Biomedical subjects

M J Elliott

Publications and source records attributed to M J Elliott.

At least 73 records · Page 4Linked to original sources

PubMed1997

Stöckert roller pump generated pulsatile flow: cerebral metabolic changes in adult cardiopulmonary bypass.

There is evidence that during cardiopulmonary bypass (CPB), pulsatile pump flow improves cerebral metabolism. This was a study to explore the effect of pulsatile versus nonpulsatile perfusion on cerebral lactate, pyruvate, glucose and beta-hydroxybutyrate using a Stöckert roller pump. We found no significant differences between the arterial-venous (A-V) differences of lactate, glucose and beta-hydroxybutyrate (p > 0.05). When the upward trend of A-V pyruvate was accounted for, there was again no difference (p = 0.2). Arterial lactate:pyruvate ratios were not significantly different between pulsatile and nonpulsatile pump flow (p > 0.05). Venous lactate:pyruvate ratios were significantly higher during pulsatile bypass, but when the downward trend was accounted for, the differences between pulsatile and nonpulsatile values were no longer significant (p = 0.4). Therefore, the metabolic changes were not significant. There was no significant difference in systemic vascular resistance (SVR) during pulsatile and nonpulsatile flow (p = 0.4). Pulsatile flow delivered by the Stöckert roller pump appears to have no metabolic or SVR advantages in adults undergoing CPB.

3-Hydroxybutyric Acid↗

PubMed1996

Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor alpha antibody in rheumatoid arthritis.

OBJECTIVE: To assess whether monoclonal antibody to tumor necrosis factor alpha (TNF alpha) reduces endothelial activation in rheumatoid arthritis (RA). METHODS: Levels of serum E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), and circulating leukocytes (differential counts) were measured in RA patients before and up to 4 weeks after infusion of either placebo or chimeric anti-TNF alpha antibody cA2 (1 or 10 mg/kg). RESULTS: Treatment with anti-TNF alpha decreased serum E-selectin and ICAM-1 levels, with the earliest detectable changes observed on days 1-3 after anti-TNF alpha infusion. No effect on VCAM-1 levels was detected. In parallel, there was a rapid and sustained increase in circulating lymphocytes. The extent of the decrease in serum E-selectin and ICAM-1 levels and the increase in lymphocyte counts was significantly higher (P < or = 0.05) in patients in whom a clinical benefit of anti-TNF alpha was observed ( > or = 20% response, by Paulus criteria, at week 4) compared with that in patients who failed to respond to anti-TNF alpha at this time point. CONCLUSION: We propose that decreased serum levels of adhesion molecules may reflect diminished activation of endothelial cells in the synovial microvasculature, leading to reduced migration of leukocytes into synovial joints, and thus prolonging the therapeutic effect of anti-TNF alpha in RA.

Antibodies, Monoclonal↗

PubMed1996

Successful complete tracheal resection in a three-month-old infant.

We report an infant with severe long-segment tracheal stenosis in whom the posterior trachea was formed by complete cartilage rings and the anterior trachea was almost totally formed by a solid cartilage plate. The child was successfully treated initially by complete resection of the trachea and primary end-to-end repair and subsequently with tracheal homograft transplantation for secondary stenosis.

Anastomosis, Surgical↗

PubMed1996

Expanded PTFE membrane to prevent cardiac injury during resternotomy for congenital heart disease.

BACKGROUND: Resternotomy for repair of congenital cardiac defects can result in cardiac injury. Closure of the pericardium during the initial operation may prevent this, and several pericardial substitutes have been tried, with variable results, in patients in whom primary pericardial closure is not possible. We conducted a multicenter observational study of the use of the expanded polytetrafluoroethylene membrane (Preclude Pericardial Membrane, formerly called the Gore-Tex Surgical Membrane; W. L. Gore & Associates, Flagstaff, AZ) in patients likely to undergo reoperation for treatment of congenital heart disease. METHODS: Data were collected retrospectively on all patients in whom the expanded polytetrafluoroethylene membrane was inserted at the initial operation for congenital heart disease at 12 centers in 1984 to 1993. RESULTS: A total of 1,085 patients (mean age, 55 +/- 2.5 months) received the membrane. During follow-up ranging from 1.3 to 10.5 years, 105 reoperations were performed. Injury during resternotomy occurred in only 1 patient (1% of reoperations). There were no membrane-related deaths or complications in the entire series of 1,085 patients. CONCLUSIONS: The expanded polytetrafluoroethylene membrane was safe and effective in helping to prevent cardiac injury during resternotomy for treatment of congenital heart disease.

Child, Preschool↗

PubMed1996

Extracorporeal membrane oxygenation as a bridge to definitive tracheal surgery in children.

Extracorporeal membrane oxygenation was used as a bridge for three infants with complicated long segment congenital tracheal stenosis to tracheal homograft transplantation with cadaveric tracheal homograft and for one child, with an extensive traumatic tracheal laceration caused by aspiration of a sharp foreign body, to definitive tracheal repair. In all four cases mechanical ventilation was impossible and death almost certain without extracorporeal membrane oxygenation.

Cadaver↗

PubMed1996

Pediatric tracheal homograft reconstruction: a novel approach to complex tracheal stenoses in children.

PURPOSE: Tracheal stenosis can be a life-threatening problem in children. Long-segment tracheal stenosis and recurrent tracheal stenosis are especially problematic. Tracheal homograft reconstruction represents a novel therapeutic modality for these patients. METHODS: Cadaveric trachea is harvested, fixed in formalin, washed in thimerosal (Methiolate), and stored in acetone. The stenosed tracheal segment is opened to widely patent segments proximally and distally. The anterior cartilage is excised and the posterior trachealis muscle or tracheal wall remains. A temporary silicone rubber intraluminal stent is placed and absorbable sutures secure the homograft. Regular postoperative bronchoscopic treatment clears granulation tissue. The stent is removed endoscopically after epithelialization over the homograft. Twenty-four children with severe tracheal stenosis (age 5 months to 18 years, mean +/- standard error of the mean = 8.18 +/- 1.21 years) underwent tracheal homograft reconstruction. All but one had had previous unsuccessful reconstructive attempts. Ten lesions were congenital, nine were posttraumatic, and five were due to prolonged intubation. RESULTS: Follow-up ranged from 5 months to 10 years (3.79 +/- 0.70 years). Twenty patients survive (20/24 = 83%), 16 without any airway problems. Four patients are still undergoing treatment. One patient requiring emergency extracorporeal membrane oxygenator support before the operation died 10 days after tracheal homograft reconstruction. Another patient with severe preoperative mediastinal sepsis died 3.5 months after tracheal homograft reconstruction. Two patients with functional airways died late of unrelated problems. CONCLUSIONS: Tracheal homograft reconstruction demonstrates encouraging short-term to medium-term results for children with severe recurrent tracheal stenosis. Postoperative bronchoscopic and histologic studies provide evidence of epithelialization and support the expectation of good long-term results.

Adolescent↗

PubMed1996

Is a high-risk biventricular repair always preferable to conversion to a single ventricle repair?

OBJECTIVES: The aim of this report is to examine the short-and intermediate-term outcome of a complex biventricular repair compared with a single ventricle repair in patients with two functional ventricles. PATIENT POPULATION: Since 1986, 34 patients with atrioventricular concordance or discordance, ventriculoarterial discordance, ventricular septal defect, and pulmonary stenosis or atresia have undergone biventricular repair (group I). Another group of 16 patients (group II) with the same diagnoses have undergone a single ventricle repair consisting of a total cavopulmonary connection because of either a straddling atrioventricular valve (11 patients) or an uncommitted ventricular septal defect (5 patients). RESULTS: The mean length of follow-up was 3.9 years in group I and 3.0 years in group II. Freedom from reoperation at 7 years was 45.5% in group I and 100% in group II (p = 0.014). The actuarial estimate of survival at 7 years was 68.0% in group I and 93.8% in group II (p = 0.048). CONCLUSION: Short- and intermediate-term morbidity and mortality were greater in patients undergoing a biventricular repair than in a similar group of patients undergoing total cavopulmonary connection. It is unknown whether the long-term results of a total cavopulmonary connection in patients with two ventricles are as good as those obtained with a biventricular approach. However, there may be situations in which the short- and intermediate-term risks of a complex biventricular repair may outweigh the long-term disadvantages of a single ventricle approach.

Actuarial Analysis↗

PubMed1996

Mixed total pulmonary venous drainage: still a surgical challenge.

OBJECTIVE: The aim of this report is to review the surgical experience of a single institution with a relatively large series of patients with mixed total pulmonary venous drainage. PATIENT POPULATION: Between January 1, 1971, and December 31, 1994, 232 patients with total pulmonary venous drainage underwent surgical correction. Twenty of these patients (8.6%) had mixed type total pulmonary venous drainage. Ages at operation ranged from 1 day to 46 months, with a median of 2.3 months. RESULTS: Both cardiac catheterization and echocardiography were performed before operation in 12 patients. Four patients underwent only cardiac catheterization, and another four patients underwent only echocardiography. The sensitivity and specificity for catheterization were 94% and 99%, respectively; they were 31% and 100%, respectively, for echocardiography. Severe pulmonary venous obstruction was present in three patients, all of whom underwent emergency operation. Three patients (15%), all of whom had preoperative pulmonary venous obstruction, died after operation. There were two late deaths, one of pulmonary vein stenosis and the other of probable pulmonary hypertension. The actuarial survival at 10 years was 73% for all patients; patients who survived the initial operation had a 10-year survival of 87%. CONCLUSION: The diagnosis of mixed total pulmonary venous drainage can be difficult to establish by echocardiography or at the time of operation. For patients in stable condition, cardiac catheterization may be considered if fewer than three pulmonary veins are identified by echocardiography. Pulmonary venous obstruction is relatively infrequent in this group of patients but when present impacts patient survival significantly. The long-term results with this lesion are excellent.

Actuarial Analysis↗

PubMed1996

Tracheal reconstruction in children using cadaveric homograft trachea.

OBJECTIVE: We report the use of cadaveric human tracheal homograft in the treatment of severe long segment congenital tracheal stenosis in children. METHODS: Five children (aged 5 months-8 years) with severe life-threatening airway obstruction due to long segment congenital tracheal stenosis had failed conventional management. All were ventilator dependent or rapidly deteriorating at the time of surgery, two were on extracorporeal membrane oxygenation, and no alternative therapy was available. The stenosed trachea was removed and the posterior trachealis muscle left in situ when possible. Surgical technique involved the use of cardiopulmonary bypass in four of five cases. Stored cadaveric tracheal homograft tissue was shaped and inserted over a silastic intra-luminal stent which was kept in place for up to 3 months. Regular bronchoscopy was necessary postoperatively to clear granulation tissue, which resolved on removal of the stent. RESULTS: Four patients are all now without stents, intubation or tracheostomy. Three are without airway problems 16, 14, and 9 months after surgery and one attends for occasional dilatation of a distal tracheal stenosis, but is now at home despite other severe multiple congenital problems. One patient presented with complete disruption of the trachea and mediastinal sepsis and was supported on extracorporeal membrane oxygenation prior to surgery; this patient eventually died of airway failure and sepsis. CONCLUSIONS: The application of cadaveric human tracheal homograft to congenital tracheal stenosis is novel. Its use in five children who would otherwise have died has provided an extra therapy in an extremely difficult group of patients.

Airway Obstruction↗

PubMed1995

TNF alpha is an effective therapeutic target for rheumatoid arthritis.

Rheumatoid arthritis is the most common of a number of diseases in which inflammation and tissue destruction is driven by an autoimmune process. Current therapy is inadequate, and this has prompted major research efforts, both in academia and industry, to understand more about the pathogenesis, and hence provide the rationale for new therapeutic strategies. Here we review our studies of cytokine expression and regulation in rheumatoid joints, which has culminated in demonstrating that TNF alpha blockade, using a chimeric (human IgG1/K, mouse Fv) anti-TNF alpha antibody, cA2, markedly ameliorates arthritis. This defines a therapeutic target for rheumatoid arthritis.

Animals↗

PubMed1995

Repair of anomalous pulmonary venous connection to the superior vena cava.

Complex forms of anomalous pulmonary venous connection to the superior vena cava (SVC) can be difficult to correct surgically. Since 1987, 11 patients have undergone repair of anomalous pulmonary venous connection to the SVC by diversion of the pulmonary venous drainage to the left atrium using a baffle with division of the SVC and reimplantation on the right atrial appendage to restore normal systemic venous drainage. Total anomalous pulmonary venous connection was present in 3 patients and partial anomalous pulmonary venous connection, in 8. All patients are alive and asymptomatic at a mean follow-up of 2.3 +/- 1.4 years. Postoperative echo-cardiograms (8 patients) revealed pulmonary venous obstruction requiring reoperation in 1 patient. No patient has clinical evidence of SVC obstruction, and all are in sinus rhythm. This is a safe and effective technique for repair of complex forms of anomalous pulmonary venous connection to the SVC, and the incidence of postoperative venous obstruction and rhythm disturbances is low.

Adolescent↗

PubMed1995

Effect of heparin anticoagulation on neutrophil adhesion molecules and release of IL8: C3 is not essential.

OBJECTIVE: To examine the role of heparin in modulating neutrophil activation and release of cytokine. BACKGROUND: Up-regulation of CD11b, down-regulation of L-selectin on neutrophil cell surface and release of IL8 occur in response to extracorporeal circulation (ECC) and were proposed to cause leakage of the capillaries in patients. DESIGN: In a series of experiments, we examined the effect of heparin (4 U/ml) comparing it with ethylenediamine tetra-acetate (EDTA, 1.5 mg/ml) and citrate mixture (100 microliters/ml), heparin dose-response, IL8 (human recombinant IL8) dose-response and protamine (80 micrograms/ml) neutralisation of heparin (4 U/ml) using donor blood (total of 38). The role of complement component type 3 (C3) was tested. Neutrophils from a patient with complete C3 deficiency were stimulated by using heparin and cobra venom factor (10 micrograms/ml) and compared with controls (n = 5). CD11b and L-selectin expressions were assayed immediately and serially up to 120 min using immune fluorescence and flow cytometry. Serum concentrations of IL8 were determined by using enzyme-linked immunosorbent assay. RESULTS: The medians of up-regulation of CD11b were 540.2 (range 235.2-653.3) for heparin vs. 186.5 (55.7-207.1) for EDTA and 192.5 (69.2-263.8) for citrate mixture, P < 0.01. The medians of down-regulation of L-selectin were 79 (32-192) for heparin vs. 18.4 (0-188) for EDTA and 36.2 (7.4-135) for citrate mixture, P < 0.05. Up-regulation of CD11b, down-regulation of L-s and release of IL8 were inversely related to heparin concentration (r = 0.87, P < 0.05). Serum concentration of IL8 had a direct relationship to the changes in CD11b and L-selectin expression (r = 0.92). Heparin-protamine complex was less stimulant to expression of CD11b and L-selectin than heparin or protamine (P < 0.05). In blood samples from C3-deficient patients, heparin and cobra venom factor caused up-regulation of CD11b and down-regulation of L-selectin similar to that of controls (P > 0.05). CONCLUSIONS: Heparin stimulates up-regulation of neutrophil adhesion molecules CD11b, down-regulation of L-selectin and release of IL8. These effects are inversely related to heparin concentration and are independent of C3 activation. IL8 has a direct relationship to activation of neutrophil adhesion molecules. Increasing heparin dosage reduces neutrophil activation and may reduce the morbidity of patients.

Adolescent↗

PubMed1995

Vascular and contractile function and tissue metabolites after prolonged hypothermic ischaemia and reperfusion: comparison of single- versus multi-dose infusions with two cardioplegic solutions in blood-perfused neonatal pig hearts.

The effects of single- and multi-dose cardioplegia on post-ischaemic vascular function and contractile activity were compared in 69 blood-perfused neonatal pig hearts, as were the protective properties of two different cardioplegic solutions. Hearts (n = 6 or 9 per group) from neonatal (3-5 days old) pigs were excised, arrested with a 2 min infusion (at 15 degrees C) of St Thomas' Hospital cardioplegic solution number 1 (STH1) or number 2 (STH2), and then maintained in a state of hypothermic (15 degrees C) ischaemia for 6 or 8 h. Hearts in the multi-dose groups received cardioplegia every hour (2 min at 15 degrees C). At the end of ischaemia all hearts were reperfused (60 +/- 2 mmHg perfusion pressure) for 40 min with blood from a support pig. Systolic and diastolic functions were assessed with an intraventricular balloon, and endothelial and smooth muscle functions by measuring the response to infusions of defined concentrations of acetylcholine (8, 16 and 32 micrograms/min) and glyceryl trinitrate (40, 80 and 160 micrograms/min). Hearts (n = 9) not subjected to ischaemia were perfused for the same duration to act as aerobic controls. At the end of the perfusion period, hearts were frozen and taken for metabolite analysis. After 8 h ischaemia, the recovery of left ventricular developed pressure was greatest in the multi-dose STH1 and single-dose STH2 groups (113 +/- 6 and 117 +/- 6 mmHg, respectively, v 128 +/- 9 mmHg in aerobic controls, at an end-diastolic pressure of between 3 and 9 mmHg; P = N.S.) and the poorest in the single-dose STH1 group (92 +/- 5 mmHg; P < 0.05 v controls). The recovery of diastolic function was greatest in the multi-dose STH2 group and again poorest in the single-dose STH1 group (left ventricular end-diastolic pressure 1 +/- 2 and 30 +/- 10 mmHg, at a ventricular volume of 3.0 ml, v -1 +/- 1 mmHg in aerobic controls). Vascular responses to acetylcholine and glyceryl trinitrate and the myocardial high-energy phosphates content were better preserved in multi-dose groups and with STH2. Inter-group differences were less when the duration of ischaemia was reduced to 6 h. In conclusion, the neonatal pig heart was best preserved with multi-dose cardioplegia and STH2 was more efficacious than STH1. However, not all indices were optimally protected by multi-dose STH2. Thus, the best protection of systolic function was obtained with multidose STH1 and this was followed by single-dose STH2. Diastolic function was best preserved with multi-dose STH2 as were vascular function and high-energy phosphates.

Animals↗

PubMed1995

TNF alpha blockade in rheumatoid arthritis: rationale, clinical outcomes and mechanisms of action.

Tumor necrosis factor alpha (TNF alpha) is a cytokine with many biological functions of relevance to inflammatory disease. Although only one of several inflammatory mediators produced in abundance in rheumatoid arthritis (RA), experimental data suggest that it is in a dominant position within a cytokine hierarchy and is therefore a prime target for directed immunotherapy in this disease. We have targeted TNF alpha in vivo using a chimerised monoclonal anti-TNF alpha antibody and have now demonstrated beneficial responses to treatment in three different clinical trials. The results confirm that TNF alpha is of central importance in the inflammatory process in RA and define a new treatment strategy in this disease.

Acute-Phase Proteins↗

PubMed1995

Anti-cytokine therapy in rheumatoid arthritis.

The past few years have seen an explosion of knowledge concerning the role of cytokines and their naturally occurring inhibitors in the promotion and modulation of inflammatory disease. In RA, this knowledge has been translated into the clinic, with ongoing evaluation of specific cytokine inhibitors, including those targeting tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6). In this review, we outline the scientific data supporting anti-cytokine therapies in RA and describe the results of published and unpublished clinical trials with biological agents. At least for anti-TNF therapy, short-term clinical efficacy and good tolerability have been confirmed in randomized, placebo controlled trials. The results of IL-1 blockade in vivo also appear encouraging, although detailed descriptions of trail outcomes are awaited. Problems associated with long-term administration of biological agents are discussed, including the development of antiglobulin responses to injected monoclonal antibodies and poor pharmacokinetics of low-molecular-weight inhibitors. Ways of facilitating the long-term use of current biological agents and alternative means for inhibiting cytokine function in future studies in RA are presented.

Animals↗

PubMed1995

Results of heart-lung transplantation in children with cystic fibrosis.

Children with cystic fibrosis represent the largest group referred for, and undergoing, heart-lung transplantation at our institute. Between June 1988 and July 1993, 76 patients were accepted for transplantation, of whom 25 were transplanted, while a further 36 died waiting. Those transplanted ranged from 5-18 years of age and included 13 males and 12 females. Organs were used from donors matched by ABO blood group, size and cytomegalovirus (CMV) status. Post-transplant maintenance immunosuppression comprised cyclosporin A, azathioprine and prednisolone. Anti-thymocyte globulin and high dose methylprednisolone were given peri-operatively and for acute rejection episodes. Actuarial survival was 67% at 1 year, 61% at 2 years and 54% at 3 years. Obliterative bronchiolitis (OB) has occurred in 13 patients (52%) and was the major cause of mortality and morbidity. In three patients, OB was associated with the development of tracheal anastomotic stenosis. Other complications included diabetes mellitus (n = 9), pancreatitis (n = 1) and hypertension (n = 8). Despite these problems, those surviving the first year post-transplant showed a mean FEV1 of 71% (compared to 29% pre-transplant) and enjoyed an overall improved quality of life.

Actuarial Analysis↗

PubMed1995

Beneficial effects of tumour necrosis factor-alpha (TNF-alpha) blockade in rheumatoid arthritis (RA)

The biological properties of TNF-alpha make it a candidate therapeutic target in RA. Our studies have demonstrated that TNF-alpha and its receptors are up-regulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Neutralizing TNF-alpha antibodies reduce the production of the many pro-inflammatory cytokines, including IL-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF), produced by mononuclear cells from RA in culture. When injected into DBA/1 mice with collagen-induced arthritis and TNF-alpha transgenic mice with arthritis, anti-TNF MoAbs decrease inflammatory damage of joints. Clinical trials employing cA2, a chimaeric anti-TNF-alpha MoAb, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute-phase responses lasting several weeks. We conclude that TNF-alpha is a critical mediator of inflammation in RA, and is an important therapeutic target in this disease.

Antibodies, Monoclonal↗

PubMed1995

Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease.

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.

Animals↗