Care-Seeking Pattern among Persons with Depression and Anxiety: A Population-Based Study in Sweden

Background. In primary care, a vast majority of patients affected with depression and anxiety present with somatic symptoms. Detection rate of psychiatric symptoms is low, and knowledge of factors influencing care seeking in persons affected by depressive and anxiety disorders on a population level is limited. Objective. This study aims to describe if persons, affected by depression and anxiety disorders, seek care and which type of care they seek as well as factors associated with care seeking. Method. Data derives from a longitudinal population-based study of mental health conducted in the Stockholm County in 1998–2010 and the present study includes 8387 subjects. Definitions of anxiety and depressive disorders were made according to DSM-IV criteria, including research criteria, using validated diagnostic scales. 2026 persons (24%) fulfilled the criteria for any depressive or anxiety disorder. Results. Forty-seven percent of those affected by depression and/or anxiety had been seeking care for psychological symptoms within the last year. A major finding was that seeking care for psychological symptoms was associated with having treatment for somatic problems. Conclusions. As a general practitioner, it is of great importance to increase awareness of mild mental illness, especially among groups that might be less expected to be affected

Targeting ErbB receptors in a three-dimensional cell culture model of K-Ras mutant colorectal cancer

K-Ras is a key signaling molecule regulating central biological processes like proliferation, polarization and survival, and is essential in the control of tissue homeostasis. Constitutive active K-Ras mutations are found in 40% of all colorectal cancers (CRC) contributing to tumor development, progression and therapy resistance. Despite constant efforts there are no targeted therapies available for K-Ras mutated CRC thus far. To develop new, mechanism-based treatment strategies the contribution of oncogenic Ras to transformation and therapy resistance has to be understood in detail. For this purpose, the human epithelial colorectal adenocarcinoma cell line Caco-2 was used as a model in this thesis. Cultured Caco-2 cells represent an early stage of CRC. They express wild-type K-Ras and have no further mutations in downstream Ras signaling pathways. Seeded into a three-dimensional culture system, Caco-2 cells are able to polarize, partly recapitulating the morphological features of the normal colorectal epithelium. By introducing an oncogenic K-Ras variant (G12V) in this organotypic model system, using an inducible expression system, two new aspects of oncogenic Ras signaling could be described for the first time: Firstly, the acute expression of K-RasG12V disrupted polarized morphogenesis of Caco-2 grown in 3D culture. I was able to identify a novel autocrine signaling loop that mediated the hyperproliferation and loss of cell polarity induced by K-RasG12V expression, which involved the receptor tyrosine kinase ErbB3 and transcriptional upregulation of its ligand heregulin (HRG). Secondly, in Caco-2 3D cultures, K-RasG12V expression led to resistance against a targeted single-chain TRAIL molecule (Db-scTRAIL) comprising an ErbB1 blocking moiety derived from cetuximab and three TRAIL monomers. Here, I identified a resistance mechanism triggered by K-RasG12V involving the upregulation of the anti-apoptotic proteins cIAP1/2. The combination of Db-scTRAIL with a new Smac mimetic (SM83) was able to override this resistance not only in the Caco-2 model but also in additional Ras-mutated CRC cell lines. Taken together these findings provide the basis for a new rational approach: combining ErbB3 blockade in Ras mutant CRC with an apoptosis inducing TRAIL molecule plus a sensitizing Smac mimetic. This combination might efficiently block the autocrine Ras-HRG-ErbB3 loop and therefore suppress transformation whilst simultaneously inducing apoptosis

Association of Catechol-Omethyltransferase (COMT Val158Met) with future risk of cardiovascular disease in depressed individuals - a Swedish population-based cohort study

Background: Catechol-O-methyltransferase (COMT Val158Met) has been implicated in both depression and cardiovascular disease. The purpose of this study was to assess if COMT Val158Met, which influences the COMT enzyme activity, has an effect on the risk of cardiovascular disease (CVD) in individuals with a history of depression and also to determine if the risk differs depending on gender. Methods: Data from a longitudinal cohort study of mental health among Swedish adults was used. Depression was assessed twice 3 years apart for each participant, in 1998-2001 and 2001-2003. Saliva DNA was contributed by 4349 (41.7%) of the participants and 3525 was successfully genotyped for COMT Val158Met. Participants were followed up until December 2014 from the National Patient register with regard to cardiovascular outcomes (hypertensive or ischemic heart disease, and stroke). Results: Those with depression and the high COMT enzyme activity genotype (Val/Val) had almost a three-fold increased risk of later CVD (OR 3.6; 95% CI: 2.0-6.6) compared to those non-depressed carrying the Val/Val allele. This effect on risk for CVD was higher in women compared to men (OR 7.0; 95% CI: 3.0-14.0 versus OR 2.1; 95% CI: 1.0-6.8). Both additive interaction (attributable proportion (AP) = 0.56; 95% CI: 0.24-0.90 and synergy index (SI) = 4.39; 1.0-18.7) and multiplicative interaction (log likelihood test p = 0.1) was present between depression and COMT Val158Met in predicting risk of later CVD. Conclusion: High COMT activity genotype Val158Met increased the risk of CVD in depressed persons. The risk was higher in women compared to men

Correction to: Severity of depression, anxious distress and the risk of type 2 diabetes - a population-based cohort study in Sweden

Abstract It was highlighted that the original article [1] contained an error in the flow chart in Fig. 1

Silexan does not affect driving performance after single and multiple dose applications: Results from a double-blind, placebo and reference-controlled study in healthy volunteers

Anxiolytic drugs often have sedative effects that impair the ability to drive. Our double-blind, randomized crossover trial investigated the effect of Silexan, a non-sedating, anxiolytic herbal medicinal product, on driving performance in healthy volunteers. Part 1 aimed at demonstrating equivalence between 80 mg/d Silexan and placebo. Part 2 was performed to demonstrate superiority of 160 and 320 mg Silexan over 1 mg lorazepam and included a placebo arm for assay sensitivity. Driving performance was assessed in a validated, alcohol-calibrated simulator test. The primary outcome was the standard deviation of the lane position (SDLP). Secondary outcomes included driving errors and sleepiness. Fifty and 25 subjects were randomized in Parts 1 and 2, respectively. In Part 1, Silexan 80 mg was confirmed to be equivalent to placebo after single administration (equivalence range: δ = ±2 cm). The 95% confidence interval (CI) for the SDLP marginal mean value difference Silexan-placebo for single administration was -1.43; +1.38 and thus similar to the 95% CI of -1.45; +0.79 cm for 7 days' multiple dosing. In Part 2, 95% CIs for SDLP marginal mean value differences to lorazepam were -8.58; -5.42 cm for Silexan 160 mg and -8.65; -5.45 cm for 320 mg (p < 0.001). Confirmatory results were supported by secondary outcomes, where results for Silexan were comparable to placebo and more favorable than for lorazepam. The study demonstrates that single doses of up to 320 mg Silexan and multiple doses of 80 mg/d have no adverse effect on driving performance

EGFR-targeted TRAIL and a Smac mimetic synergize to overcome apoptosis resistance in KRAS mutant colorectal cancer cells

TRAIL is a death receptor ligand that induces cell death preferentially in tumor cells. Recombinant soluble TRAIL, however, performs poorly as an anti-cancer therapeutic because oligomerization is required for potent biological activity. We previously generated a diabody format of tumor-targeted TRAIL termed DbαEGFR-scTRAIL, comprising single-stranded TRAIL molecules (scTRAIL) and the variable domains of a humanized variant of the EGFR blocking antibody Cetuximab. Here we define the bioactivity of DbαEGFR-scTRAIL with regard to both EGFR inhibition and TRAIL receptor activation in 3D cultures of Caco-2 colorectal cancer cells, which express wild-type K-Ras. Compared with conventional 2D cultures, Caco-2 cells displayed strongly enhanced sensitivity toward DbαEGFR-scTRAIL in these 3D cultures. We show that the antibody moiety of DbαEGFR-scTRAIL not only efficiently competed with ligand-induced EGFR function, but also determined the apoptotic response by specifically directing DbαEGFR-scTRAIL to EGFR-positive cells. To address how aberrantly activated K-Ras, which leads to Cetuximab resistance, affects DbαEGFR-scTRAIL sensitivity, we generated stable Caco-2tet cells inducibly expressing oncogenic K-RasG12V. In the presence of doxycycline, these cells showed increased resistance to DbαEGFR-scTRAIL, associated with the elevated expression of the anti-apoptotic proteins cIAP2, Bcl-xL and FlipS. Co-treatment of cells with the Smac mimetic SM83 restored the DbαEGFR-scTRAIL-induced apoptotic response. Importantly, this synergy between DbαEGFR-scTRAIL and SM83 also translated to 3D cultures of oncogenic K-Ras expressing HCT-116 and LoVo colorectal cancer cells. Our findings thus support the notion that DbαEGFR-scTRAIL therapy in combination with apoptosis-sensitizing agents may be promising for the treatment of EGFR-positive colorectal cancers, independently of their KRAS status

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Alignment of the CMS tracker with LHC and cosmic ray data

© CERN 2014 for the benefit of the CMS collaboration, published under the terms of the Creative Commons Attribution 3.0 License by IOP Publishing Ltd and Sissa Medialab srl. Any further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation and DOI.The central component of the CMS detector is the largest silicon tracker ever built. The precise alignment of this complex device is a formidable challenge, and only achievable with a significant extension of the technologies routinely used for tracking detectors in the past. This article describes the full-scale alignment procedure as it is used during LHC operations. Among the specific features of the method are the simultaneous determination of up to 200 000 alignment parameters with tracks, the measurement of individual sensor curvature parameters, the control of systematic misalignment effects, and the implementation of the whole procedure in a multi-processor environment for high execution speed. Overall, the achieved statistical accuracy on the module alignment is found to be significantly better than 10μm

Efficacy and hemodynamic effects of Lormetazepam in a new intravenous galenics and Midazolam for induction of anesthesia in cardiac surgical patients

In zwei isolierten Beobachtungsstudien wurden zur Narkoseeinleitung kardiochirurgischer Patienten intravenöses Lormetazepam oder Midazolam verwendet und die Ergebnisse auf die Wirksamkeit bezüglich der Narkoseinduktion (primärer Endpunkt) sowie auf den zeitlichen Verlauf der hämodynamischen Veränderungen und die Notwendigkeit kreislaufwirksamer Medikamente untersucht. Es ließ sich zeigen, dass Lormetazepam neben einem anderen Einschlafverhalten Vorteile hinsichtlich der hämodynamischen Stabilität gegenüber Midazolam zu bieten scheint.In two independent observational studies Lormetazepam or Midazolam were injected intravenously for induction of anesthesia in cardiac surgical patients. We investigated the efficacy regarding the induction of anesthesia (primary endpoint), the time course of hemodynamic changes and the necessity of vasoactive drugs. Besides a somewhat different kind of anesthesia induction, our data suggest that Lormetazepam might have advantages in terms of hemodynamic stability compared to Midazolam