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D Murray

Publications and source records attributed to D Murray.

At least 253 records · Page 14Linked to original sources
PubMed1988

Radioprotectors in tumor radiotherapy: factors and settings determining therapeutic ratio.

WR-2721 and DDC have been used most frequently in our studies on radioprotective agents. WR-2721 was a much more potent radioprotector of murine normal tissues, both against early and late injuries of several organs and tissues, than was DDC. Protection factors for WR-2721 usually ranged between 1.5 and 2.5. Both agents protected solid murine tumors only minimally. While WR-2721 increased therapeutic ratios commonly, DDC did so only rarely. Micrometastatic foci were amenable to radioprotection more than established solitary tumors. Additional factors that influenced the degree of therapeutic benefit included dose of WR-2721, dose of irradiation (single versus fractionated), and time of WR-2721 administration in relation to radiation delivery. The ability of WR-2721 to prevent radiation-induced immunosuppression, metastatic spread, and carcinogenesis are additional benefits in the therapeutic use of this agent. Our current research on the improvement of radioprotectors for therapeutic use is focused on (a) a search for new radioprotective agents that are equal to or better than WR-2721 but less toxic and/or more specific for normal tissue, (b) understanding the basic mechanisms of action of these radioprotective agents at the molecular level, both in cells and tissues, and thus understanding the mechanisms leading to selective or preferential radioprotection of normal tissues, and (c) in vitro testing of primary human tumor cultures for their (non)susceptibility to radioprotection.

Amifostine↗
PubMed1988

Variations in the spectrum of lesions produced in the DNA of cells from mouse tissues after exposure to gamma-rays in air-breathing or in artificially anoxic animals.

Gamma-ray-induced DNA-protein crosslinks (dpc) are preferentially induced in cultured cells irradiated at very low oxygen tensions (Meyn et al. 1987). Since some cells within mouse tumors may be radiobiologically hypoxic, dpc may also be induced in such cells after irradiation in vivo. To examine this possibility, mice bearing either an FSa or NFSa fibrosarcoma in their hind legs were whole-body irradiated either while breathing atmospheric oxygen or 15 min after cervical dislocation, which induces uniform anoxia. DNA single-strand breaks (ssb) and dpc were then assayed both in tumors and normal tissues by alkaline elution. The level of dpc was inferred from the observed increase in ssb yield after digestion of the cell lysates with proteinase K. In addition, cell suspensions were irradiated in vitro, on ice, exposed to atmospheric oxygen tensions. Few dpc were detected in the DNA from tumor cells irradiated in vitro; however, in cells from both FSa and NFSa tumors irradiated in situ there was a significant level of protein-concealed ssb, and thus of dpc. These data are most likely the result of the relative hypoxia of a proportion of cells from both the FSa and NFSa tumor in the air-breathing animals. Induction of dpc was further enhanced in the DNA from tumor cells irradiated under anoxic conditions. A significant level of dpc was also observed in jejunal and spleen cells irradiated in vivo; however, since a significant level of protein-concealed breaks was also observed in cells irradiated in vitro, oxygenation appears not to be the only parameter capable of modifying the proportion of protein-concealed ssb, and the effects of proteinase K on the DNA elution rate for normal mouse tissues may be complex.

Aerobiosis↗
PubMed1988

Radioprotection of cultured Chinese hamster ovary cells by WR-255591.

We examined the radioprotective effect of the aminothiol WR-255591 and its phosphorothioate derivative WR-3689 on aerated cultured Chinese hamster ovary cells. At concentrations up to 10 mmol dm-3, WR-3689 afforded little protection from the lethal effects of gamma-radiation. The free thiol WR-255591, on the other hand, efficiently protected these cells, giving a protection factor (PF) for cell survival of 2.3 at a concentration of 6 mmol dm-3. The effects of WR-255591 on the induction and rejoining of gamma-ray-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were measured using alkaline (pH 12.1) and neutral (pH 7.0 or 9.6) elution, respectively. PFs calculated from these data were compared with the PFs measured for cell survival. WR-255591 (6 mmol dm-3) protected against the induction of both DNA ssb and dsb; however, the magnitude of the modification of both ssb (PF of 1.23) and dsb (PF of 1.83 at pH 7.0 and 1.70 at pH 9.6) was less than that for cell survival (PF of 2.3) measured under identical conditions (irradiation on ice). Treatment of cells with WR-255591 prior to irradiation retarded the subsequent rate of ssb rejoining but had no effect on dsb rejoining. Postirradiation treatment with the drug slightly retarded ssb rejoining but had no effect on cell survival. The observation of lower PFs for DNA strand breaks than for cell survival suggests that radioprotection by WR-255591 probably does not result from a uniform decrease in the induction of all types of DNA lesions. Rather, the drug may differentially protect against the induction of subclasses of DNA damage--which could also explain the effects on the kinetics of ssb rejoining--and/or enhance cellular recovery processes.

Amifostine↗
PubMed1988

Urine specimen collection with external devices for diagnosis of bacteriuria in elderly incontinent men.

We determined the validity of using external devices for urine specimen collection from 24 elderly incontinent men residing in a nursing home by collecting three sequential specimens, two with external devices and then one by catheterization. The positive predictive value of organisms isolated in quantitative counts of greater than or equal to 10(5) CFU/ml in external devices for bladder bacteriuria was 86% for either sterile or clean collecting devices and 93% for the same organism in two consecutive specimens. The negative predictive value for organisms present in quantitative counts of less than 10(5) CFU/ml was 90% for both sterile and clean devices and 86% when the organism was present in both specimens. Contamination in external collection devices was not influenced by whether the device was clean or sterile, circumcision of the resident, or duration of time between device application and specimen collection. These data suggest that urine specimens collected by ward nursing staff with external devices are reliable for the diagnosis of bacteriuria in this patient population.

Aged↗
PubMed1988

Radioprotection of mouse jejunum by WR-2721 and WR-1065: effects on DNA strand-break induction and rejoining.

WR-2721 and its free-thiol metabolite WR-1065 have been characterized for their ability to protect mouse jejunal cells in vivo from the damaging effects of gamma rays with respect to both cytotoxicity and DNA single-strand break (SSB) induction. SSBs were measured both in the whole jejunal epithelium and in the proliferating crypt cells using an adaptation of the alkaline elution methodology. Protection factors (PFs) were also obtained using the microcolony assay for jejunal crypts. In mice treated with WR-1065 (400 mg/kg) 15 or 30 min prior to irradiation, there was a slight but significant reduction in the initial number of SSBs both in the whole jejunum (PF of between 1.17 and 1.22) and in the proliferating crypt cells (PF of between 1.13 and 1.28). At a dose of 200 mg/kg, the PF for SSBs in the proliferating crypt cells was 1.12 +/- 0.07 while that for crypt-cell survival was approximately 2.0. In mice treated with WR-2721 (400 mg/kg) 15 min prior to irradiation, there was little effect on the initial number of SSBs induced both in the whole jejunum (PF of 1.07 +/- 0.11) and in the proliferating crypt cells (PF of 1.04 +/- 0.07). WR-2721 protected jejunum in the microcolony assay with a much greater PF of 1.8. For each drug the PF for SSBs was therefore always much lower than that indicated by the biological end point under identical conditions. Both drugs also retarded the rate of SSB rejoining in each population of cells. These data suggest that mechanisms such as free-radical scavenging by these drugs may contribute to but not completely explain their protective action. Comparison with data obtained previously with cultured CHO cells supports the idea that the action of these drugs at the DNA lesion level may not be dose-modifying, but may also result in a shift in the spectrum of lesions induced by the radiation.

Amifostine↗
PubMed1988

Induction and rejoining of gamma-ray-induced DNA single- and double-strand breaks in Chinese hamster AA8 cells and in two radiosensitive clones.

The induction and rejoining of gamma-ray-induced DNA strand breaks were measured in a Chinese hamster ovary cell line, AA8, and in two radiosensitive clones (EM9 and NM2) derived from it. The kinetics of recovery from sublethal damage (SLD) and potentially lethal damage (PLD) has previously been characterized in each of these lines [vanAnkeren et al., Radiat. Res., 115, 223-237 (1988)]. No significant differences were observed among the cell lines in the yields of either DNA single-strand breaks (SSBs) or double-strand breaks (DSBs) as assayed by filter elution. Data for SSB rejoining in AA8 and NM2 cells irradiated with 7.5 Gy were fit by a biexponential process (t1/2 values of approximately 4 and 80 min). In comparison, SSB rejoining in EM9 cells was initially slower (t1/2 = 10 min) and a higher level of SSBs was unrejoined 6 h after irradiation. DSB rejoining in AA8 cells assayed at pH 9.6 was also biphasic (t1/2 values of 15 and 93 min), although when assayed at pH 7.0, most (approximately 80%) of the damage was rejoined at a constant rate (t1/2 = 45 min) during the first 2 h. EM9 cells exhibited a slower initial rate of DSB rejoining when assayed at pH 9.6 but showed no difference compared with AA8 cells in DSB rejoining when assayed at pH 7.0. These results indicate that radiosensitive EM9 cells, whose kinetics of recovery from SLD and PLD was the same as that of AA8 cells, have a defect in the fast phase of SSB rejoining but no measurable defect in DSB rejoining. Conversely, NM2 cells, which displayed a reduced shoulder width on their survival curve and decreased recovery from SLD, had no demonstrable defects in the rate or extent of rejoining of DSBs or SSBs. When compared with the SLD and PLD data reported previously, these results suggest that there is no direct correlation between either of these recovery processes and the rejoining of SSBs or DSBs as assayed here.

Animals↗
PubMed1988

Local anesthetics.

Explore the source record for details and available documents.

Anesthetics, Local↗
PubMed1988

Nitrous oxide: cardiovascular effects in infants and small children during halothane and isoflurane anesthesia.

Two-dimensional and pulsed Doppler echocardiography were used to measure cardiovascular function in 31 unmedicated infants and small children. In 15 patients, the cardiovascular effects of equipotent levels of halothane were compared with and without N2O. In 16 patients, the cardiovascular effects of isoflurane with and without N2O were compared. Prior to anesthesia induction, cardiovascular measurements of heart rate (HR), mean blood pressure (MBP), and two-dimensional and pulsed Doppler echocardiography were recorded. The echocardiographic measurements were used to determine cardiac output (CO), stroke volume (SV), ejection fraction (EF), and left ventricular end-diastolic and end-systolic volume (LVEDV and LVESV). Twenty minutes after mask inhalation induction with halothane or isoflurane with N2O and O2 (3:2 liters/min), cardiovascular measurements were repeated with end-expired halothane or isoflurane maintained at 0.9 MAC. A third set of cardiovascular data was collected 10 minutes after the discontinuation of N2O, with inspired isoflurane or halothane levels in O2 (5 liters/min) increased to maintain 1.5 MAC end-expired levels. Ventilation was controlled throughout the study period and the study was completed before intubation and the start of elective surgery. Heart rate and MBP decreased to similar degrees below awake levels in both patient groups during N2O with halothane or isoflurane. When N2O was discontinued and end-expired levels of halothane or isoflurane increased, MBP remained at levels observed during N2O-O2 with halothane or isoflurane. Heart rate increased during isoflurane in O2. Cardiac output decreased significantly and similarly below awake levels during both halothane of isoflurane with and without N2O.

Blood Pressure↗
PubMed1988

Operational criteria for the determination of suicide.

Suicide is an important public health problem for which we have an inadequate public health database. In the United States, decisions about whether deaths are listed as suicides on death certificates are usually made by a coroner or medical examiner. These certification decisions are frequently marked by a lack of consistency and clarity, and laws and procedures for guiding these decisions vary from state to state and even from county to county. Without explicit criteria to aid in this decision making, coroners or medical examiners may be more susceptible to pressures from families or communities not to certify specific deaths as suicide. In addition, coroners or medical examiners may certify similar deaths differently at different times. The degree to which suicides may be underreported or misclassified is unknown. This makes it impossible to estimate accurately the number of deaths by suicide, to identify risk factors, or to plan and evaluate preventive interventions. To remedy these problems, a working group representing coroners, medical examiners, statisticians, and public health agencies developed operational criteria to assist in the determination of suicide. These criteria are based on a definition of suicide as "death arising from an act inflicted upon oneself with the intent to kill oneself." The purpose of these criteria is to improve the validity and reliability of suicide statistics by: (1) promoting consistent and uniform classifications; (2) making the criteria for decision making in death certification explicit; (3) increasing the amount of information used in decision making; (4) aiding certifiers in exercising their professional judgment; and (5) establishing common standards of practice for the determination of suicide.

Coroners and Medical Examiners↗
PubMed1988

Visual neglect and extinction: a new test.

A new computerized test for visual neglect and extinction was developed and evaluated by testing twenty-five patients with right-hemisphere cerebrovascular accidents. The test consisted of a series of unilateral or bilateral lights on a semicircular array to which the subject responded by pushing a button. A computer controlled the sequence of stimuli and stored the responses. Results of the computer test were compared to conventional occupational therapy and beside clinical tests. Extinction was present in 16 subjects on the computerized test, and in 11 on the clinical test. Neglect was present in 13 subjects on the computerized test, in seven subjects on the occupational therapy test, and in five subjects on the clinical test. The computerized test was more sensitive than the other tests. On both computerized and clinical testing, all subjects with left-sided neglect also had left-sided extinction, but not all subjects with extinction had neglect. Neglect may represent a more severe manifestation of an underlying perceptual defect that produces both neglect and extinction.

Adolescent↗
PubMed1988

Radioprotective action of WR-1065 on radiation-induced DNA strand breaks in cultured Chinese hamster ovary cells.

We have examined the radioprotective effect of WR-1065 on cultured Chinese hamster ovary cells. The effects of the drug on the induction and rejoining of gamma-ray-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) were measured using alkaline (pH 12.1) and neutral (pH 7.0) elution, respectively. Molecular protection factors (PFs) calculated from these data allowed us to determine whether the degree of modification of strand breakage accurately predicted the PFs measured using the biological end point of cell survival. The drug did protect against the induction of both SSBs and DSBs, although to an extent that did not appear to fully account for the degree of radioprotection in terms of cell killing measured under identical conditions. It is therefore unlikely that radioprotection by WR-1065 occurs simply as a consequence of a general lowering of all types of gamma-ray-induced DNA lesions, and it is possible that the drug could differentially protect against the induction of subsets of these DNA lesions. The rate of SSB rejoining was retarded following preirradiation treatment of cells with WR-1065, but there was no effect on DSB rejoining. Postirradiation treatment with WR-1065 also appeared to retard SSB rejoining but without an accompanying effect on either DSB rejoining or cell survival; however, this effect was largely reversed by the addition of catalase and was therefore probably a result of H2O2 generated by autoxidation of the drug. Based on these observations, it would appear that the molecular actions of aminothiol radioprotective compounds that lead to reduced cell killing are much more complex than previously thought.

Animals↗
PubMed1988

Fatal pulmonary emboli in hospitalized patients. An autopsy study.

To determine the accuracy of the antemortem diagnosis of major pulmonary embolism, we reviewed 1276 autopsy reports at St Michael's Hospital, Toronto, from 1980 to 1984. Of 44 patients identified with major pulmonary embolism as the cause of death or a major factor contributing to it, 14 (31.8%) had the diagnosis suspected before death. We could not find any distinctive features separating these patients from those in whom the diagnosis of pulmonary embolism was not suspected before death. We conclude that major pulmonary embolism is still underdiagnosed in hospitalized patients, despite the availability of lung scanning and pulmonary angiography.

Cause of Death↗
PubMed1988

Cell survival and recovery processes in Chinese hamster AA8 cells and in two radiosensitive clones.

Cell survival and recovery after gamma irradiation were investigated in a Chinese hamster ovary cell line (AA8) and in two radiosensitive clones (EM9 and NM2) derived from it. When analyzed by the multitarget and linear-quadratic equations, the dose-response curves for survival of both EM9 and NM2 cells, compared with AA8 cells, were characterized by a decreased magnitude of the shoulder or single-hit region (as reflected by Dq or alpha, respectively) but no difference in the terminal slope or double-hit region (as reflected by DO or beta, respectively). Recovery from sublethal damage (SLD) and potentially lethal damage (PLD) was measured in the three cell lines to examine the relationship between the shoulder width of the survival curve and the magnitude of cellular recovery. NM2 cells exhibited a reduced shoulder on their survival curve and a reduced capacity for SLD recovery, compared with AA8 cells, after equitoxic doses of radiation. EM9 cells, which also had a reduced shoulder on their survival curve, displayed the same rate and extent of recovery as AA8 cells for both SLD and PLD. PLD recovery, as assayed in fed plateau-phase NM2 cells by delayed plating, occurred with slower initial kinetics but to the same final extent as that in AA8 cells, resulting in modification of both the shoulder and the slope of the survival curve. However, PLD recovery, as assayed in log-phase NM2 cells by postirradiation treatment with hypertonic salt, was normal and affected predominantly the slope of the survival curve. These data demonstrate that although both SLD and PLD recovery play a role in determining cell survival, cell-survival curve parameters may not always be useful in predicting cellular recovery capacity.

Animals↗
PubMed1987

DNA cross-linking following exposure to cis-platinum in primary and serially passaged cultured cells derived from two murine fibrosarcomas.

We compared the kinetics of the repair of total (ISC plus DPC) cross-links and of proteinase-resistant (ISC) cross-links in cultured cells derived from two murine fibrosarcoma tumors, FSA and NFSA, after treatment with cis-platinum (cis-DDP), using a modification of the alkaline elution technique. The two tumors had previously been characterized for their response to cis-DDP in vivo; FSA cells gradually removed cross-links from their genome, whereas the NFSA cells showed no capacity to repair these lesions. The aim of the present study was to establish whether treatment of cells from these same two tumors grown under controlled culture conditions would affect either the nature of the lesions induced by cis-DDP or the kinetics of repair of these lesions when compared with tumors treated with cis-DDP in vivo. The culture conditions represent two situations: in the first, the cells in culture approximated the proportion of tumor and normal host cells present in vivo, and in the second, the normal host cells had been eliminated by subculturing to produce cultures composed entirely of tumor cells. All cells were exposed to cis-DDP (either 10 or 20 micrograms/ml) for 1 h. The relative amounts of total cis-DDP-induced DNA crosslinks and of ISCs were then determined at various times after treatment. The results show that there was little difference in the behavior of these cultured cells compared to the in vivo response of the tumor from which they were derived. For FSA, each cell culture exhibited a capacity to repair DNA cross-links comparable to that of the tumor in vivo. For NFSA, the passaged cells again paralleled the behavior of that tumor in vivo, although in this case by showing no measurable capacity to repair cross-links. The absence of a significant repair response in the NFSA tumor therefore appears to be an intrinsic characteristic of these tumor cells.

Animals↗
PubMed1987

Applicability of the alkaline elution procedure as modified for the measurement of DNA damage and its repair in nonradioactively labeled cells.

We have critically evaluated various modifications of the alkaline elution methodology that were required to adapt the method for measuring DNA damage in cells from animal tissues treated in vivo. These modifications involved the use of a fluorometric assay for the eluted DNA using the dye Hoechst 33258, which in turn required the use of a different combination of filter and lysis conditions than those used in conventional assays. This protocol was compared with the conventional protocols by examining the DNA damage produced in cultured Chinese hamster ovary cells after treatment with three agents (gamma-rays, cis-dichlorodiammineplatinum (DDP) and trans-DDP) that differ widely in the type and repairability of the DNA lesions that they induce. For both gamma-rays and trans-DDP, the results obtained by the various protocols were equivalent with respect to the amount, type, and rate of repair of the DNA damage produced. On the other hand, for cis-DDP, where the repair time for DNA crosslinks was significantly long relative to the cell-cycle time, DNA replication appeared to be a potentially complicating factor in the measurement of crosslink repair. However, even after treatment of rapidly dividing cultured cells, where any discrepancy between the radioactivity and Hoechst assays due to DNA replication should be maximal, the resulting difference in the amount of repair measured using the two assays was relatively small. Finally, in experiments using cis-DDP and trans-DDP, the data suggested that when polycarbonate and polyvinyl chloride filters were compared using the same cell lysis conditions, their relative sensitivity to detect DNA-protein versus DNA-interstrand crosslinking were comparable. The modified alkaline elution protocol for the measurement of DNA damage in vivo therefore appears, in most cases, to produce results comparable with those obtained by the conventional protocols.

Animals↗
PubMed1987

Induction and repair of DNA single-strand breaks in EM9 mutant CHO cells treated with hydrogen peroxide.

In this study we investigated the induction and rejoining of DNA single-strand breaks (SSBs) produced by H2O2 in the repair-deficient EM9 mutant Chinese hamster ovary (CHO) cell line. The effect of the poly(ADP-ribose)-transferase inhibitor 3-aminobenzamide (3-ABA) on SSB-rejoining and on cell killing was also evaluated. Results were compared with those obtained previously with the parent cell line (AA8). Cells were treated with H2O2 on ice for 1 h, after which they were either harvested or allowed to repair their damage at 37 degrees C either in the presence or absence of 3-ABA (5 mM). The cells were then assayed either for survival using a colony-forming assay or for their level of DNA SSBs using alkaline elution. EM9 cells were somewhat more sensitive than AA8 cells to the cytotoxic effects of H2O2. However, because the repair mutant showed slightly lower levels of DNA SSBs than did its parental cell line, this sensitivity could not be explained on the basis of alterations in initial damage. The rejoining of the H2O2-induced DNA SSBs followed exponential kinetics in both cell lines; however, EM9 cells rejoined these breaks at a slower rate (t1/2 of 10 min) than did AA8 cells (t1/2 of 5 min). The increased sensitivity of the EM9 cells therefore appears to correlate with a reduced ability to remove these lesions from their DNA. As previously demonstrated for the AA8 cells, 3-ABA treatment resulted in both a retardation of the removal of H2O2-induced DNA SSBs and potentiation of cytotoxicity in the EM9 cells. However, the degree of these effects were similar for both AA8 and EM9 cells. These data provide further evidence that the cytotoxic effects of low concentrations of H2O2 are mediated by damage to DNA, and suggest that the rate at which DNA SSBs are rejoined is important for cell survival.

Animals↗
PubMed1987

Pancreatic endocrine tumour producing growth hormone-releasing hormone associated with multiple endocrine neoplasia type I syndrome.

We report the first documentation of GHRH production by a tumour associated with proven multiple endocrine neoplasia (MEN). A 30-year-old woman had hypoglycaemia, hyperparathyroidism, and pituitary adenoma with hyperprolactinaemia. Serum growth hormone elevation was attributed to hypoglycaemia but plasma GHRH was elevated. Subtotal pancreatectomy revealed multiple endocrine tumours and nesidioblastosis. Immunohistochemistry demonstrated insulin, glucagon, and somatostatin in several tumours. GHRH was localized in the largest one and was released from that tumour in vitro. Post-operative plasma GH returned to normal. Excess secretion of humoural factors by one tumour may stimulate growth of other tumours in MEN syndromes. The prevalence of GHRH in MEN-I tumours remains to be established.

Adult↗