The Vienna General Hospital (German: Allgemeines Krankenhaus der Stadt Wien), usually abbreviated to AKH, is the general hospital of the city of Vienna, Austria. It is also the city's university hospital, and the site of the Medical University of Vienna. It is Europe's fifth largest hospital, both by number of employees and bed capacity..
The stable coordination of radium-223 (223Ra) for targeted alpha therapy remains elusive. Herein, 17 chelators were investigated for the complexation of 223Ra, of which 13 have previously not been reported. MacroPa was used as a reference and control for the studies, and by a process of systematic modifications to this chelator and a range of other chelator scaffolds, a library of structurally related compounds was obtained, each differing from another by a single functional group or change in the backbone. The radiolabeling of each chelator was assessed by radio-thin layer chromatography to determine radiochemical conversion. Fourteen of the synthesized chelators provided quantitative coordination of 223Ra at room temperature and neutral pH (or close to). The stability of these complexes in human serum at 37 °C was analyzed using radio-size exclusion chromatography, where results corresponding to [223Ra][Ra(MacroMePhos)] were encouraging. However, radio-thin layer chromatography analysis of the 'small molecule' fractions revealed the presence of free 223Ra, indicating instability within 1 h. In fact, even [223Ra][Ra(MacroPa)] dissociated within 1 h, albeit at higher dilutions. Overall, this work shows that the search for a suitable 223Ra-chelator for applications in radiopharmaceuticals still requires significant attention and effort.
Fused in sarcoma (FUS) is a highly conserved RNA-binding protein with essential roles in RNA processing and genomic stability. While extensively studied in the context of neurodegeneration, its involvement in fibrotic diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unexplored. This study investigated the pathological role of FUS in IPF and assessed its viability as a therapeutic target. Specifically, we examine how FUS dysregulation contributes to fibrotic signaling and evaluate whether therapeutic silencing of FUS offers a rational strategy to modulate disease progression. To assess the effects of FUS overexpression and knockdown, functional assays were performed on primary lung fibroblasts derived from healthy donors and IPF patients. Precision-cut lung slices (PCLs) and 3D alveolosphere cultures from IPF patients were treated with a FUS-targeted antisense oligonucleotide (ASO;ION363). FUS-RNA interactions were mapped via CLIP-Seq, and global transcriptional changes following FUS inhibition were analyzed via RNA sequencing. FUS overexpression in healthy fibroblasts promoted proliferation, whereas FUS knockdown attenuated the hyperproliferative phenotype in IPF fibroblasts. IPF cells demonstrated aberrant cytoplasmic mislocalization of FUS. Standard-of-care treatments (pirfenidone, nintedanib) reduced FUS expression in PCLs. CLIP-Seq revealed that FUS binds to a distinct set of profibrotic RNAs in IPF. ION363 treatment downregulated fibrotic gene programs, including those linked to ECM remodeling, TGFβ signaling, and epithelial dysfunction. In contrast, ION363 promoted functional marker expression and improved morphology in patient-derived 3D alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and that targeting FUS via ASO represents a promising therapeutic avenue for IPF.
Abstract Curiosity, a key driver of exploration and learning, is reinforced by reward-related neurochemical systems, yet the role of the opioidergic system in modulating this behavior remains unclear. Music, as a highly rewarding stimulus, offers a unique context to investigate the neurochemical basis of curiosity, particularly the unexplored role of opioids in music-driven exploration. To fill this gap, we performed a double-blind within-subject pharmacological design, in which 26 participants received, in two different sessions, either a placebo or the opioid antagonist naltrexone. During each session, participants engaged in a music exploration/exploitation trade-off paradigm designed to assess their willingness to pay for exploring unfamiliar electronic music. Using logistic regression mixed-effects models, we found that while naltrexone did not affect overall curiosity ratings, it significantly reduced exploratory behavior in states of heightened curiosity. These findings suggest that the opioidergic system plays a critical role in regulating the relationship between curiosity and exploration, particularly in the context of novel and rewarding stimuli like music. Overall, the present research provides new and compelling evidence on the important relationship between curiosity and exploration and its regulation with the opioidergic neurotransmitter subsystem. Significance Statement The present research aimed to advance our understanding of the neurochemical mechanisms underlying curiosity and information seeking. In our study, we employed a pharmacological design to examine the role of the opioidergic system in music-related exploration. Using a novel music exploration/exploitation paradigm, we found that while naltrexone, an opioid antagonist, did not affect baseline curiosity ratings, it markedly reduced exploratory behavior during high-curiosity states in the presence of potential monetary losses. These results provide new evidence that opioidergic modulation plays a critical role in regulating curiosity-driven exploration. This new evidence might be relevant in the future for better understanding how neurochemical systems shape learning, motivation, and affective responses in complex cognitive domains such as music.
Background and Aims The effects of antihypertensive medications – particularly beta blockers and renin-angiotensin system (RAS) blockers – on resting energy expenditure (REE) remain controversial. Clarifying these effects is clinically relevant for nutritional counseling in patients with hypertension. This study examined whether long-term use of these agents is associated with alterations in REE. Methods In this strictly matched-pair, controlled, cross-sectional study, 46 hypertensive but otherwise healthy men receiving beta blockers and/or RAS blockers for ≥ 6 months (long-term users, LU) were enrolled (age: 64.0 ± 7.9 years; BMI: 28.3 ± 4.1 kg/m2; fat-free mass (FFM): 61.9 ± 6.9 kg; treatment duration 11.0 ± 7.5 years). Participants were classified as beta blocker users (LU-B; partially with RAS blockers) or users of RAS blockers alone (LU-A). Each LU was pair-matched with a healthy male non-user (NU; n = 46; age: 62.3 ± 7.9 years; BMI: 26.9 ± 4.1 kg/m2; FFM: 62.0 ± 6.2 kg) based on FFM (±5%), skeletal muscle mass (±5%), and age (±5 years). REE was measured under standardized conditions by indirect calorimetry using a flow-based dilution canopy hood system. Body composition was assessed by bioelectrical impedance analysis. Physical activity and adverse effects at therapy initiation were systematically recorded. Results Long-term antihypertensive therapy was not associated with differences in REE compared with matched NU in the total group (LU: 1668 ± 176 vs. NU: 1642 ± 145 kcal/day; p = 0.406), nor across subgroups, irrespective of normalization to body weight or FFM. Sensitivity analyses showed similar deviations (±15%) from predicted REE using the Harris-Benedict equation in all LU subgroups compared with matched NU. Linear mixed-effects models showed no independent effects of medication, identifying FFM and pulse as the only significant predictors of REE. In contrast to the findings for REE, participants receiving RAS blocker therapy with or without beta blockers (n = 38) exhibited significantly higher fat mass (FM; +3.7 kg; p = 0.029) and VCO2 production (+9 ml/min; p = 0.008) compared with NU, whereas no differences were observed with beta blocker monotherapy (n = 8, FM: +0.9 kg; p = 0.817; VCO2: -1 ml/min; p = 0.889). The positive correlation between FM and VCO2 (r = 0.363; p < 0.001) was exclusively present in LU and not observed in NU. Self-reported weight gain at therapy initiation was more frequent among LU-B versus LU-A (6/19 vs. 1/27; p = 0.015), whereas physical activity levels and adverse effects did not differ between treatment groups. Conclusion Long-term antihypertensive therapy in older men was not associated with clinically substantial deviations from expected REE. Although minor effects cannot be entirely ruled out, the results suggest that standard equations for estimating REE remain a reasonable guide for this population. However, additional verification is recommended. Despite similar physical activity and FFM, participants on RAS blocker therapy showed higher FM and VCO2 production. This may potentially reflect underlying differences in adiposity, clinical phenotype, or residual indication bias. While the cross-sectional nature of this study precludes causal inferences, these exploratory findings underscore the importance of monitoring body composition and lifestyle during antihypertensive treatment. Study ID number NCT02682537 (clinical trials.gov)
BACKGROUND:Evidence regarding the clinical course of unruptured giant intracranial aneurysms (GIAs) after conservative management (CON), microsurgical treatment (SURG) or endovascular treatment (EVT) remains limited. We aimed to assess mortality, functional outcome, symptom course and retreatment rates after different management strategies. METHODS:In this prospective, multinational registry, patients with unruptured GIAs treated at 37 neurovascular centres between 2008 and 2018 were included. Outcomes after CON, EVT or SURG were analysed with standardised 3-year follow-up. The study is registered at ClinicalTrials.gov. RESULTS:We included 339 patients of whom 22.7% received CON, 42.8% EVT and 34.5% SURG. Three-year survival was 64.0% (95% CI 53.73% to 76.20%) in the CON group, 82.0% (95% CI 75.42% to 89.17%) in the EVT group and 93.5% (95% CI 88.91% to 98.28%) in the SURG group (p<0.001). Favourable neurological outcome (modified Rankin Scale 0-2) declined to 53.0%, 66.9% and 75.7% in the CON, EVT and SURG groups, respectively (p<0.01). Symptom improvement at 3 years occurred in 10.3% of CON, 22.1% of EVT and 11.1% of SURG patients, while deterioration was observed in 7.7%, 8.5% and 15.8%, respectively. Retreatment was required in 22.8% of EVT patients and 6.2% of SURG patients (p<0.01). CONCLUSIONS:EVT and SURG were associated with significantly improved survival and functional outcomes compared with conservative management of unruptured GIAs. In patients eligible for intervention, both treatment modalities represent reasonable and effective options, with a high proportion of patients achieving favourable clinical outcomes. TRIAL REGISTRATION NUMBER:NCT02066493.
