A divergent transcriptional landscape underpins the development and functional branching of MAIT cells.

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

Cardiopulmonary bypass changes the plasma proteome in children undergoing tetralogy of Fallot repair.

INTRODUCTION: Cardiopulmonary bypass (CPB) can be associated with deleterious clinical effects. However, the impact of CPB on inflammatory, immunological and other homeostatic pathways remains poorly understood. We investigated the impact of CPB on the plasma proteome in children undergoing tetralogy of Fallot repair. METHODS: Blood samples were taken from 20 children prior to and at the end of CPB and 6h, 12h and 24h after CPB. Plasma was analysed by liquid chromatography-mass spectrometry (LC-MS) in a label-free, untargeted approach. Data were analysed using Genedata software to identify peptides that were differentially expressed (p<0.01 above a false discovery rate). Proteins were identified from peptides that demonstrated differential expression. RESULTS: The proteins that were found to be differentially expressed were haptoglobin isoform 1 preproprotein, isoform 2 of semaphorin-6C, vitamin D-binding protein, inter-alpha-trypsin inhibitor, ceruloplasmin, apolipoprotein B100 and fibrinogen alpha. CONCLUSION: CPB alters the plasma proteome with differences most apparent at 6h and 12h post CPB. There was a return to baseline with no proteins differentially regulated by 24h.

Paediatric heart transplantation in Australia comes of age: 21 years of experience in a national centre.

BACKGROUND: Heart transplantation (HT) is established therapy for end-stage heart failure in children with cardiomyopathy or congenital heart disease. AIMS: This review summarises experience at a national referral centre since the first local transplant. METHODS: Medical records of children referred for HT between 1 April 1988 and 1 January 2010 were retrospectively reviewed. All patients listed for HT were included. Survival analysis was used to summarise wait-list time to death/transplant, and separately, time to death in HT patients. RESULTS: One hundred and thirty-nine children were accepted on to the HT waiting list during the study (median age 7.7 (interquartile range (IQR) 2.5, 13.6) years), of whom 93 underwent HT (median age 10.9 (IQR 4.4, 14.6) years). Wait-list mortality was 32% (45 of 139 patients), lowest among children aged >10 years at listing (P < 0.001). Median time to HT was 69 days (range 29-146). Survival post-transplantation was 90% (95% confidence interval 82-95) at 1 year, 82% (72-89%) at 5 years and 68% (50-80%) at 10 years. Increasing case complexity over the study period included pre- and post-transplant circulatory support, management of pulmonary hypertension and introduction of ABO-incompatible HT for infants. Post-transplant survival did not vary according to age, pre-transplant diagnosis or use of pre-transplant circulatory support (all P > 0.05). CONCLUSIONS: Results of paediatric HT in Australia are comparable with international results, despite limitations of geographic isolation, small population and low organ donation rate. Increasing case complexity has not impacted on post-transplant survival.

Stabilisation of chronic flail chest: a novel approach of surgical fixation and osteogenesis.

A patient with chronic flail chest, severe persistent pain and chest wall deformity was successfully managed with open reduction and internal fixation of the ribs and application of a novel osteogenic protein.

Effects of intermittent lower limb ischaemia on coronary blood flow and coronary resistance in pigs.

AIM: Intermittent limb ischaemia prior to cardiac ischaemia is a cardioprotective stimulus. This study was to investigate whether this peripheral stimulus had any effects on basal coronary blood flow and resistance, and to explore its potential mechanisms by studying the effect of femoral nerve transection and Katp blockade by glibenclamide. METHODS: Remote ischaemic preconditioning (rIPC) was induced by four 5-min cycles of lower limb ischaemia. Coronary resistance was measured using standard formulae and coronary blood flow in the left anterior descending artery (LAD) by a flow probe. In experiment 1, coronary ischaemia was induced by inflation of a cuff placed around the mid-LAD, and inflated until cessation of flow. Left ventricular (LV) function was assessed using dp/dt and Tau at 1 and 30 min of ischaemia. Experiment 1: 20 pigs were randomized to control (n = 6), rIPC (n = 7) or femoral nerve transection + rIPC (n = 7) groups. The femoral nerve was transected before the rIPC protocol. All data were collected at fixed heart rates of 120 bpm. Coronary resistance was decreased and flow was increased significantly by the rIPC stimulus (P = 0.003, P = 0.016, paired t-test), and these changes were preserved after femoral nerve transection. Experiment 2: 19 pigs were randomized to control (n = 5), rIPC (n = 8) or glibenclamide-treated rIPC (n = 6) groups. Data were collected at baseline, and during incremental pacing between 120 and 180 bpm. RESULTS: Experiment 1: Coronary resistance was decreased and flow was increased significantly by rIPC stimulus (P = 0.003, P = 0.016, paired t-test), and these changes were preserved after femoral nerve transaction. rIPC was associated with superior LV function (dp/dt(max)) at 30 min, compared with controls and the rIPC + femoral nerve transaction group. Experiment 2: Coronary resistance was significantly lower, and LAD flow was significantly higher in rIPC group (P < 0.0001, P = 0.0008, two-way anova). These effects were reversed in the glibenclamide group. CONCLUSION: The rIPC stimulus leads to reduced coronary resistance and increased flow. This effect, while modified by glibenclamide appears to be a generic effect of remote ischaemia rather than a direct preconditioning effect.

Systemic and myocardial oxygen transport responses to brain death in pigs.

BACKGROUND: Brain death is associated with profound disturbances of systemic and myocardial oxygen transport, but little is known regarding the acute response of systemic oxygen consumption (VO(2)). METHODS: Brain death was induced in 6 pigs (30.6 +/- 3.0 kg) by balloon inflation into the cranial cavity. VO(2) was continuously measured by respiratory mass spectrometry. Blood pressures and gases were measured from the aorta, superior vena cava, and coronary sinus, with arterial epinephrine and norepinephrine, prior to brain death, at 1, 10, and 90 minutes after brain death. Cardiac output (CO), systemic vascular resistance (SVR), oxygen delivery (DO(2)), oxygen extraction (EO(2)), and myocardial oxygen (mEO(2)) and lactate extractions (mE(1ac)) were calculated. Left ventricular contractility was assessed by micromanometer tipped catheters. RESULTS: VO(2) increased from 4.8 +/- 0.9 to 6.3 +/- 0.9 mL/min/kg 1 minute after brain death (P < .001), and subsequently decreased to below baseline at 90 minutes (P < .001). Left ventricular contractility, CO, and DO(2) increased 1 minute after brain death (P < .001), followed by a rapid decrease to baseline within 10 minutes (P < .001). SVR and EO(2) decreased after brain death (P < .01) and remained low. Lactate remained unchanged. mE(1ac) decreased after brain death despite a decrease in mEO(2) (P < .01), and returned to baseline at 90 minutes. CONCLUSIONS: The initial surge in VO(2) after brain death is offset by the greater increase in DO(2), thus tissue perfusion remains adequate. The lower than baseline VO(2) and SVR at the end of the study period may indicate general metabolic and hemodynamic compromise. The information regarding the profound metabolic alterations imposed by brain death may have implications for management of brain death donors.

Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning.

Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K(+)-dependent ATP (K(ATP)) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 +/- 14.3 vs. 38.3 +/- 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 +/- 6% and 3 +/- 5% in control and PerC, respectively (P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a K(ATP) channel-dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes.

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study.

OBJECTIVES: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). DESIGN: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h. INTERVENTION: rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB. MAIN OUTCOME MEASURES: Troponin I, glial protein S-100B, lactate concentrations, load-independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB. RESULTS: Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve -57.3 (SEM 7.3) v 89.0 (11.6) ng.h/ml, p = 0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p = 0.04). S-100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p = 0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p = 0.02). Subsequently, peak inspiratory pressure was lower (p = 0.001). CONCLUSION: rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.

Management of life-threatening haemoptysis.

Massive haemoptysis represents a major medical emergency that is associated with a high mortality. Here we present two cases of life-threatening haemoptysis, the first caused by rupture of an aortic aneurysm into the lung in a 37-yr-old woman with polyarteritis nodosa and the second caused by massive bleeding from an angiectatic vascular malformation in the right main bronchus in a 21-yr-old woman. Fibreoptic bronchoscopy played an essential role in the diagnostic process and management of the respiratory tract. Diagnosis in the first case was obtained by CT scan and the aneurysm was treated surgically. In the second case, bronchial arteriography contributed to both definitive diagnosis and treatment. Initial cardiorespiratory management, diagnostic procedures and definitive therapy are described and reviewed. Adequate early management of the cardiorespiratory system is essential to the outcome. Aggressive measures to elucidate the cause of haemoptysis and prompt therapy are warranted because of the high risk of recurrence.

Aortic root replacement in a patient with vancomycin-resistant Enterococcus faecium endocarditis and leukemia.

Vancomycin-resistant Enterococcus faecium endocarditis is rare and usually occurs in immunocompromised patients. We describe a patient with hairy-cell leukemia and vancomycin-resistant E faecium endocarditis. The patient presented with severe aortic insufficiency. He underwent aortic root replacement with a cryopreserved aortic homograft and was treated with a combination of quinupristin/dalfopristin, ampicillin, and gentamicin.

Thrombosis of intracardiac or extracardiac conduits after modified Fontan operation in patients with azygous continuation of the inferior vena cava.

BACKGROUND: The Fontan procedure in patients with azygous continuation of the inferior vena cava, requires a cavo-pulmonary anastomosis, and deviation of the hepatic venous drainage to the pulmonary arteries using an intra- or extracardiac conduit. METHODS: We report thrombosis of two pericardial conduits and one Gore-Tex (W. L. Gore & Assoc, Flagstaff, AZ) graft used for deviation of hepatic venous blood to the pulmonary arterial tree in 3 patients aged 11, 24, and 28 years. Two of the conduits (pericardial) were intraatrial. The Gore-Tex graft was placed in an extracardiac position. The two pericardial conduits obstructed completely. RESULTS: One patient died at reoperation. In the 2nd patient, the conduit was excised and the hepatic veins were allowed to drain into the atrium. In the 3rd patient, partial thrombosis of the Gore-Tex conduit was noted 30 months after operation. The thrombus resolved with oral anticoagulation. CONCLUSIONS: Conduits carrying only hepatic venous blood flow may have a higher risk of thrombosis. Anticoagulation or alternative methods of directing hepatic blood flow to the pulmonary circulation must be considered in these patients.

Wilhelm Ebstein and Ebstein's malformation.

In 1866, Wilhelm Ebstein published a scholarly description of a tricuspid valve anomaly with dilation of the right atrium and patent foramen ovale that bears his name. However, his original report was almost overlooked. Despite a wide range of publications on the history of cardiac pathology and cardiac surgery, the international literature provides only scarce information regarding the personality of Wilhelm Ebstein and his original description of the anomaly that bears his name. In this article, we present biographical data of Wilhelm Ebstein and discuss how his original description of autopsy findings correlates with our current knowledge of this congenital disorder. It is the excellent correlation of Ebstein's pathologic findings with clinical notes of his colleague and Ebstein's hypotheses of the pathophysiology that made his publication a landmark in the description of a new entity. In addition, Ebstein's report provided a strong basis for the development of repair techniques for this rare anomaly 100 years later.

Surgical treatment of persistent esophageal compression by an unusual form of right aortic arch.

A 32-year-old woman with dysphagia due to an unusual form of right aortic arch and anomalous left subclavian artery had successful repair after two previous failures. The definitive repair was accomplished by resection of the retroesophageal portion of the right aortic arch. The continuity of the aorta was established with a prosthetic graft. The operation was performed through a median sternotomy with cardiopulmonary bypass and circulatory arrest.

Influence of sizing and subcoronary implantation technique on the function of porcine aortic homografts.

The function and longevity of the homograft aortic valve may be influenced by valve size and subcoronary implantation technique. Dynamic function and leaflet configuration of the porcine aortic valve were analysed first in its natural root in a left heart simulator using glycerol at 120/80 mm Hg pressure and 4 l min-1 Cardiac Output (C.O.). Then the valve was implanted in the porcine root and studied: Group I (n = 4) 1-2 mm smaller, Group II (n = 8) 3-4 mm smaller and Group III (n = 4) 5-7 mm smaller donor valve than the recipient. A silicone rubber mould of the implanted valve was made and analysed. In the donor aortic root the commissural expansion for 0 to 80 mm Hg pressure was 42% which was reduced significantly in all assemblies. Group I showed the largest decrease in the orifice area (OA). In Group III decrease in the OA was less, however, two of the four valves had aortic insufficiency (AI). In Group II decrease in the OA was only 13% and there was no AI. During opening the leaflet surface was smooth and free of wrinkles in the intact valve, but had creases and folds in all three groups. All implanted valves had an indentation along the suture line disrupting the leaflet-sinus continuity. Hence, to enhance valve longevity, donor valve 3-4 mm smaller than the recipient should be chosen and the implantation technique modified to preserve the leaflet-sinus continuity.

Yustin Y. Djanelidze and the first successful repair of an injured ascending aorta.

Yustin Y. Djanelidze is one of the little-known pioneers of cardiac surgery in the 20th century. He successfully sutured a penetrating injury of the ascending aorta in St. Petersburg, Russia, on 27 October 1913. To the best of our knowledge, this was the 1st case of ascending aorta repair described in the world medical literature.

Robert H. Goetz: the surgeon who performed the first successful clinical coronary artery bypass operation.

Robert H. Goetz performed the first successful clinical coronary artery bypass operation on May 2, 1960. He used a nonsuture technique to connect the right internal thoracic artery to the coronary artery by means of a modified Payr's cannula made of tantalum. The patency of the anastomosis was demonstrated angiographically and the patient remained free of angina pectoris for 1 year. It was an important and brave step forward, a step that was far ahead of its time. Unfortunately, his pioneering work was not appreciated and fell into oblivion.

Sergei S. Brukhonenko: the development of the first heart-lung machine for total body perfusion.

Sergei S. Brukhonenko designed and constructed one of the earliest heart-lung machines. He was the first to experimentally perform a total body perfusion with the heart of the animal isolated from the circulation. His work paved the way to the first experimental operations on heart valves. Although Brukhoneko's pioneering contributions have not received the recognition they deserve, his work represents an important landmark in cardiac surgery.