Alfred E. Wood

Statins alter neutrophil migration by modulating cellular Rho activity—a potential mechanism for statins-mediated pleotropic effects?

The ability of neutrophils to sense and migrate toward damaged tissue is a vital component of the innate immune response. Paradoxically, this same migration serves as the hallmark of a number of inflammatory conditions, including ischemic reperfusion injury, atherosclerosis, arthritis, and Crohns disease. More recent evidence suggests that neutrophil infiltration into the cardiac allograft following transplantation is a contributing factor in allograft rejection. We have demonstrated previously a positive correlation between the degree of neutrophil migration and subsequent rejection grades in a cohort of cardiac transplant recipients. Intracellular signaling pathways that are intimately involved in neutrophil migration thus offer potential targets of manipulation in the treatment of such conditions. 3‐Hydroxy‐3‐methylyglutaryl‐coenzyme A reductase inhibitors or statins are emerging as potential anti‐inflammatory agents and have a proven survival benefit in the transplant population. Yet, little is known about their ability to modulate neutrophil function and their subsequent mechanism of action. We demonstrate here that pravastatin, simvastatin, and atorvastatin significantly reduce neutrophil transendothelial migration toward the chemoattractant fMLP. This effect is independent of any change in neutrophil adhesion or adhesion molecule expression but is related to the ability of statins to reduce fMLP‐induced Rho activity in neutrophils. This was confirmed by the ability of the Rho precursor geranylgeranyl pyrophosphate to rescue the statin‐mediated reduction in neutrophil transendothelial migration. Understanding the mechanisms of action of statins in the neutrophil allows for their use in targeting excessive migration in inappropriate inflammatory conditions.

Electronic learning can facilitate student performance in undergraduate surgical education: a prospective observational study

BackgroundOur institution recently introduced a novel internet accessible computer aided learning (iCAL) programme to complement existing surgical undergraduate teaching methods. On graduation of the first full cycle of undergraduate students to whom this resource was available we assessed the utility of this new teaching facility.MethodThe computer programme prospectively records usage of the system on an individual user basis. We evaluated the utilisation of the web-based programme and its impact on class ranking changes from an entry-test evaluation to an exit examination in surgery.Results74.4% of students were able to access iCAL from off-campus internet access. The majority of iCAL usage (64.6%) took place during working hours (08:00–18:00) with little usage on the weekend (21.1%). Working hours usage was positively associated with improvement in class rank (P = 0.025, n = 148) but out-of hours usage was not (P = 0.306). Usage during weekdays was associated with improved rank (P = 0.04), whereas weekend usage was not (P = 0.504). There were no significant differences in usage between genders (P = 0.3). Usage of the iCAL system was positively correlated with improvement in class rank from the entry to the exit examination (P = 0.046). Students with lower ranks on entry examination, were found to use the computer system more frequently (P = 0.01).ConclusionElectronic learning complements traditional teaching methods in undergraduate surgical teaching. Its is more frequently used by students achieving lower class ranking with traditional teaching methods, and this usage is associated with improvements in class ranking.

Ten years' experience of an aggressive reparative approach to congenital mitral valve anomalies.

OBJECTIVE Mitral valve repair is now well established in adults. Congenital anomalies of the mitral valve, however, represent a more complex and diverse population with a high prevalence of associated cardiac anomalies. Less is known about the results of valve sparing surgery in this group of patients. We reviewed our experience to determine these results. METHODS Twenty three children with mitral valve anomalies and concordant atrioventricular and ventriculoarterial connections but excluding partial and total atrioventricular canal defect (AVC) or isolated cleft were operated on between January 1 1983 and January 1994. Mean age at operation was 3.2 years (range 2 months-10.7 years) with 10 patients less than 1 year. Eighteen patients (78%) were in New York Heart Association Functional class (NYHA) 111/1V. Aetiology of mitral valve disease was congenital in 21 (91.3) and ischaemic of congenital origin in 2 (8.7%). mitral regurgitation was dominant in 13 (57%), mitral stenosis in 10 (43%)-5 parachute valves. Associated defects occurred in 15 patients (65.2%). All mitral incompetence patients (13) had some form of annuloplasty-modified de Vega 5, Wooler Kay 5, Paneth 2 and Puig Messana 1. RESULTS Hospital mortality was 13% (3 patients). Mean follow up time was 51.3 months with a cumulative follow up of 102.6 patient years There were 2 late deaths. Repeat operations were required in 3 patients-2 reparative and 1 mitral valve replacement. One patient awaits reoperation and the remaining 17 have no, minimal or mild mitral stenosis or incompetence on echocardiography. Seventeen (94%) of the surviving patients are in NYHA 1/11. One and 7 year actuarial survival rates are 82.2% +/- 7.9% and 77.4% +/- 8.7% while actuarial freedom from reoperation was 95.5% +/- 4.3% at 1 year and 84.1% +/- 7.6% at 7 years. There has been no incidence of thromboembolism. CONCLUSIONS Reparative techniques can be successfully applied to congenital mitral valve disease, especially in children less than 1 year of age, and can be accomplished with a low hospital mortality and acceptable long term survival rates.

The Novalung interventional lung assist as bridge to lung transplantation for self-ventilating patients – initial experience

We report the use of the Novalung pumpless device in self-ventilating patients awaiting a lung transplantation. Two patients developed carbon dioxide retention with respiratory acidosis that did not respond to maximum medical therapy. The Novalung interventional lung assist was established as a bridge to lung transplantation. The first patient was successfully transplanted after 140 days, and this is the longest support that has been reported so far. The second patient was weaned off the Novalung after a short period. The Novalung is a valuable device for self-ventilating patients with carbon dioxide retention being bridged to lung transplantation.

Surgical relief of tracheobronchial obstruction in infants and children

OBJECTIVE Congenital tracheobronchial obstruction (TBO) presents a complex problem both in terms of diverse aetiology, presence of associated anomalies and the operative strategy to be adopted. We report a single centre experience in managing this difficult problem. METHODS Twenty-four infants and children with TBO referred to our unit over a 12-year period are reviewed. Aetiology of TBO included vascular rings (n = 9), anomalous innominate artery (n = 6), congenital tracheal stenosis (n = 5), segmental bronchial stenosis (n = 2) and pulmonary artery compression of the main bronchi (n = 2). Seven patients had concurrent cardiac anomalies. Stridor was the commonest presenting symptom (67%). Mean delay from onset of symptoms to referral was 19 months. One patient died preoperatively due to acute airway obstruction. Mean age at operation was 33.1 +/- 42 months (range 4 days-156 months) and 11 children were under 1 year at the time of surgery. In cases of TBO secondary to vascular rings, division of the ring resulted in relief of symptoms in seven cases, with two requiring further surgery for resultant tracheomalacia. Four of the five patients having tracheal resection were operated on with the use of cardiopulmonary bypass; three of these patients had concurrent correction of cardiac lesions, with two survivors. Tracheobronchial anastomoses were carried out using continuous polydioxanone (PDS). Patients with anomalous innominate arteries required aortopexy in five and innominate artery suspension in one, while those with pulmonary artery compression of the main bronchi had correction of their intracardiac defects (n = 2). RESULTS Hospital mortality was 8.7% and there has been one late death due to Eisenmenger syndrome secondary to pulmonary regurgitation, atrial septal defect (ASD) and patent ductus arteriosus (PDA). On follow-up (mean 40 +/- 31 months), 19 patients are alive and symptom free. There have been no anastomotic strictures following tracheobronchial resection. The single most important predictor of mortality was the presence of associated cardiac anomalies. CONCLUSIONS TBO can be managed effectively by a single operation in both infants and children without a detrimental effect on tracheal growth. We advocate consideration of concurrent repair of the tracheal and cardiac lesions. Cardiopulmonary bypass (CPB) allows this concurrent correction of cardiac lesions and also facilitates tracheal resection.

Calcification of homograft valves in the pulmonary circulation — is it device or donation related?

OBJECTIVE Homograft valved conduits are used in the reconstruction of right ventricular outflow tract (RVOT), and calcification is a recognised phenomenon in these devices. The purpose of this study was to assess the effect of type (pulmonary and aortic) and mode of harvest of these cryopreserved homografts (cadaveric and beating heart) on the incidence of calcification of these conduits when used in the pulmonary circulation. METHODS A retrospective study was carried out on 60 patients with congenital heart defects who underwent reconstruction of RVOT using cryopreserved homograft valved conduits. The homografts were harvested from two different groups of donors; beating heart donors and cadaveric donors. The period of study was from 1st January 1990 to 31st December 2000. There were 34 males and 26 females, and the median age was 75 months. The 30-day mortality was 10 (16.7%). The 50 survivors were followed-up 3-108 months (median 36 months). Twenty-four had aortic homografts and 26 pulmonary homografts. Twenty-four devices were from cadaveric donors and 26 from beating heart donors. RESULTS There were 10 (20%) calcified devices, all aortic in origin. In a logistic regression analysis, aortic homografts were significant risk factor for calcification (P=0.0006). However, source of harvest was not significantly related to the incidence of calcification (P=0.6). CONCLUSION Cryopreserved pulmonary homografts placed in the right side of the heart are less likely to undergo calcification. Homografts harvested from beating heart donors do not appear to reduce the incidence of calcification.

Delayed Discovery of Diaphragmatic Injury After Blunt Trauma : Report of Three Cases

Blunt diaphragmatic injury is an increasingly common occurrence, frequently associated with considerable comorbidity. This injury is often missed at the time of the initial event, but may present some time later. We report three cases of diaphragmatic injury diagnosed 3 weeks, 6 months, and 12 years after the original diaphragmatic injury, respectively. Two of the injuries resulted from side-impact road traffic accidents and one followed a fall from a height. Gastrointestinal obstruction and respiratory compromise were the major presenting symptoms. All three patients were managed with a thoracotomy and the defect was closed without the need for prosthetic mesh. They all recovered uneventfully and have remained well since.

Quality control in homograft valve processing: when to screen for microbiological contamination?

Human donor heart valves remain essential for many reconstructive heart procedures. Heart valve donations are a scarce resource which must be used efficiently and safely. Infection transmission remains a potential risk with homograft valve use. Early experience with homograft valves identified high rates of microbial contamination at collection and initiated the practise of immersion in an antibiotic cocktail. Many centres rely on the microbiology screening after exposure to the antibiotic cocktail. We in our centre accept or reject valves on the basis of the microbiology screening at the time of collection prior to immersion in antibiotic solution. We wanted to compare our rate of valve discard and the rate of microbial contamination at implant with other centres. Valves are collected for the Irish Heart Valve Tissue Bank through partnership between the National Centre for Cardiothoracic Surgery and the Irish Blood Transfusion Service. Valves are collected in a surgical theatre setting and processed in dedicated section of the Irish Blood Transfusion Board. Tissues are screening for microbiology at collection and also at implantation. A total of 564 human heart valves and valve conduits were processed through the service during the study period. 167 (29.6%) were discarded during the processing and storage stages. The major reason for this in 117 cases was unsatisfactory microbiology on initial tissue screening. Repeat screening of accepted valves at the time of implantation identified positive cultures in only 0.9%. Optimal use of these limited resources is clearly important. However recipient safety remains paramount. One-fifth of collected valves are discarded at the processing stage due to positive microbiology screening. This is a higher rate of discard then other centres which reject 5.6–10% due to positive microbiology. However our rate of contamination at time of implant is lower then the 3% rate reported elsewhere. We are satisfied that our current discard rate, although significant, reflects rigorous quality control and the optimal balance between valve availability and patient safety.

LUNG TISSUE STORAGE: OPTIMIZING CONDITIONS FOR FUTURE USE IN MOLECULAR RESEARCH

The quality of tissue studied impacts greatly on oligonucleotide microarray results, emphasizing the importance of harvesting techniques. The analyzed RNA extracted from human lung samples preserved via 4 different storage conditions (RNAlater, phosphate-buffered saline, TRIzol, liquid nitrogen). RNA was assessed by denaturing gel electrophoresis, Agilent bioanalysis, real-time polymerase chain reaction (PCR), and Test3 Affymetrix chip hybridization. Results revealed better quality RNA from RNAlater samples on gel electrophoresis and bioanalysis. RNAlater samples also showed greater yield (r18s via PCR P <.05) and resulted in better Test3 chips hybridization (p <.05), suggesting RNAlater was superior at preserving lung tissue nucleic acid.

Pre-operative Determination of an Individual's Neutrophil Response: A Potential Predictor of Early Cardiac Transplant Cellular Rejection

BACKGROUND Success of heart transplantation is affected by allograft rejection, which is known as a lymphocyte-mediated process. Recent studies suggest that neutrophils contribute to this process. We hypothesized that the severity of cardiac rejection can be predicted by evaluating an individuals neutrophil transendothelial migration potential, which can be assessed through artificial stimulation of neutrophils. METHODS Eleven patients were recruited from the active heart transplant list. Pre-operative blood samples were stained with neutrophil adhesion molecule (CD11b, CD62L, and PSGL-1) antibodies before and after in vitro stimulation with phorbol 12-myristate 13-acetate (PMA; 1 ng/ml) and lipopolysaccharide (LPS 1 microg/ml), and assessed using flow cytometry. Stimulated neutrophil responses were correlated with rejection grade of the first endomyocardial biopsy sampled 10 days post-operatively. RESULTS Neutrophil adhesion molecules are upregulated after artificial stimulation. Pre-operative neutrophil surface CD11b expression after in vitro lipopolysaccharide stimulation correlated with rejection grade detected in the first endomyocardial biopsy sample (R = 0.677; p = 0.022). CONCLUSION Pre-operative neutrophil response to in vitro stimuli predicted the rejection grade in the first post-transplant endomyocardial biopsy specimen, suggesting that neutrophils may contribute more to cardiac allograft rejection than previously thought.