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Biomedical subjects

C J Morgan

Publications and source records attributed to C J Morgan.

At least 55 records · Page 3Linked to original sources
PubMed1993

Continuous veno-venous haemofiltration following cardio-pulmonary bypass. Indications and outcome in 35 patients.

OBJECTIVE: To study the impact of continuous veno-venous haemofiltration on survival in patients with acute renal failure (ARF) following cardio-pulmonary bypass (CPB) surgery. DESIGN: A retrospective study of all patients requiring haemofiltration after CPB over a 2 year period. SETTING: A 20 bedded, adult cardothoracic intensive care unit in a postgraduate teaching hospital. PATIENTS: 35 patients (26 male, age range 24-74 years) required haemofiltration (2.7% of the total number of patients undergoing CPB). MAIN RESULTS: Cardiovascular failure post CPB was the commonest causes of ARF (n = 16). Indications for haemofiltration were uremia (21), oligo-anuria (11), volume overload (2) and hyperkalaemia (1). Mean time from CPB to the initiation of haemofiltration was 8 days (range 0-15 days). Mean urea was 30 mmol/l and creatinine 362 mumol/l immediately prior to treatment. Urea was well-controlled in all patients, although 2 needed haemodiafiltration. Twenty-six patients died during their admission to the ICU (74% mortality). A further 3 patients died during their hospital admission, following discharge from ICU. Outcome was particularly poor in patients with cardiovascular failure following CPB (16 cases, 0 survivors). Survivors tended to commence filtration earlier (mean of 4 vs 7 days for non-survivors) and required treatment for a mean period of 8 days (range 1-26 days). Survival was determined by the number of failed organ systems at the start of haemofiltration. Thus, 100% of patients with single system failure survived, compared to only 10% with 3 or more system failure. CONCLUSIONS: Despite the theoretical advantages of haemofiltration and the effective control of uraemia the mortality associated with ARF following CPB remains high and is probably determined by the number of failed organs systems.

Acute Kidney Injury↗
PubMed1993

Analysis of inflammatory endothelial changes, including VCAM-1 expression, in murine cardiac grafts.

We have employed a murine model of cardiac transplantation and two monoclonal antibodies, M/K-2 and MECA-32, to study the responses of graft endothelia during allograft rejection. Using immunohistologic techniques, we demonstrate that the monoclonal antibody M/K-2, which binds to the murine cellular adhesion molecule VCAM-1, reacts with an inducible endothelial epitope found in rejecting cardiac allografts, but not in cardiac isografts, normal cardiac tissues, or extracardiac vasculature from allografted mice. Similar, but focal, M/K-2 reactivity is also found in nontransplanted hearts undergoing virally induced myocarditis. M/K-2 reactivity does not develop in the nonrejecting cardiac allografts from nu/nu mice, and M/K-2 reactivity is found only in grafts that develop CD25+ graft-infiltrating cells--i.e., allografts but not isografts. PCR analyses of grafts during development of VCAM-1 expression indicate that allografts, but not isografts, contain mRNA for the cytokines IL-2 and IFN-gamma, and either of these cytokines may be associated with the expression of M/K-2 reactivity in rejecting allografts. Unlike M/K-2, MECA-32 identifies an inducible epitope that is observed on myocardial endothelia of both isografts and allografts, but not normal cardiac tissues. Further, expression of the MECA-32 epitope can occur in grafts that do not develop CD25+ infiltrating lymphocytes, since it is observed in isografts and the native hearts of transplanted or sham-operated mice. Indeed, MECA-32 reactivity may be T cell independent, since it is also found in nonrejecting allografts of nu/nu mice. PCR analyses of grafts during development of MECA-32 reactivity indicate that cardiac isografts contain mRNA for IL-1, IL-6, TNF, and lymphotoxin. One or more of these might be associated with induction of MECA-32 reactivity.

Animals↗
PubMed1993

Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts.

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.

Animals↗
PubMed1993

Detection of cytokine mRNA in vivo by polymerase chain reaction. Problems and solutions.

The expression of cytokine mRNAs in murine sponge matrix graft infiltrates was studied using the polymerase chain reaction (PCR). In infiltrates of both C57B1/6 > C57B1/6 isografts and DBA/2 > C57B1/6 allografts, a similar pattern of cytokine expression was observed. On days 6, 8, and 10 postimplant, mRNAs encoding IL-4, IL-6, and IFN-gamma were detected. On days 8 and 10, mRNAs encoding IL-1 alpha, TNF, and lymphotoxin/TNF beta were also expressed. Surprisingly, no IL-2 mRNA was observed in isografts or allografts. Two modified PCR techniques were utilized to compare the level of expression of cytokine mRNAs in isografts versus allografts and to detect the expression of IL-2 mRNA in this system. A semiquantitative PCR protocol based on limiting cycles of amplification is described that was used to determine the amount of IL-4 mRNA expressed in isograft and allograft infiltrates relative to beta-actin mRNA. Using this method, no difference was found in the amount of IL-4 mRNA in infiltrates of day 8 isografts and allografts. The validation of this technique by analysis of samples with known relative mRNA levels is presented. A nested PCR protocol is described that provided greatly enhanced sensitivity over standard PCR analysis. Using this technique, IL-2 mRNA was detected in infiltrates from sponge allografts on all days tested, beginning on day 2 postimplant. No IL-2 mRNA was detected in isograft infiltrates or in peripheral blood from allograft-bearing animals. The pattern of cytokine mRNA expression observed in sponge matrix allografts is consistent with the presence of a weak alloreactive response superimposed upon an intense granulomatous process that occurs in both the isografts and allografts. This report demonstrates modified PCR techniques that can be used to resolve experimental problems associated with the analysis of cytokine mRNA expression in vivo.

Animals↗
PubMed1993

Tryptophan and 5-hydroxytryptamine metabolism in alcoholism.

Alcohol (ethanol) exerts a variety of effects on tryptophan (Trp) and 5-hydroxytryptamine (5-HT, serotonin) metabolism in man and experimental animals. In human healthy volunteers, acute ethanol consumption lowers circulating Trp availability to the brain, almost certainly leading to inhibition of cerebral 5-HT synthesis, possibly by enhancing liver Trp pyrrolase activity. In non-abstinent chronic alcoholics, however, Trp pyrrolase activity may be inhibited; here acute ethanol intake fails to lower circulating Trp concentration. Hepatic Trp degradation seems to be greater during abstinence, and chronic alcoholics then exhibit a decrease in Trp availability to the brain. It is, however, not clear whether this decrease and the likely associated higher liver Trp pyrrolase activity in abstinence are due to previous long-term alcohol consumption, or are inherent biological determinants of the low brain 5-HT in alcoholism. The latter possibility is supported by the recent implication of the Trp pyrrolase gene in alcoholism. In alcohol-preferring C57BL mice, the low brain [5-HT] is due to a higher liver Trp pyrrolase activity associated with a higher circulating [corticosterone]. Activity or expression of liver Trp pyrrolase and/or their induction by glucocorticoids may be important biological determinants of predisposition to alcohol consumption, and further work in this area may therefore be fruitful.

Alcoholism↗
PubMed1993

Measurement of carbon monoxide transfer and lung volume in ventilated subjects.

A simple method for measuring lung volume and carbon monoxide transfer factor (TLCO) by a rebreathing technique was assessed in nine healthy volunteers undergoing intermittent positive pressure ventilation (IPPV). Measurements of TLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO) made at three inspired oxygen concentrations (21, 35 and 70%) during IPPV were compared to those obtained during spontaneous breathing. The effects of 10 cmH2O positive end expiratory pressure (PEEP) were also studied. Pulmonary capillary blood volume (Vc) and the diffusing capacity of the alveolar capillary membrane (Dm) were derived. There was a close correlation between measurements of TLCO during IPPV (TLCOIPPV) and spontaneous breathing (TLCOSV) (r = 0.92). Ventilated TLCO was 64 +/- 8% of spontaneously breathing TLCO. There was a close agreement between ventilated and spontaneously breathing measurements of KCO (r = 0.95; mean difference 0.14, 95% limits of agreement +0.37 to -0.09 mmol.min-1 x kPa-1 x l-1). Vc was 92 +/- 23 ml during spontaneous breathing and 72 +/- 21 ml during IPPV (p < 0.05). PEEP of 10 cmH2O significantly increased functional residual capacity (2.3 +/- 0.5 to 3.5 +/- 0.6 l) and decreased TLCO (5.9 +/- 1.0 to 5.3 +/- 1.2 mmol.min-1 x kPa-1), KCO (1.7 +/- 0.2 to 1.1 +/- 0.3 mmol.min-1 x kPa-1 x l-1) and Vc (82 +/- 22 to 56 +/- 20 ml). Dm did not change with PEEP. This simple method may be a useful means of assessing gas exchange and lung volume in ventilated subjects. It showed that PEEP increased lung volume but reduced TLCO and that this reduction appeared to be due to a reduction in capillary blood volume.

Adult↗
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↗