[Show abstract][Hide abstract] ABSTRACT: Objective
The c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR−/− mice.
Methods and results
To assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLR−/− or LDLR−/−/JNK1−/− mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLR−/−/MKP-1−/− mice compared to LDLR−/− mice, lesion formation was unaltered.
We conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation.
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: might digital drains speed up the time to thoracic drain removal in terms of time till chest drain removal, hospital stay and overall cost? A total of 296 papers were identified as a result of the search as described below. Of these, five papers provided the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. A literature search revealed that several single-centre prospective randomized studies have shown significantly earlier removal of chest drains with digital drains ranging between 0.8 and 2.1 days sooner. However, there was heterogeneity in studies in the management protocol of chest drains in terms of the use of suction, number of drains and assessment for drain removal. Some protocols such as routinely keeping drains irrespective of the presence of air leak or drain output may have skewed results. Differences in exclusion criteria and protocols for discharging home with portable devices may have biased results. Due to heterogeneity in the management protocol of chest drains, there is conflicting evidence regarding hospital stay. The limited data on cost suggest that there may be significantly lower postoperative costs in the digital drain group. All the studies were single-centre series generally including patients with good preoperative lung function tests. Further larger studies with more robust chest drain management protocols are required especially to assess length of hospital stay, cost and whether the results are applicable to a larger patient population.
Interactive Cardiovascular and Thoracic Surgery 04/2014; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether manual closure of the bronchial stump is safer with lower failure rates than mechanical closure using a stapling device following anatomical lung resection. One hundred and twenty-nine papers were identified using the search below. Eight papers presented the best evidence to answer the clinical question as they included sufficient number of patients to reach conclusions regarding the issues of interest for this review. Complications, complication rates and operation time were included in the assessment. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. When looking at manual vs mechanical staples, it was noted that stapler failure can occur in around 4% of cases. The rate of bronchopleural fistula (BPF) development varied more in patients who underwent manual closure (1.5-12.5%) than in patients who underwent mechanical closure (1-5.7%). Although most of the studies reviewed showed no statistical differences between manual and mechanical closure in terms of BPF development, one study, however, showed that manual closure was significantly associated with lower numbers of postoperative BPF, while another study showed that mechanical closure is significantly associated with lower incidence of BPF. When looking at the role of the learning curve and training opportunities, it seems that the surgeon's inexperience when using mechanical staples can contribute to BPF development. A surgeon's experience can play a major role in the prevention of BPF development in patients having manual closure. Manual closure can provide a cheap and reliable technique when compared with costs incurred from using staplers, it is applicable in all situations and can be taught to surgeons in training with an acceptable risk. However, there is a lack of evidence to suggest that manual closure is better than mechanical stapler closure following anatomical lung resection.
Interactive Cardiovascular and Thoracic Surgery 12/2013; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Is perioperative corticosteroid administration associated with a reduced incidence of postoperative atrial fibrillation (POAF) in adult cardiac surgery? A total of 70 papers were identified using the search as described below. Of these, eight were identified to provide best evidence to answer the clinical question. These papers consisted of well-designed, double-blinded randomized control trials (RCTs) or meta-analysis of RCTs that presented sufficient data to reach conclusions regarding the issues of interest for this review. Postoperative atrial fibrillation occurrence, outcomes and complications were included in the assessment. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. Literature search showed that the prophylactic use of hydrocortisone (100 mg/day, 4 days) can reduce the incidence of POAF to 30%, compared with 48% in the control group (P = 0.004). One gram of methylprednisolone before surgery followed by 4 mg of dexamethasone every 6 h for 1 day after surgery was also associated with a significant reduction in POAF (21 vs 51%; P = 0.003). Moreover, a single dose of dexamethasone (0.6 mg/kg) can significantly diminish POAF (18.95 vs 32.3%; P = 0.027). The changes in POAF appeared greatest in patients receiving intermediate doses of corticosteroid (50-210 mg of dexamethasone equivalent), while both lower (up to 8 mg) and higher (236-2850 mg) dosing resulted in blunted effects. Similarly, a moderate dose of hydrocortisone (200-1000 mg/day) is as effective as high (1001-10 000 mg/day) and very high doses (10 000 mg/day). Although the optimal dose, dosing interval and duration of therapy are unclear, meta-analysis suggests that a single dose can be as effective as multiple doses. No statistically significant complications associated with the use of corticosteroids were reported in any of the studies. We conclude that a single prophylactic moderate dose of corticosteroid (50-210 mg of dexamethasone equivalent or 200-1000 mg/day hydrocortisone) can significantly reduce the risk of POAF with no significant increase in morbidity or mortality.
Interactive Cardiovascular and Thoracic Surgery 11/2013; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether gabapentin, a commonly prescribed neuropathic analgesic and anticonvulsant, is safe and beneficial in patients with post-thoracotomy pain following thoracic surgery. Seventeen papers were identified using the search described below, and five papers presented the best evidence to reach conclusions regarding the issues of interest for this review. Side effects and complications as well as evidence of benefit, typically using various pain-scoring systems, were included in the assessment. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. The systematic review of two randomized controlled trials (RCTs) demonstrated that the use of a single dose gabapentin does not reduce pain scores or the need for epidural or morphine immediately in hospital following thoracic surgery. One double-blinded RCT used multiple doses of gabapentin perioperatively and showed that oral gabapentin administered preoperatively and during the first 2 days postoperatively, in conjunction with patient controlled analgesia morphine, provides effective analgesia in thoracic surgery with a consequent improvement in postoperative pulmonary function and less morphine consumption. One prospective clinical study comparing a 2-month course of gabapentin with naproxen sodium for chronic post thoracotomy pain following surgery showed significant improvement in both the visual analogue scale (VAS) score and the Leeds assessment of neuropathic symptoms and signs (LANSS) at 60 days in the gabapentin (P = 0.001). One prospective study of out-patients with chronic pain (>4 weeks since thoracotomy performed) suggested that gabapentin is effective, safe and well tolerated when used for persistent postoperative and post-traumatic pain in thoracic surgery patients. We conclude that there is no evidence to support the role of a single preoperative oral dose of gabapentin in reducing pain scores or opioid consumption following thoracic surgery. Multiple dosing regimens may be beneficial in reducing acute and chronic pain; however, more robust randomized control studies are needed.
Interactive Cardiovascular and Thoracic Surgery 07/2013; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids can play a pivotal role in modulating different immune responses. The role of glucocorticoids in cardiac surgery is still controversial as many surgeons are concerned about the potential side effects.In this review, we looked at the role of glucocorticoid administration in modulating postoperative inflammatory responses, atrial fibrillation (AF) and intimal hyperplasia and whether glucocorticoid use is associated with a significant increase in undesirable postoperative complication.
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: Is sub-lobar resection equivalent to lobectomy in terms of operative morbidity and mortality, long-term survival and disease recurrence in patients with peripheral carcinoid lung cancer? A total of 342 papers were identified using the search as described below. Of these, 10 papers presented the best evidence to answer the clinical question as they presented sufficient data to reach conclusions regarding the issues of interest for this review. Long-term survival, disease recurrence and operative morbidity were included in the assessment. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. A literature search showed that there is a good prognosis after resection of lung carcinoid with the 10-year disease-free survival rate ranging between 77 and 94%, and suggested that sub-lobar resection of a typical carcinoid did not compromise the long-term survival. The proportion of peripheral tumours ranged between 22.6 and 100% and the proportion of patients with a preoperative diagnosis of carcinoid ranged between 51.9 and 86.7%, with many series not providing either or both of these data. As a result, a lobectomy or greater resection was necessary on anatomical or diagnostic grounds and led to a low number of sub-lobar resections. Owing to the high heterogeneity within and between series and small numbers of cases included, it is difficult to draw conclusions on disease recurrence and postoperative morbidity. All studies available retrospectively compared heterogeneous groups of non-matched group of patients, which can bias the outcomes reported. There is a lack of comprehensive randomized studies to compare a lobectomy or greater resection and sub-lobar resection. We conclude that there is little objective evidence to show the equivalence or superiority of lobectomy over sub-lobar resection.
Interactive Cardiovascular and Thoracic Surgery 03/2013; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether video-assisted mediastinoscopy (VAM) is a more effective procedure than conventional mediastinoscopy (CM). A total of 108 papers were identified using the search as discussed below. Of which, eight papers presented the best evidence to answer the clinical question as they included a sufficient number of patients to reach conclusions regarding the issues of interest for this review. Complications, complication rates, number of lymph nodes biopsies, number of stations sampled and training opportunities were included in the assessment. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. Literature search revealed that CM is a safe procedure associated with low mortality (0-0.05%) and morbidity (0-5.3%). CM has high levels of accuracy (83.8-97.2%) and negative predictive value (81-95.7%). Training in CM can be difficult as the limited vision means that the trainer cannot monitor directly the dissection and the areas biopsied by the trainee as one operator and effectively see at any time. VAM is also a safe procedure with comparable results to that of CM in term of mortality (0%), morbidity (0.83-2.9%), accuracy (87.9-98.9%) and negative predictive values (83-98.6%). The main advantage is higher number of biospsies taken (VAM, 6-8.5; CM, 5-7.13) and number of mediastinal lymph node stations sampled (VAM, 1.9-3.6; CM, 2.6-2.98). VAM can be associated with more aggressive dissecting and that can lead to more complications. The use of VAM can provide a better and safer training opportunity since both trainer and trainee can share the magnified image on the monitor. All studies available are comparing heterogeneous groups of non-matched group of patients which can bias the outcomes reported. There is a lack of comprehensive randomized studies to compare both procedures and to support any preference towards VAM over CM. We conclude that there is actually very little objective evidence of VAM superiority over CM.
Interactive Cardiovascular and Thoracic Surgery 11/2011; 14(1):81-4. · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accelerated intimal hyperplasia (IH) is an important cause of morbidity and mortality in patients with atherosclerotic vascular disease treated with bypass vein grafts. We used an interposition vein graft model to determine the source of neointimal cells in a clinically relevant large animal model.
Jugular vein segments from sex-mismatched, MHC-in-bred pigs were implanted into common carotid arteries bilaterally and harvested up to 8 weeks postsurgery for stereological, histological, and immunofluorescence analyses.
Progressive IH lesions contained macrophages and smooth muscle cells (SMC). Fluorescent in situ hybridization following grafting of female veins into male arteries revealed that only ∼10% of the SMC were male, confirming that the majority of intimal SMC derived from the local vessel wall.
The majority of neointimal SMC in the IH seen after interposition vein grafting derive from the engrafted local vessel wall. These are the first results from a clinically relevant large animal model that confirm data from rodent models. They have implications for the utility of therapeutic stem cells in this type of intimal hyperplasia.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 05/2011; 20(3):e91-4. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vein grafting in coronary artery surgery is complicated by a high restenosis rate resulting from the development of vascular inflammation, intimal hyperplasia, and accelerated atherosclerosis. In contrast, arterial grafts are relatively resistant to these processes. Vascular inflammation is regulated by signaling intermediaries, including p38 mitogen-activated protein (MAP) kinase, that trigger endothelial cell (EC) expression of chemokines (eg, interleukin-8, monocyte chemotactic protein-1) and other proinflammatory molecules. Here, we have tested the hypothesis that p38 MAP kinase activation in response to arterial shear stress (flow) may occur more readily in venous ECs, leading to greater proinflammatory activation.
Comparative reverse-transcriptase polymerase chain reaction and Western blotting revealed that arterial shear stress induced p38-dependent expression of monocyte chemotactic protein-1 and interleukin-8 in porcine jugular vein ECs. In contrast, porcine aortic ECs were protected from shear stress-induced expression of p38-dependent chemokines as a result of rapid induction of MAP kinase phosphatase-1. However, we observed with both cultured porcine jugular vein ECs and perfused veins that venous ECs can be protected by brief treatment with dexamethasone, which induced MAP kinase phosphatase-1 to suppress proinflammatory activation.
Arterial but not venous ECs are protected from proinflammatory activation in response to short-term exposure to high shear stress by the induction of MAP kinase phosphatase-1. Dexamethasone pretreatment arterializes venous ECs by inducing MAP kinase phosphatase-1 and may protect veins from inflammation.
[Show abstract][Hide abstract] ABSTRACT: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain.
We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation.
Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1.
We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis.
Circulation Research 02/2011; 108(8):950-9. · 11.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a simple and practical method of eliminating anastomotic suture line bleeding that we believe is a safer method than the traditional approach of taking extra stitches around the suture line.
The Annals of thoracic surgery 09/2010; 90(3):1030-1. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atherosclerosis develops predominantly at branches and bends in arteries that are exposed to disturbed flow which exerts low, oscillatory shear stress on endothelial cells (ECs). We demonstrated that c-Jun N-terminal kinase (JNK) is activated in ECs at atherosusceptible but not atheroprotected sites. Transcriptome profiling of cultured ECs treated with a pharmacological inhibitor revealed that JNK functions as a positive regulator of NF-kappaB transcription factors, which promote inflammation by inducing inflammatory molecules (eg, VCAM-1). This observation was confirmed by silencing of JNK1 and ATF2 (a downstream transcription factor), which led to reduced NF-kappaB expression in cultured ECs. We validated our findings by demonstrating that EC expression of NF-kappaB and VCAM-1 and the accumulation of CD68-positive macrophages was elevated at atherosusceptible sites compared with atheroprotected sites in aortas of wild-type mice. Genetic deletion of JNK1 suppressed NF-kappaB and VCAM-1 expression, and reduced macrophage accumulation at the atherosusceptible site, indicating that JNK1 positively regulates NF-kappaB expression and inflammation. To establish a causal relationship between shear stress and JNK activity, we altered blood flow in the murine carotid artery by placing a constrictive cuff. We observed that low, oscillatory shear stress can enhance JNK activity, NF-kappaB and VCAM-1 expression in ECs and promote macrophage accumulation in arteries. We conclude that JNK1-ATF2 signalling promotes EC activation and inflammation at atheroprone sites exposed to low, oscillatory shear stress by enhancing NF-kappaB expression. Our findings illuminate a novel level of cross-talk between the NF-kappaB and JNK signalling pathways that may influence the spatial distribution of atherosclerotic lesions.
[Show abstract][Hide abstract] ABSTRACT: Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites.
We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1(-/-), and MKP-1(-/-) mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1.
Spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries.
[Show abstract][Hide abstract] ABSTRACT: The mitral valve is a complex, dynamic and functional apparatus that can be altered by a wide range of disorders leading to stenosis or regurgitation. Surgical management of mitral valve disease may be difficult. Planned intervention may not always be feasible when the surgeon is faced with complex pathology that cannot be assessed fully by conventional 2D echocardiography. Transthoracic and transesophageal 3D echocardiography can provide a more reliable functional and anatomical assessment of the different valve components and evaluation of its geometry, which can aid the surgeon in planning a more suitable surgical intervention and improve outcomes. Although 3D echocardiography is a new technology, it has proven to be an important modality for the accurate assessment of valvular heart disease and in the future, it promises to be an essential part in the routine assessment of cardiovascular patients.