Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.

A note on the selection of priority rules in software packages for project management

Various software packages for project management include a procedure for resource-constrained scheduling. In several packages, the user can influence this procedure by selecting a priority rule. However, the resource-allocation methods that are implemented in the procedures are proprietary information; therefore, the question of how the priority-rule selection impacts the performance of the procedures arises. We experimentally evaluate the resource-allocation methods of eight recent software packages using the 600 instances of the PSPLIB J120 test set. The results of our analysis indicate that applying the default rule tends to outperform a randomly selected rule, whereas applying two randomly selected rules tends to outperform the default rule. Applying a small set of more than two rules further improves the project durations considerably. However, a large number of rules must be applied to obtain the best possible project durations.

Quantitative multi-slice computed tomography assessment of the mitral valvular complex for transcatheter mitral valve interventions part 1: systematic measurement methodology and inter-observer variability

AIMS Transcatheter mitral valve replacement (TMVR) is an emerging technology with the potential to treat patients with severe mitral regurgitation at excessive risk for surgical mitral valve surgery. Multimodal imaging of the mitral valvular complex and surrounding structures will be an important component for patient selection for TMVR. Our aim was to describe and evaluate a systematic multi-slice computed tomography (MSCT) image analysis methodology that provides measurements relevant for transcatheter mitral valve replacement. METHODS AND RESULTS A systematic step-by-step measurement methodology is described for structures of the mitral valvular complex including: the mitral valve annulus, left ventricle, left atrium, papillary muscles and left ventricular outflow tract. To evaluate reproducibility, two observers applied this methodology to a retrospective series of 49 cardiac MSCT scans in patients with heart failure and significant mitral regurgitation. For each of 25 geometrical metrics, we evaluated inter-observer difference and intra-class correlation. The inter-observer difference was below 10% and the intra-class correlation was above 0.81 for measurements of critical importance in the sizing of TMVR devices: the mitral valve annulus diameters, area, perimeter, the inter-trigone distance, and the aorto-mitral angle. CONCLUSIONS MSCT can provide measurements that are important for patient selection and sizing of TMVR devices. These measurements have excellent inter-observer reproducibility in patients with functional mitral regurgitation.

Sicherheit und Zuverlässigkeit der Nebenschilddrüsenchirurgie bei Patienten mit Hyperparathyreoidismus und intraoperativ gemessenem intakten Parathormon

In der vorliegenden Arbeit wurde die Sicherheit und Zuverlässigkeit der Nebenschilddrüsenchirurgie beim Hyperparathyreoidismus mit intraoperativer Bestimmung des intakten Parathormons (Parathormonschnelltest) untersucht. Im Zeitrahmen zwischen 1/2004 und 12/2008 wurden an der universitären Klinik für viszerale Chirurgie und Medizin bei 194 operierten Patienten 150 Adenome, 39 Hyperplasien, sowie 5 Doppeladenome der Nebenschilddrüsen gefunden. Das intakte Parathormons (iPTH) im Serum wurde zu Beginn der Operation, nach Präparation der vergrösserten Nebenschilddrüse bei noch erhaltenem Gefässstiel, sowie 5, 10 und 15 Minuten nach der Parathyreoidektomie gemessen. Für den Erfolg der Operation wurde ein Abfall des iPTH um mehr als 50% vom Ausgangswert innerhalb der ersten 5 Minuten, sowie um mehr als 60% innerhalb der ersten 10 Minuten festgelegt. Bei solitären Adenomen der Nebenschilddrüse kam es bereits 5 Minuten nach der Parathyreoidektomie zu einem durchschnittlichen Abfall des iPTH um 61±19% vom Ausgangswert und nach 10 Minuten um 73±17%. Bei einer Hyperplasie der Nebenschilddrüse blieb dieser schnell eintretende steile Abfall des iPHT aus, der Rückgang des iPHT-Spiegels war zögerlich und erreichte erst nach subtotaler Parathyreoidektomie Normalwerte. In dem vorliegenden Patientengut wurden drei falsch-negative sowie ein falsch-positiver Befund beobachtet. Prognostisch ergibt sich für ein solitäres Adenom unserem Patientengut eine Sensitivität von 96% und eine Spezifität von 91% für den 10 Minuten-Wert. Der prädiktive Wert des positiven Tests beträgt 97%. Die vorliegende Arbeit zeigt, dass mit Hilfe der intraoperativen iPTH-Messung die Sicherheit in der Chirurgie des Parathyreoidismus gesteigert werden kann, vor allem beim Vorliegen eines Doppeladenoms oder bei schwierigen Rezidiveingriffen.

Is The Allergen Really Needed in Allergy Immunotherapy?

Immunotherapy for type I allergies is well established and is regarded to be the most efficient treatment option besides allergen avoidance. As of today, different forms of allergen preparations are used in this regard, as well as different routes of application. Virus-like particles (VLPs) represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances activation of innate as well as adaptive immune responses. CpG motifs represent intensively investigated and potent direct stimulators of plasmacytoid dendritic cells and B cells, while T cell responses are enhanced indirectly through increased antigen presentation and cytokine release. This article will focus on the function of VLPs loaded with DNA rich in nonmethylated CG motifs (CpGs) and the clinical experience gained in the treatment of allergic rhinitis, demonstrating clinical efficacy also if administered without allergens. Several published studies have demonstrated a beneficial impact on allergic symptoms by treatment with CpG-loaded VLPs. Subcutaneous injection of VLPs loaded with CpGs was tested with or without the adjuvant alum in the presence or absence of an allergen. The results encourage further investigation of VLPs and CpG motifs in immunotherapy, either as a stand-alone product or as adjuvants for allergen-specific immunotherapy.

Development of an Interleukin-1β Vaccine in Patients with Type 2 Diabetes

Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).Molecular Therapy (2016); doi:10.1038/mt.2015.227.

MAL-PDT mit Tageslicht - Aktuelle Datenlage und praxisorientierte Empfehlungen eines Expertentreffens

Die photodynamische Therapie (PDT) gehört zu den Standardverfahren in der Therapie aktinischer Keratosen (AK). Bei der Tageslicht-PDT (Daylight PDT, DL-PDT) mit MAL-Creme handelt es sich um eine neuere Entwicklung, bei der anstelle eines Belichtungssystems das Tageslicht zur Aktivierung des Photosensibilisators genutzt wird. Der vorliegende Review fasst die aktuelle Studienlage basierend auf einer selektiven Literaturrecherche zusammen, fokussiert auf praktische Aspekte in der Durchführung und reflektiert insbesondere auch die Expertenerfahrung der Autoren mit der DL-PDT. Studiendaten zeigen, dass die DL-PDT der konventionellen PDT in ihrer Wirksamkeit nicht unterlegen ist. Sie ist jedoch signifikant besser verträglich, da sie zu deutlich weniger Schmerzen während der Therapie führt. Sie kann in Mitteleuropa von März bis Oktober sowohl an bewölkten als auch an sonnigen Tagen durchgeführt werden. Hierbei ist auf UV-Schutz auch der nicht behandelten Körperareale zu achten. Die Außentemperatur sollte 10°C nicht unterschreiten. An heißen Tagen sollte ein Aufenthalt im Schatten, soweit erforderlich, eingeplant werden. Die DL-PDT mit MAL ist u. a. für Patienten mit Feldkanzerisierung und/oder negativer Schmerzerfahrung bei der cPDT geeignet und stellt eine sinnvolle Ergänzung der aktuellen Therapiemöglichkeiten dar.

Use of minimal invasive extracorporeal circulation in cardiac surgery: principles, definitions and potential benefits. A position paper from the Minimal invasive Extra-Corporeal Technologies international Society (MiECTiS).

Minimal invasive extracorporeal circulation (MiECC) systems have initiated important efforts within science and technology to further improve the biocompatibility of cardiopulmonary bypass components to minimize the adverse effects and improve end-organ protection. The Minimal invasive Extra-Corporeal Technologies international Society was founded to create an international forum for the exchange of ideas on clinical application and research of minimal invasive extracorporeal circulation technology. The present work is a consensus document developed to standardize the terminology and the definition of minimal invasive extracorporeal circulation technology as well as to provide recommendations for the clinical practice. The goal of this manuscript is to promote the use of MiECC systems into clinical practice as a multidisciplinary strategy involving cardiac surgeons, anaesthesiologists and perfusionists.

Blick in die Vergangenheit im Bereich Hören

Referat anlässlich der Vorstellung des Audiopädagogischen Dienstes Solothurn

Klecksereien zwischen Kunst und Wissenschaft

Referat im Begleitprogramm zur Ausstellung von Christian Andersson "From Lucy with Love" im Kunstmuseum Thun