New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study

Objectives: Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA), a fatal progressive neurodegenerative disorder associated with autonomic failure, parkinsonism and ataxia. This study aims (1) to determine the clinical spectrum of OH in a large European cohort of patients with MSA and (2) to investigate whether a prolonged postural challenge increases the sensitivity to detect OH in MSA. Methods: Assessment of OH during a 10 min orthostatic test in 349 patients with MSA from seven centres of the European MSA-Study Group (age: 63.6±8.8 years; disease duration: 4.2±2.6 years). Assessment of a possible relationship between OH and MSA subtype (P with predominant parkinsonism or C with predominant cerebellar ataxia), Unified MSA Rating Scale (UMSARS) scores and drug intake. Results: 187 patients (54%) had moderate (>20 mm Hg (systolic blood pressure (SBP)) and/or >10 mm Hg (diastolic blood pressure (DBP)) or severe OH (>30 mm Hg (SBP) and/or >15 mm Hg (DBP)) within 3 min and 250 patients (72%) within 10 min. OH magnitude was significantly associated with disease severity (UMSARS I, II and IV), orthostatic symptoms (UMSARS I) and supine hypertension. OH severity was not associated with MSA subtype. Drug intake did not differ according to OH magnitude except for antihypertensive drugs being less frequently, and antihypotensive drugs more frequently, prescribed in severe OH. Conclusions: This is the largest study of OH in patients with MSA. Our data suggest that the sensitivity to pick up OH increases substantially by a prolonged 10 min orthostatic challenge. These results will help to improve OH management and the design of future clinical trials.Fil: Pavy Le Traon, Anne. University Hospital of Toulouse; Francia. Inserm; FranciaFil: Piedvache, A.. Université Paul Sabatier; FranciaFil: Pérez Lloret, Santiago. University Hospital of Toulouse; Francia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Calandra Buonara, G.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Cochen De Cock, V.. University Hospital of Toulouse; Francia. University of Montpellier; FranciaFil: Colosimo, C.. Sapienza Università di Roma; ItaliaFil: Cortelli, P.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Debs, R.. University Hospital of Toulouse; FranciaFil: Duerr, S.. Universidad de Innsbruck; AustriaFil: Fanciulli, A.. Universidad de Innsbruck; AustriaFil: Foubert Samier, A.. Centre Hospitalier Universitaire de Bordeaux; Francia. Universite de Bordeaux; FranciaFil: Gerdelat, Angela. University Hospital of Toulouse; FranciaFil: Gurevich, T.. Tel-Aviv University; IsraelFil: Krismer, F.. Universidad de Innsbruck; AustriaFil: Poewe, W.. Universidad de Innsbruck; AustriaFil: Tison, Francois. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Tranchant, C.. University Hospital Hautepierre; FranciaFil: Wenning, G.. Universidad de Innsbruck; AustriaFil: Meissner, Wassilios G.. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Rascol, Olivier. University Hospital of Toulouse; Franci

Key signalling nodes in mammary gland development and cancer. The Snail1-Twist1 conspiracy in malignant breast cancer progression

Breast cancer is the most common cancer among women, and despite significant advances in diagnosing and treating it, metastatic spread of cancer cells results in a high mortality rate. Epithelial-to-mesenchymal transition (EMT) is an embryonic program in which epithelial cells lose their characteristics and gain mesenchymal features. Therefore, EMT might play a very important role during malignant tumour progression. In this review we summarise recent advances in breast cancer research with a particular focus on the transcription factors Snail1 and Twist1. Besides discussing the role of EMT in normal mammary gland development, we describe regulatory mechanisms involving newly discovered upstream regulators and microRNAs, the association of EMT with breast cancer stem cells, and the involvement of the tumour microenvironment in breast cancer progression

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

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