The severity of neural invasion is associated with shortened survival in colon cancer

PURPOSE Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer. EXPERIMENTAL DESIGN NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)-neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined. RESULTS NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer. CONCLUSION NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer.

Die Kurzversion der NMR Skala (NMR-SF) zur Erfassung der selbsteingeschätzten Fähigkeit zur Regulation negativer Stimmungen: Überblick und Konstruktvalidierung

Die NMR-SF ist die Kurzversion der NMR Skala. Die NMR-SF misst die selbsteingeschätze Fähigkeit zur Regulation negativer Stimmungen. Das von der NMR-SF erfasste Konstrukt spielt in der Ätiologie und Psychotherapie psychischer Störungen eine wichtige Rolle. Die vorliegende Studie untersucht die Konstruktvalidität des Verfahrens in 2 nicht-klinischen und einer depressiven Stichprobe. Die NMR-SF korreliert positiv mit funktionalen Strategien zum Umgang mit negativen Stimmungen und negativ mit dysfunktionalen Strategien. Hohe Werte in der NMR-SF gehen weiterhin mit weniger psychischen Beschwerden einher. Die NMR-SF korreliert leicht positiv mit sozialer Erwünschtheit. Die Ergebnisse der aktuellen Studie unterstützen die Kon­struktvalidität der NMR-SF. Die NMR-SF stellt sich als ein psychometrisch gutes Verfahren zur Messung von NMR-Erwartungen dar. Aufgrund ihrer Ökonomie empfiehlt sich die NMR-SF für die Anwendung in klinischen Stichproben, insbesondere im Rahmen von Verlaufsmessungen.

Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.

Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.

Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes--including that encoding the epithelial Na+ channel (ENaC), a key arbiter of Na+ transport in the kidney and other epithelia--have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCalpha by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release of this repression by aldosterone treatment. Here we provide evidence from renal collecting duct cells and serum- and glucocorticoid-induced kinase-1 (Sgk1) WT and knockout mice that Sgk1 phosphorylated Af9, thereby impairing the Dot1a-Af9 interaction and leading to targeted histone H3 Lys79 hypomethylation at the ENaCalpha promoter and derepression of ENaCalpha transcription. Thus, Af9 is a physiologic target of Sgk1, and Sgk1 negatively regulates the Dot1a-Af9 repressor complex that controls transcription of ENaCalpha and likely other aldosterone-induced genes.

Internetbasierte geleitete Selbsthilfeansätze bei Angststörungen und Depressionen

Das Spektrum internetbasierter psychologischer Behandlungsangebote bei psychischen Problemen und Erkrankungen bewegt sich zwischen webbasierten Selbsthilfeprogrammen, die das Internet als Informationsmedium verwenden, und Email-, Chat- und Video-Therapien, in welchen das Internet zu Kommunikationszwecken zwischen Hilfesuchenden und Professionellen genutzt wird. Dieser Beitrag fokussiert auf eine Beratungs- und Therapieform, die die Möglichkeiten des Internets als Informations- und Kommunikationsmedium in sogenannten geleiteten Selbsthilfeansätzen kombiniert. Internetbasierte geleitete Selbsthilfeansätze, in welchen Klienten während der Bearbeitung eines Selbsthilfeprogramms von Therapeuten via Internet (z.B. Email) unterstützt werden, wurden in den letzten Jahren intensiv erforscht. Im Bereich von Angststörungen und Depressionen liegen besonders viele Studien vor. Verschiedene Forschergruppen haben hier in der Regel große Behandlungseffekte gefunden, die mit der Wirkung von Face-to-Face-Therapien vergleichbar sind. In diesem Beitrag wird der geleitete Selbsthilfeansatz dargestellt und die empirische Evidenz diskutiert.

Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites

Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets. Methods Discovery (N = 33) and replication (N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis (NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD. Results In a two-stage metabolic screening, hydroquinone (HQ, pcombined = 3.0 × 10−4) and nicotinic acid (NA, pcombined = 3.9 × 10−9) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression. Conclusion This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD.

Internet-based individually versus group guided self-help treatment for social anxiety disorder: protocol of a randomized controlled trial

BACKGROUND: Social anxiety disorder (SAD) is one of the most common mental disorders and causes subjective suffering and economic burden worldwide. Although effective treatments are available, a lot of cases go untreated. Internet-based self-help is a low-threshold and flexible treatment alternative for SAD. Various studies have already shown that internet-based self-help can be effective to reduce social phobic symptoms significantly. Most of the interventions tested include therapist support, whereas the role of peer support within internet-based self-help has not yet been fully understood. There is evidence suggesting that patients' mutual exchange via integrated discussion forums can increase the efficacy of internet-based treatments. This study aims at investigating the added value of therapist-guided group support on the treatment outcome of internet-based self-help for SAD. METHODS/DESIGN: The study is conducted as a randomized controlled trial. A total of 150 adults with a diagnosis of SAD are randomly assigned to either a waiting-list control group or one of the active conditions. The participants in the two active conditions use the same internet-based self-help program, either with individual support by a psychologist or therapist-guided group support. In the group guided condition, participants can communicate with each other via an integrated, protected discussion forum. Subjects are recruited via topic related websites and links; diagnostic status will be assessed with a telephone interview. The primary outcome variables are symptoms of SAD and diagnostic status after the intervention. Secondary endpoints are general symptomology, depression, quality of life, as well as the primary outcome variables 6 months later. Furthermore, process variables such as group processes, the change in symptoms and working alliance will be studied. DISCUSSION: The results of this study should indicate whether group-guided support could enhance the efficacy of an internet-based self-help treatment for SAD. This novel treatment format, if shown effective, could represent a cost-effective option and could further be modified to treat other conditions, as well.

Optimizing Triage and Hospitalization in Adult General Medical Emergency Patients. The Triage Project

Background: Patients presenting to the emergency department (ED) currently face inacceptable delays in initial treatment, and long, costly hospital stays due to suboptimal initial triage and site-of-care decisions. Accurate ED triage should focus not only on initial treatment priority, but also on prediction of medical risk and nursing needs to improve site-of-care decisions and to simplify early discharge management. Different triage scores have been proposed, such as the Manchester triage system (MTS). Yet, these scores focus only on treatment priority, have suboptimal performance and lack validation in the Swiss health care system. Because the MTS will be introduced into clinical routine at the Kantonsspital Aarau, we propose a large prospective cohort study to optimize initial patient triage. Specifically, the aim of this trial is to derive a three-part triage algorithm to better predict (a) treatment priority; (b) medical risk and thus need for in-hospital treatment; (c) post-acute care needs of patients at the most proximal time point of ED admission. Methods/design: Prospective, observational, multicenter, multi-national cohort study. We will include all consecutive medical patients seeking ED care into this observational registry. There will be no exclusions except for non-adult and non-medical patients. Vital signs will be recorded and left over blood samples will be stored for later batch analysis of blood markers. Upon ED admission, the post-acute care discharge score (PACD) will be recorded. Attending ED physicians will adjudicate triage priority based on all available results at the time of ED discharge to the medical ward. Patients will be reassessed daily during the hospital course for medical stability and readiness for discharge from the nurses and if involved social workers perspective. To assess outcomes, data from electronic medical records will be used and all patients will be contacted 30 days after hospital admission to assess vital and functional status, re-hospitalization, satisfaction with care and quality of life measures. We aim to include between 5000 and 7000 patients over one year of recruitment to derive the three-part triage algorithm. The respective main endpoints were defined as (a) initial triage priority (high vs. low priority) adjudicated by the attending ED physician at ED discharge, (b) adverse 30 day outcome (death or intensive care unit admission) within 30 days following ED admission to assess patients risk and thus need for in-hospital treatment and (c) post acute care needs after hospital discharge, defined as transfer of patients to a post-acute care institution, for early recognition and planning of post-acute care needs. Other outcomes are time to first physician contact, time to initiation of adequate medical therapy, time to social worker involvement, length of hospital stay, reasons fordischarge delays, patient’s satisfaction with care, overall hospital costs and patients care needs after returning home. Discussion: Using a reliable initial triage system for estimating initial treatment priority, need for in-hospital treatment and post-acute care needs is an innovative and persuasive approach for a more targeted and efficient management of medical patients in the ED. The proposed interdisciplinary , multi-national project has unprecedented potential to improve initial triage decisions and optimize resource allocation to the sickest patients from admission to discharge. The algorithms derived in this study will be compared in a later randomized controlled trial against a usual care control group in terms of resource use, length of hospital stay, overall costs and patient’s outcomes in terms of mortality, re-hospitalization, quality of life and satisfaction with care.

A Process Model of the Formation of Spatial Presence Experiences

In order to bridge interdisciplinary differences in Presence research and to establish connections between Presence and “older” concepts of psychology and communication, a theoretical model of the formation of Spatial Presence is proposed. It is applicable to the exposure to different media and intended to unify the existing efforts to develop a theory of Presence. The model includes assumptions about attention allocation, mental models, and involvement, and considers the role of media factors and user characteristics as well, thus incorporating much previous work. It is argued that a commonly accepted model of Spatial Presence is the only solution to secure further progress within the international, interdisciplinary and multiple-paradigm community of Presence research.

The modified Lapidus fusion.

Due to its proximal correction site and long lever arm, the Lapidus fusion, modified or not, is a powerful technique to correct hallux valgus deformities. The disadvantages are a high complication rate and a long postoperative rehabilitation period. It is only performed in 5% to 10% of all hallux valgus deformity corrections but remains, however, an important procedure, especially in moderate to severe deformities with intermetatarsal angles more than 14°, hypermobility of the first ray, arthritis of the first tarsometatarsal joint, and recurrent deformities. This article provides an overview of the procedure with special focus on the surgical technique.

Feasibility platform for stroke studies: an online tool to improve eligibility criteria for clinical trials

BACKGROUND AND PURPOSE Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial. METHODS We identified relevant inclusion and exclusion criteria of acute stroke trials. Based on these criteria and using a cohort of 1537 consecutive patients with acute ischemic stroke from 3 stroke centers, we developed a web portal feasibility platform for stroke studies (FePASS) to estimate proportions of eligible patients for acute stroke trials. We applied the FePASS resource to calculate the proportion of patients eligible for 4 recent stroke studies. RESULTS Sixty-one eligibility criteria were derived from 30 trials on acute ischemic stroke. FePASS, publicly available at http://fepass.uni-muenster.de, displays the proportion of patients in percent to assess the effect of varying values of relevant eligibility criteria, for example, age, symptom onset time, National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale, on this proportion. The proportion of eligible patients for 4 recent stroke studies ranged from 2.1% to 11.3%. Slight variations of the inclusion criteria could substantially increase the proportion of eligible patients. CONCLUSIONS FePASS is an open access online resource to assess the effect of inclusion and exclusion criteria on the proportion of eligible patients for a stroke trial. FePASS can help to design stroke studies, optimize eligibility criteria, and to estimate the potential recruitment rate.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

BACKGROUND AND PURPOSE To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. METHODS After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. RESULTS Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. CONCLUSIONS Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.