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J L Moran

Publications and source records attributed to J L Moran.

50 records · Page 3Linked to original sources
PubMed1996

Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and a potential role for modulation of apoptosis in benzene toxicity.

The role of cell-specific metabolism in benzene toxicity was examined in both murine and human bone marrow. Hemopoietic progenitor cells and stromal cells are important control points for regulation of hemopoiesis. We show that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a high peroxidase/nicotanimide adenine dinucleotide phosphate, reduced [NAD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hydroquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 activity in human stromal cultures vary as a function of time in culture, with peroxidase activity decreasing and NQO1 activity increasing with time. Peroxidase activity and, more specifically, myeloperoxidase, which had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34+ progenitor cells. This provides a metabolic mechanism whereby phenolic metabolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Consequences of a high peroxidase/NQO1 ratio in HL-60 cells were shown to include hydroquinone-induced apoptosis. Hydroquinone can also inhibit proteases known to play a role in induction of apoptosis, suggesting that it may be able to inhibit apoptosis induced by other stimuli. Modulation of apoptosis may lead to aberrant hemopoiesis and neoplastic progression. This enzyme-directed approach has identified target cells of the phenolic metabolites of benzene in bone marrow and provided a metabolic basis for benzene-induced toxicity at the level of the progenitor cell in both murine and human bone marrow.

Animals↗
PubMed1996

Induction of apoptosis by benzene metabolites in HL60 and CD34+ human bone marrow progenitor cells.

Two cell types, HL60 human promyelocytic leukemia cells and CD34+ human bone marrow progenitor cells, were used as model systems to explore a possible role for apoptosis in the myelotoxicity of the phenolic metabolites of benzene. HL60 cells were treated with either phenol, catechol, hydroquinone, or 1,2,4-benzenetriol and then stained with Hoechst 33342 and propidium iodide and subjected to fluorescent microscopy. Cells with nuclear condensation and fragmentation were scored as apoptotic, and etoposide (40 microM) was used as a positive control. Catechol, 1,2,4-benzenetriol, and hydroquinone induced marked time- (0-24 hr) and concentration- (25-100 microM) dependent apoptosis, whereas phenol (750 microM) did not. Under these conditions, no significant necrosis was observed. The induction of apoptosis was confirmed by internucleosomal cleavage of DNA, assessed by agarose gel electrophoresis. CD34+ cells treated with etoposide (40 microM) or hydroquinone (50 microM) for 18 hr were stained and subjected to fluorescent microscopy as above. The percentage of cells exhibiting nuclear condensation and/or fragmentation as well as high intensity staining significantly increased in both cases. The induction of apoptosis was confirmed using a terminal deoxynucleotidyl transferase assay. These data show that apoptosis can be induced in both HL60 and CD34+ human bone marrow progenitor cells by benzene metabolites. The ability of phenolic metabolites of benzene to induce apoptosis in human bone marrow progenitor cells may contribute to benzene myelotoxicity.

Adult↗
PubMed1995

Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study.

OBJECTIVE: To compare the efficacy of parenteral magnesium sulfate vs. amiodarone in the therapy of atrial tachyarrhythmias in critically ill patients. DESIGN: Prospective, randomized study. SETTING: Multidisciplinary intensive care unit (ICU) at a university teaching hospital. PATIENTS: Forty-two patients, 21 medical and 21 surgical, of mean (SD) age 67 +/- 15 yrs and mean Acute Physiology and Chronic Health Evaluation II score of 22 +/- 6, with atrial tachyarrhythmias (ventricular response rate of > or = 120 beats/min) sustained for > or = 1 hr. INTERVENTIONS: After correction of the plasma potassium concentration to > or = 4.0 mmol/L, patients were randomly allocated to treatment with either a) magnesium sulfate 0.037 g/kg (37 mg/kg) bolus followed by 0.025 g/kg/hr (25 mg/kg/hr); or b) amiodarone 5 mg/kg bolus and 10 mg/kg/24-hr infusion. Therapeutic plasma magnesium concentration in the magnesium sulfate group was 1.4 to 2.0 mmol/L. Therapeutic end point was conversion to sinus rhythm over 24 hrs. MEASUREMENTS AND MAIN RESULTS: At study entry (time 0), initial mean ventricular response rate and systolic blood pressure were 151 +/- 16 (SD) beats/min and 127 +/- 30 mm Hg in the magnesium sulfate group vs. 153 +/- 23 beats/min and 123 +/- 23 mm Hg in the amiodarone group, respectively (p = .8 and .65). Plasma magnesium (time 0) was 0.84 +/- 0.20 vs. 1.02 +/- 0.22 mmol/L in the magnesium and amiodarone group, respectively (p = .1). Eight patients had chronic dysrhythmias (magnesium 3, amiodarone 5). Excluding the two patient deaths (amiodarone group, time 0 + 12 to 24 hrs), no significant change in systolic blood pressure subsequently occurred in either group. In the magnesium group, mean plasma magnesium concentrations were 1.48 +/- 0.36, 1.82 +/- 0.41, 2.16 +/- 0.45, and 1.92 +/- 0.49 mmol/L at time 0 + 1, 4, 12 and 24 hrs, respectively. By logistic regression, the probability of conversion to sinus rhythm was significantly better for magnesium than for amiodarone at time 0 + 4 (0.6 vs. 0.44), 12 (0.72 vs. 0.5), and 24 (0.78 vs. 0.5) hrs. In patients not converting to sinus rhythm, a significant decrease in ventricular response rate occurred at time 0 + to 0.5 hrs (mean decrease 19 beats/min, p = .0001), but there was no specific treatment effect between the magnesium and the amiodarone groups; thereafter, there was no significant reduction in ventricular response rate over time in either group. CONCLUSIONS: Intravenous magnesium sulfate is superior to amiodarone in the conversion of acute atrial tachyarrhythmias, while initial slowing of ventricular response rate in nonconverters appears equally efficacious with both agents.

APACHE↗
PubMed1994

Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock.

OBJECTIVE: To characterise the plasma cortisol profile and adreno-cortial responsiveness (short Synacthen test) of patients in septic shock. DESIGN: Retrospective assessment using case-notes and ICU charts. SETTING: University teaching hospital ICU. PATIENTS: 68 septic shock patients with plasma cortisol and/or short Synacthen test measured at ICU-admission or onset of shock post ICU-admission. Patients were identified from a total population of 155 patients who had PCL and/or SST measured over a 4.5 year period. INTERVENTION: None. MEASUREMENTS AND RESULTS: Patients with septic shock had a plasma cortisol ranging from 210-8900 nmol/l and mortality of 56%. There were 22 (32%) below (low) and 46 (68%) above (high) a 'critical' plasma cortisol of 500 nmol/l. Using stepwise logistic regression, mortality was adequately predicted by and increased with, increasing plasma cortisol and onset of shock remote from ICU-admission. Short Synacthen tests were available in 33 patients: 11 responders (cortisol increment > 200 nmol/l above baseline 30 min after 0.25 mg intravenous Synacthen) and 22 hypo-responders. Mortality in patients was adequately predicted by and increased with a decrease in cortisol increment post-Synacthen. Thirteen patients (plasma cortisol 606 +/- [SD] 297 nmol/l) had complete haemodynamic profiles before inotropic therapy; no relationship was demonstrated between plasma cortisol and circulatory variables. Follow-up revealed no cases of Addison's disease. CONCLUSIONS: In septic shock, 'hypocortisolaemia' is not uncommon and does not predict a high mortality; adrenocortical hypo-responsiveness may be associated with poor outcome.

Adrenal Cortex↗
PubMed1993

Management of atrial tachyarrhythmias in the critically ill: a comparison of intravenous procainamide and amiodarone.

OBJECTIVE: To compare the efficacy and safety of intravenous (IV) amiodarone and procainamide for the treatment of atrial tachyarrhythmias (AT) in the critically ill. DESIGN: In this prospective study, patients were allocated to drug treatment on the basis of hospital identification number, even for procainamide and odd for amiodarone. SETTING: Patients were recruited from a teaching hospital ICU and did not include postoperative cardiac patients. PATIENTS AND PARTICIPANTS: 26 patients with AT sustained for at least 1 h and failure to respond to correction of possible precipitating factors were entered in the study. Exclusion criteria were systolic blood pressure (SBP) < 80 mmHg, and known hypersensitivity to either drug. Two patients with chronic atrial fibrillation (who received amiodarone) were later excluded from the analysis. In the final analysis, 14 patients received procainamide and 10 amiodarone. INTERVENTIONS: IV amiodarone (3 mg/kg followed by 10 mg/kg/24 h, with repeat dose of 3 mg/kg at 1 h if no response) or i.v. procainamide (10 mg/kg at 1 mg/kg/min followed by infusion of 2-4 mg/min for 24 h, with repeat dose of 5 mg/kg at 1 h if no response). MEASUREMENTS AND RESULTS: In the procainamide group 10/14 (71%) and in the amiodarone group 7/10 (70%) had converted to sinus rhythm by 12 h. There was no significant difference in response between the groups. SBP was not significantly different from baseline after administration of either drug. CONCLUSIONS: Procainamide and amiodarone appear to be safe and equally effective in the treatment of AT in the critically ill.

Aged↗
PubMed1993

Epinephrine as an inotropic agent in septic shock: a dose-profile analysis.

OBJECTIVE: To characterize the acute actions and physiologic dose profile of epinephrine, as a single inotrope, in patients with septic shock. DESIGN: Prospective clinical study. The relationship between epinephrine dose and cardiovascular variables was analyzed using repeated-measures analysis of variance. SETTING: ICU in a university teaching hospital. PATIENTS: Eighteen patients with septic shock, mean age 64 +/- 8 (SD) yrs, and with a mean admission Acute Physiology and Chronic Health Evaluation (APACHE II) score of 23 (range 14 to 35). INTERVENTIONS: Initial volume loading and the measurement of a baseline hemodynamic profile were followed by the administration of an epinephrine infusion at 3 microgram/min with subsequent increments of 3 micrograms/min and the determination of a hemodynamic profile after each dose increment. Therapy was titrated to clinical goals of perfusion and restoration of premorbid systolic arterial BP. MEASUREMENTS AND MAIN RESULTS: After volume loading, mean hemodynamic indices were as follows: mean arterial pressure (MAP) 62 +/- 7 mm Hg; cardiac index 3.8 +/- 1.1 L/min/m2; left ventricular stroke work index 25 +/- 11 g.m/m2; oxygen delivery (Do2) index 460 +/- 168 mL/min/m2; and oxygen consumption (VO2) index 165 +/- 64 mL/min/m2. In the dose range of 3 to 18 microgram/min, epinephrine produced linear increases in average heart rate, MAP, cardiac index, left ventricular stroke work index, stroke volume index, VO2, and DO2. No effect was noted on pulmonary artery occlusion pressure (PAOP), mean pulmonary arterial pressure, or systemic vascular resistance index. CONCLUSIONS: Epinephrine increases DO2 in septic shock by increasing cardiac index without an effect on systemic vascular resistance index or PAOP.

Aged↗
PubMed1992

Inspiratory work imposed by continuous positive airway pressure (CPAP) machines: the effect of CPAP level and endotracheal tube size.

Inspiratory work imposed by Continuous Positive Airway Pressure (CPAP) machines has been a matter of concern. The imposed inspiratory work of CPAP machine circuits (Wcir) and the effect of the total breathing apparatus with endotracheal tube (ETT) and connector included in the circuit (Wapp), were measured in three continuous flow (CF) and various configurations of three demand flow (DF) CPAP machines. The performance was assessed at 0, 5, 10 and 15 cmH2O CPAP using a Michigan Instruments Test Lung Model 1600, internal compliance set at 50 ml/cmH2O, driven at square wave inspiratory flows (VI) of 20, 40 and 60 l/min at a tidal volume of 500 ml. Work, expressed in mJ/l, was calculated from the area of pressure-volume loops. Inspiratory work, Wcir and Wapp, was dependent upon the particular CPAP machine, VI and ETT size, but not upon CPAP level, being maximum at VI 601/min and with ETT 7.0 mm i.d. Work values (Wcir) varied from 50 to 325 mJ/l with both CF and DF machines and up to 1100 mJ/l with ETT and connector (Wapp). No consistent advantage of CF over DF machines was demonstrated. There was little advantage of high gas flows (greater than 5 l/min) in various DF circuits. Within an individual machine maximum negative pressures generated during inspiration correlated with both Wcir and Wapp.

Equipment Design↗
PubMed1988

A high flow turbine CPAP system.

A continuous high flow CPAP system incorporating a turbine blower is described. The system achieves inspiratory flow rates of 150 l/min or more by means of reticulated gas flow and inspired oxygen fractions of 0.21-0.95. Positive airway pressure is provided by weighted disc valves and a modified aviation-type CPAP face mask provides electronic communication with the patient. The mobility of the system also enables its use as an intermittent physiotherapy aid. Work of breathing of the system, as assessed by total pressure fluctuations is at a minimum.

Acute Disease↗
PubMed1986

Trends in the severity of self-poisoning.

Of 2947 patients admitted to a district general hospital over an 11-year period for the management of self-poisoning, 148 (5%) required intensive care unit (ICU) treatment. There was a significant increase in the number of self-poisonings admitted each year, whereas the number requiring ICU admission did not change. Therefore the proportion of patients requiring ICU admission fell significantly over the study period (P less than 0.0005). Of 898 patients admitted from 1973 to 1977, 62 (6.9%) were treated in ICU. Of 2049 patients admitted from 1978 to 1983, 86 (4.2%) required ICU treatment. It is felt that this trend is explained by a rise in parasuicidal self-poisonings. The impact of change in drug availability is evident in the significant reduction in ingestion of sedative barbiturates.

Adolescent↗
PubMed1985

A comparison of dopamine, dobutamine and isoproterenol in the treatment of shock.

Twelve patients in shock, defined as being present if the mean arterial blood pressure was less than 60 mm Hg, pulmonary arterial occlusion pressure was 15 mm Hg or greater, urine output was 20 ml or less for 2 consecutive hours, and there was clinical evidence of poor peripheral perfusion, underwent a comparative therapeutic trial with dopamine at 200 micrograms . min-1 and 400 micrograms . min-1 (2.5-5.5 micrograms . kg-1 . min-1), dobutamine 250 micrograms . min-1 and 500 micrograms . min-1 (3.5-7 micrograms . kg-1 . min-1) and isoproterenol 2 micrograms . min-1 and 4 micrograms . min-1 (0.025-0.055 micrograms . kg-1 . min-1). Isoproterenol at 2 micrograms . min-1, produced a significant increase in pulse rate, cardiac output, left ventricular stroke work index and decrease in mean pulmonary blood pressure and pulmonary arterial occlusion pressure and at 4 micrograms . min-1 a significant increase in stroke volume, mixed venous oxygen tension and decrease in right atrial pressure and systemic vascular resistance was also observed. Dopamine at 200 micrograms . min-1 produced a significant increase in cardiac output, pulmonary arterial occlusion pressure and mixed venous oxygen tension and at 400 micrograms . min-1 a significant increase in pulse rate, mean arterial blood pressure mean pulmonary blood pressure, right ventricular stroke work index, right atrial pressure and pulmonary arterial occlusion pressure and decrease in arterial oxygen tension was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗