PubMed Health⌕ Search

Biomedical subjects

J H Dark

Publications and source records attributed to J H Dark.

At least 19 recordsLinked to original sources
PubMed1998

Differential effects of cyclosporin A and tacrolimus on the production of TGF-beta: implications for the development of obliterative bronchiolitis after lung transplantation.

The development of obliterative bronchiolitis is a common cause for failure of lung allografts. Fibrinogenesis can occur for a number of different reasons but some groups have suggested that cyclosporin A (CsA) and tacrolimus (FK506) have different effects on the cytokines which induce fibrinogenesis. We investigated the effect of tacrolimus and CsA in tissue culture and found that there was indeed a negative effect on human lung small airway epithelial cell proliferation by recombinant transforming growth factor-beta (TGF-beta), which was reversed by anti-TGF-beta. The same effect was seen with CsA at immunosuppressive concentrations, which was also reversed by anti-TGF-beta, whereas no such inhibition was seen with tacrolimus at immunosuppressive doses unless high concentrations were used. Free TGF-beta was confirmed as being elevated in the supernatant of cell culture wells with standard dose CsA as opposed to low dose CsA or tacrolimus using an ELISA assay.

Bronchiolitis Obliterans↗
PubMed1998

Controlled reperfusion and pentoxifylline modulate reperfusion injury after single lung transplantation.

OBJECTIVE: Rodent models have suggested that initial low-pressure reperfusion of transplanted lungs reduces injury after ischemia. We investigated this phenomenon and the use of pentoxifylline in a porcine model of left single lung transplantation. METHODS: Donor lungs were preserved with Euro-Collins solution for a mean ischemic time of 18.4 hours. Neutrophil trapping in the graft, pulmonary artery pressure, and gas exchange were assessed over a 12-hour period. Partial occlusion of the contralateral pulmonary artery allowed manipulation of the pulmonary artery pressure in the transplanted lung. Group A (n = 5) was perfused at a mean pulmonary artery pressure of 20 mm Hg, group B was reperfused at a mean pulmonary artery pressure of 45 mm Hg for 10 minutes before reducing the pressure to the same as group A, and group C was reperfused at a mean pressure of 20 mm Hg for 10 minutes, then increased to a mean of 45 mm Hg for the remainder of the experiment. Group D was reperfused as in group A with the addition of intravenous pentoxifylline. RESULTS: Leukocyte sequestration was observed in the first 10 minutes after reperfusion in groups A, B, and C, with maximal sequestration at 2 minutes. Significantly more sequestration was observed in the first 6 minutes in group B than in groups A and C, which were similar. Pentoxifylline significantly reduced leukocyte sequestration. Pulmonary venous oxygen tension in the allograft lung was worst in group B. Groups A and C were similar, but group D was superior to all other groups (p < 0.001). CONCLUSIONS: Low-pressure reperfusion, even when limited to the first 10 minutes, modulates reperfusion injury possibly through a leukocyte-dependent mechanism. The addition of pentoxifylline in the recipient confers significant additional benefit.

Animals↗
PubMed1998

Orthotopic cardiac transplantation for the failing Fontan circulation.

OBJECTIVE: Modified Fontan procedures are now employed in several conditions unsuitable for bi-ventricular repair. Selection criteria have been relaxed. The procedure is palliative. Longterm outlook is unknown. This study evaluated factors associated with the development of a failing Fontan circulation and transplantation results. METHODS: Retrospective review of patients referred to a single centre for cardiac transplant assessment. RESULTS: Between 1985 and 1996, 46 of 448 cardiac transplants were performed for congenital heart disease. Nine of these were performed in patients with a failing Fontan circulation (four adults, five children). In six cases, the dominant ventricle had left ventricular (LV) morphology. Congenital anomalies included double outlet right ventricle (three cases), double inlet left ventricle (two cases), tricuspid atresia (two cases), and pulmonary atresia with intact ventricular septum (one case). Fontan procedures were performed in absence of sinus rhythm (four cases), atrio-ventricular (AV) valve regurgitation (two cases), aortic regurgitation and systolic LV dysfunction (one case), elevated mean pulmonary artery pressure (one case), and older age (>7 years, eight cases). Three patients required early re-operation and two needed permanent pacing. Subsequent deterioration associated with loss of sinus rhythm (four cases) and progressive AV valve regurgitation (seven cases) led to transplant assessment (at < 1 year, five cases; at 2-12 years, four cases). All patients were listed for transplantation. Three patients required intravenous inotropic support and three patients with lymphocytotoxic antibodies needed prospective crossmatching. Donor cardiectomy was modified to facilitate implantation. The recipient operation involved pulmonary artery reconstruction (using pericardium), modified atrial and direct caval anastomoses. Three patients died within 24 h of surgery (two graft failures, one haemorrhage). In operative survivors (n = 6), intensive care stay was 3-16 days, and hospital stay ranged from 14 to 32 days. There have been no subsequent deaths (follow up, 0.5-4.7 years). CONCLUSION: In high-risk Fontan candidates, transplantation may be preferable at the outset. Previous surgery, lymphocytotoxic antibodies, indeterminate pulmonary vascular resistance, emergency status, sub-optimal donor selection, and perioperative bleeding contribute to peri-operative mortality. In survivors, the outcome remains very encouraging.

Antilymphocyte Serum↗
PubMed1998

Exercise response of the recipient atrial remnant after orthotopic cardiac transplantation: implications for recipient atrial triggered pacing.

The assumption that the recipient atrial remnant in the cardiac transplant recipient is normal has led to the suggestion that it is an appropriate trigger for permanent pacing in transplant recipients who need pacing or to restore chronotropic competence and/or mechanical synchrony of the composite atrium. We examined the chronotropic response to exercise in 12 orthotopic cardiac transplant recipients (mean age 49 years) at a mean time of 17 months posttransplantation. Recipient and donor atrial rates were noted and compared and chronotropic competence determined. Two of 12 recipient atrial remnants were in atrial fibrillation. Only six of the remaining 10 recipient atria exhibited chronotropic competence. Seven of 10 recipient atria had rates higher than that of the donor. Only four of ten recipient atria in sinus rhythm satisfied both criteria. Two of these had abnormally high atrial responses early into exercise. Of the remaining two, only one recipient atrial remnant demonstrated a > or = 20% increase in heart rate above that of the donor at peak exercise. Hence only 1 of 12 (8.3%) transplant recipients potentially could benefit from recipient atrial triggered pacing. While recipient atrial triggered pacing is an attractive theoretical concept for restoring chronotropic competence following orthotopic cardiac transplantation, it may rarely be practical because the recipient atrial remnant displays rhythm abnormalities, chronotropic incompetence, and abnormalities in its exercise response.

Atrial Function↗
PubMed1998

Declining need for pacemaker implantation after cardiac transplantation.

The need for permanent pacemaker implantation was retrospectively reviewed in 436 consecutive cardiac transplant recipients at our center between 1985 and 1998. The incidence of pacemaker implantation was examined in three arbitrarily defined periods: period 1, 1985-1990, before a review of pacemaker implantation policy; period 2, 1991-1995, after a change in policy to delay pacemaker implantation resulting from the review; and period 3, 1996-1998, after audit of this policy change, and the introduction of a change in surgical technique, from the standard atrial anastomosis to the bicaval anastomosis. Pacemaker implantation was not required in any recipient after the change in surgical technique, suggesting that the bicaval technique preserves sinus node function much better than does the standard atrial anastomosis.

Cardiac Pacing, Artificial↗
PubMed1998

Comparison of the functional results of single lung transplantation for pulmonary fibrosis and chronic airway obstruction.

BACKGROUND: Single lung transplantation (SLT) is now a treatment option for patients with both pulmonary fibrosis and advanced chronic airway obstruction. Lung function after transplantation might be expected to be different in these two groups of patients because of the effect of the remaining native lung, but the implications of these differences have not been fully explored. METHODS: The functional results of a stable population of 20 patients (13 chronic airway obstruction, seven pulmonary fibrosis) after SLT with no evidence of obliterative bronchiolitis were analysed. The differences between the two populations in the interrelations between and determinants of total lung capacity (TLC), subdivisions of lung volume, airway function (spirometry, maximum expiratory flow volume curves, and moments analysis of the spirogram) respiratory mechanics (PV curves and maximal respiratory pressures), CO transfer factor (TLCO) and the distribution of perfusion, ventilation and volume of the transplanted and native lungs were compared. RESULTS: Total lung capacity after SLT (TLCpost) was normal in the patients with pulmonary fibrosis (mean (SE) 103.9 (6.9)% predicted) but remained significantly elevated in patients with airway obstruction (126.4 (4.4)%. Forced expiratory volume in one second (FEV1) and vital capacity (VC) improved to similar values after SLT in both groups with a final VC of 76.8 (5.9)% and 66.7 (3.9)% in patients with fibrosis and airway obstruction, respectively. Maximum expiratory flows were generally lower and moments analysis of the spirogram showed slower lung emptying with significantly greater second and third moments (alpha 2 and alpha 3) in patients with airway obstruction. Relative ventilation and perfusion of the transplanted lung were both greater in both populations but relative ventilation of the transplanted lung was significantly greater in patients treated for airway disease than in those with pulmonary fibrosis. TLCO was also significantly higher in patients who had received a transplant for chronic airway obstruction. CONCLUSIONS: These results suggest that differences in the functional results of SLT for airway disease and pulmonary fibrosis are relatively minor. In this series the native hyperinflated lung in chronic airway disease was not more disadvantageous to overall function than the native lung in pulmonary fibrosis. However, tests of lung function based on the terminal portion of the forced spirogram are likely to be less sensitive for the detection of obliterative bronchiolitis in patients who have received a transplant for advanced airway obstruction than in those with pulmonary fibrosis.

Female↗
PubMed1998

Cross sectional study of exhaled nitric oxide levels following lung transplantation.

BACKGROUND: The role of nitric oxide (NO) in the pathophysiology of graft dysfunction following lung transplantation remains unclear. To determine whether measurement of NO in the exhaled breath of lung transplant recipients provides useful information about graft pathology, a cross sectional study was performed on a cohort of recipients as they attended for review. METHODS: One hundred and four lung transplant recipients and 55 healthy non-smoking controls were included in the study. Each subject performed three consecutive single breath NO manoeuvres. In recipients NO levels were compared according to current clinical status, presence of any graft pathology, type of lung transplant procedure, indication for transplantation, and current level of immunosuppression. RESULTS: Mean (SE) exhaled NO levels were 6.5 (0.61) ppb in the control group, 5.3 (0.46) in clinically well recipients, 10.3 (1.4) in those with lymphocytic bronchiolitis, 10.5 (1.0) in recipients with infection, and 2.5 (0.6) in those with acute vascular rejection. There was no significant difference in NO levels between the control group and lung transplant recipients as a whole (mean difference 0.29 (95% CI -1.17 to 1.75), p = 0.7). Levels were increased significantly in the presence of lymphocytic bronchiolitis (4.98 (95% CI 1.6 to 8.36), p = 0.0002) and infection (5.28 (95% CI 2.9 to 7.56), p < 0.0001), but not in acute vascular rejection (2.76 (95% CI 0.97 to 4.55), p = 0.1) compared with exhaled NO in clinically well recipients. Recipients with obliterative bronchiolitis were subdivided according to the grade of their bronchiolitis obliterans syndrome (BOS). Exhaled NO levels in those with BOS grade 1 were 10.0 (1.3) ppb and in those with BOS grades 2 or 3 were 5.1 (0.7) ppb. Compared with those who were clinically well, NO levels were increased in those with BOS grade 1 (4.74 (95% CI 1.8 to 7.69), p < 0.0001) but not in those with BOS grades 2 or 3 (0.19 (95% CI -1.55 to 1.93), p = 0.82). CONCLUSIONS: Exhaled NO levels are increased in lung transplant recipients with lymphocytic bronchiolitis, early obliterative bronchiolitis, and infection. These conditions are all associated with the presence of airway inflammation within the graft. The findings suggest that exhaled NO measurements may have a role as a marker of pulmonary allograft dysfunction.

Breath Tests↗
PubMed1997

High prevalence of anemia after cardiac transplantation in children.

BACKGROUND: Chronic anemia is common in adults after successful cardiac transplantation. However, the prevalence of anemia in children after cardiac transplantation is uncertain. The purpose of this study was to investigate the prevalence and causes of chronic anemia in well children after cardiac transplantation and in particular to define the role, if any, of iron deficiency, which is important and relatively common in normal children. METHODS: Twenty children (ages 7 months to 16 years) who were well 4 months to 6 years after cardiac transplantation were studied. Fourteen children (70%) were anemic and enrolled in a prospective trial of iron supplementation. RESULTS: In the majority of children, serum iron and erythropoietin levels were low, although serum ferritin and zinc protoporphyrin levels tended to be normal or high. Only one child demonstrated a definite response to iron supplementation, although the hemoglobin level remained low. CONCLUSIONS: Anemia is highly prevalent in this population, and, despite the presence of low serum iron and transferrin saturation, anemia is not usually due to iron deficiency. Although the diagnosis of iron deficiency in this group is difficult and must not be missed, inappropriate therapy should be avoided. In the majority of children, there appears to be an anemia of chronic disease which may be secondary to chronic inflammation or an effect of cyclosporine on erythropoietin production.

Adolescent↗
PubMed1997

Examination of the mechanism by which heparin antagonizes activation of a model endothelium by interferon-gamma (IFN-gamma).

IFN-gamma increases the potential immunogenicity of vascular endothelial cells by up-regulation of intercellular adhesion molecule-1 (ICAM-1) and class I MHC antigen expression and by induction of class II MHC antigens and certain chemokines. In this study the mechanism by which the glycosaminoglycan (GAG) heparin antagonizes the activation of a model endothelium by IFN-gamma was investigated. Radioligand binding assays demonstrated that total binding of 125I-IFN-gamma to the EAhy.926 endothelial hybridoma cell line was reduced in the presence of heparin or heparan sulphate (HS); the structurally dissimilar GAG chondroitin sulphate had no effect. Treatment of the cells with chlorate, a metabolic inhibitor of GAG sulphation, was found to reduce both the subsequent binding of IFN-gamma and its ability to induce expression of class II MHC antigens. Treatment with heparinase II dramatically reduced the binding of IFN-gamma, while chondroitin ABC lyase had no effect. A cationic peptide from the C-terminal region of IFN-gamma was also found to reduce binding of intact IFN-gamma to the cells. These results appear to demonstrate that IFN-gamma is sequestered at the surface of endothelial cells by electrostatic interaction between specific basic amino acid residues and sulphated domains on HS, the most abundant endothelial GAG. This interaction is competitively inhibited by heparin, which is structurally related to HS. These observations are consistent with the model that IFN-gamma is bound by membrane-associated HS before engagement with the high-affinity receptor and signal transduction. Inhibition of the interaction between proinflammatory cytokines and membrane-associated GAG molecules may provide a mechanism for inducing clinically useful immunosuppression.

Cell Division↗
PubMed1997

Lung: living related transplantation.

As with other paired and lobed solid organs, surgical techniques have now evolved to permit safe live donation. Almost all the published experience comes from one centre, with cystic fibrosis recipients receiving right and left lower lobes, typically one from each parent. Donor morbidity has been acceptable, with no known deaths. Early survival, perhaps because patients are only transplanted in extremis, has been less good than can be achieved in cadaver transplantation. Early and late rejection remain at least as common as after conventional transplants, but is nearly always asynchronous, affecting one lung at a time. There remain significant ethical difficulties, and the approach has yet to prove itself.

Decision Making↗
PubMed1997

The use of 99Tcm-DTPA aerosol and caesium iodide mini-scintillation detectors in the assessment of lung injury during cardiopulmonary bypass surgery.

Lung injury is a well-documented adverse effect of cardiopulmonary bypass. The mechanism of injury is not fully understood, but pulmonary hypoxia may be a factor. Post-operative pulmonary epithelial permeability (PEP) in ventilated versus non-ventilated lungs was measured within 2 h of return to the intensive care unit using a 99Tcm-diethylenetriamine pentaacetate aerosol technique. A portable scintillation detector system was required. Sodium iodide detectors have been used previously with this technique but are cumbersome. This study used mini caesium iodide detectors (Oakfield Instruments, Oxon, UK), which can be attached directly to the patient and are more suited to the intensive care setting. The clearance half-time from lung to blood (T1/2LB) was measured in 31 patients (62 lungs). The mean (+/- S.E.M.) clearance half-times were 42.3 +/- 2.7 and 45.7 +/- 3.8 min for non-ventilated and ventilated lungs respectively, with a mean difference of 3.4 +/- 3.1 min (P > 0.05). We conclude that, using this technique, no significant difference in PEP is observed between ventilated and non-ventilated lungs in patients undergoing cardiopulmonary bypass.

Adult↗
PubMed1997

Sympathetic reinnervation and heart rate variability after cardiac transplantation.

BACKGROUND: Heart rate variability is thought to measure autonomic modulation, but the relation has never been demonstrated directly in humans. AIM: To test the hypothesis that increased low frequency heart rate variability reflects sympathetic reinnervation after cardiac transplantation. PATIENTS: 24 cardiac transplant recipients at the time of routine surveillance coronary angiography two or more years after cardiac transplantation, and 10 controls with normal coronary arteries undergoing angiography for investigation of chest pain. SETTING: Regional cardiothoracic centre. METHODS: Sympathetic effector function at the sinus node was assessed by measuring the fall in cycle length for two minutes after injection of tyramine to the artery supplying the sinus node. Heart rate variability was measured from three-minute RR interval sequences at rest, during metronomic respiration, and before and after atropine. RESULTS: The logarithm of the low frequency component of heart rate variability during metronomic respiration was linearly related to the logarithm of the change in cycle length after injection of tyramine (R2 = 0.28, P = 0.007). Absolute units more accurately reflected sympathetic effector function than did normalised units or the ratio of low frequency to high frequency. Atropine did not affect high frequency heart rate variability in transplant recipients. CONCLUSIONS: The low frequency component of heart rate variability is directly related to sympathetic reinnervation to the sinus node.

Coronary Angiography↗