Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

Downregulation of CPPED1 Expression Improves Glucose Metabolism In Vitro in Adipocytes

We have previously demonstrated that the expression of calcineurin-like phosphoesterase domain containing 1 (CPPED1) decreases in adipose tissue (AT) after weight reduction. However, the function of CPPED1 in AT is unknown. Therefore, we investigated whether the change in CPPED1 expression is connected to changes in adipocyte glucose metabolism. First, we confirmed that the expression of CPPED1 decreased after weight loss in subcutaneous AT. Second, the expression of CPPED1 did not change during adipocyte differentiation. Third, CPPED1 knockdown with small interfering RNA increased expression of genes involved in glucose metabolism (adiponectin, adiponectin receptor 1, and GLUT4) and improved insulin-stimulated glucose uptake. To conclude, CPPED1 is a novel molecule involved in AT biology, and CPPED1 is involved in glucose uptake in adipocytes.Lifestyle modification improves glucose metabolism and results in a substantial reduction in the risk of type 2 diabetes in the long-term (1). In searching new putative genes related to obesity and type 2 diabetes, we have previously demonstrated a multitude of changes in adipose tissue (AT) gene expression in response to weight reduction in individuals with metabolic syndrome (2,3). Among the downregulated genes was calcineurin-like phosphoesterase domain containing 1 (CPPED1) (2); its function in AT is completely unknown.Therefore, we continued to study the role of CPPED1 in AT in more detail. Interestingly, the experiment using a Simpson-Golabi-Behmel syndrome (SGBS) cell strain demonstrated an impact of CPPED1 small interfering RNA (siRNA) on insulin-stimulated glucose uptake in mature adipocytes. Overall, the results demonstrate that CPPED1 is a novel molecule expressed in AT and is related to adipocyte function.     

Canadian Cardiovascular Society/Canadian Anesthesiologists' Society/Canadian Heart Rhythm Society joint position statement on the perioperative management of patients with implanted pacemakers, defibrillators, and neurostimulating devices

There are more than 200,000 Canadians living with permanent pacemakers or implantable defibrillators, many of whom will require surgery or invasive procedures each year. They face potential hazards when undergoing surgery; however, with appropriate planning and education of operating room personnel, adverse device-related outcomes should be rare. This joint position statement from the Canadian Cardiovascular Society (CCS) and the Canadian Anesthesiologists' Society (CAS) has been developed as an accessible reference for physicians and surgeons, providing an overview of the key issues for the preoperative, intraoperative, and postoperative care of these patients. The document summarizes the limited published literature in this field, but for most issues, relies heavily on the experience of the cardiologists and anesthesiologists who contributed to this work. This position statement outlines how to obtain information about an individual's type of pacemaker or implantable defibrillator and its programming. It also stresses the importance of determining if a patient is highly pacemaker-dependent and proposes a simple approach for nonelective evaluation of dependency. Although the document provides a comprehensive list of the intraoperative issues facing these patients, there is a focus on electromagnetic interference resulting from electrocautery and practical guidance is given regarding the characteristics of surgery, electrocautery, pacemakers, and defibrillators which are most likely to lead to interference. The document stresses the importance of preoperative consultation and planning to minimize complications. It reviews the relative merits of intraoperative magnet use vs reprogramming of devices and gives examples of situations where one or the other approach is preferable.     

Ten-year natural course of habitual snoring and restless legs syndrome in a population aged 61–63?years at the baseline

Purpose

We investigated the prevalence, natural course, and associated risk factors of habitual snoring (HS) and restless legs syndrome (RLS) over a period of 10?years among an aging population from their early sixties to their seventies.

Methods

A population-based follow-up study among all persons born in 1935 and living in the city of Oulu in northern Finland was conducted. In this study, we examined subjects who had participated in two subsequent surveys conducted in 1996?C1998 and 2007?C2008. The data were gathered by questionnaires, as well as by laboratory and clinical measurements.

Results

Altogether 457 (55%) of the 838 eligible subjects participated in both surveys. The prevalence of both RLS and HS decreased during the 10?years from 21% to 15% and from 26% to 19%, respectively. Half of those who snored in 1996?C1998 stopped snoring in 10?years time, and half of those who suffered from restless legs at least three times per week in 1996?C1998 suffered from this syndrome never or less than once a week in 2007?C2008. The 10-year incidence of new cases of both HS and RLS was 7%. Male gender predicted best the incidence of new HS in 10?years, while the Zung sum score as a marker of depressive symptoms and waist circumference predicted RLS.

Conclusions

Overall, the prevalence of both HS and RLS seems to diminish during aging. The causes behind this still remain unknown and should be investigated with more sophisticated methods.     

Transseptal Left Heart Catheterization and Left Atrial Angiocardiography in the Diagnosis of Cor Triatrium

The necessity for postoperative inhaled nitric oxide (NO) therapy and predictive factors for that need were retrospectively analysed in 457 paediatric patients at risk of pulmonary hypertensive events following open-heart surgery for congenital heart disease. Inhaled NO was given postoperatively to 46% of the study group and to 23% of all patients undergoing open-heart surgery during the study period. Factors associated with increased need for postoperative NO were age &lt;1 year, Down's syndrome, preoperative pulmonary hypertension and increased pulmonary vascular resistance. Using a multivariate model based on these factors, 73% of the patients who were given NO were identified. Thus, in a setting with unrestricted access to NO therapy, almost half of the patients with cardiac lesions that commonly give rise to postoperative pulmonary hypertension were given postoperative NO. Seventy-three percent of postoperative NO treatment was associated with a relatively small number of pre- and perioperative patient-related risk factors.     

Preoperative and Postoperative Response to Inhaled Nitric Oxide

The preoperative dose response to inhaled nitric oxide (NO) was compared with the need for and response to NO after cardiac surgery in patients with congenital heart defect and secondary pulmonary hypertension. In a preoperative vasodilator test with inhaled NO 20, 40 and 80 ppm and oxygen, mean pulmonary artery pressure (PAP) was at least 40 mmHg and/or the pulmonary vascular resistance index (PVRI) 4 Wood units. Preoperatively, NO 40 ppm and Fi0₂ 0.9 reduced systolic pulmonary/systemic arterial pressure (PAPs/SAPs) from 0.89 (SD 0.10) to 0.80 (0.18) and pulmonary/systemic vascular resistance (PVR/SVR) from 0.26 (0.13) to 0.13 (0.08). Haemodynamic assessment was repeated in 11 patients postoperatively. NO treatment was started if PAPs/SAPs rose to 0.8 or the pulmonary oximetry fell below 40%. Postoperatively, eight of 11 patients, including 6 patients with Down's syndrome, needed NO. PAPs/SAPs decreased more than preoperatively: 48.5% vs 11.2, p = 0.0045. Pulmonary oximetry increased by 15.7%, p = 0.02. The degree of preoperative response to NO did not differ between the patients with postoperative pulmonary hypertension and the other children. Patients with early pulmonary hypertensive crisis (first 24 h; n = 6) had a higher PVRI (7.6 vs 4.4 Um²; p = 0.003) and PVR/SVR (0.34 VS 0.17; p = 0.02) preoperatively. Two patients died in pulmonary hypertensive crisis.     

Mitral annulus motion compared with wall motion scoring index in the assessment of left ventricular ejection fraction.

The biplane disc summation method is the recommended echocardiographic procedure to determine left ventricular (LV) ejection fraction (EF). Assessment of mitral annulus motion (MAM) or wall motion scoring index (WMI) has been reported to be less dependent on image quality compared with the recommended method, and proposed as a surrogate to the disc summation method in calculation of LVEF. We aimed to compare MAM and WMI in the echocardiographic assessment of LVEF. In a randomly selected population-based sample of 75-year-old men and women in sinus rhythm (n = 409) MAM, as measured by M-mode, was compared with WMI, calculated as the mean value of wall motion scoring in 9 LV segments. LVEF, as measured by the biplane disc summation method was used as reference. The limits of agreement (mean difference +/- 1.96 SD) between LVEF and corresponding MAM values were -18 to +13 LVEF%, and between LVEF and corresponding WMI values were -12 to +13 LVEF%. The areas under the receiver operating characteristic curves for MAM and WMI to predict a LVEF < 50% were 0.892 and 0.998, respectively (95% confidence interval of the difference 0.062-0.149). The corresponding areas for MAM and WMI to predict a LVEF < 40% were 0.955 and 0.998, respectively (95% confidence interval of the difference 0.017-0.069). In conclusion, the ability of WMI to estimate LVEF was more favorable than MAM in this population-based sample of 75-year-old participants. The findings suggest that the WMI is preferable to MAM in estimating LVEF.     

Peri-anastomotic microdialysis lactate assessment after esophagectomy

Esophagus - Esophagectomy is the cornerstone in curative treatment for esophageal and gastroesophageal junctional cancer. Esophageal resection is an advanced procedure with many complications,...     

Associations of left atrial volumes and Doppler filling indices with left atrial function in acute myocardial infarction

Recent findings suggest that left atrial (LA) function is more strongly related to adverse prognosis than LA volumes. We aimed to evaluate the associations between LA volumes and Doppler filling indices with LA function. Echocardiographic LA volumes (LAVs), mitral valve early (MV‐E) and late (MV‐A) peak flow velocities, and mitral atrioventricular plane tissue‐Doppler early (TD‐e′) and late (TD‐a′) peak velocities were obtained in 320 patients with acute myocardial infarction (AMI) free from atrial fibrillation and more than moderate valvular disease. LA function was estimated as the LA emptying fraction (LAEF), that is 100× (LAVmax‐LAVmin)/LAVmax. LA reservoir volume was calculated as LAVmax‐LAVmin and LA transit volume as LV stroke volume‐reservoir volume. In restricted cubic spline regression analyses with multivariable adjustment, a reduced LAEF was strongly associated with smaller reservoir volume, larger transit volume, LAVmax, LAVpreA and especially LAVmin. MV‐E linearly increased with a lower LAEF, whereas MV‐A decreased but only below LAEF levels of approximately 45%. The resulting E/A ratio showed a sudden increase in LAEF levels below ~45%. Lower TD‐a′ was linearly associated with a lower LAEF. In conclusion, a reduced atrial function was associated with smaller LA reservoir volume, larger LA transit volume, lower TD‐a′, a non‐linear decrease in MV‐A and a non‐linear increase in E/A. Our findings are likely a reflection of the adaptation to sustain LV filling volume and counteracting a rise in pulmonary venous pressure in face of an enhanced LV end‐diastolic pressure.