Search PubMed⌕ Search

Biomedical subjects

D O'Neill

Publications and source records attributed to D O'Neill.

At least 145 records · Page 8Linked to original sources
PubMed1988

Regulation of fetal globin gene expression in human erythroleukemia (K562) cells.

We have analyzed the transcription and induction of fusion globin genes comprised of portions of either gamma and beta globin sequences or gamma and neomycin resistance gene sequences. The analysis of gamma promoter beta and gamma-neo fusion genes indicates that 5' gamma flanking sequences are sufficient for tissue specific expression but not induction in K562 cells. A beta gene containing only the substitution of gamma IVS 2 for beta IVS 2 is expressed and induced when transcripts are analyzed with a 3' probe in contrast to the lack of expression seen with an intact beta gene. Thus, fusion globin genes containing gamma IVS 2 are both expressed and induced indicating that this region may be involved in the response to hemin stimulation, however, the mechanism is unclear. A gamma-neo fusion gene containing the gamma 5' region is expressed but not induced. When an EcoRI-Bg1 II fragment containing the beta 3' enhancer is ligated downstream of the gamma-neo gene this gene is now inducible. Multiple genetic elements are involved in the regulated expression of gamma genes in fetal erythroid cells. These experiments begin to localize these sequences to specific regions within the gamma globin gene.

Enhancer Elements, Genetic↗
PubMed1987

Chronic vascular pulmonary dysplasia associated with neonatal hyperoxia exposure in the rat.

Chronic sequelae of neonatal hyperoxia was studied in male rats exposed to 0.96-1.0 FiO2 for the first 8 days of life. At 58 days of age functional and morphologic cardiopulmonary changes were compared with controls. Right ventricular systolic pressure was measured percutaneously under anesthesia and was increased in the O2 group (29.5 mm Hg +/- 3.1 versus 23.2 mm Hg +/- 3.5, p less than 0.001). Lung and heart weights were similar between groups. Right ventricular weights however were increased in the O2 group (0.197 g +/- 0.023 versus 0.175 g +/- 0.020, p less than 0.001). Air pressure-volume curves were similar but in the O2 rats saline deflation curves were shifted left and maximal fluid lung volumes were greater (14.1 +/- 1.2 versus 12.0 +/- 0.7 ml, p less than 0.001). Pulmonary arteries were perfused at 100 cm H2O with a barium-gel mixture and lungs were fixed at 25 cm H2O with formalin. Microscopic examination of lungs revealed dysplastic changes of alveolar architecture which included irregularly enlarged alveoli and incomplete alveolar septation. Morphometric studies of the lungs showed that the O2 rats had an increased volume proportion of parenchyma (0.865 +/- 0.020 versus 0.850 +/- 0.019, p less than 0.05), increased mean linear intercept (72.3 microns +/- 9.5 versus 53.6 microns +/- 5.0, p less than 0.001), decreased number of alveoli per mm2 (207 +/- 34 versus 319 +/- 39, p less than 0.001) and fewer small arteries (20-200 microns) per mm2 (8.7 +/- 1.3 versus 14.9 +/- 2.4, p less than 0.001). The number of small arteries/100 alveoli was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

A method to determine the true angulation of long bone deformity.

A new method of geometrical analysis is capable of determining bone deformity from routine anteroposterior (AP) and lateral roentgenograms. The maximum angulation may occur in a plane other than the AP or lateral roentgenogram planes. Therefore, the maximum angulation may exceed the apparent angulation seen on routine AP and lateral views. The AP and lateral views will underestimate the true angulation most when the angulation seen on the AP and lateral views is similar.

Bone and Bones↗
PubMed1985

Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery.

Interferons are currently undergoing clinical testing in patients with cancer and other diseases. A variety of routes of administration are being utilized, and there is particular interest in delivery of interferon to the central nervous system. A biphasic decline in plasma concentrations was observed in monkeys following an i.v. bolus, with initial half-times of 15 to 33 min and terminal half-times of 1.7 to 4.6 hours. Total body clearance ranged from 24 to 39 ml/sq. m/min and steady-state volume of distribution was similar to extracellular space. CSF exposure was 1% or less than that of plasma. Intramuscular injections produced lower peak concentrations and more sustained levels, but there was substantial variation in bioavailability (range 19-103%). Levels in the CSF were not detectable for the i.m. route. For intraventricular doses, CSF exposure was 3,000-fold greater than for i.v. doses, despite a 20-fold lower dose.

Animals↗
PubMed1985

Myocardial infarction and the normal arteriogram--possible role of viral myocarditis.

In a prospective study we identified a group of 12 patients diagnosed as having acute myocardial infarction but with electrocardiographic features of non-transmural infarction and serological evidence of recent Coxsackie B infection favouring the possibility of myocarditis. The group included 9 females and 3 males, aged from 38-60 y. Coronary arteriography was carried out in 11 patients. Eight of the 11 patients showed no significant (greater than or equal to 50%) coronary arterial obstruction. We suggest that coronary artery disease did not contribute to the clinical presentation in the majority of these patients and that the likely diagnosis was viral myocarditis in at least 6 of them. We conclude that viral myocarditis may simulate myocardial infarction and contribute to the uncommon but controversial syndrome of myocardial infarction with a normal coronary arteriogram.

Adult↗
PubMed1984

Intrathecally administered m-AMSA in the rhesus monkey.

4'-(9-Acridinylamino)-methanesulfon-m-anisidide (m-AMSA) is an acridine compound that has been found useful in the systemic treatment of acute leukemia. This paper specifically investigates the CSF pharmacokinetics of m-AMSA following both intravenous and intraventricular administration in a subhuman primate model. Following intravenous administration, m-AMSA crossed the blood-brain barrier poorly; cerebrospinal fluid (CSF) concentrations were only 1-3% of systemic concentrations. Intraventricular administration of drug achieved high initial ventricular fluid concentrations, but the drug was rapidly cleared with a half-life of 115 min. Following 500 micrograms of intraventricular drug, CSF concentrations of m-AMSA remained above 1 microM for only 6 h. These data suggest that m-AMSA has potential as an intrathecal agent against meningeal leukemia refractory to more conventional therapy, but detailed toxicology and neurohistopathology will be required before intra-CSF m-AMSA can be considered for human use.

Aminoacridines↗
PubMed1984

Detection of bacteriuria by leukocyte esterase, nitrite, and the automicrobic system.

The predictive value for detection of significant bacteriuria was determined for use of the Chemstrip leukocyte esterase-nitrite dipstick (LN) and the Vitek Automicrobic System (AMS) using a conventional culture method (CM) as the reference procedure. The predictive values for positive and negative tests for detection of greater than or equal to 10(5) bacteria/mL for LN testing alone (2,782 specimens), AMS testing alone (729 specimens), and AMS testing of only LN positive specimens (253 specimens) were 29% and 97%, 67% and 99.5%, and 74.7% and 99.4%. The low predictive values for positive AMS tests were the result of discrepancies in enumeration in which counts of 10(4)/mL by CM often were classified as 10(5)/mL by AMS. Screening of specimens by LN reduces the cost of subsequent processing of LN positive specimens. Processing of LN positives by CM yielded the lowest total cost. Processing of LN positives by AMS resulted in the lowest labor cost.

Autoanalysis↗
PubMed1984

Purulent pericarditis following myocardial infarction.

A 75-year-old man required prolonged intravenous drug therapy for post-myocardial infarction arrhythmias and developed infection with Staphylococcus aureus at the site of his indwelling cannula. He received prompt antibiotic therapy but was readmitted to hospital five weeks later with a terminal illness which proved at post-mortem to be a staphylococcal pleuropericarditis. We consider that this fatal infection originated at his venous cannula site. The problems of diagnosis are discussed.

Aged↗
PubMed1984

Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.

There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.

Animals↗
PubMed1984

Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone.

The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration. Initial studies were performed in six rhesus monkeys with chronic indwelling Ommaya reservoirs. Following intraventricular administration of 0.2 mg of AZQ, elimination was monoexponential with half-lives of 32 and 39 min in ventricular and lumbar CSF, respectively. AZQ clearance (0.2 ml/min) was 5-fold greater than estimated CSF bulk flow, indicating that transcapillary passage and/or metabolism may be important clearance mechanisms for this drug. In spite of its rapid clearance from ventricular CSF, a substantial peak AZQ concentration was achieved in lumbar CSF (12 microM), which was 7 times higher than the peak ventricular CSF level (1.7 microM) achieved following i.v. AZQ administration (16 mg/sq m). Moreover, the mean area under the CSF concentration-time curve in ventricular CSF was 20-fold greater following intraventricular versus i.v. AZQ dosing, despite an 80-fold-lower dose. AZQ was not detectable in plasma (less than 0.06 microM) following intraventricular administration. No animals demonstrated clinical evidence of acute neurotoxicity. Subsequently, intraventricular AZQ was administered to a patient with refractory meningeal leukemia. Intraventricular AZQ (0.5 mg) resulted in a peak ventricular (56 microM) CSF level which was 80-fold higher than ventricular CSF levels achieved following systemic AZQ administration of a dose of 24 mg/sq m in humans. Moreover, intraventricular AZQ yielded substantial CSF levels without detectable plasma concentrations. These data suggest that intraventricular administration of AZQ is feasible and may have pharmacological advantages over systemic administration for the treatment of meningeal neoplasia.

Animals↗
PubMed1983

Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol.

Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.

Administration, Oral↗
PubMed1983

Coxsackie B virus infection in coronary care unit patients.

It has been suggested that Coxsackie B virus infections may play a part in causing or triggering myocardial infarction. This study was designed to compare the incidence of such infections in Coronary Care Unit patients and normal controls. The choice of a suitable criterion for diagnosis of Coxsackie infection is discussed fully. Two hundred and fifty admissions to a Coronary Care Unit and 100 control subjects had a serum sample tested by microneutralisation for Coxsackie B antibodies. The incidence of infection among 130 patients diagnosed as acute myocardial infarction was 5% compared with 4% in the control group. In a subgroup classified as non-transmural myocardial infarction, the incidence of infection was 14%. The sex ratio of this group differed from the myocardial infarction group as a whole suggesting that the non-transmural group may not have been homogeneous. Normal coronary arteriograms were subsequently found in three patients who were diagnosed as non-transmural myocardial infarction but who had serological evidence of recent Coxsackie infection. This study does not demonstrate an association between Coxsackie infection and myocardial infarction as a whole and does not support the view that Coxsackie infection causes or provokes myocardial infarction. It does, however, suggest that myocarditis may simulate non-transmural infarction.

Antibodies, Viral↗
PubMed1982

Effects of cranial radiation on hypothalamic-adenohypophyseal function: abnormal growth hormone secretory dynamics.

The function of the hypothalamic-adenohypophyseal unit was tested in 2 groups of rhesus monkeys before and at periodic intervals after the administration of 2400 and 4000 rads cranial radiation. This therapy was given in 10 fractions over a 2-week period. Plasma TSH, basally and after TRH administration, and LH and FSH, before and after gonadotropin-releasing hormone stimulation, were normal up to 1 yr after radiation. Plasma GH at the basal state and after arginine and L-dopa stimulation was also normal. An insulin tolerance test, however, demonstrated a blunted GH response at a dose (0.1 U/kg) that caused brisk stimulation of GH secretion in normal control monkeys. A larger dose of insulin (0.2 U/kg) resulted in ample secretion of GH in these animals, suggesting decreased hypothalamic sensitivity to insulin in treated animals. The measurement of GH every 20 min for 24 h in animals treated with 4000 rads showed a dramatically altered secretory pattern of GH 1 yr after radiation. GH secretory spikes were markedly decreased in both frequency and amplitude, suggesting a reduction in the normal daily production of GH.

Animals↗