PubMed Health⌕ Search

Biomedical subjects

M J Elliott

Publications and source records attributed to M J Elliott.

At least 109 records · Page 6Linked to original sources
PubMed1993

Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha.

OBJECTIVE: To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor alpha (TNF alpha) in the treatment of patients with rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were treated with 20 mg/kg of anti-TNF alpha in an open phase I/II trial lasting 8 weeks. RESULTS: The treatment was well tolerated, with no serious adverse events. Significant improvements were seen in the Ritchie Articular Index, which fell from a median of 28 at study entry to a median of 6 by week 6 (P < 0.001), the swollen joint count, which fell from 18 to 5 (P < 0.001) over the same period, and in the other major clinical assessments. Serum C-reactive protein levels fell from a median of 39.5 mg/liter at study entry to 8 mg/liter at week 6 (P < 0.001), and significant decreases were also seen in serum amyloid A and interleukin-6 levels. CONCLUSION: Treatment with anti-TNF alpha was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNF alpha is an important regulator in RA, and suggest that it may be a useful new therapeutic target in this disease.

Adult↗
PubMed1993

Histamine release during paediatric cardiopulmonary bypass.

Histamine release is part of the general inflammatory response and occurs during surgery and cardiopulmonary bypass (CPB) in adults. Few data are available for children. Histamine release was studied in 23 children undergoing CPB with standard anaesthetic and CPB techniques. Blood sampling was performed in relation to specific anaesthetic and surgical events, e.g., start of CPB, removal of aortic clamps, reventilation of the lungs. Plasma histamine was determined by a single isotope radioenzymatic technique. There was no consistent histamine release in the study population although there was an increase in plasma histamine concentration in some subjects after initiation of CPB (P < 0.05) and on removal of the aortic cross-clamp (P < 0.05). No correlation was demonstrated between histamine concentration and systolic arterial pressure, temperature, duration of CPB or cross-clamp time. Histamine concentration was positively correlated with heart rate.

Adolescent↗
PubMed1993

Cerebral hemodynamics during cardiopulmonary bypass in children using near-infrared spectroscopy.

We describe a new noninvasive method using near-infrared spectroscopy for monitoring cerebral hemodynamics during cardiopulmonary bypass in children. All patients were undergoing open heart operations for repair of congenital heart defects. Standardized anesthesia, an alpha-stat method of blood gas management, and nonpulsatile flow were used in all cases. All measurements during bypass were made after steady-state conditions had been reached. Cerebral blood flow was measured on 13 occasions in 4 children, aged between 4 and 10 months (median, 5 months). Values of 15.9 to 53.5 mL x 100 g-1 x min-1 were obtained. Cerebral blood volume was measured in 1 patient, aged 4 months. Volumes of 4.3 to 8.0 mL x 100 g-1 were obtained on bypass at full pump flow (2.4 L.min-1 x m-2). On bypass at half flow, the volume increased to 14.7 mL x 100 g-1. Change in cerebral blood volume with changing carbon dioxide tension (CBVR) was measured in 13 patients aged from 1 to 90 months (median, 13.5 months). Preoperatively, CBVR was 0.12 +/- 0.07 mL x 100 g-1 x kPa-1 and was independent of mean arterial pressure, which remained between 40 and 80 mm Hg in all cases. During hypothermic bypass (25 degrees C), CBVR was significantly reduced to 0.05 +/- 0.02 mL x 100 g-1 x kPa-1. In addition, there were three values at mean arterial pressure of lower than 40 mm Hg in which CBVR was negative (-0.04 +/- 0.01 mL x 100 g-1 x kPa-1). We conclude that near-infrared spectroscopy is useful for the noninvasive investigation of cerebral hemodynamics during cardiopulmonary bypass.

Carbon Dioxide↗
PubMed1993

Interaction between neutrophils and endothelium.

The endothelial permeability associated with cardiopulmonary bypass in children is due, at least in part, to an inflammatory response. Neutrophils and their relationship with endothelium are fundamental to the production of capillary leak. This review discusses current concepts of the mechanisms involved in adhesion between neutrophils and the endothelium and its control. Evidence for modulation of these changes during bypass in children is reviewed. We have shown that cardiopulmonary bypass in children is associated with down-regulation (or shedding) of L-selectin and up-regulation of expression of CD11b/CD18. There may be a role for the cytokine interleukin-8 in the modulation of this process. We have demonstrated in vitro that certain of the procedures associated with bypass are associated with up-regulation of circulating neutrophil adhesion molecules and with the release of interleukin-8. These factors include changes in temperature and circulation. More research is required to tease out the most important components of the mechanisms of adhesion, and clinical correlations must be defined.

Capillary Permeability↗
PubMed1993

Ultrafiltration and modified ultrafiltration in pediatric open heart operations.

The capillary leak associated with cardiopulmonary bypass results in an increase in content of water in the tissues measurable by an increase in total body water after cardiac operation. Following work by Magilligan in the 1970s, ultrafiltration was introduced during bypass as a means of hemoconcentrating patients and potentially removing water from the tissues. Conventional methods proved inconsistent; thus, we modified the technique to ultrafilter the patients immediately after cessation of bypass. Modified ultrafiltration takes 10 minutes and results in an elevation of the on-bypass hematocrit to about 35% or 40%. In pilot studies comparing bypass in absence of ultrafiltration with conventional ultrafiltration and modified ultrafiltration, only the modified technique was seen reliably to reduce the elevation in total body water to only 4%, within a narrow range. Subsequent prospective studies confirmed the reduction in accumulation of total body water and also demonstrated a reduction in blood loss and in requirements for blood transfusion. Systolic blood pressure was observed to increase uniformly in all patients undergoing modified ultrafiltration. This effect was investigated and found to be associated with a marked increase in cardiac index, no change in systemic vascular resistance, a decrease in heart rate, and a marked decrease in pulmonary vascular resistance. Recently, we have demonstrated an increase in contractility and a decrease in myocardial wall volume. The modified technique of ultrafiltration has been employed successfully in more than 400 patients in our institution, and represents an excellent option for perioperative management of both accumulation of fluid in the tissues and hemodynamics after hypothermic bypass.

Adolescent↗
PubMed1993

Phrenic nerve damage via a right thoracotomy in older children with secundum ASD.

Phrenic nerve damage (PND) in children after cardiac operations is now recognized as being more frequent than previously thought. In a prospective study on 400 children, we previously demonstrated electrophysiologic evidence of postoperative PND in approximately 16% of patients, with one third of cases occurring in children under 18 months. In the past 18 months, 30 children have had atrial septal defect (ASD) repairs as their only operative procedure. Fourteen children had ASD repairs via a midline incision, and 16 ASD repairs were via a right thoracotomy. No PND (assessed by phrenic nerve latency) was found after a midline approach. In the right thoracotomy group, 5 children had evidence of PND (31%; p = 0.05). Four of these 5 patients were female and more than 14 years of age. The incidence of damage in this pubescent group was 80% (p < 0.05). In the older age group the duration of ventilation was not prolonged, but affected patients had symptoms of fatigue and breathlessness postoperatively. These data suggest a strong association between right thoracotomies for ASD repairs and PND, especially in the female pubescent group when a low submammary skin incision (seventh to eighth space) is used with a fifth to sixth space entry into the thoracic cavity. In conclusion, the right thoracotomy approach for ASD repair appears to be a significant risk factor for PND in older children.

Adolescent↗
PubMed1993

Congenital left ventricular outflow tract obstruction.

Congenital obstruction of the left ventricular outflow tract remains a significant problem. Obstruction may involve the subvalvar, valvar or supravalvar portion of the aortic valve complex. Congenital valvar stenosis presenting in the neonatal period represents a spectrum of disorders ranging from the hypoplastic left heart syndrome to almost normal hearts. Preoperative echocardiography may allow the selection of infants who are suitable for biventricular repair, with the therapeutic options including open valvotomy and balloon valvotomy, but the determination of the optimal method of treatment will require long term follow up data. Subvalvar obstruction may be discrete or diffuse, and the extent will determine the appropriate therapy. Discrete membranes may be managed by a simple excision while diffuse involvement of the subvalvar region may require a more extensive reconstructive procedure such as the Konno procedure. Supravalvar aortic stenosis is the least common form of aortic stenosis and may be associated with abnormalities of the pulmonary arteries. Treatment is often palliative rather than corrective with all types of congenital left ventricular outflow tract obstruction, and many patients will require reoperations, especially those with valvar and subvalvar obstruction. The lack of long term follow up data for patients treated in the neonatal period makes the choice of an optimal therapy difficult. New methods of valve replacement such as the pulmonary autograft may improve long term results.

Aortic Stenosis, Subvalvular↗
PubMed1993

Increased plasma levels of endothelin-1 after cardiopulmonary bypass in patients with pulmonary hypertension and congenital heart disease.

The plasma level of the potent vasoconstrictor endothelin-1 was measured in children who underwent cardiac operations. Forty-five patients were divided into two groups, those with a high pulmonary blood flow (HF group; n = 23) and those with a normal or low flow (NF group; n = 22). Seven blood samples were taken: immediately before cardiopulmonary bypass, immediately after removing the aortic cross-clamps, immediately after discontinuing bypass, and at 20 minutes and 3, 6, and 24 hours after termination of bypass. The plasma levels of endothelin-1 were similar in both groups before bypass. From the time the aortic crossclamps were removed, the plasma endothelin-1 levels in both groups increased significantly, to reach a peak level at 3 to 6 hours. The increase was significantly greater in the HF than in the NF group, and the maximum values in the two groups were 12.6 +/- 1.1 and 9.6 +/- 0.8 fmol/ml, respectively (mean +/- standard error of the mean, p < 0.05). The value 20 minutes after bypass showed a positive correlation with the mean pulmonary arterial pressure measured at the preoperative cardiac catheterization study (r = 0.41, p < 0.05). In addition, a significant positive correlation was obtained between endothelin-1 3 hours after bypass and the maximum pulmonary/systemic arterial pressure ratio during the first 12 hours after operation (r = 0.86, p < 0.05). These results suggest that cardiopulmonary bypass is associated with an immediate postoperative increase in circulating endothelin and that patients who had a high pulmonary blood flow before the operation are particularly vulnerable, bypass having a more injurious effect on a lung with preexisting endothelial dysfunction. A high level of circulating endothelin may predispose to pulmonary vascular lability and pulmonary hypertensive crises in the postoperative period.

Adolescent↗
PubMed1992

Plasminogen activator in granulocyte-macrophage-CSF transgenic mice.

The pattern of expression of urokinase type plasminogen activator (PA) in granulocyte-macrophage-CSF transgenic mice and their normal littermates was studied using RNAse protection assays and a plasminogen-dependent fibrinolytic assay for PA. Urokinase type PA mRNA was expressed at a high level in transgenic peritoneal cells and at a lower level in transgenic eye tissue and spleen, but not in equivalent tissue from the normal mice. Enzymically active PA was detectable in protein extracts from peritoneal cells taken from transgenic mice of less than 8 wk of age (young mice) but not from normals. Paradoxically, extracts from transgenic mice of more than 12 wk of age (old mice) showed little detectable PA activity despite continuing transcription in some mice of this age. The production of PA by peritoneal cells may be responsible for the spontaneous i.p. bleeding which is a feature of the transgenic mice and production in other tissues may help explain the local pathologic changes.

Age Factors↗
PubMed1992

The excess numbers of peritoneal macrophages in granulocyte-macrophage colony-stimulating factor transgenic mice are generated by local proliferation.

Mice transgenic for the hemopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), exhibit a sustained elevation of GM-CSF levels and a 50-100-fold elevation of peritoneal macrophage cell numbers. The excess cell numbers were found to be generated in pre-adult life, with numbers remaining relatively constant thereafter. In the pre-adult period, no abnormalities were noted in the number or composition of blood, bone marrow, or spleen cells, the type or number of GM progenitor cells in the marrow or spleen, or the rate of appearance of newly formed monocytes in the peripheral blood. Peritoneal macrophages in pre-adult transgenic mice exhibited elevated mitotic activity and, after tritiated thymidine labeling, a more rapid accumulation of labeled progeny. The increase in peritoneal macrophage cell numbers appears, therefore, to be based on a GM-CSF-induced increase in local proliferative activity by peritoneal macrophages. This increased activity declined at the age of 8-10 wk, in parallel with a change in the morphology of the transgenic macrophages and an increase in binucleate and multinucleate macrophages arising by cell fusion. This change in macrophage phenotype was restricted to the transgenic mice and may therefore be a consequence of continued overstimulation by GM-CSF.

Age Factors↗
PubMed1992

Pulmonary artery sling.

Eighteen patients who underwent surgical treatment of pulmonary artery sling at this institution since 1969 were reviewed. Four of them had associated tracheal stenoses produced by complete cartilaginous rings (stovepipe trachea). All patients underwent operation. The median age at operation was 180 days (range, 27 days to 54 months). In the 14 patients with isolated pulmonary sling, the operation consisted of division of left pulmonary artery and reimplantation into the main pulmonary artery anterior to the trachea. In the 4 patients with stovepipe trachea, the stenotic tracheal segment was resected on cardiopulmonary bypass and the left pulmonary artery was brought anterior to the trachea before the latter was reanastomosed to the main pulmonary artery. There were no early deaths. One patient died late. The pulmonary artery anastomosis was patent in all 14 patients investigated postoperatively. Three patients have residual tracheobronchial problems. One patient is mentally retarded and is institutionalized. All other patients are symptom-free and growing normally and have normal chest radiographs.

Child, Preschool↗
PubMed1992

GM-CSF, IL-3 and IL-5: cross-competition on human haemopoietic cells.

The biological properties of GM-CSF, IL-3 and IL-5 are multiple; initially described as haemopoietic growth factors, they also regulate inflammation, allergic reactions and cell adherence. The receptors for these three cytokines share a common component which may play a key role in their biological activity. This review describes the potential roles of GM-CSF, IL-3 and IL-5 in inflammation and discusses approaches to modulate their function.

Binding, Competitive↗
PubMed1992

Differential binding of IL-3 and GM-CSF to human monocytes.

Human monocytes respond to IL-3 and GM-CSF with a similar range of functional activities, and at similar cytokine concentrations. We have recently shown, however, that the rate of monocyte activation is greater in response to GM-CSF than to IL-3. In order to understand the basis of this phenomenon we investigated the interaction of IL-3 and GM-CSF with their surface receptors by means of kinetic binding experiments. 125I-GM-CSF showed very rapid association to monocytes at 37 degrees C, with a half-time of only 40 sec. The pattern of binding with this ligand was complex, with a decline in overall cell-associated radioactivity after 2 min of incubation. In contrast, 125I-IL-3 showed slower association, with a half-time at 37 degrees C of 2.5 min. The different rates of association correlated well with the different rates of cell activation induced by the two cytokines. On the other hand, rates of internalisation were similar for the two cytokines, with half-times of 14-15 min. Competition binding experiments performed under high affinity conditions showed that IL-3 and GM-CSF cross-competed for binding on the surface of monocytes. In contrast, under low affinity conditions IL-3 did not compete for 125I-GM-CSF binding while GM-CSF was a strong competitor of 125I-IL-3 binding. In quantitative inhibition experiments GM-CSF showed inhibitory effects on low affinity 125I-IL-3 binding at lower concentrations than those needed with unlabelled IL-3. It is suggested that current models of IL-3/GM-CSF receptor interactions need to be revised in order to accommodate the unique pattern of competition on human monocytes presented here.

Binding, Competitive↗
PubMed1992

Noninvasive estimation of total body water in critically ill children after cardiac operations. Validation of a bioelectric impedance method.

The understanding of fluid fluxes in pediatric cardiac critical care is crucial to effective management. Knowledge of variations in total body water in this situation would aid this understanding, but most available methods are unsuitable for routine use. Recently, estimation of total body water by a tetrapolar bioelectric impedance has been validated in older children and adolescents. We undertook a study to validate the method in the taxing conditions of pediatric cardiac critical care. A prospective comparative study was done in 16 children whose ages ranged from 6 days to 10 years (mean 23 months) after a variety of cardiac operations. Total body water was estimated by a standard isotope dilution method (deuterium oxide) and by bioelectric impedance by means of a Holtain body composition analyzer. Individual estimations of total body water were made on two successive days on each patient at varying intervals after a cardiac operation, bioelectric impedance being measured hourly during 4 hourly urine collections for the deuterium oxide method. Thirty-two simultaneous values of total body water (by isotope and by impedance) were collected. Population-specific regression relationship was established by plotting total body water (isotope) against height2/bioelectric impedance. From this data plot r = 0.911, giving this equation: total body water = 0.158 +/- 0.662 x (height2/bioelectric impedance). Levels of agreement of -1.771 to +1.725 were observed, with a standard error of measurement of 16% across the range. The data suggest that bioelectric impedance is a satisfactory and reliable method of estimating total body water in children requiring cardiac critical care. The standard error of 16% suggests that the method may be more useful for measuring trends than absolute values, but the technique should be a valuable noninvasive tool both for continuous monitoring of total body water and in longitudinal research studies of rapid fluid flux and in the assessment of capillary leak.

Body Water↗
PubMed1991

Interleukin-5, interleukin-3, and granulocyte-macrophage colony-stimulating factor cross-compete for binding to cell surface receptors on human eosinophils.

Human interleukin (IL)-5 receptors were characterized by means of binding studies using bioactive 125I-labeled IL-5. Of purified primary myeloid cells, eosinophils and basophils but not neutrophils or monocytes expressed surface receptors for IL-5. Binding studies showed that eosinophils expressed a single class of high affinity receptors (Ka = 1.2 x 10(10) M-1) with the number of receptors being small (less than 1000 receptors/cell) and varying between individuals. Among several cell lines examined only HL-60 cells showed detectable IL-5 receptors which were small in numbers (200 receptors/cell) and also bound 125I-IL-5 with high affinity. The binding of IL-5 was rapid at 37 degrees C while requiring several hours to reach equilibrium at 4 degrees C. Specificity studies revealed that the two other human eosinophilopoietic cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited the binding of 125I-IL-5 to eosinophils. No competition was observed by other eosinophil activating or nonactivating cytokines. The inhibition of 125I-IL-5 binding by IL-3 and GM-CSF was partial up to a concentration of competitor of 10(-7) M with GM-CSF consistently being the stronger competitor. Converse experiments using IL-5 as a competitor revealed that this cytokine inhibited the binding of 125I-IL-3 and of 125I-GM-CSF in some but not all the individuals tested, perhaps reflecting eosinophil heterogeneity in vivo. Cross-linking experiments on HL-60 cells demonstrated two IL-5-containing complexes of Mr 150,000 and Mr 80,000 both of which were inhibited by GM-CSF. The competition between IL-5, IL-3, and GM-CSF on the surface of mature eosinophils may represent a unifying mechanism that may help explain the common biological effects of these three eosinophilopoietic cytokines on eosinophil function. This unique pattern of competition may also be beneficial to the host by preventing excessive eosinophil stimulation.

Binding, Competitive↗
PubMed1991

Selective up-regulation of macrophage function in granulocyte-macrophage colony-stimulating factor transgenic mice.

Peritoneal and pleural cells from mice transgenic for GM-CSF were studied with regard to their phenotype and functional capacity, and compared with cells from normal littermates. Transgenic mice showed markedly elevated peritoneal and pleural cell counts compared with littermates, and a significantly higher proportion of cells in the transgenic populations were macrophage in phenotype. Transgenic macrophages were larger than the littermate cells, showing abundant foamy cytoplasm and enhanced spreading on plastic. Analysis by flow cytometry showed a more than sixfold increased expression of the macrophage activation markers MAC-2 and MAC-3, but not other markers, on transgenic macrophages. Superoxide production was measured in whole cell populations, both in their basal state and in response to particulate (zymosan) and soluble (PMA) stimuli. Both basal and stimulated superoxide production were markedly elevated in transgenic mice of 12 wk of age, with the largest differences seen in response to PMA. In younger mice, however, only PMA-stimulated superoxide production was significantly greater in transgenic macrophages than in littermate cells and levels of superoxide were generally lower than those seen in 12-wk-old mice. These findings suggest that the enhanced functional capacity of transgenic cells is a maturation-dependent event. In contrast to these findings, drug-dependent cytotoxicity assays performed on cells from 12-wk-old mice revealed no significant differences in killing capacity between the two mouse strains. Taken together these data indicate a selective rather than uniform functional up-regulation in transgenic macrophages compared with their littermates, with a time scale suggestive of a maturational rather than activation process. These findings may provide an indication of the functional macrophage phenotype resulting from long term exposure to GM-CSF in vivo, and help to explain the macrophage-associated pathology seen in GM-CSF-transgenic mice.

Animals↗