The glucocorticoid receptor DNA-binding domain recognizes RNA hairpin structures with high affinity

The glucocorticoid receptor (GR) binds the noncoding RNA Gas5 via its DNA-binding domain (DBD) with functional implications in pro-apoptosis signaling. Here, we report a comprehensive in vitro binding study where we have determined that GR-DBD is a robust structure-specific RNA-binding domain. GR-DBD binds to a diverse range of RNA hairpin motifs, both synthetic and biologically derived, with apparent mid-nanomolar affinity while discriminating against uniform dsRNA. As opposed to dimeric recognition of dsDNA, GR-DBD binds to RNA as a monomer and confers high affinity primarily through electrostatic contacts. GR-DBD adopts a discrete RNA-bound state, as assessed by NMR, distinct from both free and DNA-bound. NMR and alanine mutagenesis suggest a heightened involvement of the C-terminal &alpha;-helix of the GR-DBD in RNA-binding. RNA competes for binding with dsDNA and occurs in a similar affinity range as dimer binding to the canonical DNA element. Given the prevalence of RNA hairpins within the transcriptome, our findings strongly suggest that many RNAs have potential to impact GR biology.</p

Persistence survey of Toxic Shock Syndrome toxin-1 producing Staphylococcus aureus and serum antibodies to this superantigen in five groups of menstruating women

Background: Menstrual Toxic Shock Syndrome (mTSS) is thought to be associated with the vaginal colonization with specific strains of Staphylococcus aureus TSST-1 in women who lack sufficient antibody titers to this toxin. There are no published studies that examine the seroconversion in women with various colonization patterns of this organism. Thus, the aim of this study was to evaluate the persistence of Staphylococcus aureus colonization at three body sites (vagina, nares, and anus) and serum antibody to toxic shock syndrome toxin-producing Staphylococcus aureus among a small group of healthy, menstruating women evaluated previously in a larger study. Methods: One year after the completion of that study, 311 subjects were recalled into 5 groups. Four samples were obtained from each participant at several visits over an additional 6-11 month period: 1) an anterior nares swab; 2) an anal swab; 3) a vagina swab; and 4) a blood sample. Gram stain, a catalase test, and a rapid S. aureus-specific latex agglutination test were performed to phenotypically identify S. aureus from sample swabs. A competitive ELISA was used to quantify TSST-1 production. Human TSST-1 IgG antibodies were determined from the blood samples using a sandwich ELISA method. Results: We found only 41% of toxigenic S. aureus and 35.5% of non-toxigenic nasal carriage could be classified as persistent. None of the toxigenic S. aureus vaginal or anal carriage could be classified as persistent. Despite the low persistence of S. aureus colonization, subjects colonized with a toxigenic strain were found to display distributions of antibody titers skewed toward higher titers than other subjects. Seven percent (5/75) of subjects became seropositive during recall, but none experienced toxic shock syndrome-like symptoms. Conclusions: Nasal carriage of S. aureus appears to be persistent and the best predicator of subsequent colonization, whereas vaginal and anal carriage appear to be more transient. From these findings, it appears that antibody titers in women found to be colonized with toxigenic S. aureus remained skewed toward higher titers whether or not the colonies were found to be persistent or transient in nature. This suggests that colonization at some point in time is sufficient to elevate antibody titer levels and those levels appear to be persistent. Results also indicate that women can become seropositive without experiencing signs or symptoms of toxic shock syndrome

Preoperative calculation of risk for prolonged intensive care unit stay following coronary artery bypass grafting

OBJECTIVE: Patients who have prolonged stay in intensive care unit (ICU) are associated with adverse outcomes. Such patients have cost implications and can lead to shortage of ICU beds. We aimed to develop a preoperative risk prediction tool for prolonged ICU stay following coronary artery surgery (CABG). METHODS: 5,186 patients who underwent CABG between 1st April 1997 and 31st March 2002 were analysed in a development dataset. Logistic regression was used with forward stepwise technique to identify preoperative risk factors for prolonged ICU stay; defined as patients staying longer than 3 days on ICU. Variables examined included presentation history, co-morbidities, catheter and demographic details. The use of cardiopulmonary bypass (CPB) was also recorded. The prediction tool was tested on validation dataset (1197 CABG patients between 1(st )April 2003 and 31(st )March 2004). The area under the receiver operating characteristic (ROC) curve was calculated to assess the performance of the prediction tool. RESULTS: 475(9.2%) patients had a prolonged ICU stay in the development dataset. Variables identified as risk factors for a prolonged ICU stay included renal dysfunction, unstable angina, poor ejection fraction, peripheral vascular disease, obesity, increasing age, smoking, diabetes, priority, hypercholesterolaemia, hypertension, and use of CPB. In the validation dataset, 8.1% patients had a prolonged ICU stay compared to 8.7% expected. The ROC curve for the development and validation datasets was 0.72 and 0.74 respectively. CONCLUSION: A prediction tool has been developed which is reliable and valid. The tool is being piloted at our institution to aid resource management

Carotid Baroreflex Activation: Past, Present, and Future

Electrical activation of the carotid baroreceptor system is an attractive therapy for the treatment of resistant hypertension. In the past, several attempts were made to directly activate the baroreceptor system in humans, but the method had to be restricted to a few selected patients. Adverse effects, the need for better electrical devices and better surgical techniques, and the lack of knowledge about long-term effects has greatly hampered developments in this area for many years. Recently, a new and promising device was evaluated in a multicenter feasibility trial, which showed a clinically and statistically significant reduction in office systolic blood pressure (>20 mm Hg). This reduction could be sustained for at least 2 years with an acceptable safety profile. In the future, this new device may stimulate further application of electrical activation of the carotid baroreflex in treatment-resistant hypertension

Helicobacter Genotyping and Detection in Peroperative Lavage Fluid in Patients with Perforated Peptic Ulcer

Introduction and Objectives Certain Helicobacter pylori genotypes are associated with peptic ulcer disease; however, little is known about associations between the H. pylori genotype and perforated peptic ulcer (PPU). The primary aim of this study was to evaluate which genotypes are present in patients with PPU and which genotype is dominant in this population. The secondary aim was to study the possibility of determining the H. pylori status in a way other than by biopsy. Materials and Methods Serum samples, gastric tissue biopsies, lavage fluid, and fluid from the nasogastric tube were collec

Intensive Care Unit Admission Parameters Improve the Accuracy of Operative Mortality Predictive Models in Cardiac Surgery

BACKGROUND: Operative mortality risk in cardiac surgery is usually assessed using preoperative risk models. However, intraoperative factors may change the risk profile of the patients, and parameters at the admission in the intensive care unit may be relevant in determining the operative mortality. This study investigates the association between a number of parameters at the admission in the intensive care unit and the operative mortality, and verifies the hypothesis that including these parameters into the preoperative risk models may increase the accuracy of prediction of the operative mortality. METHODOLOGY: 929 adult patients who underwent cardiac surgery were admitted to the study. The preoperative risk profile was assessed using the logistic EuroSCORE and the ACEF score. A number of parameters recorded at the admission in the intensive care unit were explored for univariate and multivariable association with the operative mortality. PRINCIPAL FINDINGS: A heart rate higher than 120 beats per minute and a blood lactate value higher than 4 mmol/L at the admission in the intensive care unit were independent predictors of operative mortality, with odds ratio of 6.7 and 13.4 respectively. Including these parameters into the logistic EuroSCORE and the ACEF score increased their accuracy (area under the curve 0.85 to 0.88 for the logistic EuroSCORE and 0.81 to 0.86 for the ACEF score). CONCLUSIONS: A double-stage assessment of operative mortality risk provides a higher accuracy of the prediction. Elevated blood lactates and tachycardia reflect a condition of inadequate cardiac output. Their inclusion in the assessment of the severity of the clinical conditions after cardiac surgery may offer a useful tool to introduce more sophisticated hemodynamic monitoring techniques. Comparison between the predicted operative mortality risk before and after the operation may offer an assessment of the operative performance

Helicobacter species are associated with possible increase in risk of biliary lithiasis and benign biliary diseases

<p>Abstract</p> <p>Background</p> <p>Hepato-biliary tract lithiasis is common and present either as pain or as asymptomatic on abdominal ultrasonography for other causes. Although the DNA of <it>Helicobacter </it>species are identified in the gallbladder bile, tissue or stones analyzed from these cases, still a causal relationship could not be established due to different results from different geographical parts.</p> <p>Methods</p> <p>A detailed search of pubmed and pubmedcentral was carried out with key words <it>Helicobacter </it>and gallbladder, gallstones, hepaticolithiasis, cholelithiasis and choledocholithiasis, benign biliary diseases, liver diseases. The data was entered in a data base and meta analysis was carried out. The analysis was carried out using odds ratio and a fixed effect model, 95% confidence intervals for odds ratio was calculated. Chi square test for heterogeneity was employed. The overall effect was calculated using Z test.</p> <p>Results</p> <p>A total of 12 articles were identified. One study used IgG for diagnosis while others used the PCR for Ure A gene, 16 S RNA or Cag A genes. A couple of studies used culture or histopathology besides the PCR. The cumulative results show a higher association of <it>Helicobacter </it>with chronic liver diseases (30.48%), and stone diseases (42.96%)(OR 1.77 95% CI 1.2–2.58; Z = 2.94, p = 0.003), the effect of each could not be identified as it was difficult to isolate the effect of helicobacter due to mixing of cases in each study.</p> <p>Conclusion</p> <p>The results of present meta analysis shows that there is a slight higher risk of cholelithiasis and benign liver disease (OR 1.77), however due to inherent inability to isolate the effect of stone disease from that of other benign lesions it is not possible to say for sure that <it>Helicobacter </it>has a casual relationship with benign biliary disease or stone disease or both.</p

Change Point Estimation in Monitoring Survival Time

Precise identification of the time when a change in a hospital outcome has occurred enables clinical experts to search for a potential special cause more effectively. In this paper, we develop change point estimation methods for survival time of a clinical procedure in the presence of patient mix in a Bayesian framework. We apply Bayesian hierarchical models to formulate the change point where there exists a step change in the mean survival time of patients who underwent cardiac surgery. The data are right censored since the monitoring is conducted over a limited follow-up period. We capture the effect of risk factors prior to the surgery using a Weibull accelerated failure time regression model. Markov Chain Monte Carlo is used to obtain posterior distributions of the change point parameters including location and magnitude of changes and also corresponding probabilistic intervals and inferences. The performance of the Bayesian estimator is investigated through simulations and the result shows that precise estimates can be obtained when they are used in conjunction with the risk-adjusted survival time CUSUM control charts for different magnitude scenarios. The proposed estimator shows a better performance where a longer follow-up period, censoring time, is applied. In comparison with the alternative built-in CUSUM estimator, more accurate and precise estimates are obtained by the Bayesian estimator. These superiorities are enhanced when probability quantification, flexibility and generalizability of the Bayesian change point detection model are also considered

Outcome of cardiac surgery in patients with low preoperative ejection fraction

Background: In patients undergoing cardiac surgery, a reduced preoperative left ventricular ejection fraction (LVEF) is common and is associated with a worse outcome. Available outcome data for these patients address specific surgical procedures, mainly coronary artery bypass graft (CABG). Aim of our study was to investigate perioperative outcome of surgery on patients with low pre-operative LVEF undergoing a broad range of cardiac surgical procedures. Methods: Data from patients with pre-operative LVEF ≤40 % undergoing cardiac surgery at a university hospital were reviewed and analyzed. A subgroup analysis on patients with pre-operative LVEF ≤30 % was also performed. Results: A total of 7313 patients underwent cardiac surgery during the study period. Out of these, 781 patients (11 %) had a pre-operative LVEF ≤40 % and were included in the analysis. Mean pre-operative LVEF was 33.9 ± 6.1 % and in 290 patients (37 %) LVEF was ≤30 %. The most frequently performed operation was CABG (31 % of procedures), followed by mitral valve surgery (22 %) and aortic valve surgery (19 %). Overall perioperative mortality was 5.6 %. Mitral valve surgery was more frequent among patients who did not survive, while survivors underwent more frequently CABG. Post-operative myocardial infarction occurred in 19 (2.4 %) of patients, low cardiac output syndrome in 271 (35 %). Acute kidney injury occurred in 195 (25 %) of patients. Duration of mechanical ventilation was 18 (12-48) hours. Incidence of complications was higher in patients with LVEF ≤30 %. Stepwise multivariate analysis identified chronic obstructive pulmonary disease, pre-operative insertion of intra-aortic balloon pump, and pre-operative need for inotropes as independent predictors of mortality among patients with LVEF ≤40 %. Conclusions: We confirmed that patients with low pre-operative LVEF undergoing cardiac surgery are at higher risk of post-operative complications. Cardiac surgery can be performed with acceptable mortality rates; however, mitral valve surgery, was found to be associated with higher mortality rates in this population. Accurate selection of patients, risk/benefit evaluation, and planning of surgical and anesthesiological management are mandatory to improve outcome

Utilizing Risk Scores in Determining the Optimal Revascularization Strategy for Complex Coronary Artery Disease

Percutaneous coronary intervention (PCI) of multivessel and/or left main stem disease have been shown to be potentially legitimate revascularization alternatives in appropriately selected patients. Risk stratification is an important component in guiding patients to identify the most appropriate revascularization modality (PCI or coronary artery bypass grafting [CABG]) in conjunction with the Heart Team. The aim of this paper is to give the clinician a concise overview of the important established and evolving contemporary risk models in aiding this decision-making process. Risk models, based on clinical and anatomical variables alone, the novel concept of functional anatomical risk scores, and risk models combining aspects from both clinical and anatomical scores, are all discussed. The emerging concepts of the patient-empowered risk/benefit tradeoff between PCI and CABG to help personalize the choice of revascularization modality are also explored