Propofol Versus 4-hydroxybutyric Acid in Pediatric Cardiac Catheterizations

Introduction: Pediatric patients require deep sedation at least for cardiac catheterizations (CCs). Usually, we perform these CCs applying propofol, but we have seen several side effects of this sedative. We have had good experience with 4-hydroxybutyric acid for other sedations. To optimize our standardized CC procedure, we initiated a prospective, randomized trial to compare the two substances. Methods: We analyzed our sedation protocols of all CCs within a period of 12 months. In addition to the primary endpoints, the feasibility of the CCs and the occurrence of severe complications, several other parameters were included in the analysis (vital parameters, blood gas analysis, intervention measures). The protocols were blinded for the first part of the evaluation. Results: During the 12-month-period, 36 patients were included in each group. The propofol group showed lower blood pressure values towards the end of the sedations, while the blood gas analyses revealed lower pH levels and higher pCO2 values. The complication rate was low in both groups. Conclusion: Both procedures are suited for the safe performance of deep sedations for CCs. The application of 4-hydroxybutyric acid seems to have a few advantages with regard to spontaneous breathing, gas exchange, stability of cardiocirculatory parameters and sedation quality

Fertigung eines Nistkastens in der Grundschule. Praxisorientierter Technikunterricht

Das Arbeiten mit Holz in der Grundschule ist von großer Bedeutung. Durch praktische Erfahrungen mit Holzarbeiten entwickeln Kinder ein Verständnis für Materialien und Werkzeuge. Bei der Fertigung eines Nistkastens durchlaufen die Schüler*innen verschiedene Arbeitsschritte, die relevante Verfahren bei der Bearbeitung von Holz beinhalten. Zudem unterstützen Nistkästen die Artenvielfalt und tragen zum Naturschutz bei. Die Fertigung bietet deshalb eine ideale Gelegenheit, praktische Elemente des Technikunterrichts in den Sachunterricht zu integrieren. Die Schüler*innen können konkret erleben, wie ihr Handeln einen positiven Beitrag zum Naturschutz leisten kann. (DIPF/Orig.

A Single Bout of Aerobic Exercise Improves Motor Skill Consolidation in Parkinson’s Disease

Background: Motor learning is impaired in Parkinson’s disease (PD), with patients demonstrating deficits in skill acquisition (online learning) and consolidation (offline learning) compared to healthy adults of similar age. Recent studies in young adults suggest that single bouts of aerobic exercise (AEX), performed in close temporal proximity to practicing a new motor task, may facilitate motor skill learning. Thus, we aimed at investigating the effects of a single bout of aerobic cycling on online and offline learning in PD patients.Methods: 17 PD patients (Hoehn and Yahr 1 – 2.5, age: 64.4 ± 6.2) participated in this crossover study. Immediately prior to practicing a novel balance task, patients either performed 30 min of (i) moderate intensity (60–70% VO2max) aerobic cycling, or (ii) seated rest (order counterbalanced). The task required patients to stabilize a balance platform (stabilometer) in a horizontal position for 30 s. For each experimental condition, patients performed 15 acquisition trials, followed by a retention test 24 h later. We calculated time in balance (platform within ± 5° from horizontal) for each trial, and analyzed within- and between-subjects differences in skill acquisition (online learning) and skill retention (offline learning) using mixed repeated-measures ANOVA.Results: We found that the exercise bout had no effect on performance level or online gains during acquisition, despite affecting the time course of skill improvements (larger initial and reduced late skill gains). Aerobic cycling significantly improved offline learning, as reflected by larger 24-h skill retention compared to the rest condition.Conclusion: Our results suggest that a single bout of moderate-intensity AEX is effective in improving motor skill consolidation in PD patients. Thus, acute exercise may represent an effective strategy to enhance motor memory formation in this population. More work is necessary to understand the underlying mechanisms, the optimal scheduling of exercise, and the applicability to other motor tasks. Further, the potential for patients in later disease stages need to be investigated. The study was a priori registered at ClinicalTrials.gov (NCT03245216)

Perturbation During Treadmill Training Improves Dynamic Balance and Gait in Parkinson’s Disease: A Single-Blind Randomized Controlled Pilot Trial

Background. Gait and balance dysfunction are major symptoms in Parkinson’s disease (PD). Treadmill training improves gait characteristics in this population but does not reflect the dynamic nature of controlling balance during ambulation in everyday life contexts. Objective. To evaluate whether postural perturbations during treadmill walking lead to superior effects on gait and balance performance compared with standard treadmill training. Methods. In this single-blind randomized controlled trial, 43 PD patients (Hoehn & Yahr stage 1-3.5) were assigned to either an 8-week perturbed treadmill intervention (n = 21) or a control group (n = 22) training on the identical treadmill without perturbations. Patients were assessed at baseline, postintervention, and at 3 months’ follow-up. Primary endpoints were overground gait speed and balance (Mini-BESTest). Secondary outcomes included fast gait speed, walking capacity (2-Minute Walk Test), dynamic balance (Timed Up-and-Go), static balance (postural sway), and balance confidence (Activities-Specific Balance Confidence [ABC] scale). Results. There were no significant between-group differences in change over time for the primary outcomes. At postintervention, both groups demonstrated similar improvements in overground gait speed (P = .009), and no changes in the Mini-BESTest (P = .641). A significant group-by-time interaction (P = .048) existed for the Timed Up-and-Go, with improved performance only in the perturbation group. In addition, the perturbation but not the control group significantly increased walk ing capacity (P = .038). Intervention effects were not sustained at follow-up. Conclusions. Our primary findings suggest no superior effect of perturbation training on gait and balance in PD patients. However, some favorable trends existed for secondary gait and dynamic balance parameters, which should be investigated in future trials

New Binding Mode to TNF-Alpha Revealed by Ubiquitin-Based Artificial Binding Protein

A variety of approaches have been employed to generate binding proteins from non-antibody scaffolds. Utilizing a beta-sheet of the human ubiquitin for paratope creation we obtained binding proteins against tumor necrosis factor (TNF)-alpha. The bioactive form of this validated pharmacological target protein is a non-covalently linked homo-trimer. This structural feature leads to the observation of a certain heterogeneity concerning the binding mode of TNF-alpha binding molecules, for instance in terms of monomer/trimer specificity. We analyzed a ubiquitin-based TNF-alpha binder, selected by ribosome display, with a particular focus on its mode of interaction. Using enzyme-linked immunosorbent assays, specific binding to TNF-alpha with nanomolar affinity was observed. In isothermal titration calorimetry we obtained comparable results regarding the affinity and detected an exothermic reaction with one ubiquitin-derived binding molecule binding one TNF-alpha trimer. Using NMR spectroscopy and other analytical methods the 1∶3 stoichiometry could be confirmed. Detailed binding analysis showed that the interaction is affected by the detergent Tween-20. Previously, this phenomenon was reported only for one other type of alternative scaffold-derived binding proteins – designed ankyrin repeat proteins – without further investigation. As demonstrated by size exclusion chromatography and NMR spectroscopy, the presence of the detergent increases the association rate significantly. Since the special architecture of TNF-alpha is known to be modulated by detergents, the access to the recognized epitope is indicated to be restricted by conformational transitions within the target protein. Our results suggest that the ubiquitin-derived binding protein targets a new epitope on TNF-alpha, which differs from the epitopes recognized by TNF-alpha neutralizing antibodies

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2\u2009cm; P\u20091.5\u2009cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8\u2009cm vs 652.8\u2009cm (94% vs 85% by 10 years; P\u2009=\u20090.020; 80% vs 50% at 10 years; P\u2009=\u20090.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8\u2009cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification