Biomedical subjects

J J O'Neil

Publications and source records attributed to J J O'Neil.

At least 19 recordsLinked to original sources

PubMed1992

Multiple TCR V beta usage by infiltrates of young NOD mouse islets of Langerhans. A polymerase chain reaction analysis.

Because a restricted repertoire of T-cell receptor (TCR) V beta gene expression has been reported in other autoimmune diseases, the possibility of similarly restricted V beta gene expression by T-cell infiltrates of NOD mouse islets was examined. With isolated islets from 4- to 12-wk-old NOD mice, a prospective polymerase chain reaction analysis with 18 V beta-specific oligonucleotide primers was performed on the noncloned and unexpanded islet-infiltrating T cells. The methodology used permitted the detection of a minimum of 50 T cells. In contrast to the restricted TCR V beta gene usage reported for other autoimmune diseases, infiltrates of even the youngest mice were characterized by expression of multiple V beta gene segments.

Animals↗

PubMed1991

Effects of 4 percent and 6 percent carboxyhemoglobin on arrhythmia production in patients with coronary artery disease.

In this study, we assessed the effects of exposure to 4 percent and 6 percent carboxyhemoglobin on ventricular arrhythmias in 41 subjects (nonsmokers) with documented coronary artery disease. We used a randomized, double-blind, crossover design. On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 through 4, subjects were exposed to room air, 100 parts per million (ppm)2 carbon monoxide (target, 4 percent blood carboxyhemoglobin), or 200 ppm carbon monoxide (target, 6 percent blood carboxyhemoglobin), and they then did a supine bicycle exercise test. Radionuclide ventriculography was performed at rest and during exercise. Ambulatory electrocardiogram recordings were made during the four consecutive days to determine the frequency of premature ventricular contractions at various intervals. The frequency of single premature ventricular contractions per hour during exercise was significantly greater on the 6 percent carboxyhemoglobin day than on the room air day (167.72 +/- 37.99 for 6 percent carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, p = 0.03). The frequency of multiple premature ventricular contractions per hour was also significantly greater during exercise on the 6 percent carboxyhemoglobin day compared with the room air day (9.59 +/- 3.70 for the 6 percent carboxyhemoglobin day compared with 3.18 +/- 1.67 for the room air day, p = 0.02). Patients who developed increased arrhythmias during exercise on the 6 percent carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, and, in addition, exercised longer and had a higher peak workload during exercise. No effect of carbon monoxide exposure was seen on the 4 percent carboxyhemoglobin day.

Aged↗

PubMed1990

Production of arrhythmias by elevated carboxyhemoglobin in patients with coronary artery disease.

OBJECTIVE: To assess the effects of exposure to 4% and 6% carboxyhemoglobin on ventricular arrhythmias in patients with coronary artery disease. DESIGN: Randomized, double-blind, crossover design. SETTING: Exercise laboratory with an environmentally controlled exposure. PATIENTS: Forty-one nonsmokers with documented coronary artery disease. INTERVENTION: On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 to 4, patients were exposed to room air, 100 ppm carbon monoxide (target, 4% carboxyhemoglobin) or 200 ppm carbon monoxide (target, 6% carboxyhemoglobin), and they then did supine bicycle exercise with radionuclide ventriculography. Ambulatory electrocardiogram recordings were made during the 4 consecutive days to determine the frequency of ventricular premature depolarization (VPD) at various intervals. MEASUREMENTS AND MAIN RESULTS: The frequency of single VPD/h was significantly greater on the 6% carboxyhemoglobin day than on the room air day during the exercise period (167.72 +/- 37.99 for 6% carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, P = 0.03). During exercise, the frequency of multiple VPD/h was greater on the 6% carboxyhemoglobin day compared with room air (9.59 +/- 3.70 on the 6% carboxyhemoglobin compared with 3.18 +/- 1.67 on room air, P = 0.02). Patients who developed increased single VPD during exercise on the 6% carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, whereas patients who developed complex arrhythmias were also older and, in addition, exercised longer and had a higher peak workload during exercise. CONCLUSION: The number and complexity of ventricular arrhythmias increases significantly during exercise after carbon monoxide exposure producing 6% carboxyhemoglobin compared with room air but not after exposure producing 4% carboxyhemoglobin.

Age Factors↗

PubMed1988

Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice.

The nonobese diabetic mouse is a model of spontaneous type I diabetes mellitus. It is possible to induce diabetes in young, irradiated nonobese diabetic mice by using adoptive transfer of splenocytes or splenic T cells obtained from diabetic donors. This study demonstrates that the induction of diabetes in the adoptive transfer system is dependent on both the L3T4+ and Lyt-2+ subsets of T cells. Neither of these T cell subsets alone mediates the development of severe insulitis or diabetes when adoptively transferred to young, irradiated recipients. In addition, we show that both the L3T4+ and Lyt-2+ subsets must be obtained from diabetic donors in order to transfer diabetes; neither subset can be replaced with cells obtained from young, nondiabetic donors.

Age Factors↗

PubMed1988

Acute elevation of blood carboxyhemoglobin to 6% impairs exercise performance and aggravates symptoms in patients with ischemic heart disease.

Acute exposure to carbon monoxide has the potential to impair exercise capacity in patients with ischemic heart disease. The effect of sufficient inhalation of this compound to gradually produce a level of 6% carboxyhemoglobin was studied in 30 nonsmoking patients with obstructive coronary artery disease and evidence of exercise-induced ischemia. After an initial training session, subjects were exposed to air or carbon monoxide on successive days in a randomized double-blind crossover fashion. Cardiac function and exercise capacity were assessed during symptom-limited supine radionuclide ventriculography. On the carbon monoxide day, mean postexposure carboxyhemoglobin was 5.9 +/- 0.1% compared with 1.6 +/- 0.1% (p less than 0.01) after air exposure. The mean duration of exercise was significantly longer after air compared with carbon monoxide exposure (626 +/- 50 s for air versus 585 +/- 49 s for carbon monoxide, p less than 0.05). Actuarial methods suggested that subjects were likely to experience angina earlier during exercise on the day of carbon monoxide exposure (p less than 0.05). Both the level (62 +/- 2.4 versus 60 +/- 2.4%, p = 0.05) and change in left ventricular ejection fraction at submaximal exercise (1.6 +/- 1.6 versus -1.2 +/- 1.6%, p = 0.05) were greater on the air exposure day compared with the carbon monoxide day. The peak exercise left ventricular ejection fraction was not different for the two exposures (57 +/- 2.5% for both). These results demonstrate earlier onset of ventricular dysfunction, angina and poorer exercise performance in patients with ischemic heart disease after acute carbon monoxide exposure sufficient to increase blood carboxyhemoglobin to 6%.

Aged↗

PubMed1988

The influence of fentanyl upon cerebral high-energy metabolites, lactate, and glucose during severe hypoxia in the rat.

The effects of intravenous administration of high-dose fentanyl (100 micrograms.kg-1, loading dose followed by an infusion of 200 micrograms.kg-1.h-1) were compared with those of a barbiturate (pentobarbital sodium 25 mg.kg-1, intraperitoneal) or hypothermia (rectal temperature 32 degrees C) on changes in cerebral cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine (PCr), lactate, and glucose in severely hypoxemic rats (PaO2 13-23 mmHg for 20 min) with unilateral (left side) carotid ligation (10-12 animals in each group). Ligation of the carotid artery alone produced no change in brain high-energy metabolites, lactate, or glucose. The control values on the ligated side (nitrous oxide, 70%, + normoxia group) for cortical ATP, PCr, lactate, and glucose were 2.86 +/- 0.09 (mumol.g-1 wet weight, mean +/- 1 SE), 3.83 +/- 0.11, 1.68 +/- 0.21, and 3.29 +/- 0.47, respectively. Hypoxia (nitrous oxide, 70%, + hypoxia group) produced a significant (P less than 0.05) decrease in ATP (1.83 +/- 0.37) and PCr (1.93 +/- 0.48) and an increase in lactate (15.8 +/- 1.77) compared with the normoxic group, whereas brain glucose was not significantly changed (1.97 +/- 0.65). Fentanyl (fentanyl + hypoxia group) did not prevent the deleterious effects of hypoxia on cortical high energy metabolites (ATP, 2.0 +/- 0.27; PCr, 2.24 +/- 0.3) or lactate (19.33 +/- 3.16); however, fentanyl caused no alteration in high-energy cerebral metabolite concentrations in normoxic rats, nor did fentanyl produce a significant difference in brain tissue glucose or lactate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1988

Extrathoracic and intrathoracic removal of O3 in tidal-breathing humans.

We measured the efficiency of O3 removal from inspired air by the extrathoracic and intrathoracic airways in 18 healthy, nonsmoking, young male volunteers. Removal efficiencies were measured as a function of O3 concentration (0.1, 0.2, and 0.4 ppm), mode of breathing (nose only, mouth only, and oronasal), and respiration frequency (12 and 24 breaths/min). Subjects were placed in a controlled environmental chamber into which O3 was introduced. A small polyethylene tube was then inserted into the nose of each subject, with the tip positioned in the posterior pharynx. Samples of air were collected from the posterior pharynx through the tube and into a rapidly responding O3 analyzer yielding inspiratory and expiratory O3 concentrations in the posterior pharynx. The O3 removal efficiency of the extrathoracic airways was computed with the use of the inspiratory concentration and the chamber concentration, and intrathoracic removal efficiency was computed with the use of the inspiratory and expiratory concentrations. The mean extrathoracic removal efficiency for all measurements was 39.6 +/- 0.7% (SE), and the mean intrathoracic removal efficiency was 91.0 +/- 0.5%. Significantly less O3 was removed both extrathoracically and intrathoracically when subjects breathed at 24 breaths/min compared with 12 breaths/min (P less than 0.001). O3 concentration had no effect on extrathoracic removal efficiency, but there was a significantly greater intrathoracic removal efficiency at 0.4 ppm than at 0.1 ppm (P less than 0.05). Mode of breathing significantly affected extrathoracic removal efficiency, with less O3 removed during nasal breathing than during either mouth breathing or oronasal breathing (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Ozone exposure increases respiratory epithelial permeability in humans.

Ozone is a respiratory irritant that has been shown to cause an increase in the permeability of the respiratory epithelium in animals. We used inhaled aerosolized 99mTc-labeled diethylene triamine pentacetic acid (99mTc-DTPA) to investigate whether human respiratory epithelial permeability is similarly affected by exposure to ozone. In a randomized, crossover double-blinded study, 8 healthy, nonsmoking young men were exposed for 2 h to purified air and 0.4 ppm ozone while performing intermittent high intensity treadmill exercise (minute ventilation = 66.8 L/min). SRaw and FVC were measured before and at the end of exposures. Seventy-five minutes after the exposures, the pulmonary clearance of 99mTc-DTPA was measured by sequential posterior lung imaging with a computer-assisted gamma camera. Ozone exposure caused respiratory symptoms in all 8 subjects and was associated with a 14 +/- 2.8% (mean +/- SEM) decrement in FVC (p less than 0.001) and a 71 +/- 22% increase in SRaw (p = 0.04). Compared with the air exposure day, 7 of the 8 subjects showed increased 99mTc-DTPA clearance after the ozone exposure, with the mean value increasing from 0.59 +/- 0.08 to 1.75 +/- 0.43%/min (p = 0.03). These data show that ozone exposure sufficient to produce decrements in the pulmonary function of human subjects also causes an increase in 99mTc-DTPA clearance.

Adult↗

PubMed1986

Differential regulation of glucokinase activity in pancreatic islets and liver of the rat.

The differential tissue-specific regulation of glucokinase activity in liver and pancreatic islet cells was investigated in the insulinoma-bearing rat. A transplantable insulinoma caused hyperinsulinemia and hypoglycemia in the host by 2-3 months after implantation. Suppression of the pancreatic B-cells by the high insulin and/or low glucose manifested itself by a decrease of insulin in islet tissue. Removal of the tumor initiated transient insulin deficiency and hyperglycemia with extremes of these changes at 24 h after tumor resection. These conditions markedly affected glucose phosphorylation in the islet cells: glucokinase activity was reduced 71% in islet samples from insulinoma-bearing rats, and the enzyme fully recovered within 24 h after tumor resection. Hexokinase activity, by contrast, was not affected by these manipulations. To evaluate the relative contributions of hypoglycemia and hyperinsulinemia in islet glucokinase adaptation, glucose was intravenously infused to insulinoma-bearing rats; glycemia in excess of 150 mg/100 ml combined with excessive hyperinsulinemia resulted in a partial recovery of islet glucokinase activity, first apparent after 9 h of glucose infusion and with doubling of the activity after 24 h after glucose loading. In contrast, liver glucokinase was increased nearly 4-fold at the time of extreme hypoglycemia and hyperinsulinemia and rapidly fell to control rates following tumor removal. Intravenous infusion of glucose for 24 h into the tumor-bearing rat (i.e. hyperglycemia combined with excessive plasma insulin) had no influence on liver glucokinase activity. Liver hexokinase was not influenced by any of these experimental manipulations. The data indicate that the activities of pancreatic islet and liver glucokinase are regulated in a differential manner. Insulin is apparently the primary determinant of liver glucokinase and glucose seems to control islet glucokinase. Biochemical mechanisms for differential organ-specific regulation of glucokinase activity seem to have evolved such that this enzyme may play a dual role in glucose homeostasis, namely to serve as insulin-dependent glucose sensor in the B-cells and as insulin-sensitive determinant of hepatic glucose use.

Adenoma, Islet Cell↗

PubMed1984

Pulmonary function testing in small laboratory mammals.

The lung is the primary organ likely to be exposed by inhalation studies and, therefore, measurement of changes in lung function are of particular interest to the pulmonary physiologist and toxicologist. Tests of pulmonary function have been developed which can be used with small animals to measure spirometry (lung volumes), mechanics, distribution of ventilation, gas exchange or control of ventilation. These tests were designed on the basis of similar tests which are used in humans to diagnose and manage patients with lung disease. A major difference is that many of the measurements are performed in anesthetized animals, while human pulmonary function is usually measured in awake cooperating individuals. In addition, the measurement of respiratory events in small animals requires sensitive and rapidly responding equipment, because signals may be small and events can occur quickly. In general, the measurements described provide information on the change in normal lung function which results primarily from structural changes. These tests of pulmonary function can be repetitively and routinely accomplished and the results appear to be highly reproducible. Although some are quite sophisticated, many can be undertaken with relatively inexpensive equipment and provide useful information for toxicological testing.

Anesthesia↗

PubMed1984

Tissue slices in the study of lung metabolism and toxicology.

Lung tissue slices are model systems for the study of pulmonary metabolism. Because of the speed and simplicity of slice preparation, lung slices have been used in studies of oxygen, amino acid, carbohydrate and lipid utilization and adenine nucleotide metabolism. Dose-response characteristics for toxicants are readily described because multiple lung samples can be studied from the same animal or a population of animals. Lung slices prepared from animals exposed to oxidant air pollutants exhibit alterations in respiration, glucose consumption and lipid metabolism. These studies have indicated both direct toxic effects of air pollutants on enzyme systems and also air pollutant-induced changes in the cellularity of lungs.

Air Pollutants↗

PubMed1983

Pulmonary function in normal and elastase-treated hamsters exposed to a complex mixture of olefin-ozone-sulfur dioxide reaction products.

An elastase-induced emphysema model was utilized to determine if hamsters with preexisting lung disease were more susceptible to lung damage from air pollutant exposure. Male golden hamsters, divided into two treatment groups, were given a single intratracheal injection of either 6 units of porcine pancreatic elastase (EMP) or buffer (CNT). After a 4-week recovery period, equal numbers of each group were exposed 23 hr/day X 28 day to filtered air (AIR) or to the complex by-products from a dark phase reaction mixture of trans-2-butene, ozone, and sulfur dioxide (MIX). Lung function measurements on the elastase-treated groups showed changes consistent with mild emphysema. There were no significant differences in lung volumes or lung compliance between the AIR- and MIX-exposed animals. However, the nitrogen washout slope decreased (P less than 0.05), and the diffusing capacity for carbon monoxide increased (P less than 0.05) in both the CNT and EMP hamsters exposed to the MIX. The change in diffusing capacity was greater (P less than 0.05) in normal hamsters than in hamsters with emphysema, and it is hypothesized that animals with impaired lung function had a decreased ability to respond to a pulmonary insult from the mix.

Air Pollutants↗

PubMed1983

Maximal oxygen consumption and pulmonary diffusing capacity: a direct comparison of physiologic and morphometric measurements in canids.

The purpose of this study was to check the validity of the morphometric model for estimating physiological conductances for gases, DL. We make a direct comparison between the lung's conductance for carbon monoxide, measured physiologically using the single breath method, DLCO (sb), and that measured morphometrically using the previously published model, DLCO(mm). We also make a direct comparison between the maximum rate of oxygen uptake by the lung during exercise, VO2max, and the lung's conductance for oxygen DLO2(mm). We made these measurements on four species of canids (foxes, coyotes, dogs and wolves). We find a direct proportionality between morphometric and physiologic DLCO measurements, the morphometric being consistently larger by a factor of two. We also find that both DLCO and DLO2 increase more steeply with body mass than VO2max, the difference between the allometric slopes being the same as we had found previously in a wide range of mammalian species ranging from 2 g to 700 kg, although the slopes themselves were different. We conclude that the discordant scaling of DLO2 and VO2max with respect to body mass is not an artifact of the model for calculating DLO2 from morphometric data.

Animals↗

PubMed1983

Can animal pulmonary function testing provide data for regulatory decision making?

The process of setting health standards requires rigorous, scientifically sound data that relate to man's interaction with his environment. Tests of pulmonary function are especially useful, since they may permit some direct comparisons between animals and man. The development of tests to measure pulmonary function in small animals has been important, and research into the health effects of air pollution may be greatly strengthened with the use of data from such measurements.

Air Pollutants↗

PubMed1982

Morphologic changes in the lung during the lifespan of Fischer 344 rats.

Pulmonary structure and function were quantitatively investigated over the lifespan of the Fischer 344 rat by morphometric and physiologic techniques. Male animals 1 week, 6 weeks, 5 months, 14 months, and 26 months of age and female animals 5 months, 14 months, and 26 months of age were studied. All alveolar tissue compartments demonstrated significant increases in volume, surface area, and cell number during the first 5 months of life. From 5 to 26 months of age, remodelling in the epithelial and interstitial compartments continued to take place while the endothelial compartment remained relatively unchanged. In the epithelial compartment the ratio of type II cells to type I cells lining the alveolar surface decreased as age increased. In the interstitial compartment the volume of the noncellular components of the interstitium increased by 39% in males and by 89% in females from 5 to 26 months of age. Physiologic measurements of lung volumes in males at 6 weeks, 14 months, and 26 months demonstrated progressive increases in vital capacity (VC) and total lung capacity (TLC). Morphometric pulmonary-diffusion capacity (DLO2) increased in males from 1 week to 5 months of age and remained relatively unchanged from 5 to 26 months of age in both sexes.

Aging↗

PubMed1982

Oxygen consumption measured with microcomputer-assisted Warburg manometry.

We have developed and tested an automated system that measures in vitro oxygen consumption by Warburg manometry in as many as 16 units that are under the simultaneous control of a microcomputer which requires attention at the beginning of the study only. The all-glass Submarine Volumometers used are readily adapted to automation using a microcomputer that interacts with an infrared photodetector sensitive to manometric changes in the reaction vessel and a stepper motor that can advance the calibrated micrometer in response to these changes. The microcomputer interacts with the user at the start of the study during data entry and subsequently determines volume changes related to oxygen consumption, calculates respiration rates, and prints or graphs the results without further user interaction. We compared this automated system with manual methods by measuring the oxygen consumption of lung tissue slices and by determining the ability of the system to match known volumes entered manually. We found that the results obtained using the automated system were not significantly different from known manual methods (P less than 0.05).

Animals↗

PubMed1982

Dose response of elastase-induced emphysema in hamsters.

Elastase-induced emphysema in hamsters was studied using pulmonary function tests in an effort to develop techniques for determining the effects of air pollutants on the progression of this disease. Single intratracheal injections of 6, 12, or 24 units of porcine pancreatic elastase produced dose-related changes in pulmonary function after 4 wk when compared with sham-injected control animals. Boyle's law end-expiratory volume and residual volume, measured by gas dilution, increased (p less than 0.05) at 12 and 24 units, respectively, whereas vital capacity, determined plethysmographically, and total lung capacity wee increased (p less than 0.05) at all 3 elastase doses. Respiratory system compliance, calculated by a nonlinear least squares regression fit of the deflation pressure-volume curve, increased (p less than 0.05) at 24 units only. The multiple-breath nitrogen washout slope (N2 slope) and the single-breath diffusing capacity for carbon monoxide (DLCO) decreased (p less than 0.05) at all 3 doses of elastase. Both histologic and physiologic evaluation showed dose-related pulmonary impairment. It appears, therefore, that as little as 6 units of elastase produces mild emphysema in hamsters, which is detectable by pulmonary function testing. Of these tests, the DLCO and N2 slope were the most effective in detecting the degree of impairment.

Animals↗

PubMed1981

Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days.

Morphological, biochemical, and physiological studies were done on rats exposed to 60% O2 for 7 days. This exposure did not induce O2 tolerance but instead caused a significant decrease in survival time of animals subsequently exposed to pure O2. The activity of lung superoxide dismutases and glucose-6-phosphate dehydrogenase were unchanged after exposure to 60% O2. A decrease in lung compliance was suggested by changes in the total lung capacity and in the pressure-volume curves of excised lungs. Ventilation of these animals with large tidal excursion resulted in pulmonary edema. Morphometric analyses revealed a significant decrease in alveolar air volume and an increase in the number of alveolar macrophages. The most significant lesions involved the pulmonary vascular bed. The volume and thickness of the capillary endothelium was decreased. There were focal areas of pericapillary fluid accumulations, and a number of the smaller vessels had perivascular edema. These findings suggest that significant pulmonary injury occurs in rats exposed to 60% O2 and that the primary site of injury is the pulmonary capillary endothelium.

Animals↗