Left cardiac sympathetic denervation: case series and technical report.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) is a surgical procedure that has been shown to have an antiarrhythmic and antifibrillatory effect. Evidence indicating its antiarrhythmic effect has been available for over 100 years. It involves the removal of the lower half of the stellate ganglion and T2-T4 of the sympathetic ganglia and is carried out as either a unilateral or bilateral procedure. With advancements in thoracic surgery, it can be safely performed via a minimally invasive Video-Assisted Thoracoscopic Surgery (VATS) approach resulting in significantly less morbidity and a shortened inpatient stay. LCSD provides a valuable treatment option for patients with life-threatening channelopathies and cardiomyopathies. AIMS AND METHODS: This case series reports the preliminary paediatric and adult experience in the Republic of Ireland with LCSD and describes five cases recently treated in addition to an outline of the operative procedure employed. Of the five cases included, two were paediatric cases and three were adult cases. RESULTS: One of the paediatric patients had a diagnosis of the rare catecholaminergic polymorphic ventricular tachycardia (CPVT) and the other a diagnosis of long-QT syndrome. Both paediatric patients experienced excellent outcomes. Of the three adult patients, two benefitted greatly and remain well at follow-up (one inappropriate sinus tachycardia and one CPVT). One patient with idiopathic ventricular fibrillation unfortunately passed away from intractable VF despite all attempts at resuscitation. CONCLUSION: In this case series, we highlight that LCSD provides a critical adjunct to existing medical therapies and should be considered for all patients with life-threatening refractory arrhythmias especially those patients on maximal medical therapy.

Understanding STAT3 signaling in cardiac ischemia.

Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.

Advances in the management of severe aortic stenosis.

BACKGROUND: Recent developments in the management of severe aortic stenosis have resulted in a paradigm shift in the way we view the condition. Patients previously denied intervention in the form of surgical aortic valve replacement (SAVR) are now candidates for transcatheter aortic valve implantation and the risk and age profiles of those undergoing SAVR are rising with the ageing population. This review article is designed to provide an overview of developments in the surgical management of severe aortic stenosis. We also discuss the expanding role of minimally invasive surgical approaches to outline the current techniques available to treat patients with severe aortic stenosis. METHODS: PubMed was searched using the terms 'severe aortic stenosis', 'surgical aortic valve replacement', 'transcatheter aortic valve replacement', 'mechanical aortic valve replacement' and 'sutureless aortic valve replacement'. Selection of articles was based on peer review, journal and relevance. Where possible articles from high-impact factor peer review journals were included. RESULTS: Minimally invasive operative approaches include mini-sternotomy and mini-thoracotomy. Sutureless aortic prostheses reduce aortic cross-clamp time and cardiopulmonary bypass time; however, long-term follow-up data are unavailable at this time. Mechanical prostheses are advised for those under 60. CONCLUSION: Multiple advances in the surgical management of aortic stenosis have occured in the past decade. An evolving spectrum of surgical and transcatheter interventions is now available depending on patient age and operative risk.

Nutrient and plant secondary compound composition and iron-binding capacity in leaves and green stems of commonly used plant browse (Carolina willow; Salix caroliniana) fed to zoo-managed browsing herbivores.

Plant secondary compounds are diverse structurally, and associated biological effects can vary depending on multiple factors including chemical structure and reaction conditions. Phenolic compounds such as tannins can chelate dietary iron, and supplementation of animal species sensitive to iron overload with tannins may prevent/treat iron overload disorder. We assessed the nutrient and phenolic composition and iron-binding capacity of Carolina willow (Salix caroliniana), a plant fed to zoo-managed browsing herbivores. Based on studies in other plant species and the chemical structures of phenolic compounds, we hypothesized that the concentration of condensed tannins in willow would be inversely related to the concentration of phenolic glycosides and directly related to iron-binding capacity. Our results indicated that willow nutrient composition varied by year, season, and plant part, which could be taken into consideration when formulating animal diets. We also found that the predominant plant secondary compounds were condensed tannins with minimal phenolic glycosides. Instead of binding to iron, the willow leaf extracts reduced iron from the ferric to ferrous form, which may have prooxidative effects and increase the bioavailability of iron depending on animal species, gastrointestinal conditions, and whole animal processes. We recommend identifying alternative compounds that effectively chelate iron in vitro and conducting chelation therapy trials in vivo to assess potential effects on iron balance and overall animal health.

Understanding Complete Pathologic Response in Oesophageal Cancer: Implications for Management and Survival.

Despite significant improvement over recent decades, oesophageal cancer survival rates remain poor. Neoadjuvant chemoradiotherapy followed by oesophageal resection is mainstay of therapy for resectable oesophageal tumours. Operative morbidity and mortality associated with oesophagectomy remain high and complications arise in up to 60% of patients. Management strategies have moved towards definitive chemoradiotherapy for a number of tumour sites (head and neck, cervical, and rectal) particularly for squamous pathology. We undertook to perform a review of the current status of morbidity and mortality associated with oesophagectomy, grading systems determining pathologic response, and data from clinical trials managing patients with definitive chemoradiotherapy to inform a discussion on the topic.

The 100 most cited publications in cardiac surgery: a bibliometric analysis.

INTRODUCTION: This study is a citation analysis of the top 100 most cited papers in adult cardiac surgery. Bibliometric analyses are viewed as a proxy marker of a paper's influence and, therefore, an analysis of the most influential papers published in recent decades. METHODS: Impact factor ranking as of 2012 was used to decide which journals to include in our searches. The Thompson Reuters Web of Knowledge was used to search for citations of all papers relevant to cardiac surgery within selected journals. Journals in the areas of surgery, cardiothoracic surgery, general medicine, anaesthesia, perfusion and pathology were included. RESULTS: The most frequently cited paper was found to be that of Nashef et al. (Eur J Cardiothorac Surg 16(1):9-13, 1999) introducing the EuroSCORE operative risk evaluation system. A number of authors including Alderman, Carpentier and Cox had more than one paper in the top 100. CONCLUSION: Despite the potential flaws with bibliometric analysis, and its application to cardiac surgery, there is inherent merit in an analysis of this type.

Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus.

INTRODUCTION: Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. AIMS: Long-term results of two simultaneous randomised controlled trials (RCTs) comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of adenocarcinoma (AC) and squamous cell carcinoma (SCC) to identical regimens compared. METHODS: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately-randomised to identical protocols of MMT or surgical monotherapy. RESULTS: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0.004), SCC (P=0.01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery (64% versus 29%, P<0.001). MMT produced a pathologic complete response (pCR) in 25% and 31% of AC and SCC, respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR versus surgical monotherapy (P=0.001); residual disease following MMT versus surgical monotherapy (P=0.008); SCC pCR versus surgical monotherapy (P=0.033). CONCLUSIONS: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumour down-staging to extinction in 25-31% of patients, potentially permitting personalised treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localised disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.

Experience of a high-risk aortic valve clinic in Ireland.

BACKGROUND: The advent of transcatheter aortic valve implantation (TAVI) has broadened the management options for severe aortic stenosis. The indications for TAVI are narrow. Selecting those that will benefit most from this intervention warrants careful consideration and input from cardiologists, anaesthetists and cardiac surgeons familiar with TAVI and surgical aortic valve replacement (SAVR). AIMS: The aims of this paper were to assess the feasibility of establishing a high-risk aortic clinic in Ireland, and report stratification of the referred group into those suitable for SAVR, TAVI and conservative management. METHODS: Patient data was prospectively collected by a dedicated clinical nurse specialist. ANOVA was used to assess variance in means between groups. Analyses were performed using IBM SPSS v20 (Armonk, NY: IBM Corp.). RESULTS: A total of 105 patients were assessed. Eighty-five patients were deemed suitable for TAVI, 9 (10.5 %) died awaiting the procedure and a further 6 (7 %) declined intervention. Eleven (10.5 %) underwent conventional SAVR, 1 (0.9 %) a balloon valvuloplasty, 4 (3.8 %) entered surveillance and 4 (3.8 %) were declined treatment. CONCLUSIONS: Establishment of a high-risk aortic clinic is feasible in the Irish context. The advent of TAVI has reduced the proportion of patients denied intervention to a minority. Despite being considered high risk, a number of patients were suitable candidates for SAVR. Measuring frailty continues to provide a challenge; a TAVI-specific frailty assessment tool would be advantageous to patient stratification.

The esophagitis to adenocarcinoma sequence; the role of inflammation.

Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fueled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.

Burden of copy number variation in common variable immunodeficiency.

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.

Curative surgical management of isolated adrenal recurrence of oesophageal adenocarcinoma.

Adrenal metastases of oesophageal adenocarcinoma are rarely detected in the clinical setting, more frequently being found as an incidental postmortem finding in the presence of widespread metastases. With improvements in the sensitivity of radiological diagnostic modalities, the incidence of adrenal tumour detection is on the rise. We report herein a particularly rare case of primary operative management by adrenalectomy for an isolated right-sided adrenal metastasis secondary to oesophageal adenocarcinoma, with a long-term survival.

Necrotising pancreatitis presenting as a painful mass in the groin and sepsis.

Acute pancreatitis is typically associated with classical clinical and radiological features. The sensitivity of CT to diagnose acute pancreatitis depends on the severity of the attack and ranges from 77% to 92% with a specificity approaching 100%. Despite the fact this is a common disease, there are myriad clinical presentations of acute pancreatitis. We report herein an especially rare presentation where severe acute necrotising pancreatitis presented with a tender inguinoscrotal swelling with a normal pancreas on CT imaging.

Basic surgical training in Ireland: the impact of operative experience, training program allocation and mentorship on trainee satisfaction.

BACKGROUND: Application to the Irish basic surgical training (BST) program in Ireland has decreased progressively over the past 5 years. We hypothesised that this decline was secondary to dissatisfaction with training correlated with reduced operative experience and lack of mentorship among BSTs. METHODS: An anonymous 15 question electronic survey was circulated to all BSTs appraising their impression of the operative experience available to them, their mentorship and their opinions of critical aspects of training. RESULTS: Fifty trainees responded to the survey. At the commencement of training 98 % (n = 43) intended to stay in surgery, decreasing to 79 % (n = 34) during the BST. Trainees who felt they had a mentor were three times more likely to be content in surgical training (OR 3.11; 95 % CI 0.94-10.25, P = 0.06). Trainees satisfied with their allocated rotation were more likely to be content in surgical training (OR 4.5; 95 % CI 1.03-19.6, P = 0.045). Individual trainee comments revealed dissatisfaction with operative exposure. CONCLUSION: Mentorship and satisfaction with allocated training rotation had a positive impact on trainee satisfaction and correlated with contentedness in surgical training. Operative experience is the main element that trainees report as lacking. This highlights the need for reform of the training system to improve current levels of mentorship and increase operative exposure to enhance its attractiveness to the best quality medical graduates.

Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus.

Integrin very late antigen-4 (VLA4) is induced during inflammation and can regulate monocyte migration. It has been implicated in atherogenesis, a significant concern in systemic lupus erythematosus (SLE). The aim of this study was to define VLA4 expression in SLE monocytes. Flow cytometry, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry staining with confocal microscopy were used to evaluate VLA4 expression in SLE patients and controls. We found elevated expression of VLA4 in SLE patients with significantly increased VLA4 staining intracellularly compared to control. Exposure of control monocytes to SLE sera or immune complexes led to increased intracellular expression, and immune complexes were capable of driving redistribution of surface VLA4 to the cytoplasm. Therefore, VLA4 was found to be subject to complex regulation with SLE sera driving both RNA expression and redistribution of protein. Stimulation of SLE monocytes with a VLA4 ligand induced significant TNFα expression, confirming a functional effect. This behavior may contribute to increased atherosclerosis and monocyte infiltrates in end organs.

Monocyte polarization: the relationship of genome-wide changes in H4 acetylation with polarization.

The character of monocytes is both molded by and contributes to ongoing immune responses. We hypothesized that monocyte polarization could have durable qualities and these would be mediated partly by changes in the chromatin. We defined genome-wide expression and histone H4 acetylation (H4ac) changes after γ-interferon (IFN), α-IFN and interleukin-4 treatment. To identify genes with altered potential for expression, we stimulated polarized monocytes and identified genes up- or downregulated after polarization and stimulation but not either treatment alone. We also defined durability after an 18-h or 3-day washout. Genes uniquely regulated after the combination of polarization and stimulus were durably altered, with 51% of the effects being durable. This gene set was highly enriched for cytokine-induced alterations in H4ac, with P-values ranging from 10(-24) to 10(-37). Certain regulons defined by patterns of expression were also associated with altered H4ac, with P-values ranging from 10(-4) to 10(-29). Networking software revealed a high density of mitogen-activated protein (MAP) kinase nodes in these clusters. Therefore, some changes in monocyte gene expression were sustained over a 3-day period. These durably altered gene sets were enriched for changes in H4ac and were associated with potential MAP kinase effects.

Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum--a single-center pediatric experience.

BACKGROUND: Dyskeratosis Congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow failure, somatic abnormalities, and cancer predisposition resulting from defective telomere maintenance. The immunologic features of DKC remain under diagnosed and under treated despite the fact that immunodeficiency is a major cause of premature mortality in DKC. METHODS: This study undertook a retrospective review of 7 DKC patients diagnosed at the Children's Hospital of Philadelphia. In parallel, we reviewed previously reported immunologic findings in DKC patients. RESULTS: Immunologic abnormalities (lymphopenia, low B-cell numbers, hypogammaglobulinemia, and decreased T-cell function) were the most frequent laboratory findings at initial presentation, preceding the development of significant anemia or thrombocytopenia. Recurrent sinopulmonary or opportunistic infections were present in 6/7 patients. Infant-onset patients had more severe immunologic and somatic features (particularly severe enteropathy). CONCLUSION: In DKC, development of immunologic abnormalities can precede bone marrow failure, highlighting the importance of proper immunodeficiency management to minimize morbidity and premature mortality in this disease.

Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes.

Systemic lupus erythematosus (SLE) is a polygenic disorder affecting approximately 1 in 1000 adults. Recent data have implicated interferons (IFN) in the pathogenesis, and the expressions of many genes downstream of IFNs are regulated at the level of histone modifications. We examined H4 acetylation (H4ac) and gene expression in monocytes from patients with SLE to define alterations to the epigenome. Monocytes from 14 controls and 24 SLE patients were used for analysis by chromatin immunoprecipitation for H4ac and gene expression arrays. Primary monocytes treated with alpha-IFN were used as a comparator. Data were analyzed for concordance of H4ac and gene expression. Network analyses and transcription factor analyses were conducted to identify potential pathways. H4ac was significantly altered in monocytes from patients with SLE. In all, 63% of genes with increased H4ac had the potential for regulation by IFN regulatory factor (IRF)1. IRF1 binding sites were also upstream of nearly all genes with both increased H4ac and gene expression. alpha-IFN was a significant contributor to both expression and H4ac patterns, but the greatest concordance was seen in the enrichment of certain transcription factor binding sites upstream of genes with increased H4ac in SLE and genes with increased H4ac after alpha-IFN treatment.

Epigenetic regulation of tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNF-alpha) is a potent cytokine which regulates inflammation via the induction of adhesion molecules and chemokine expression. Its expression is known to be regulated in a complex manner with transcription, message turnover, message splicing, translation, and protein cleavage from the cell surface all being independently regulated. This study examined both cell lines and primary cells to understand the developmental regulation of epigenetic changes at the TNF-alpha locus. We demonstrate that epigenetic modifications of the TNF-alpha locus occur both developmentally and in response to acute stimulation and, importantly, that they actively regulate expression. DNA demethylates early in development, beginning with the hematopoietic stem cell. The TNF-alpha locus migrates from heterochromatin to euchromatin in a progressive fashion, reaching euchromatin slightly later in differentiation. Finally, histone modifications characteristic of a transcriptionally competent gene occur with myeloid differentiation and progress with differentiation. Additional histone modifications characteristic of active gene expression are acquired with stimulation. In each case, manipulation of these epigenetic variables altered the ability of the cell to express TNF-alpha. These studies demonstrate the importance of epigenetic regulation in the control of TNF-alpha expression. These findings may have relevance for inflammatory disorders in which TNF-alpha is overproduced.

Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia).

Congenital disorder of glycosylation Ia is the most common defect of glycosylation and is due to mutations in phosphomannomutase 2. This leads to aberrant N-linked oligosaccharides. The phenotype of CDG Ia reflects the essential nature of glycosylation and patients typically present with multiple organs affected, with hypotonia, developmental delay, inverted nipples and abnormal fat pads. Later features include retinitis pigmentosa, stroke, cerebellar atrophy and malabsorption. Approximately 20% of patients die in the first year of life and infection is the most common cause of death. Immunological function has not previously been investigated in these patients and the critical role of oligosaccharides on adhesion molecules suggested that haematopoietic cell migration and communication could be disrupted by mutations in phosphomannomutase 2. We characterized the clinical features, performed standard immunological evaluations, and performed specific analyses of neutrophil adhesion molecules on two patients to address this question. Patient neutrophils had diminished chemotaxis but expressed comparable levels of adhesion molecules and rolled on artificial endothelium equivalently to control neutrophils. The most significant feature of the patients' immunological function was poor vaccine responses. These two affected patients were begun on intravenous immunoglobulin with some improvement in their infections.

Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus.

OBJECTIVES: Patients with chronic granulomatous disease and carrier mothers of patients with chronic granulomatous disease are predisposed to developing various forms of lupus. This disorder is a neutrophil defect in intracellular killing. Abnormal apoptosis has been described. We hypothesized that abnormal apoptosis occurring in neutrophils of patients made them more immunogenic. METHODS: Human patients with chronic granulomatous disease were examined for abnormalities of neutrophil apoptosis by flow cytometry. To model the effect of abnormal apoptosis, a murine model was used. Apoptotic cells from either wild type or mice with chronic granulomatous disease were injected into either wild type or chronic granulomatous disease mice and autoantibodies were determined by ELISA. RESULTS: Our studies found that human and murine neutrophils carrying the gp91 form of chronic granulomatous disease had impaired exposure of phosphatidyl serine on the surface. Other markers of apoptosis were largely normal. Injection of apoptotic neutrophils from gp91 knockout mice into gp91 knockout mice led to the development of characteristic autoantibodies of lupus. CONCLUSIONS: Humans with chronic granulomatous disease may be at an increased risk of developing lupus due to abnormal apoptosis and abnormal clearance of apoptotic cells.