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Biomedical subjects

D Murray

Publications and source records attributed to D Murray.

At least 235 records · Page 13Linked to original sources
PubMed1990

Radioprotection of hematopoietic tissues in mice by indomethacin.

We recently reported that indomethacin, an inhibitor of prostaglandin (PG) synthesis, increased the radioresponse of PG-producing murine tumors, but it protected the hematopoietic system from radiation damage [Furuta et al., Cancer Res. 48, 3008-3013 (1988)]. Here we have investigated possible mechanisms responsible for the radioprotective effect of indomethacin. In the exogenous spleen colony assay, bone marrow cells from indomethacin-treated mice showed a similar radioresponse to those from mice not treated with indomethacin, thus excluding true radioprotection as a mechanism. Also, neither the total number of bone marrow cells nor the number of stem cells in bone marrow were affected by the treatment with indomethacin. However, indomethacin induced significant splenomegaly, which was associated with an increased number of both nucleated cells and hematopoietic stem cells in the spleen. The latter was determined by the exogenous spleen colony assay. Thus indomethacin protected hematopoietic tissue indirectly through stimulation of hematopoietic cells in the spleen. When indomethacin was combined with WR-2721, which is a true radioprotector, we obtained a greater radioprotective effect than with either used alone according to the endogenous spleen colony assay.

Amifostine↗
PubMed1990

Using EGS4 Monte Carlo in medical radiation physics.

Monte Carlo modelling of particle transport problems in medical radiation physics offers significant advantages over other techniques. Experiments can be performed without having to set up the physical situation, and "impossible" experiments can be performed, such as labelling multiple-scattered particles or simulating the effect of chamber walls on dosimetry. The availability of standardised Monte Carlo packages (EGS4 and ETRAN/ITS), along with the development of more powerful and inexpensive computers has allowed more widespread use of the technique. This report discusses the principles of Monte Carlo modelling in general, then examines the EGS4 Monte Carlo package in more detail, with particular reference to its use in medical physics applications.

Biological Transport↗
PubMed1990

Stage-dependent variation in the radiosensitivity of DNA in developing male germ cells.

The induction and rejoining of gamma-ray-induced DNA single-strand breaks (SSBs) were measured in the spermatogenic cells of mice using the alkaline elution technique. The animals were injected with [3H]thymidine and sacrificed on subsequent days to examine selectively cohorts of radiolabeled cells in the successive stages of maturation. A significantly increased frequency of SSB was observed in the unirradiated early spermatocytes and late spermatids, associated with genetic recombination and chromatin compaction, respectively. The frequency of SSBs induced by irradiation of animals in vivo remained constant from the early spermatocyte through mid-spermatid stages and decreased significantly only after the cells matured to the late spermatid stage. The frequency of SSBs after in vitro irradiation of testicular cell suspensions also decreased as round spermatids matured to late spermatids. Such decreases for both modes of irradiation may result from maturation-dependent alterations in chromatin in late spermatids, such as condensation and replacement of histones with protamines, rather than from changes in oxygen tension. Rejoining of SSBs in vivo was efficient in the spermatocytes and early spermatids but declined in late spermatids. Possible reasons for the discrepancy between the greater number of unrepaired lesions and lower susceptibility to mutation induction in late spermatids than in round spermatids are discussed.

Animals↗
PubMed1989

Hydrogen peroxide insult in cultured mammalian cells: relationships between DNA single-strand breakage, poly(ADP-ribose) metabolism and cell killing.

We examined the effect of exposure to H2O2 at 37 degrees C on Chinese hamster ovary cell survival, DNA single-strand break (SSB) induction and rejoining, and activation of poly(ADP-ribose) (ADPR) polymerase. The effect of the ADPR polymerase inhibitor 3-aminobenzamide on each of these processes was also determined. SSB induction increased progressively with increasing H2O2 concentration. SSB levels were maximal after approx. 5 min of exposure to H2O2 (100 microM) and then decreased at longer times. This decrease, which paralleled the time-dependent depletion of H2O2, was due to the rejoining of SSBs. 3-Aminobenzamide enhanced the level of SSBs at each time point. H2O2 increased the level of both ADPR synthesis and NAD+ depletion (both measures of ADPR polymerase activity) in a concentration-dependent fashion, with the maximum effect being reached after approx. 20 min. After 100 microM H2O2, the effects on both ADPR and NAD+ were reversible. 3-Aminobenzamide completely blocked the effects of the oxidant on both NAD+ and ADPR levels. Thus, SSB induction by H2O2 at 37 degrees C was accompanied by a marked but reversible stimulation of ADPR polymerase. However, cell killing by H2O2 was only slightly enhanced in the presence of 3-aminobenzamide (5 mM), so the above-mentioned effects do not appear to be relevant to the cytotoxic effect of H2O2 under these conditions. Comparing these results with data obtained previously for cells treated with H2O2 at 4 degrees C suggests that the mechanisms of DNA strand breakage and cell killing may be quite different at the two temperatures, and that DNA damage at 37 degrees C may be indirectly mediated by temperature-dependent metabolic events.

Animals↗
PubMed1989

Changes in Na,K-ATPase, sodium ion, and glucose transport in isolated enterocytes in an experimental model of malabsorption.

Nippostrongylus brasiliensis infection of the rat resulted, at day 10 of infection, in decreased levels of jejunal enterocyte sodium-potassium-activated adenosine triphosphatase (Na,K-ATPase) and potassium-activated p-nitrophenyl phosphatase (K-pNPPase) activities. Parallel decreases occurred in active sodium efflux from jejunal enterocytes in the presence and absence of actively transported monosaccharides. Ileal enterocyte Na,K-ATPase and K-pNPPase activities were significantly increased, as was active sodium efflux. In contrast to controls, the presence of monosaccharides produced a stimulation of active sodium efflux from ileal enterocytes derived from infected rats. Enzyme and sodium transport changes in the jejunal enterocytes probably reflect cellular immaturity. Functional changes in ileal enterocytes probably represent a compensatory phenomenon.

Animals↗
PubMed1989

Protection of cultured Chinese hamster ovary cells by the aminothiol WR-255591 from the lethal and DNA-damaging effects of fast neutrons.

We examined the radioprotective effect of the aminothiol WR-255591 on cultured aerated Chinese hamster ovary cells irradiated with cyclotron-generated fast neutrons. The effects of a 30 min pretreatment with 6 mM WR-255591 on the induction of DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) were measured using alkaline (pH 12.1) and neutral (pH 7.0) filter elution, respectively. Molecular protection factors (PFs) calculated from these data were compared with the PF measured using the biological endpoint of cell survival. WR-255591 afforded significant protection against cell killing by neutrons (PF = 1.36) although protection was less efficient than against cell killing by gamma-rays (PF = 2.30). Whereas for gamma-rays, the PFs were in the order survival greater than or equal to DSB induction much greater than SSB induction, the magnitude of the modification of the induction of both SSBs (PF = 1.38) and DSBs (PF = 1.38) after neutron irradiation was the same as that of cell killing.

Animals↗
PubMed1989

Protection by WR-3689 against gamma-ray-induced intestinal damage: comparative effect on clonogenic cell survival, mouse survival, and DNA damage.

The aminophosphorothioate WR-3689 was characterized for its ability to protect mouse jejunal cells in vivo from single doses of X or gamma radiation. First, the effect of the drug on the survival of jejunal stem cells was examined using a clonogenic end point, the crypt microcolony assay. When WR-3689 was administered 30 min prior to whole-body irradiation, the number of surviving crypt cells was markedly increased at all doses of the drug, although protection began to level out at doses larger than 600 mg/kg. Protection was maximal when the drug was given 30 min before whole-body irradiation and declined rapidly with both shorter and longer intervals. Protection factors (PFs) were obtained by measuring survival curves for clonogenic crypt cells as a function of radiation dose; WR-3689 given 30 min before whole-body irradiation protected jejunum in the microcolony assay with a PF of 1.26 +/- 0.02, 1.50 +/- 0.10, and 1.65 +/- 0.10 at doses of 200, 400, and 800 mg/kg, respectively. Next, the effect of WR-3689 on the survival of jejunal stem cells was determined by assaying the survival of mice given X-ray doses to the whole abdomen in the range leading to death from the gastrointestinal syndrome. The PFs based on the LD50 values for 11-day survival were 1.31 +/- 0.05 (200 mg/kg) and 1.48 +/- 0.05 (400 mg/kg). Crypt-cell survival and animal survival were thus modified to a similar extent by this agent. Finally, the effect of WR-3689 on the induction of DNA single-strand breaks (SSBs) in jejunal cells was measured using an adaptation of the alkaline elution methodology. In mice treated with WR-3689 (400 or 800 mg/kg) 30 min prior to whole-body irradiation with 10 Gy there was no significant reduction in the number of DNA SSBs induced either in samples of the jejunum or in the cycling crypt cells, providing further evidence that there is no simple relationship between the modification of DNA SSBs and the survival of jejunal stem cells.

Amifostine↗
PubMed1989

The presence of Sjögren's syndrome is a major determinant of the pattern of interstitial lung disease in scleroderma and other connective tissue diseases.

A number of patients with scleroderma, Sjögren's syndrome and other connective tissue diseases (CTD) were assessed to ascertain the prevalence of respiratory abnormalities as defined by bronchoalveolar lavage (BAL), standard respiratory function studies and gallium scan of the lung, and the relationship of these abnormalities to the presence or absence of dyspnea. These results suggest that respiratory symptoms are very common in CTD and in scleroderma, particularly if Sjögren's syndrome is also present. Our findings also suggest the presence of 2 patterns of interstitial lung involvement in scleroderma. In scleroderma alone this appears to be characterized by the presence of increased neutrophil proportions in the BAL, decreased DLCO, and no increase in gallium uptake within the lung. Where scleroderma is associated with Sjögren's syndrome, there is an increase in the proportion of lymphocytes in the BAL and respiratory symptoms are very prominent, the latter associated with an increase in gallium uptake within the lung. This suggests that Sjögren's is a major determinant of the pattern of interstitial lung disease seen in CTD.

Bronchoalveolar Lavage Fluid↗
PubMed1989

Fat embolism in acute pancreatitis.

A patient who developed progressive hypoxemia and multiple system failure during the course of acute pancreatitis is described. Autopsy showed fat emboli to the lungs, kidneys, and heart, as well as multiple petechial hemorrhages in the brain. We conclude that fat embolism should be considered in the differential diagnosis of progressive hypoxemia in patients with acute pancreatitis.

Acute Disease↗
PubMed1989

Radioprotection of cultured mammalian cells by the aminothiols WR-1065 and WR-255591: correlation between protection against DNA double-strand breaks and cell killing after gamma radiation.

We compared the effects of the radioprotective aminothiols WR-1065 and WR-255591 on the induction of DNA double-strand breaks (DSBs) and on the survival of aerated Chinese hamster ovary cells exposed to 60Co gamma radiation. DSBs were measured using the pH 9.6 neutral elution method. In agreement with earlier studies, protection factors for both drugs measured using the end point of clonogenic cell survival were significantly greater than the protection factors for DSB induction when DSBs were measured after gamma-ray doses ranging from 20 to 90 Gy. However, when DSBs and cell survival measurements were made on the same cell populations after low radiation doses (between 3 and 30 Gy) using the replicate plating method, there appeared to be a close correlation between the modification of DSB induction and the modification of cell survival produced by both drugs. The major influence accounting for the differences between these and previously obtained results appears to be the range of radiation doses used, suggesting that protection against DSB induction is radiation-dose dependent.

Animals↗
PubMed1989

Adrenal myelolipomatous nodules mimicking adrenal neoplasms: report of three cases.

The authors describe three cases of adrenal myelolipoma. In the first two, unilateral adrenal masses, assumed to represent adrenal neoplasms, were found during urologic examination; the correct diagnosis was made by frozen-section examination during operation. The third case involved bilateral adrenal lesions diagnosed at autopsy in a patient suspected to have metastatic cancer. Histologic, immunohistochemical and electron microscopic studies revealed polyclonal lesions composed of hematopoietic cells and fat cells. Radiologic recognition and fine-needle biopsy of these lesions are important to avoid unnecessary surgery in asymptomatic cases. Since the lesions cannot be regarded as true neoplasms, the authors suggest that the name myelolipoma should be replaced by the term myelolipomatous nodule.

Adenoma↗
PubMed1988

Cholecystectomy and adenomatous polyps of the colon in women.

The relationship between prior cholecystectomy and colon cancer in women has been a subject of recent research interest. No study has yet reported on cholecystectomy and adenomatous polyps, a precursor lesion for most colon cancers. This pilot case-control study interviewed 245 women who had undergone colonoscopy between 1983 and 1985 at Columbia-Presbyterian Medical Center with a structured telephone-administered questionnaire. Fifty-six were colon cancer cases, 105 were adenomatous polyp (AP) cases, and 84 were controls (without colonic neoplasia). Adjusted for age and educational attainment, the odds ratio for prior cholecystectomy among colon cancer cases compared to controls was 1.79 (95% confidence limits, 0.59 to 5.44) and 2.26 for right-sided colon cancer cases (95% confidence limits, 0.61 to 8.42). Despite a lack of statistical power, these estimates are consistent with earlier reports. The odds ratio for adenomatous polyp cases was 1.02 (95% confidence limits, 0.40 to 2.64), suggesting no association between prior cholecystectomy and adenomatous polyps. These preliminary findings are currently being explored in a large-scale case-control study.

Aged↗
PubMed1988

Experimental interstitial keratitis induced by Onchocerca volvulus antigens.

To elucidate the pathogenic mechanisms involved in onchocercal sclerosing keratitis in humans, we developed a model of onchocercal interstitial keratitis in guinea pigs. Onchocerca volvulus antigens injected intrastromally into corneas of preimmunized Hartley guinea pigs induced an intense stromal keratitis with corneal edema, neovascularization, and infiltration with acute and chronic inflammatory cells. This reaction subsided after two weeks. Repeated intrastromal injection resulted in an exacerbation of the keratitis and ultimately in residual scarring. These findings are consistent clinically and histopathologically with the chronic interstitial keratitis observed in humans. To define which antigens induce the corneal reaction, O volvulus antigens were separated by molecular sieve chromatography and injected intrastromally. The highest activity was shown to reside in the fraction containing molecules of intermediate molecular weight. This model will be useful in defining O volvulus antigens and their role in sclerosing keratitis as well as in elucidating the immune mechanisms involved.

Animals↗
PubMed1988

Mitoxantrone-induced DNA damage in leukemia cells is enhanced by treatment with high-dose arabinosylcytosine.

In a phase II study, patients with chronic myelogenous leukemia in blast crisis (CML-BC) were treated with intravenous (IV) mitoxantrone (5 mg/m2 per day given over 30 min x 5 days and high-dose arabinosylcytosine (ara-C) (3 g/m2 IV q 12 h x 6). The effect of this treatment on DNA damage was studied in the leukemia cells of four patients using the alkaline elution technique modified to measure DNA in unlabeled human cells. A fluorescence assay using Hoechst 33258 dye was applied for the determination of eluted DNA. After a single infusion of mitoxantrone, neither frank nor protein-associated single-strand breaks (SSB) were observed. Even repeated treatment with mitoxantrone on 3 consecutive days did not induce significant SSB. However, after the combined sequential infusion of ara-C and mitoxantrone the DNA elution pattern changed, showing significant DNA damage. SSB remained apparent after 24 h and increased with subsequent doses of ara-C and mitoxantrone. Studies of other patients treated with ara-C alone did not reveal significant SSB (n = 5). Following mitoxantrone infusion the median peak concentrations of intracellular ara-CTP (the triphosphate of ara-C) exceeded 900 microM, a value greater than that observed in CML-BC patients receiving ara-C alone (230 microM, n = 15, P less than 0.02). The present study shows the applicability of the alkaline elution method for the assay of DNA damage in vivo. The enhanced DNA damage after combined treatment with mitoxantrone and high-dose ara-C suggests a synergistic drug effect.

Adult↗