The mitochondrial DNA T16189C polymorphism and HIV-associated cardiomyopathy: a genotype-phenotype association study

<p>Abstract</p> <p>Background</p> <p>The mitochondrial DNA (mtDNA) T16189C polymorphism, with a homopolymeric C-tract of 10–12 cytosines, is a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations. We hypothesized that this variant may predispose to dilated cardiomyopathy in people who are infected with the human immunodeficiency virus (HIV).</p> <p>Methods</p> <p>A case-control study of 30 HIV-positive cases with dilated cardiomyopathy and 37 HIV-positive controls without dilated cardiomyopathy was conducted. The study was confined to persons of black African ancestry to minimize confounding of results by population admixture. HIV-positive patients with an echocardiographically confirmed diagnosis of dilated cardiomyopathy and HIV-positive controls with echocardiographically normal hearts were studied. Patients with secondary causes of cardiomyopathy (such as hypertension, diabetes, pregnancy, alcoholism, valvular heart disease, and opportunistic infection) were excluded from the study. DNA samples were sequenced for the mtDNA T16189C polymorphism with a homopolymeric C-tract in the forward and reverse directions on an ABI3100 sequencer.</p> <p>Results</p> <p>The cases and controls were well matched for age (median 35 years versus 34 years, P = 0.93), gender (males 60% vs 53%, P = 0.54), and stage of HIV disease (mean CD4 T cell count 260.7/μL vs. 176/μL, P = 0.21). The mtDNA T16189C variant with a homopolymeric C-tract was detected at a frequency of 26.7% (8/30) in the HIV-associated cardiomyopathy cases and 13.5% (5/37) in the HIV-positive controls. There was no significant difference between cases and controls (Odds Ratio 2.33, 95% Confidence Interval 0.67–8.06, p = 0.11).</p> <p>Conclusion</p> <p>The mtDNA T16189C variant with a homopolymeric C-tract is not associated with dilated cardiomyopathy in black African people infected with HIV.</p

Excision of sympathetic ganglia and the rami communicantes with histological confirmation offers better early and late outcomes in Video assisted thoracoscopic sympathectomy

<p>Abstract</p> <p>Background</p> <p>Video-Assisted Thoracoscopic Sympathectomy (VATS) is an established minimally invasive procedure for thoracic sympathetic blockade in patients with hyperhidrosis, facial flushing and intractable angina. Various techniques using clips, diathermy and excision are used to perform sympathectomy. We present our technique of excision of the sympathetic chain with histological proof and the analysis of the early and late outcomes.</p> <p>Methods</p> <p>We evaluated 200 procedures in 100 consecutive patients, who underwent Video Assisted Thoracoscopic Sympathectomy by a single surgeon in our centre between September 1996 to March 2007. All patients had maximum medical therapy prior to surgery and were divided into 3 groups based on indications, Group 1(hyperhidrosis: 48 patients), Group 2 (facial flushing: 26 patients) and Group 3(intractable angina: 26 patients). The demography and severity of symptoms for each group were analysed. The endpoints were success rate, 30 day mortality, complications and patient's satisfaction.</p> <p>Results</p> <p>99 patients had bilateral VATS sympathectomy and 1 had unilateral sympathectomy. The conversion rate to open was 1(1%). All patients had successful removal of ganglia proven histologically with no perioperative mortality in our series. The complications included pneumothorax (5%), acute coronary syndrome (2%), transient Horner's syndrome (1%), transient paraesthesia (1%), wound infection (4%), compensatory hyperhidrosis (18%), residual flushing (3%) and wound pain (5%). There were five late deaths in the intractable angina group at a mean follow up of 36.7 months. Overall success rates of abolishing the symptoms were 96.3%, 87.5% and 95.2% for Group 1, 2 and 3 respectively.</p> <p>Conclusion</p> <p>Excision of the sympathetic chain with histological confirmation during VATS sympathectomy is a safe and effective method in treating hyperhidrosis, facial flushing and intractable angina with good long term results and satisfaction.</p

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations.

Idiopathic dilated cardiomyopathy is a recognised manifestation of mitochondrial disease due to specific mitochondrial (mt) DNA mutations. However, whether mtDNA polymorphisms predispose to sporadic dilated cardiomyopathy is not known. We analysed two populations with this disorder for a general mtDNA variant (T16189C), previously implicated in susceptibility to type 2 diabetes. We noted an increased frequency of the polymorphism in both populations compared with controls (p=0.002). The polymorphism occurred on different mtDNA backgrounds, suggesting that it might be a functional variant. This association of an mtDNA variant with increased susceptibility to dilated cardiomyopathy provides evidence for a mitochondrial cause in sporadic disease

A common mitochondrial DNA variant is associated with idiopathic dilated cardiomyopathy in two different populations

Dilated Cardiomyopathy (DCM) is a devastating disease. It is a recognised manifestation of mitochondrial disease and in some cases the only clinical abnormality. Although specific mitochondrial DNA(mtDNA) mutations in tRNAleu/lle have been identified in mitochondrial disease associated with DCM, it is not known whether any mtDNA variants predispose to sporadic DCM. We aimed to determine the prevalence of a mtDNA variant (T16189C), in DCM; this variant has been previously implicated in susceptibility to type 2 diabetes and is thought to impair energy production. We screened leucocyte DNA from 24 non-diabetic Black South African DCM patients and 19 normal Black South African controls for the T16189C polymorphism. PCR amplification and sequencing of the D-loop segment was performed. Sequence analyses revealed a positive association of the 16189 polymorphism with DCM in this population. In order to test our hypothesis that this variant may itself play a pathogenic role in DCM, we investigated the prevalence of the same polymorphism in a different population of non-diabetic caucasian DCM patients with no family history. DNA extracted from leucocytes and cardiac biopsies from 93 DCM patients were analysed for the T16189C polymorphism by PCR and sequencing and the prevalence compared to that in 545 normal Caucasian European controls, previously analysed. Analysis of the T16189C polymorphism in the Black South African DCM patients and controls revealed that the polymorphism (with associated length variation) was present in 46% (11/24) compared with only 16% (3/19) of Black South African controls(p=0.036). Of the caucasian(UK) DCM patients, 17.2% (16/93) had the T16189C polymorphism compared with 8.8% (48/545) of controls (p=0.01; O.R.=2.15 [95% Cl 1.06-3.92]). As the T16189C variant has arisen in several distinct maternal lineages, this association is unlikely to be due to a founder effect. The association of the 16189 mtDNA variant with DCM in two different populations, and in different lineages, suggests that this variant may play a direct role in the pathogenesis of DCM. The critical position of nucleotide 16189 within the control region of mtDNA, is such that variations in this region may directly affect mitochondrial function. This is the first association of DCM with a common population polymorphism