Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.

We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFκB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFκB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain

Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.

BACKGROUND AND PURPOSE The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. EXPERIMENTAL APPROACH Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect. KEY RESULTS For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively. CONCLUSIONS AND IMPLICATIONS Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans

On distinguishing the direct causal effect of an intervention from its efficiency-enhancing effects

Copyright © 2023 The Authors. This paper proposes an innovative methodology for handling endogeneity issues in the evaluation of policy performance. By estimating a regression discontinuity design with a four-component stochastic frontier panel data model, we estimate the causal impact of a policy intervention on the outcome variable, whenever the treatment status depends on an exogenous threshold. We distinguish between (i) the direct effect of the intervention, (ii) the efficiency-enhancing effect, or (iii) their combination. Moreover, we distinguish between persistent (time-invariant) and transient (time-varying) inefficiency components while accounting for unobserved heterogeneity, which is important for policy implications. We showcase the practical usefulness of the proposed approach by estimating the effect of providing additional resources on schools that exceed an exogenously set share of disadvantaged students in secondary schools in Flanders, Belgium. We also demonstrate the trade-off between balance of the covariates in the treated and control group and statistical power. Thus, despite insignificant effects in a balanced but smaller sample close to the discontinuity, the results become significant in the unbalanced sample with more statistical power. In both samples, we observe that the policy had an effect on the outcome mostly through the efficiency-enhancing channel. To this extent, we show that the model specification including both direct and indirect effects outperforms the other two specifications and it offers a more exhaustive perspective from a policy view point.Research Foundation – Flanders, FWO (Postdoctoral Fellowship 12U0219N)

beta-decay study of Cu-77

A beta-decay study of Cu-77 has been performed at the ISOLDE mass separator with the aim to deduce its beta-decay properties and to obtain spectroscopic information on Zn-77. Neutron-rich copper isotopes were produced by means of proton- or neutron-induced fission reactions on U-238. After the production, Cu-77 was selectively laser ionized, mass separated and sent to different detection systems where beta-gamma and beta-n coincidence data were collected. We report on the deduced half-live, decay scheme, and possible spin assignment of 77Cu

An Observational Study of the First Experience with Bevacizumab for the Treatment of Patients with Recurrent High-Grade Glioma in Two Belgian University Hospitals

Background. Bevacizumab (BEV), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF has demonstrated activity against recurrent high-grade gliomas (HGG) in phase II clinical trials. Patients and Methods. Data were collected from patients with recurrent HGG who initiated treatment with BEV outside a clinical trial protocol at two Belgian university hospitals. Results. 19 patients (11 M/8 F) were administered a total of 138 cycles of BEV (median 4, range 1–31). Tumor response assessment by MRI was available for 15 patients; 2 complete responses and 3 partial responses for an objective response rate of 26% for the intent to treat population were observed on gadolinium-enhanced T1-weighted images; significant regressions on T2/FLAIR were documented in 10 out of 15 patients (67%). A reduced uptake on PET was documented in 3 out of 4 evaluable patients. The six-month progression-free survival was 21% (95% CI 2.7–39.5). Two patients had an ongoing tumor response and remained free from progression after 12 months of BEV treatment. Conclusions. The activity and tolerability of BEV were comparable to results from previous prospective phase II trials. Reduced uptake on PET suggests a metabolic response in addition to an antiangiogenic effect in some cases with favorable clinical outcome

Sn ion energy distributions of ns- and ps-laser produced plasmas

Ion energy distributions arising from laser-produced plasmas of Sn are measured over a wide laser parameter space. Planar-solid and liquid-droplet targets are exposed to infrared laser pulses with energy densities between 1 J cm(-2) and 4 kJ cm(-2) and durations spanning 0.5 ps to 6 ns. The measured ion energy distributions are compared to two self-similar solutions of a hydrodynamic approach assuming isothermal expansion of the plasma plume into vacuum. For planar and droplet targets exposed to ps-long pulses, we find good agreement between the experimental results and the self-similar solution of a semi-infinite simple planar plasma configuration with an exponential density profile. The ion energy distributions resulting from solid Sn exposed to ns-pulses agrees with solutions of a limited-mass model that assumes a Gaussian-shaped initial density profile.</p

Exploring pelvic floor muscle activity in men with lower urinary tract symptoms

Aim We aimed to explore the utility of the Multiple Array Probe Leiden (MAPLe) device to assess pelvic floor muscle activity in men with lower urinary tract symptoms (LUTS). Methods This was an observational cohort study performed at the urology outpatient department of a large teaching hospital in the Netherlands between April and October 2018. We recruited male patients referred for the assessment of LUTS, without a history of prostate surgery, if they had an International Prostate Symptom Score greater than or equal to 8. The MAPLe device was then used to assess the puborectalis, pubococcygeus, iliococcygeus, urogenital diaphragm, and the internal and external anal sphincters during three tasks: a rest period (1 minute), five maximum voluntary contractions (held for 3 seconds each), and three maximal endurance contractions (held for 15 seconds each). Results In total, 57 patients were included, 5 of which had diabetes mellitus. Muscle activity at rest was significantly lower than during either contraction task and did not differ between the muscle groups. By contrast, the external anal sphincter had significantly less activity than any other muscle group during the endurance task, and the internal anal sphincter and puborectalis had significantly less activity during the maximum voluntary contraction task. No association was found between pelvic floor muscle activity and LUTS severity during any task. Conclusion Pelvic floor muscle activity and LUTS severity appear to be unrelated, but this does not completely exclude the possibility of muscle involvement in the development or experience of symptoms. Further research is needed

Study of bound states in 12Be through low-energy 11Be(d,p)-transfer reactions

The bound states of 12Be have been studied through a 11Be(d,p)12Be transfer reaction experiment in inverse kinematics. A 2.8 MeV/u beam of 11Be was produced using the REX-ISOLDE facility at CERN. The outgoing protons were detected with the T-REX silicon detector array. The MINIBALL germanium array was used to detect gamma rays from the excited states in 12Be. The gamma-ray detection enabled a clear identification of the four known bound states in 12Be, and each of the states has been studied individually. Differential cross sections over a large angular range have been extracted. Spectroscopic factors for each of the states have been determined from DWBA calculations and have been compared to previous experimental and theoretical results

Controlling ion kinetic energy distributions in laser produced plasma sources by means of a picosecond pulse pair

The next generation of lithography machines uses extreme ultraviolet (EUV) light originating from laser-produced plasma (LPP) sources, where a small tin droplet is ionized by an intense laser pulse to emit the requested light at 13.5 nm. Numerous irradiation schemes have been explored to increase conversion efficiency (CE), out of which a double-pulse approach comprising a weak picosecond Nd:YAG pre-pulse followed by a powerful pulse is considered to be very promising [1]. Nevertheless, even for such CE-optimized schemes, ion debris ejected from the plasma with kinetic energies up to several keV remain a factor that hampers the maximum performance of LPP sources. In this letter we propose a novel pre-pulse scheme consisting of a picosecond pulse pair at 1064 nm, which decreases the amount of undesirable fast ions, avoids back-reflections to the lasers and enables one to tailor the target shape.Comment: 12 pages, 3 figures, 45 reference

Expansion Dynamics After Laser-Induced Cavitation in Liquid Tin Microdroplets

The cavitation-driven expansion dynamics of liquid tin microdroplets is investigated, set in motion by the ablative impact of a 15-ps laser pulse. We combine high-resolution stroboscopic shadowgraphy with an intuitive fluid dynamic model that includes the onset of fragmentation, and find good agreement between model and experimental data for two different droplet sizes over a wide range of laser pulse energies. The dependence of the initial expansion velocity on these experimental parameters is heuristically captured in a single power law. Further, the obtained late-time mass distributions are shown to be governed by a single parameter. These studies are performed under conditions relevant for plasma light sources for extreme-ultraviolet nanolithography.Comment: 7 pages, 6 figure