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Biomedical subjects

C J Morgan

Publications and source records attributed to C J Morgan.

At least 19 recordsLinked to original sources
PubMed1992

Alloantigenicity of human endothelial cells. 1. Frequency and phenotype of human T helper lymphocytes that can react to allogeneic endothelial cells.

To determine the relative ability of allogeneic endothelial cells to stimulate helper T lymphocytes (HTL), human PBMC or purified T cells were incubated in conventional lymphocyte microcultures or in limiting dilution microcultures with allogeneic human umbilical vein endothelia (HUVE), with cytokine-treated allogeneic HUVE, or with allogeneic peripheral blood monocytes. These cultures were tested for IL-2 production as an index of HTL stimulation. Dose-response studies in conventional lymphocyte cultures indicated that allogeneic monocytes were better than allogeneic HUVE at stimulating IL-2 production. Limiting dilution analyses revealed that untreated HUVE and TNF-treated HUVE stimulated small numbers of HTL (approximately 1 HTL/30,000 PBMC), whereas 5 to 10 times more HTL were stimulated by IFN-gamma-treated HUVE and 10 to 20 times more HTL were stimulated by allogeneic monocytes. Serologic deletion studies revealed that most of the high frequency HTL responding to IFN-gamma-treated HUVE were CD4+, whereas most of the low frequency HTL responding to nontreated HUVE or to TNF-treated HUVE were CD8+. Interestingly, mAb to MHC class I and class II molecules, which significantly impaired HUVE-induced proliferation, caused little interference with HUVE-induced IL-2 production. Finally, polymerase chain reaction analysis demonstrated that untreated allogeneic HUVE cells could stimulate PBMC to produce mRNA for IFN-gamma, as well as for IL-2. These data demonstrate the following hierarchy of allogeneic stimulatory capacity for human HTL: monocytes greater than IFN-gamma-treated HUVE much greater than TNF-treated HUVE = nontreated HUVE. Further, these data suggest that non-activated allogeneic endothelial cells can initiate immune responses by inducing IL-2 and IFN-gamma. Because IFN-gamma can induce MHC class II expression by the endothelial cells, this could recruit large numbers of CD4+ T cells for IL-2 production.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Effects of acute carbamazepine administration on haem metabolism in rat liver.

The effects of acute carbamazepine (CBZ) administration on haem metabolism in rat liver were examined in relation to the mechanism by which it exacerbates hepatic porphyrias. In a screening test for drug exacerbation of porphyria developed in this laboratory, CBZ at a very small dose (1.5 mg/kg, p.o.) behaved as an exacerbator, potentiating the loss of haem utilized by tryptophan pyrrolase (TP; tryptophan 2,3-dioxygenase; L-tryptophan-O2 oxido-reductase, decyclizing; EC 1.13.11.11) and the associated induction of activity of the rate-limiting enzyme of haem biosynthesis, 5-aminolaevulinate synthase (5-ALA-S) caused by the experimental porphyrogen 3,5-diethoxycarbonyl-1,4-dihydrocollidine. A larger dose of CBZ (50 mg/kg, i.p.) induced 5-ALA-S activity by 40-100% at 3 hr. This induction was preceded by an increase in the haem saturation of TP, and was abolished when such an increase was prevented by allopurinol. 5-ALA-S induction by CBZ was not associated with decreased turnover of the enzyme, nor with any significant changes in concentration of the major hepatic haemoprotein, cytochrome P450. It is suggested that CBZ may exacerbate the hepatic porphyrias by inducing 5-ALA-S activity secondarily to an increased utilization of haem by TP.

5-Aminolevulinate Synthetase↗
PubMed1992

Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction.

The outcome of adult respiratory distress syndrome complicating cardiopulmonary bypass has changed little in recent years. A retrospective, case-controlled study was designed to assess the incidence of the adult respiratory distress syndrome in these circumstances and the extent to which it could be linked with pre and peri-operative predictive factors. Eleven patients who developed the syndrome out of 840 who underwent cardiopulmonary bypass over a 9 month period were compared with 53 controls matched for sex, operation and surgeon. The incidence of adult respiratory distress syndrome and its mortality were 1.3% and 53% respectively. Significant predictors were a high intra and postoperative intervention score, the total volume of blood pumped during bypass (greater than 300 l) and age (greater than 60 years). These risk factors should alert the clinician to the possibility of severe postoperative pulmonary complications.

Adult↗
PubMed1992

Pulmonary endothelial permeability following lung transplantation.

During lung transplantation, a number of factors may cause endothelial injury to the donor organ, including ischemia, inadequate preservation, cardiopulmonary bypass, high potassium concentrations, and reperfusion. In this study, protein accumulation index (PAI) was used to assess pulmonary endothelial permeability (PEP) in ten patients immediately after lung transplantation. Six were studied sequentially every other day for ten days postoperatively. The PAI was also measured using the same technique in a group of 11 normal volunteers. Mean PAI x 10(-3)/min +/- (SEM) for ten patients measured within 36 h of transplantation was 1.27 (0.56) compared with 0.45 (0.08) for the normal group (p = 0.09). No correlation was found between preservation time and PAI following reperfusion. Three episodes of lung rejection were observed in two patients during the first ten postoperative days, during which PAI rose to 2.26 (0.26) compared with 0.73 (0.11) for all other studies in the group (p less than 0.01). We conclude that no increase in PEP could be demonstrated after graft reperfusion following lung transplantation as assessed by PAI in this small group of patients. However, further studies may show the technique to be useful in the detection of subsequent episodes of graft rejection.

Cell Membrane Permeability↗
PubMed1991

The effects of lofepramine and desmethylimipramine on tryptophan metabolism and disposition in the rat.

Acute and chronic administration of lofepramine and its major metabolite desmethylimipramine (DMI) to rats elevates brain tryptophan concentration, thereby enhancing cerebral 5-hydroxytryptamine (5-HT) synthesis, by increasing the availability of circulating tryptophan to the brain, secondarily to inhibition of liver tryptophan pyrrolase (tryptophan 2,3-dioxygenase, L-tryptophan:O2 oxidoreductase, decyclizing; EC 1.13.11.11) activity. The pyrrolase inhibition by lofepramine occurs independently of metabolism to DMI, because it can be demonstrated directly in vitro. Lofepramine also differs from DMI in its action profile on the above and related aspects of tryptophan metabolism and disposition. These results demonstrate that lofepramine influences tryptophan and 5-HT metabolism and disposition independently of its major metabolite DMI, and are discussed briefly in relation to the mechanism of action of antidepressants.

Animals↗
PubMed1991

Independently arising macrophage mutants dissociate growth factor-regulated survival and proliferation.

Analysis of a simian virus 40-immortalized colony-stimulating factor 1 (CSF-1) -dependent macrophage cell line (BAC1.2F5) and independently arising autonomous mutants derived from it (aut4A, aut4A.1, aut2A, and aut2A.1) revealed distinct phenotypes. The parental line, BAC1.2F5, is dependent on CSF-1 for survival and growth. Of the mutants derived from BAC1.2F5, aut4A has lost the requirement of CSF-1 for survival; aut4A.1 (derived from aut4A) and aut2A grow in the absence of growth factor but proliferate more rapidly in its presence, and aut2A.1 (derived from aut2A) produces CSF-1 and proliferates as rapidly in the presence as in the absence of exogeneous CSF-1. The separation of the CSF-1 requirement for survival and proliferation observed in aut4A is also observed in a temperature-sensitive (ts) mutant tsgro1. At the nonpermissive temperature, tsgro1 cell proliferation is arrested, but the cells survive provided CSF-1 is present. The four cellular phenotypes observed--immortalization, loss of growth factor requirement for survival, loss of growth factor requirement for proliferation, and loss of growth factor-stimulated proliferation--indicate a divergence of the pathways of growth factor-regulated survival and proliferation and may represent phenotypes occurring at intermediate stages in tumor-cell progression.

Animals↗
PubMed1991

Blood lactate and mixed venous-arterial PCO2 gradient as indices of poor peripheral perfusion following cardiopulmonary bypass surgery.

Conventional indices of tissue perfusion after surgery involving cardiopulmonary bypass (CPB) may not accurately reflect disordered cell metabolism. Venous hypercarbia leading to an increased veno-arterial difference in CO2 tensions (V-aCO2 gradient) has been shown to reflect critical reductions in systemic and pulmonary blood flow that occur during cardiorespiratory arrest and septic shock. We therefore measured plasma lactate levels and V-aCO2 gradients in 10 patients (mean age 57.2 years) following CPB and compared them with conventional indices of tissue perfusion. Plasma lactate levels, cardiac index (CI) and oxygen uptake (VO2) all increased significantly (p less than 0.05 vs baseline levels) up to 3 h following surgery. Oxygen delivery (DO2) did not change. Plasma lactate levels correlated significantly with CI (r = 0.47, p less than 0.01). V-aCO2 fell significantly with time (p less than 0.01 vs baseline). There was an inverse relationship between V-aCO2 and cardiac index and V-aCO2 and lactate (r = -0.37, p less than 0.05; r = -0.3, p less than 0.05 respectively). We conclude that blood lactate, CI and VO2 increase progressively following CPB. An increase in lactate was associated with a decrease in V-aCO2. An increase in V-aCO2 was not therefore associated with evidence of inadequate tissue perfusion as indicated by an increased blood lactate concentration.

Acidosis, Lactic↗
PubMed1991

Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat.

1 The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat. 2 Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg-1 dose. 3 Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine. 4 Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase-inhibitory mechanism. Cerebral 5-hydroxytryptamine (5-HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg-1. With larger doses, decreased 5-HT turnover, probably as a result of 5-HT uptake inhibition, was the more dominant feature. 5 Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non-esterified fatty acids or glucose. 6 It is concluded that, in addition to inhibiting brain 5-HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5-HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.

Administration, Oral↗
PubMed1991

Adenosine as a vasodilator in primary pulmonary hypertension.

BACKGROUND: The acute administration of vasodilator drugs to patients with primary pulmonary hypertension has been advocated to identify those with reversible pulmonary vasoconstriction. Unfortunately, the usefulness of the drugs currently available is limited by accompanying systemic hypotension. A vasodilator with effects confined to the pulmonary circulation would therefore be advantageous in such patients. METHODS AND RESULTS: The purine nucleoside adenosine was infused into the pulmonary artery in seven patients with primary pulmonary hypertension (baseline pulmonary vascular resistance [PVR], 442-1,295 dyne/cm/sec-5) to determine its effect on PVR. In all patients, there was a dose-dependent and significant reduction (mean maximal percent decrease from baseline, 38.9%; p less than 0.001) in PVR mediated through a decrease in pulmonary artery pressure and an increase in cardiac output. Systemic vascular resistance (SVR) also decreased, but the ratio of PVR to SVR decreased (maximal mean percent decrease from baseline) by 10.5% (p less than 0.025), indicating that adenosine has a preferential vasodilator effect on the pulmonary circulation when administered in this manner. CONCLUSIONS: Because of its pharmacokinetic and vasodilator properties, adenosine may have a specific role in the investigation of primary pulmonary hypertension.

Adenosine↗
PubMed1991

Acute physiology and chronic health evaluation (APACHE II) scoring in a cardiothoracic intensive care unit.

OBJECTIVE: To evaluate the predictive value of the Acute Physiology and Chronic Health Evaluation (APACHE II) scoring system in cardiothoracic surgical patients. DESIGN: Prospective survey with follow-up to hospital discharge. SETTING: A cardiothoracic surgical ICU in a tertiary referral center. PATIENTS: Eight hundred sixty-nine consecutive patients admitted to the ICU were entered into this study. Data on 12 patients were incomplete. Forty-three patients had nonsurgical diagnoses. Three patients had noncardiothoracic operations. These exclusions left 811 patients for analysis, and all results pertain to these 811 cardiothoracic surgical patients. INTERVENTIONS: Demographic and physiologic data relevant to the APACHE II score were collected on all patients and entered into a microcomputer database for analysis. MEASUREMENTS AND MAIN RESULTS: The following procedures were performed: 65% of patients had coronary artery bypass grafts; 23% had heart valve surgery; 5% had thoracic surgical procedures; and the remainder had a variety of cardiothoracic operations. The mean duration of ICU care was 2.3 days and the mean age was 57 yrs. The mean APACHE II score was 9.5 and the overall predicted risk of dying was 4.59%, with an actual ICU mortality rate of 4.56%. The relationship between the APACHE II score and mortality rate was linear and significant (p less than .001). Patients with an APACHE II score of less than 10 had a mortality rate of 0.93%. Only a score of greater than 30 was uniformly associated with death, and then only in one patient. A chronic disease history, emergency surgery, and a longer ICU stay were significant markers for mortality. CONCLUSIONS: There was a good relationship between the APACHE II score and mortality rate. Low APACHE II scores accurately predicted survival but only very high scores accurately predicted death.

Adolescent↗
PubMed1990

Pulmonary function testing in the intensive care unit.

A number of tests of pulmonary function have been successfully developed for use in the intensive care unit. When performed in the ICU on critically ill patients, many of the traditional laboratory-based tests will have different clinical implications than when performed in ambulatory patients, for example vital capacity measurement. Also, the clinical questions posed in the ICU are often different, such that estimates of lung water may be clinically more useful than more traditional measures, such as the flow-volume loop. There is a need for further research to identify the clinical utility of these measurements. As the understanding of ARDS and MOF improves, new therapies may be developed which will require sensitive methods in order that they can be evaluated accurately. Similarly, the potential for new methods of respiratory support such as jet ventilation, extracorporeal techniques and lung transplantation reinforce the need for the pulmonary physician to be able to make an accurate assessment of respiratory function on the intensive care unit.

Extravascular Lung Water↗
PubMed1990

The use of caesium iodide mini scintillation counters for dual isotope pulmonary capillary permeability studies.

A commercially available system of caesium iodide crystal mini-detectors (Oakfield Instruments, Oxon, UK) was modified so that it was suitable for dual isotopic measurement of the plasma protein accumulation index (PPA)- a measure of pulmonary endothelial permeability. Using this modified system the mean PPA x 10(-3) min-1 +/- (S.E.M.) recorded in 11 normal subjects (22 lungs) was 0.18 (0.08) and in 6 patients (9 lungs) with the adult respiratory distress syndrome was 2.88 (0.63) (P less than 0.02). These values for PPA concur with those found by other groups using larger sodium iodide detectors. We conclude that with simple modification caesium iodide mini-detectors may be used successfully for the measurement of PPA in the intensive care setting.

Capillary Permeability↗
PubMed1989

Liver tryptophan pyrrolase. A major determinant of the lower brain 5-hydroxytryptamine concentration in alcohol-preferring C57BL mice.

The lower brain 5-hydroxytryptamine concentration in alcohol-preferring C57BL, compared with -non-preferring CBA, mice is caused by a decrease in circulating tryptophan availability to the brain secondarily to a higher liver tryptophan pyrrolase activity associated with a higher circulating corticosterone concentration. Activity or expression of liver tryptophan pyrrolase and/or their induction by glucocorticoids may be important biological determinants of predisposition to alcohol consumption.

Alcoholism↗
PubMed1989

Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity.

1. Liver 5-aminolaevulinate (ALA) synthase activity of 24 h-starved rats is maximally increased at 4 h after intraperitoneal administration of a 1.6 g/kg body wt. dose of ethanol. Larger doses cause a dose-dependent decrease in the extent of this stimulation, exhibiting a reciprocal relationship with an elevation of hepatic haem concentration, as suggested by the simultaneous increase in the haem saturation of tryptophan pyrrolase. 2. ALA synthase induction by ethanol is abolished if the above increase in pyrrolase saturation with haem is enhanced by theophylline, but is potentiated when the increase in the haem saturation is inhibited by anti-lipolytic agents. 3. ALA synthase induction by ethanol is also inhibited by inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde and acetate are, however, not responsible; they both decrease ALA synthase activity and increase the haem saturation of tryptophan pyrrolase. These latter effects of acetaldehyde are not mediated by acetate. 4. ALA synthase activity is also stimulated by succinate, which, however, also increases the haem saturation of tryptophan pyrrolase. 5. Ethanol does not influence the rate of ALA synthase degradation. 6. It is suggested that ethanol increases rat liver ALA synthase activity as a result of its own metabolism by the alcohol dehydrogenase-dependent pathway by a mechanism not involving decreased degradation of the former enzyme or the participation of the metabolites acetaldehyde and acetate.

5-Aminolevulinate Synthetase↗