Nuclear organization in the nematode C. elegans.

With its invariant cell lineage, easy genetics and small genome, the nematode Caenorhabditis elegans has emerged as one of the prime models in developmental biology over the last 50 years. Surprisingly however, until a decade ago very little was known about nuclear organization in worms, even though it is an ideal model system to explore the link between nuclear organization and cell fate determination. Here, we review the latest findings that exploit the repertoire of genetic tools developed in worms, leading to the identification of important sequences and signals governing the changes in chromatin tridimensional architecture. We also highlight parallels and differences to other model systems.

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.

Internetbasierte geleitete Selbsthilfe bei verschiedenen Angststörungen: Eine randomisiert kontrollierte Studie zum Vergleich eines individualisierten vs. standardisierten Ansatzes

Hintergrund und Ziel: Internetbasierte psychotherapeutische Interventionen wurden in den letzten Jahren intensiv erforscht. Als besonders vielversprechend haben sich therapeutengeleitete Selbsthilfeprogramme bei verschiedenen Angststörungen erwiesen. Eine neue Entwicklung sind transdiagnostische und individualisierte Ansätze, in welchen auch komorbide Probleme und Störungen, und breitere Patientengruppen angesprochen werden. Beim individualisierten Ansatz werden dem Selbsthilfeprogramm in Abhängigkeit der Probleme der Patienten unterschiedliche Inhalte zugeschaltet. Das Ziel dieser Studie ist die Evaluation einer internetbasierten, individualisierten, geleiteten Selbsthilfeintervention für verschiedene Angststörungen. Methode: In einer kontrolliert-randomisierten Studie wurde der individualisierte Ansatz mit einer standardisierten Intervention, die sich nur auf die primäre Störung der Klienten bezieht, verglichen. 132 StudienteilnehmerInnen, diagnostiziert mit einer Sozialen Angststörung, Panikstörung mit oder ohne Agoraphobie, und/ oder einer Generalisierten Angststörung wurden randomisiert einer der beiden Behandlungsbedingungen oder einer Warteliste zugeteilt. Die Selbsthilfebehandlung dauerte 8 Wochen und wurde von Therapeuten via Email unterstützt. Erhebungszeitpunkte waren Prä, Post und 6 Monate nach Ende der Behandlung. Primäre Ergebnismasse sind störungsübergreifende Masse wie das Beck Angstinventar (BAI) und Daten aus einem diagnostischen Interview. Sekundäre Ergebnismasse sind störungsspezifische Fragebogen. Ergebnisse: Beide Behandlungsgruppen zeigten gegenüber der Warteliste-Kontrollgruppe signifikante Veränderungen auf allen Ergebnismassen. Auf der Basis der Intent-to-treat-Stichprobe betrugen die über die verschiedenen Ergebnismasse gemittelten Effektstärken im Vergleich zur Warteliste-Kontrollgruppe d=.80 für die individualisierte und d=.82 für die standardisierte Behandlungsbedingung. Die Symptomreduktion wurde bis zum 6-Monats-Follow-Up aufrechterhalten. Zwischen den beiden aktiven Behandlungsbedingungen wurden keine Unterschiede gefunden. Diskussion: Die Ergebnisse zeigen, dass sowohl individualisierte wie auch standardisierte internetbasierte Ansätze zur Behandlung verschiedener Angststörungen vielversprechend sind

International standards for programmes of training in intensive care medicine in Europe.

PURPOSE To develop internationally harmonised standards for programmes of training in intensive care medicine (ICM). METHODS Standards were developed by using consensus techniques. A nine-member nominal group of European intensive care experts developed a preliminary set of standards. These were revised and refined through a modified Delphi process involving 28 European national coordinators representing national training organisations using a combination of moderated discussion meetings, email, and a Web-based tool for determining the level of agreement with each proposed standard, and whether the standard could be achieved in the respondent's country. RESULTS The nominal group developed an initial set of 52 possible standards which underwent four iterations to achieve maximal consensus. All national coordinators approved a final set of 29 standards in four domains: training centres, training programmes, selection of trainees, and trainers' profiles. Only three standards were considered immediately achievable by all countries, demonstrating a willingness to aspire to quality rather than merely setting a minimum level. Nine proposed standards which did not achieve full consensus were identified as potential candidates for future review. CONCLUSIONS This preliminary set of clearly defined and agreed standards provides a transparent framework for assuring the quality of training programmes, and a foundation for international harmonisation and quality improvement of training in ICM.

Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan

Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.

A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Both environmental and genetic factors are thought to contribute to the pathogenesis of PD. Although several genes linked to rare familial PD have been identified, endogenous risk factors for sporadic PD, which account for the majority of PD cases, remain largely unknown. Genome-wide association studies have identified many single nucleotide polymorphisms associated with sporadic PD in neurodevelopmental genes including the transcription factor p48/ptf1a. Here we investigate whether p48 plays a role in the survival of DA neurons in Drosophila melanogaster and Caenorhabditis elegans. We show that a Drosophila p48 homolog, 48-related-2 (Fer2), is expressed in and required for the development and survival of DA neurons in the protocerebral anterior medial (PAM) cluster. Loss of Fer2 expression in adulthood causes progressive PAM neuron degeneration in aging flies along with mitochondrial dysfunction and elevated reactive oxygen species (ROS) production, leading to the progressive locomotor deficits. The oxidative stress challenge upregulates Fer2 expression and exacerbates the PAM neuron degeneration in Fer2 loss-of-function mutants. hlh-13, the worm homolog of p48, is also expressed in DA neurons. Unlike the fly counterpart, hlh-13 loss-of-function does not impair development or survival of DA neurons under normal growth conditions. Yet, similar to Fer2, hlh-13 expression is upregulated upon an acute oxidative challenge and is required for the survival of DA neurons under oxidative stress in adult worms. Taken together, our results indicate that p48 homologs share a role in protecting DA neurons from oxidative stress and degeneration, and suggest that loss-of-function of p48 homologs in flies and worms provides novel tools to study gene-environmental interactions affecting DA neuron survival.

Intervertebral Disc Repair using Fleece-Membrane Composite Silk Material and Genipin-enhanced Fibrin Hydrogel

Introduction: Treating low back pain (LBP) has become an increasing challenge, as it is one of the main factors causing pain and is accompanied by high costs for the individual and the society. LBP can be caused by trauma of the intervertebral disc (IVD) or IVD degeneration. In the case of disc herniation the inner gelatinous part of the IVD, called nucleus pulposus, is pressed through the fibrous, annulus fibrosus that forms the outer part of the IVD. Today’s gold standard for treatment is extensive surgery as removal of the IVD and fusion of the vertebrae. In order to find a more gentle way to treat LBP and restore the native IVD we use a novel silk fleece-membrane composite from genetically modified silk worms whose silk contains a growth factor (GDF-6) that is associated with pushing stem cells towards a disc like phenotype (1). By combining it with a genipin-enhanced fibrin hydrogel we tested its suitability in organ culture on prior injured bovine IVD in our custom built two-degree of freedom bioreactor to mimic natural loading conditions. Material & Methods: Bovine IVDs of 12-17 months old animals were isolated by first removing all surrounding tissue followed by cutting out the IVDs as previously described (2). Culturing of discs occurred in high glucose Dulbecco's Modified Eagle Medium (HG-DMEM) supplemented with 5% serum as previously described (2). On the next day injury was induced using a 2mm biopsy punch (Polymed, Switzerland). The formed cavity was filled with (0.4%) genipin-enhanced human based fibrin hydrogel (35-55mg/mL human fibrinogen, Baxter, Austria) and sealed with a silk fleece-membrane composite (Spintec Engineering, Germany). Different culture conditions were applied: free swelling, static diurnal load of 0.2MPa for 8h/d and complex loading at 0.2MPa compression combined with ± 2° torsion at 0.2Hz for 8h/d (2). After 14 days of culture cell activity was determined with resazurin assay. Additionally, glycosaminoglycan (dimethyl-methylene blue), DNA (Hoechst) and collagen content (hydroxy- proline) were determined. Finally, real-time qPCR of major IVD marker and inflammation genes was performed to judge integrity of IVDs. Results: The fibrin hydrogel is able to keep the silk seal in place throughout the 14 days of in organ culture under all conditions. Additionally, cell activity showed optimistic results and we could not confirm negative effects of the repaired discs regarding overexpression of inflammation markers. Conclusions: The genipin-enhanced fibrin hydrogel in combination with the silk fleece- membrane composite seems to be a promising approach for IVD repair. Currently we assess the capability of GDF-6 incorporated in our silk composites on human mesenchymal stem cells and later on in organ culture. References 1. Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA. Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition and micromechanical properties of nucleus pulposus constructs. Arthritis Res Ther 2014, Mar 12;16(2):R67. 2. Chan SC, Gantenbein-Ritter B. Preparation of intact bovine tail intervertebral discs for organ culture. J Vis Exp 2012, Feb 2;60(60):e3490. Acknowledgements. This work is funded by the Gebert Rüf Foundation, project number GRS-028/13.

Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).

Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. II. Puerperal metritis and clinical endometritis

The aim of the study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with puerperal metritis and clinical endometritis (part 2). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The following main symptoms of puerperal metritis were stated by the practitioners: purulent vaginal discharge, fever and reduced appetite. A vaginal and rectal examination was performed to diagnose the disease. Usually, an intrauterine treatment with tetracycline or cefapirin was done. Parenteral administration of tetracycline or penicillin was often combined with PGF(2α), NSAIDS or cortisone. Clinical endometritis was also diagnosed by vaginal and rectal examination and the main symptom indicated was purulent vaginal discharge. The therapy consisted of the administration of PGF(2α), uterine infusions predominantly with cefapirin, and rarely with parenteral administration of antibiotics. Further diagnostic tools were not used and normally cows were not rechecked. The success of the therapy of puerperal metritis and clinical endometritis was judged to be satisfactory to excellent.

Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. I Retained fetal membranes

The aim of this study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with retained fetal membranes (RFM) (part 1). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The manual removal of the fetal membranes is practiced by 129 of the responding veterinarians. Cows with/without fever are treated usually with intrauterine antibiotics. Cows with RFM with/without fever are most commonly treated parenterally with tetracycline or penicillin. The use of cephalosporins and quinolones in cows with fever is more common than in cows without fever. With the present results of the survey veterinarians should critically question the supposed benefits of the manual removal of the placenta and the use of antibiotics in cows with RFM.

Transfer and effects of 1,2,3,5,7-pentachloronaphthalene in an experimental food chain.

Polychlorinated naphthalenes are environmentally relevant compounds that are measured in biota at concentrations in the μg/kg lipid range. Despite their widespread occurrence, literature data on the accumulation and effects of these compounds in aquatic ecosystems are sparsely available. The goal of this study was to gain insights into the biomagnification and effects of 1,2,3,5,7-pentachloronaphthalene (PeCN52) in an experimental food chain consisting of benthic worms and juvenile rainbow trout. Worms were contaminated with PeCN52 by passive dosing from polydimethylsiloxane silicone. The contaminated worms were then used to feed the juvenile rainbow trout at 0.12, 0.25 or 0.50 μg/g fish wet weight/day, and the resulting internal whole-body concentrations of the individual fish were linked to biological responses. A possible involvement of the cellular detoxification system was explored by measuring PeCN52-induced expression of the phase I biotransformation enzyme gene cyp1a1 and the ABC transporter gene abcb1a. At the end of the 28-day study, biomagnification factors were similar for all dietary intake levels with values between 0.5 and 0.7 kg lipid(fish)/kg lipid(worm). The average uptake efficiency of 60% indicated that a high amount of PeCN52 was transferred from the worms to the fish. Internal concentrations of up to 175 mg/kg fish lipid in the highest treatment level did not result in effects on survival, behavior, or growth of the juvenile trout, but were associated with the induction of phase I metabolism which was evident from the significant up-regulation of cyp1a1 expression in the liver. In contrast, no changes were seen in abcb1a transcript levels.

Internet-basierte Selbsthilfe bei Verfolgungsideen - Eine Pilotstudie

Kognitive Interventionen haben sich bei der Behandlung von Schizophrenie als wirksam erwiesen und werden in nationalen Behandlungsleitlinien empfohlen. Viele Patienten mit Schizophrenie-Diagnose haben jedoch keinen Zugang zu ambulanten Psychotherapie-Plätzen nach stationären Klinikaufenthalten. Ein alternativer Zugangsweg zu kognitiven Interventionen sind Online- Selbsthilfe-Programme, welche sich bei anderen psychischen Störungen wie Depression und Angststörungen bereits als effektiv erwiesen haben. Im Rahmen einer Pilotstudie wird ein Symptom-orientiertes, KVT-basiertes Online-Selbsthilfe-Programm für Menschen mit Verfolgungsideen getestet. Das Programm besteht aus acht Einheiten und beinhaltet neben Psychose-bezogenen Inhalten (Störungsmodell, Rückfallprophylaxe, etc.) auch Einheiten zu Selbstwert, Umgang mit Sorgen und Schlafhygiene. Die TeilnehmerInnen werden wöchentlich von klinischen PsychologInnen per eMail kontaktiert (geleitete Selbsthilfe). Primäres Outcome-Maß ist das Ausmaß von Verfolgungswahn (Paranoia Checklist), sekundäre Outcome-Maße beinhalten Abbruchquoten, allgemeine Psychopathologie, Nebenwirkungen und Zufriedenheit. In die aktuell laufende Studie sollen insgesamt N=20 Teilnehmer eingeschlossen werden. Chancen und Einschränkungen von internet-basierter Selbsthilfe bei Psychose werden vor dem Hintergrund der vorläufigen Ergebnisse diskutiert.