Doses of > 15 Gy are unlikely to result in elimination of the restenosis problem but should delay onset of restenosis for a significant period; the larger the dose, the longer the delay. Successful trials of endovascular radiation completed to date involve y-rays, while many systems being developed are based on beta-emitting radionuclides. Experimental data are urgently needed so that allowances can be made for the difference in dose-rate and radiation quality between gamma and beta-emitting radionuclides.

Angioplasty, Balloon↗
PubMedDate not supplied

An immunohistochemical study of histiocytic ulcerative colitis in boxer dogs.

Histiocytic ulcerative colitis (HUC) is an inflammatory bowel disease (IBD) that occurs predominantly in dogs of the boxer breed. The lesions are characterized by mucosal ulceration and mixed inflammatory cell infiltrate that includes the presence of periodic acid-Schiff (PAS)-positive macrophages. However, the phenotype of the inflammatory cells has not been characterized further. In the present study, immunohistochemistry and computer-aided morphometric analysis were used to define populations of leucocyte subsets in the colon of 14 boxer dogs with HUC. Biopsies from six of these dogs included both lesional and non-lesional regions. Colonic tissue from 11 dogs of various breeds without evidence of gastrointestinal disease served as controls. In HUC lesions there were significantly more IgG(+), IgG3(+), IgG4(+)plasma cells, CD3(+)T cells, MHC class II(+)cells, L1(+)cells and PAS(+)cells in the lamina propria than in both control colon and non-lesional colonic regions of affected dogs. In the epithelial compartment, goblet cells were significantly decreased in HUC lesions compared to both control and non-lesional HUC colon, and intensity of enterocyte MHC class II expression was significantly increased. These observations are similar to those documented in human IBD, especially ulcerative colitis, and suggest an important role for the mucosal immune system in the pathogenesis of canine HUC.

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Immune cell populations within the duodenal mucosa of dogs with enteropathies.

The mucosal immune system may play a critical role in the pathogenesis of small intestinal enteropathies. The aim of the current study was to assess mucosal immune cell populations in dogs with inflammatory bowel disease (IBD), idiopathic antibiotic-responsive diarrhea (ARD), and adverse reactions to food (FR). Endoscopic biopsies were performed of the duodenum of dogs with these conditions and from a group of dogs without enteric disease. Additional control samples were collected after death from other dogs that did not have evidence of enteric disease. Immunohistochemistry and computer-aided morphometry were used to assess the distribution of immune cell subsets in both lamina propria and intestinal epithelium. Compared with controls, dogs with ARD had increased numbers of lamina propria immunoglobulin (Ig) A- plasma cells and CD4+ cells. More marked alterations were noted in dogs with IBD, with significant increases in lamina propria IgG+ plasma cells, T cells (CD3+), CD4+ cells, macrophages, and neutrophils, but with reduced mast cell numbers. Increased intraepithelial CD3+ T cells were also present in the dogs with IBD, compared with controls. However, lamina propria and epithelial populations were unaltered in dogs with FR when compared with controls. The altered mucosal immune cell populations observed in dogs with ARD or IBD may reflect an underlying immunologic pathogenesis in these disorders.

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