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 Crohn's 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.

An eocene hystricognathous rodent from Texas: its significance in interpretations of continental drift.

The earliest known representative of the fundamentally South American and African hystricognathous rodents has recently been found in the middle or late Eocene of southwestern Texas; this discovery supports the postulate of a northern and independent origin for the two southern groups and increases the evidence against mid-Tertiary trans-Atlantic migration of these rodents at a time when the South Atlantic was narrower than it is at present. The fossil seems to be related to the North American Eocene family Sciuravidae.

Pleuropulmonary blastoma type I following resection of incidentally found congenital lobar emphysema.

Pleuropulmonary blastoma (PPB) is an aggressive tumour accounting for less than 1% of all primary malignant lung tumours in the paediatric population. It can be associated with cystic pulmonary lesions, which may be evident at the time of diagnosis or predate the appearance of the tumour. There are contradictory reports about the value of prophylactic resection of pulmonary cysts in protecting patients from developing PPB. We report an individual case where asymptomatic congenital lobar emphysema was incidentally picked up on CXR. Following a period of surveillance the lesion was resected due to increasing size. The histology of the lesion revealed PPB Type I.

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.

Differential white cell count relationships with human cardiac allograft rejection.

The focus of research in allograft rejection has targeted the lymphocyte, with little attention given to the neutrophil. Recent data indicate that a perioperative neutrophil influx into the cardiac allograft influences early rejection. Factors that influence neutrophil transendothelial migration might offer predictive markers of rejection. We explored the relationship between the number of circulating neutrophils in heart transplant recipients and the development of rejection. Differential white cell counts were obtained prior to transplantation and concurrently with subsequent endomyocardial rejection surveillance biopsies for 53 heart transplant recipients undergoing 410 biopsies. Preoperative differential white cell counts had no relationship with rejection. In the first 3 months after transplantation, no relationship was found between contemporary differential white cell counts and rejection. However, more than 3 months following surgery, rejection grade positively correlated on univariate analysis with neutrophil counts and the usage of cyclosporine, prednisolone, and mycophenolate. There was no relationship with eosinophils or lymphocytes. Multivariate analysis demonstrated a persistent relationship among rejection severity, neutrophil count, and prednisolone usage. A significant positive association of higher steroid usage with higher rejection grades must reflect efforts to treat patients with rejection. The significant association of higher neutrophil counts with higher rejection severity might suggest a pathological contribution to rejection. However, given the neutrophilia response to acute steroid administration, we must conclude that the neutrophil association was related to steroid administration. The absence of a relationship between white cell counts and rejection suggests that functional rather than antiproliferative strategies may offer the greatest therapeutic potential.

A step towards being EWTD compliant: a single institution study of the cardiothoracic surgery experience.

The introduction of the European Working Time Directive has led to intensive debate regarding the working conditions, training and service delivery of Non Consultant Hospital Doctors. Surgical specialties are especially affected by the directive as they have always been associated with long working hours. These have been defended on the basis that these were required to achieve surgical competence. This study aims to survey the working hours and examine the activity of cardiothoracic surgery trainees, who traditionally worked long hours, in a single institution. Arising from the survey results, a novel working model is proposed.

The first 20 years of heart transplantation in Ireland.

BACKGROUND: The first Irish heart transplant was performed on the 10th of September 1985. Over the next 20 years, 229 transplants were performed in 228 recipients. AIMS: To evaluate the success of the first generation of cardiac transplantation in Ireland. METHODS: Analysis of clinical outcomes and survival statistics for patients undergoing heart transplantation in Ireland and comparison with international standards. RESULTS: There has been a steady improvement in transplant outcome over this time and survival figures for recipients between 2000 and 2004 show a hospital, 1-year and 5-year survival rate of 85.7%, 84.1% and 76.8% respectively. Thirty-eight of the 99 heart transplants performed between 1985 and 1994 are still alive more than 10 years later and the longest survivor is now 19 years post transplantation. CONCLUSIONS: The results compare favourably with international figures. Heart transplantation offers excellent longterm survival and quality of life but remains challenged by a shortage of suitable donor organs.

Traumatic rupture of the aorta in an 11-year-old patient: surgical considerations in the technique of repair.

We describe an 11-year-old child who presented with a traumatic aortic transection. This is an extremely rare occurrence in this age group. In managing the injury the future growth of the child must be considered. Primary repair is ideal when possible, but in choosing a graft, the choice of size and material should take cognisance of the risk of a coarctation-like syndrome in the future.

Heart transplant candidates: factors influencing waiting list mortality.

Cardiac transplantation is a successful treatment for end-stage heart disease. However the number of potential candidates is significantly greater then number of suitable organ donors. We reviewed the characteristics of new transplant candidates presenting for assessment for cardiac transplantation to the Irish Heart & Lung Transplant programme over a one year period. Of 44 patients referred for assessment, 24 (54.5%) were listed for cardiac transplantation. Six have died while awaiting transplantation, seven have been transplanted and eleven remain on the active transplant list. The six month survival rate on the transplant waiting list is 74%. Although the Irish system of organ donation has traditionally provided high organ donation rates in comparison with other countries, the demand for suitable heart donors exceeds supply. Newer methods of promoting and facilitating organ donation may prove beneficial in improving the number of donations and addressing the long waiting time for cardiac transplantation.

Video-assisted thoracic surgery for delayed pericardial effusion post-CABG.

Delayed-onset pericardial effusion following coronary artery bypass grafts can give rise to significant morbidity in its presentation and in its management by traditional surgical techniques. A video-assisted thoracoscopic technique to create a pericardial window, with the advantage of a minimally invasive approach combined with excellent visualization in such a patient is described.

The Mustard procedure in transposition of the great arteries associated with juxtaposition of the atrial appendages with and without dextrocardia.

Left-sided juxtaposition of the right atrial appendage (LJRAA) was seen in 10 patients in a series of 361 consecutive Mustard procedures for transposition of the great arteries (TGA). Dextrocardia complicated LJRAA in four cases. Right atrial capacity and free atrial wall size were smaller than normal in all patients, and a Mustard intra-atrial baffle repair was performed in all instances. Direct caval cannulation or cannulation of either atrial appendage facilitated intra-atrial repair. Nine patients in whom the pulmonary venous atrium was enlarged with a patch survived. One child who did not have a right atrial patch died 1 hour postoperatively of pulmonary edema. Two late deaths occurred 1 year postoperatively. Seven children survived and are well. In one child, superior vena caval baffle obstruction is controlled by digoxin and diuretic therapy. TGA associated with juxtaposition of the atrial appendages (JAA) and dextrocardia may be successfully repaired by the Mustard procedure, provided that the tricuspid valve and right ventricle are normal, an adequate superior vena caval channel is created, and patch enlargement of the pulmonary venous atrium is undertaken.

Acute hepatic failure following cardiac operation in children.

A retrospective analysis has been performed of children who have undergone cardiac operations during the past 6 years to determine the clinical presentation and management of acute hepatic failure (AHF) in the postoperative period. Eleven patients had a clinical picture of AHF with jaundice, elevation of the levels of serum glutamic oxaloacetic transaminase (SGOT) and serum ammonia, and marked prolongation of the prothrombin time associated with failure of hemostasis. Hypoglycemia developed in seven. All patients had evidence of low cardiac output and acute renal failure. Patients with AHF had evidence of reduced hepatic perfusion during the previous 24 hours with reduced mean arterial pressure and elevated central venous pressure. Six children died of myocardial failure. A modified Fontan procedure was performed in six children, of whom four died. All had a right atrial pressure of 21 torr or greater. Five children survived the acute episode of hepatic failure. The importance of early diagnosis and effective management of complications such as hypoglycemia and the bleeding tendency are emphasized.

Myocardial performance after repair of congenital cardiac defects in infants and children. Response to volume loading.

The hemodynamic response to increasing left atrial pressure by volume loading was evaluated in 70 children during the first 24 hours after repair of congenital cardiac defects. The children were grouped into four diagnostic categories: atrial septal defect or pulmonary valve stenosis (n = 8), ventricular septal defect (n = 36), complete transposition after Mustard's operation (n = 13), and tetralogy of Fallot (n = 13). Within 2 hours of bypass, both cardiac index and left ventricular stroke work index were adequate and increased appropriately with volume loading in all four diagnostic groups. The atrial septal defect group demonstrated a similar response to volume loading 4 and 24 hours after bypass. However, the other three diagnostic groups had a higher filling pressure, lower cardiac index and stroke work index, and a depressed response to increasing preload 4 hours postoperatively, which indicated a deterioration in cardiac performance. The deterioration was maximal between 4 and 12 hours after bypass, and performance tended to recover 24 hours postoperatively. The transposition group had a more profound depression in cardiac performance than the other two groups. Within the ventricular septal defect group, smaller children (body surface area less than 0.36 m2) had a more profound depression in performance than larger children. These results demonstrate a significant alteration in cardiac performance during the first 24 hours after repair of congenital cardiac defects in children. These changes should be considered when postoperative management is being planned.

Pulmonary artery sling with tracheal stenosis: one-stage repair.

Pulmonary artery sling with tracheal stenosis is a difficult management problem. We describe the use of cardiopulmonary bypass as a method to facilitate one-stage repair.

Aortobronchial fistula: a late complication of division of the persistent ductus arteriosus.

An 11-year-old girl had nearly fatal hemoptysis due to false aneurysm and aortobronchial fistula following ductus division 9 years previously. Silk suture material was implicated as a causative agent in association with dilation of the aortic isthmus. To our knowledge, no previous report of this complication exists in the literature. Twenty-two cases of false aneurysm have been described, 86.3% following ligation. The use of elective hypotension during ligation and monofilament suture during division may prevent this serious late complication in the future.

Mitral annuloplasty in endomyocardial fibrosis: an alternative to valve replacement.

The case of a patient with left ventricular endomyocardial fibrosis (EMF) causing severe mitral regurgitation is presented. Excision of the fibrotic tissue through the left atrium and mitral annuloplasty resulted in symptomatic relief and uncomplicated pregnancy. An X-linked congenital dermatological condition, Bloch-Sulzberger syndrome (incontinentia pigmenti), associated with chronic eosinophilia, was also present. This occurrence with EMF has not previously been reported. Atrioventricular valve reconstruction is a feasible alternative to valve replacement in EMF.

Superoxide radical and xanthine oxidoreductase activity in the human heart during cardiac operations.

BACKGROUND: The results of clinical trials of xanthine oxidoreductase inhibition in cardiac surgery are encouraging, although studies have failed to localize the enzyme to the human heart and to localize free radical activity to fresh human heart. METHODS: We adapted a histochemical staining technique based on the reduction of nitro blue tetrazolium to formazan by superoxide radical. In six samples of right atrium graded blindly on a scale of 0 through 4, strong staining (median grade, 3) of the microvasculature was seen. This was blocked by allopurinol in paired sections (median grade, 1; p < 0.01). Chemiluminescence can be used as an index of superoxide radical activity. Atrial samples were taken from 13 patients at five time points during coronary bypass grafting and placed in buffered luminol. Then chemiluminescence was measured. RESULTS: A 15-fold rise in chemiluminescence (295.93 +/- 39.47 mV) was demonstrated during reperfusion compared with the control value (19.06 +/- 0.47 mV). Chemiluminescence at 1 minute after release of the cross-clamp was significantly higher (p < 0.05) by analysis of variance versus values obtained before bypass and 1 minute before and 30 minutes after reperfusion. CONCLUSIONS: In this study we have identified superoxide radical activity and a possible generating system (xanthine oxidoreductase) in the human heart.

Ischaemic optic neuropathy complicating cardiopulmonary bypass.

Bilateral anterior ischaemic optic neuropathy occurred in two patients undergoing cardiopulmonary bypass grafting. The causes may have been vasoconstriction of the posterior ciliary arteries by increased circulating angiotensin and diminished ciliary blood flow in the setting of systemic hypotension and elevated intraocular pressure.

Intraocular pressure during cardiopulmonary bypass.

Intraocular pressure was measured in 24 patients undergoing elective cardiopulmonary bypass surgery. There was a rapid rise when the bypass circulation began, and this was maintained for about 30 minutes. A simultaneous drop in arterial perfusion pressure and packed cell volume occurred. We suggest that marked haemodilution is responsible for this effect, through increased ocular blood flow and low colloidal osmotic pressure. The possible aetiological significance in relation to ischaemic optic neuropathy complicating cardiopulmonary bypass is discussed.