Newly Diagnosed IDH-Wildtype Glioblastoma and Temporal Muscle Thickness: A Multicenter Analysis

Background: Reduced temporal muscle thickness (TMT) has been discussed as a prognostic marker in IDH-wildtype glioblastoma. This retrospective multicenter study was designed to investigate whether TMT is an independent prognostic marker in newly diagnosed glioblastoma. Methods: TMT was retrospectively measured in 335 patients with newly diagnosed glioblastoma between 1 January 2014 and 31 December 2019 at the University Hospitals of Leipzig and Rostock. The cohort was dichotomized by TMT and tested for association with overall survival (OS) after 12 months by multivariate proportional hazard calculation. Results: TMT of 7.0 mm or more was associated with increased OS (46.3 ± 3.9% versus 36.6 ± 3.9%, p > 0.001). However, the sub-groups showed significant epidemiological differences. In multivariate proportional hazard calculation, patient age (HR 1.01; p = 0.004), MGMT promoter status (HR 0.76; p = 0.002), EOR (HR 0.61), adjuvant irradiation (HR 0.24) and adjuvant chemotherapy (HR 0.40; all p < 0.001) were independent prognostic markers for OS. However, KPS (HR 1.00, p = 0.31), BMI (HR 0.98, p = 0.11) and TMT (HR 1.06; p = 0.07) were not significantly associated with OS. Conclusion: TMT has not appeared as a statistically independent prognostic marker in this cohort of patients with newly diagnosed IDH-wildtype glioblastoma

Recurrence of chronic subdural hematoma due to low-grade infection

Despite the high incidence and multitudes of operative techniques, the risk factors for chronic subdural hematoma (CSDH) recurrence are still under debate and a universal consensus on the pathophysiology is lacking. We hypothesized that clinically inapparent, a low-grade infection could be responsible for CSDH recurrence. This investigation is a single-center prospective observational study including patients with recurrent CSDH. In total, 44 patients with CSDH recurrence received an intraoperative swab-based microbiological test. The intraoperative swab revealed an inapparent low-grade hematoma infection in 29% of the recurrent CSDH cases. The majority (69%) of the identified germs belonged to the staphylococcus genus. We therefore, propose a novel potential pathophysiology for CSDH recurrence

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy

Frailty in cerebellar ischemic stroke—The significance of temporal muscle thickness

While comprising only 2% of all ischemic strokes, cerebellar strokes are responsible for substantial morbidity and mortality due to their subtle initial presentation and the morbidity of posterior fossa swelling. Furthermore, low temporal muscle thickness (TMT) has recently been identified as a prognostic imaging parameter to assess patient frailty and outcome. We analyzed radiological and clinical data sets of 282 patients with cerebellar ischemic stroke. Our analysis showed a significant association between low TMT, reduced NIHSS and mRS at discharge (p = 0.035, p = 0.004), and reduced mRS at 12 months (p = 0.001). TMT may be used as a prognostic imaging marker and objective tool to assess outcomes in patients with cerebellar ischemic stroke

Icodextrin does not impact infectious and culture-negative peritonitis rates in peritoneal dialysis patients: a 2-year multicentre, comparative, prospective cohort study

Background. Icodextrin is a glucose polymer derived by hydrolysis of cornstarch. The different biocompatibility profile of icodextrin-containing peritoneal dialysis (PD) solutions may have a positive influence on peritoneal host defence. Furthermore, cases of sterile peritonitis potentially associated with icodextrin have been reported

Triplet Repeat–Derived siRNAs Enhance RNA–Mediated Toxicity in a Drosophila Model for Myotonic Dystrophy

More than 20 human neurological and neurodegenerative diseases are caused by simple DNA repeat expansions; among these, non-coding CTG repeat expansions are the basis of myotonic dystrophy (DM1). Recent work, however, has also revealed that many human genes have anti-sense transcripts, raising the possibility that human trinucleotide expansion diseases may be comprised of pathogenic activities due both to a sense expanded-repeat transcript and to an anti-sense expanded-repeat transcript. We established a Drosophila model for DM1 and tested the role of interactions between expanded CTG transcripts and expanded CAG repeat transcripts. These studies revealed dramatically enhanced toxicity in flies co-expressing CTG with CAG expanded repeats. Expression of the two transcripts led to novel pathogenesis with the generation of dcr-2 and ago2-dependent 21-nt triplet repeat-derived siRNAs. These small RNAs targeted the expression of CAG-containing genes, such as Ataxin-2 and TATA binding protein (TBP), which bear long CAG repeats in both fly and man. These findings indicate that the generation of triplet repeat-derived siRNAs may dramatically enhance toxicity in human repeat expansion diseases in which anti-sense transcription occurs

Méthode multipôle pour l'évaluation au vol de la dépendance en température des sections efficaces nucléaires

In nuclear reactor physics, the knowledge of the cross-sections describing interactions of neutrons with the medium through which they diffuse is of paramount importance. These sections depend both on the energy of the neutron and the temperature of the medium. Concerning the energy dependency, cross-section profiles display, in general, numerous resolved resonances on the energy range of interest. The multipole representation is an additive and exact description of the resonant cross-sections at zero temperature. The temperature dependency is then computed by a linear operation using analytical tools such as the Faddeeva function.This thesis is devoted to the theoretical aspects of the multipole representation as well as two main applications. Concerning the theoretical study, we show that the number of required poles for the representation of sections under the Multi-Level Breit-Wigner and Reich-Moore formalisms can be reduced compared to previously established results. This requires, notably, a formal study of rational functions and solving polynomials of very high degree (superior to 50 and potentially reaching the thousands).Concerning the applications, the first one focuses on the implementation of the original theoretical elements found during the thesis. A reconstruction of sections at zero temperature and a comparison with reference results is proposed in order to prove the relevance and correctness of the newly computed multipole parameters. The results are extrememly satisfying albeit limited by nature to resonant cross-sections. The second application consists in using the multipole representation for the Doppler broadening of cross-sections : a comparison to sections broadened with the usual method (so-called « sigma-1 ») is presented. The results of this comparison are also very satisfying although some efforts are still necessary on the border of the energy domain of resolved resonances.In the context of Monte Carlo transport simulations, the linearity of the Doppler broadening and the additive nature of the multipole representation suggest that it is possible to compute cross-sections « on-the-fly », at each neutron collision, which would allow strongly reducing the memory footprint compared to current approaches (tabulation in energy of the cross-section profiles at multiple temperatures).Dans le contexte de la physique des réacteurs nucléaires, la connaissance des sections efficaces décrivant les interactions des neutrons avec le milieu traversé est primordiale. Ces sections dépendent à la fois de l’énergie du neutron et de la température du milieu. Concernant la dépendance en énergie, les profils des sections efficaces présentent en général de nombreuses résonances résolues sur le domaine d’énergie d’intérêt. La représentation multipôle est une description additive et exacte des sections efficaces résonantes à température nulle. La dépendance en température est ensuite calculée par une opération linéaire faisant intervenir des outils analytiques tels que la fonction de Faddeeva. Cette thèse se concentre sur les aspects théoriques de la représentation multipôle ainsi que sur deux applications principales. Concernant l’étude théorique, on démontre que le nombre de pôles nécessaires pour la représentation des sections aux formalismes Multi-Level Breit-Wigner et Reich-Moore peut être réduit par rapport aux résultats précédemment établis en littérature. Cela nécessite notamment une étude formelle de fractions rationnelles et la résolution de polynômes de très haut degré (supérieur à 50 et pouvant atteindre plusieurs milliers).Concernant les applications, la première se concentre sur la mise en oeuvre informatique des éléments théoriques originaux trouvés durant les travaux de thèse. Une reconstruction des sections à température nulle et une comparaison à des résultats de référence est présentée afin de démontrer la pertinence et l’exactitude des paramètres multipôles nouvellement calculés. Les résultats sont extrêmement satisfaisants quoique limités par nature aux sections résonantes. La seconde application est l’utilisation de la représentation multipôle pour l’élargissement Doppler des sections efficaces : une comparaison à des sections élargies par la méthode classique (dite « sigma-1 ») est présentée. Les résultats de cette comparaison sont aussi très satisfaisants mais des efforts sont encore nécessaires aux frontières du domaine d’énergie des résonances résolues.Dans le cadre des simulations de transport par méthode de Monte-Carlo, la linéarité de l’élargissement et la nature additive de la représentation multipôle suggèrent la possibilité de calculer la section efficace « au vol » à chaque collision du neutron, ce qui permettrait de réduire très fortement l’encombrement mémoire par rapport à l’approche actuelle (tabulation de ces profils à de multiples températures)

Rab6A as a pan-astrocytic marker in mouse and human brain, and comparison with other glial markers (GFAP, GS, Aldh1L1, SOX9)

Astrocytes contribute to many higher brain functions. A key mechanism in glia-to-neuron signalling is vesicular exocytosis; however, the identity of exocytosis organelles remains a matter of debate. Since vesicles derived from the trans-Golgi network (TGN) are not considered in this context, we studied the astrocyte TGN by immunocytochemistry applying anti-Rab6A. In mouse brain, Rab6A immunostaining is found to be unexpectedly massive, diffuse in all regions, and is detected preferentially and abundantly in the peripheral astrocyte processes, which is hardly evident without glial fibrillary acid protein (GFAP) co-staining. All cells positive for the astrocytic markers glutamine synthetase (GS), GFAP, aldehyde dehydrogenase 1 family member L1 (Aldh1L1), or SRY (sex determining region Y)-box 9 (SOX9) were Rab6A+. Rab6A is excluded from microglia, oligodendrocytes, and NG2 cells using cell type-specific markers. In human cortex, Rab6A labelling is very similar and associated with GFAP+ astrocytes. The mouse data also confirm the specific astrocytic labelling by Aldh1L1 or SOX9; the astrocyte-specific labelling by GS sometimes debated is replicated again. In mouse and human brain, individual astrocytes display high variability in Rab6A+ structures, suggesting dynamic regulation of the glial TGN. In summary, Rab6A expression is an additional, global descriptor of astrocyte identity. Rab6A might constitute an organelle system with a potential role of Rab6A in neuropathological and physiological processes