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Biomedical subjects

E J Hall

Publications and source records attributed to E J Hall.

334 records · Page 19Linked to original sources
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Chronic intestinal inflammation and intestinal disease in dogs.

Normal individuals maintain tolerance to the endogenous bacterial flora residing within their alimentary tract, a phenomenon mediated by the gastrointestinal lymphoid tissue. Loss of this tolerance is a key factor in the development of chronic intestinal inflammation. Manifestations of such uncontrolled inflammation in humans include inflammatory bowel disease and celiac disease. Dogs may similarly be affected, and although the etiopathogenesis is likely similar, the lesions differ. This review includes discussion of the factors involved in breakdown of mucosal tolerance, the immunologic basis of canine enteropathies, and the use of novel immunotherapies for these diseases.

Animals↗
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Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs.

Controversy exists over the diagnosis of idiopathic small intestinal bacterial overgrowth (SIBO) in dogs and some clinicians use the term antibiotic-responsive diarrhea (ARD) in preference. However, whether such terms are interchangeable is not clear. To examine the relationship between duodenal bacterial numbers and a clinical response to antibiotics, SIBO and ARD were defined by nonoverlapping criteria. Quantitative duodenal juice bacteriology and indirect serum biochemical tests were used to assess small intestinal bacterial populations in 30 dogs with gastrointestinal disorders, including 9 with ARD. Serum total unconjugated bile acid (TUBA) concentrations were measured in all dogs, serum folate and cobalamin concentrations were measured in 29 of 30 dogs, and quantitative culture of duodenal juice was performed in 22 of 30 dogs. Serum TUBA concentrations also were measured in samples from 38 control dogs. Twenty of 22 affected (clinical) dogs in which quantitative bacteriology was performed were classified as having SIBO (>10(5) colony-forming units of total bacteria per milliliter of duodenal juice), but bacterial numbers did not differ significantly between dogs with ARD and dogs with other disorders. Increased folate (19/29), decreased cobalamin (16/ 29), or a combination (9/29) were common, but increased TUBA concentrations were documented in only 5 of 30 clinical dogs. Again, no significant differences were observed between dogs with ARD and those with other disorders, and a similar proportion (5/38) of controls had abnormally high TUBA concentrations. Finally, no significant differences were noted when duodenal bacteriology and TUBA concentrations were assessed before and during antibiotic therapy. These results question the utility of quantitative duodenal juice bacteriology and indirect biochemical marker tests for SIBO in the investigation of canine gastrointestinal disorders.

Animals↗
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Hyperthermia, chemotherapeutic agents and oncogenic transformation.

The modulating effects of hyperthermia on cytotoxity and oncogenicity of several chemotherapeutic agents were investigated using the C3H 10T1/2 cell system. Logarithmic phase cultures of 10T1/2 cells were treated with various doses of cis-platinum or bleomycin sulphate for 2 h, either alone or with simultaneous hyperthermia (42 degrees C for 2 h). In a second set of experiments, cells were treated for 24 h with either melphalan or cis-platinum followed by a 2 h heat treatment. While hyperthermia alone was found to be ineffective in inducing oncogenic transformation and was only moderately cytotoxic, concurrent hyperthermia with drug treatment enhanced both the toxicity and oncogenic transforming potential of drugs 3-4-fold in C3H 10T1/2 cells. Sequential heat after drug treatment, however, was found to increase toxicity slightly but had no effect on the oncogenicity of the drugs.

Animals↗
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Interaction of heat with X-rays and cis-platinum; cell lethality and oncogenic transformation.

There is increasing concern for the oncogenic potential of agents used to treat cancer. Hyperthermia is one of the few modalities that does not, of itself, produce transformed foci in vitro. The adjuvant use of heat with X-rays or chemotherapy agents is an interesting approach to increasing the cell-killing potential while decreasing the oncogenicity of combined-modality therapy. Following a priming heat dose in C3H 10T1/2 cells, resistance to cell killing by a second heat dose develops and is maximal by 10 h. This is known as thermotolerance, and can be monitored by the appearance of proteins of specific molecular weight known as heat-shock proteins. By contrast, a priming heat dose does not confer resistance to killing by cis-platinum (cis-DDP). Indeed, heat potentiates the cytotoxicity due to cis-DDP. The interaction is greatest if heat and drug are applied simultaneously, but is still substantial if the drug is applied many hours after heating. The loss of interaction between heat and cis-DDP occurs slowly, but by 48 h, heat and drug act independently. Thermotolerant cells are less sensitive to the induction of transformation by X-rays than previously unheated cells. On the other hand, 48 h after a heat exposure, when cells have regained their normal sensitivity to killing by cis-DDP, their sensitivity to the induction of transformation by cis-DDP has also returned to normal.

Animals↗
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Interaction of hyperthermia and chemotherapy agents; cell lethality and oncogenic potential.

Hyperthermia was combined with bleomycin, melphalan and cis-platinum in order to examine cell lethality and oncogenic transformation in C3H10T1/2 cells from the adjuvant use of heat with chemotherapy agents. When cells were exposed concurrently to 42.5 degrees C and each of the three chemotherapy agents, heat enhanced both the cytotoxic and oncogenic potential of the drugs. Hyperthermia-enhanced ratios were largest for bleomycin-treated cells. Examination of transformation incidences expressed as a function of surviving fraction, i.e. the cytotoxicity of treatment and therefore drug-heat efficacy, showed that for a given level of cell killing the combination of heat and cis-platinum resulted in fewer transformants per surviving cell than for cis-platinum alone. Hyperthermia appears to reduce the oncogenic potential of low concentrations of melphalan but has no effect on bleomycin-induced oncogenic transformation.

Animals↗
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Radiation, the two-edged sword: cancer risks at high and low doses.

Diagnostic Radiology and Radiation Oncology represent beneficial uses of radiation. The possible price tag is that radiation can cause, as well as diagnose or cure, cancer. Cancer risks at high doses are well known from epidemiologic studies of the Japanese survivors. Risks at low doses must be extrapolated from the high-dose data. The standard-setting bodies recommend a linear no-threshold extrapolation, but this is controversial. A knowledge of mechanisms, while not replacing epidemiology as a source of radiation-induced cancer risks, may provide insights into the shape of the dose-response relationships, and therefore on the validity of the linear extrapolation. The spectrum of second malignancies in radiotherapy patients sheds some light on mechanisms. More useful are new experiments involving the single-particle microbeam; these have demonstrated a bystander effect, that is, biologic effects in cells that are not directly irradiated, as well as mutations in cells where the cytoplasm, but not the nucleus, has been traversed by an alpha-particle.

Alpha Particles↗
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Radiation and life.

Explore the source record for details and available documents.

Abnormalities, Radiation-Induced↗
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A preliminary report: frequency of A-T heterozygotes among prostate cancer patients with severe late responses to radiation therapy.

PURPOSE: To investigate whether a significant proportion of prostate cancer patients who have late sequelae after high-dose external-beam conformal radiation therapy are radio-sensitive because they are carriers of ataxia-telangiectasia, that is, are heterozygous for mutations in the ATM gene. PATIENTS AND METHODS: A group of prostate cancer patients were selected who experienced severe late sequelae, specifically proctitis or cystitis, after high-dose external-beam conformal radiation therapy, together with a control group of patients treated in the same way but who did not have severe late effects. Blood samples were taken from these patients, genomic DNA extracted, and mutations sought in the ATM gene. RESULTS: Of 17 late-effect patients in whom most or all of the ATM gene has been examined, significant mutations (17.6%) were identified in three. No significant mutations were found in the control group. The incidence of ataxia- telangiectasia heterozygotes in the United States population is 1% to 2%. DISCUSSION: These preliminary data suggest that a disproportionate number, but by no means all, of prostate cancer radiotherapy patients who experience severe late effects are ataxia-telangiectasia heterozygotes. If this conclusion is confirmed, these individuals could be identified prospectively and, with dose de-escalation, spared a great deal of discomfort and suffering. As a corollary, if most of the small late-effects population were prospectively identifiable, the dose to the remaining population could potentially be escalated. Present methods of identifying mutations in a large gene, such as ATM, are cumbersome and expensive, but the technology is evolving rapidly, so that rapid screening of the ATM gene is imminent.

Ataxia Telangiectasia↗
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Penclomedine-induced DNA fragmentation and p53 accumulation correlate with reproductive cell death in colorectal carcinoma cells with altered p53 status.

Penclomedine, a synthetic pyridine derivative, has documented antitumor activity and is being investigated in clinical trials. Its mechanism of action is unknown although it may be metabolized to a free radical, DNA-reactive species. We previously reported that telomerase positive colorectal carcinoma (RKO) cells with abrogated p53 function were more sensitive to penclomedine than were telomerase positive cells with wild-type p53. The present study demonstrates that significant differences in DNA fragmentation in response to penclomedine were observed in RKO cells lacking functional p53 compared with RKO cells with normal p53 function. No differences in DNA fragmentation in response to ionizing radiation were seen in RKO cells with normal or abrogated p53 function. RKO cells with functional p53 respond to penclomedine treatment with a dose-dependent increase in p53 protein levels. However, RKO cells with abrogated p53 function did not show any such change in p53 protein levels. Further, p53-independent increase of p21 was observed, although the significance of this response remains uncertain. These studies suggest that penclomedine may have a therapeutic advantage in killing cells that have abrogated p53 function.

Antineoplastic Agents↗