Utilisation des toxines botuliniques pour soulager la douleur réfractaire et d’autres symptômes du parkinsonisme

Background: Parkinson's disease (PD) and other parkinsonian syndromes are chronic, progressive neurodegenerative diseases. With advancing disease, both motor and non-motor symptoms represent a considerable burden and symptom relief and quality of life improvement become the main goal of treatment. Botulinum toxins (BTX) are an effective treatment modality for many neurological conditions. Methods: To understand the potential usefulness of BTX in this population, we performed a retrospective chart review of all patients with a clinical diagnosis of idiopathic PD and atypical parkinsonism who received treatment with BTX injections in our center from 1995 to 2014 for a variety of symptoms. Response to BTX was assessed using a subjective Clinical Global Impression. Results: Records of 160 patients were reviewed. Probable idiopathic PD was the diagnosis in 117 patients (73.1%). The main indication for BTX treatment was pain (50.6% of cases). Other indications were the treatment of functional impairment resulting from dystonia (26.25%), sialorrhea (18.75%), freezing of gait, and camptocormia. Considering pain as indication, 81% of all patients with PD reported benefits after the first BTX injections. This benefit was maintained after the last recorded visit without significant difference in outcome compared with the first injection (p=0.067). Similar results were observed in patients with atypical parkinsonism. Conclusions: Our results confirm the safety and efficacy of different uses of BTX in the symptomatic treatment of patients with parkinsonism even in advanced stages of the disease, and suggest BTX treatment could have a safe and useful role in the treatment of pain in this population.Contexte: La maladie de Parkinson (MP) et les divers syndromes parkinsoniens sont des affections neuro-dégénératives chroniques et évolutives. Avec la progression de la maladie, tant ses symptômes moteurs que ses symptômes non-moteurs finissent par représenter un fardeau considérable. Le soulagement de ces symptômes et l’amélioration de la qualité de vie des patients deviennent alors le principal objectif d’un traitement. À cet égard, les toxines botuliniques (« BTX ») demeurent une modalité de traitement efficace dans le cas de nombreux troubles neurologiques. Méthodes: Afin de comprendre l’utilité potentielle des toxines botuliniques, nous avons procédé à un examen rétrospectif des dossiers de tous les patients qui, après avoir reçu un diagnostic de MP idiopathique et de syndrome parkinsonien atypique, ont bénéficié dans notre centre, de 1995 à 2014, d’un traitement par injection de toxines botuliniques pour toute une gamme de symptômes. La réponse à ces toxines a ensuite été évaluée au moyen de l’échelle Clinical Global Impression. Résultats: Nous avons passé en revue les dossiers de 160 patients. Des cas probables de MP idiopathiques ont été diagnostiqués chez 117 patients (73,1 %). Fait à noter, le soulagement de la douleur était le principal motif justifiant un traitement par injection de toxines botuliniques (50,6 % des cas). D’autres motifs étaient avancés : traiter un handicap fonctionnel résultant de la dystonie (26,25 %), la sialorrhée (18,75 %), des blocages (freezing of gait) et la camptocormie. Si l’on s’en tient à la douleur, 81 % des patients atteints de la MP ont signalé des bienfaits à la suite des premières injections de toxines botuliniques. Ces bienfaits ont perduré après leur dernière visite attestée, et ce, sans qu’on ait observé de différences significatives dans les résultats par rapport à la première injection (p = 0,067). Des résultats identiques ont été constatés chez des patients atteints d’un syndrome parkinsonien atypique. Conclusions: Nos résultats confirment à la fois la sécurité et l’efficacité des différents usages des toxines botuliniques dans le soulagement, même à un stade avancé, des symptômes de patients atteints de parkinsonisme. Ils suggèrent aussi qu’un traitement par injection de toxines botuliniques pourrait, sans danger, jouer un rôle utile dans le traitement de la douleur éprouvée par cette catégorie de patients.Fil: Bruno, Veronica Andrea. University Health Network. Toronto Western Hospital; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fox, Susan H.. University Health Network. Toronto Western Hospital; CanadáFil: Mancini, Deborah. University Health Network. Toronto Western Hospital; CanadáFil: Miyasaki, Janis M.. University of Alberta; Canad

The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury

BACKGROUND: Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs). Several studies have reported the existence of a resident population of MSCs within the glomeruli (Gl-MSCs). However, their contribution towards kidney repair still remains to be elucidated. The aim of the present study was to evaluate whether Gl-MSCs and Gl-MSC-EVs promote the recovery of AKI induced by ischemia-reperfusion injury (IRI) in SCID mice. Moreover, the effects of Gl-MSCs and Gl-MSC-EVs were compared with those of CD133(+) progenitor cells isolated from human tubules of the renal cortical tissue (T-CD133(+) cells) and their EVs (T-CD133(+)-EVs). METHODS: IRI was performed in mice by clamping the left renal pedicle for 35 minutes together with a right nephrectomy. Immediately after reperfusion, the animals were divided in different groups to be treated with: Gl-MSCs, T-CD133(+) cells, Gl-MSC-EVs, T-CD133(+)-EVs or vehicle. To assess the role of vesicular RNA, EVs were either isolated by floating to avoid contamination of non-vesicles-associated RNA or treated with a high dose of RNase. Mice were sacrificed 48 hours after surgery. RESULTS: Gl-MSCs, and Gl-MSC-EVs both ameliorate kidney function and reduce the ischemic damage post IRI by activating tubular epithelial cell proliferation. Furthermore, T-CD133(+) cells, but not their EVs, also significantly contributed to the renal recovery after IRI compared to the controls. Floating EVs were effective while RNase-inactivated EVs were ineffective. Analysis of the EV miRnome revealed that Gl-MSC-EVs selectively expressed a group of miRNAs, compared to EVs derived from fibroblasts, which were biologically ineffective in IRI. CONCLUSIONS: In this study, we demonstrate that Gl-MSCs may contribute in the recovery of mice with AKI induced by IRI primarily through the release of EVs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-017-0478-5) contains supplementary material, which is available to authorized users

Temperature response of luminescent tris(bipyridine)ruthenium(II)-doped silica nanoparticles

Nanoparticle-based temperature imaging is an emerging field of advanced applications. Herein, the sensitivity of the phosphorescence of tris(bipyridine)ruthenium(II)-doped silica nanoparticles towards temperature is studied. 130 nm size particles were prepared by a modification of Stöber’s method, that allows the incorporation of Ru[(bpy)3]2+ into the outer particle shell. The entrapped Ru[(bpy)3]2+ retains its photophysical properties, yet the emission of the particles is not affected by the presence of O2, neither by anionic quenchers; quenching by MV2+, on the other hand, is strongly dependent on pH. Between 20 and 60 °C, the steady-state emission of the particles decreases linearly with increasing temperature. The slope of the straight line diminishes slightly on thermal cycling, but soon stabilizes. Fluorescence measurements by scanning confocal microscopy indicate that the silica nanoparticles doped with Ru[(bpy)3]2+ can indeed be employed to probe thermal processes in micro-environments.Fil: Mirenda, Martin. Comision Nacional de Energia Atomica. Centro Atomico Constituyentes; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Levi, Valeria. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bossi, Mariano Luis. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bruno, Luciana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bordoni, Andrea Veronica. Comision Nacional de Energia Atomica. Centro Atomico Constituyentes; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Regazzoni, Alberto Ernesto. Comision Nacional de Energia Atomica. Centro Atomico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wolosiuk, Alejandro. Comision Nacional de Energia Atomica. Centro Atomico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Anatomo-radiological study of the internal pudendal perforator vessels : clinical relevance in reconstructive surgery of the perineal region

Introduction. The mobilization of muscular and fasciocutaneous flaps represents a mandatory reconstructive surgery in a variety of soft tissue defects of the the pelvi-perineal area. Often oncological surgery, trauma or severe soft tissue infections such as Fournier’s gangrene, produce functional and morphological deformities of this region. An appropriate soft tissue reconstruction may limit the development of scar contractures and stenosys. The possibility to better localize the main vascular perforators may help the surgeon in a safe flap mobilization. Methods. To objectively document the topografical location of external and internal pudendal arteries and respectively perforators branches, an anatomo-radiological study on 24 CT angiographies of 12 lower limbs (multidetector CT 16 slides), and analysis of multiplannar images and 3D reconstructions (Terarecon™) were performed. The origin, number, course and location of perforators of the internal pudendal artery in vivo were recorded. Results. Superficial landmarks (anus, external urethral meatus and ischiatic tuberosity) may describe a safe cutaneous perineal region in which is possible to localize all internal pudendal perforator arteries. In this area the mean number of perforators was 2,6 (range: 0-4). In one case (4%) the perforators vessels originated from the inferior gluteal artery. The mean diameter of perforators was 2,3 mm (0,47SD; range 1,4-3,4). The most proximal perforator of the internal pudendal artery presented a mean caliber of 2,6 mm (range 2-3,4). Discussion. This study confirms the presence of a rich vascular network between the internal and external pudendal artery. Moreover a reliable caliber and constant location of the perforators of the internal pudendal artery are documented. These observations are also confirmed intraoperatively during the mobilization of perforators flaps for the reconstruction of perineal area. The knowledge of the rich vascular plexus allows to plan a variety of fascio-cutaneous perforator flaps that may guarantee better reconstruction results then the past

An NMR‐based biosensor to measure stereo‐specific methionine sulfoxide reductase (MSR) activities in vitro and in vivo

Oxidation of protein methionines to methionine-sulfoxides (MetOx) is associated with several age-related diseases. In healthy cells, MetOx is reduced to methionine by two families of conserved methionine sulfoxide reductase enzymes, MSRA and MSRB that specifically target the S- or R-diastereoisomers of methionine-sulfoxides, respectively. To directly interrogate MSRA and MSRB functions in cellular settings, we developed an NMR-based biosensor that we call CarMetOx to simultaneously measure both enzyme activities in single reaction setups. We demonstrate the suitability of our strategy to delineate MSR functions in complex biological environments, including cell lysates and live zebrafish embryos. Thereby, we establish differences in substrate specificities between prokaryotic and eukaryotic MSRs and introduce CarMetOx as a highly sensitive tool for studying therapeutic targets of oxidative stress-related human diseases and redox regulated signaling pathways.Fil: Sanchez Lopez, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Labadie, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Lombardo, Veronica Andrea. Universidad Nacional de Rosario. Centro de Estudios Interdisciplinarios; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Biglione, Franco Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Manta, Bruno. Harvard Medical School; Estados UnidosFil: Jacob, Reeba. Weizmann Institute Of Science.; IsraelFil: Gladyshev, Vadim. Harvard Medical School; Estados UnidosFil: Abdelilah Seyfried, Salim. Universitat Potsdam; Alemania. Leibniz Universitat Hannover; AlemaniaFil: Selenko, Philipp. Weizmann Institute Of Science.; IsraelFil: Binolfi, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

Anatomic-radiologic study of the anterolateral ligament of the knee

Recent anatomic investigations of the lateral structures of the knee have identified a new ligament, called the anterolateral ligament (ALL). To date, the anterolateral ligament has not been microscopically analysed. A retrospective MRI study was carried out in 50 patients by two observers. MRI has been performed for various indications excluding trauma. 10 specimens of ALL were sampled from bodies of the Donation to Science program of the University of Padova. A thin linear structure originating at the lateral epicondyle, running obliquely downwards and forwards and inserting at the lateral aspect of the proximal tibia was observed in 18 cases (90%), with a mean length of 3.8 cm and mean thickness of 1.9 mm. The ALL was hyposignal on both T1- and T2-weighted sequences. From the microscopic point of view the ALL corresponds to a fibrous connective tissue, organised in 2-3 layers of collagen tissue (mean thickness 983+423 micron), with scarce elastic fibres, separated by a thin layer of fibroadipose tissue from the adjacent structures. The ALL appears as almost constantly depicted by MRI and shows a fibrous structure. Its layered organisation could account for its mechanical importance, as a presumed stabilizer of the medial rotation of the kne

TRAIL reduces impaired glucose tolerance and NAFLD in the high-fat diet-fed mouse

Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis inducing ligand) may have an important role in the treatment of type 2 diabetes. It has been shown that TRAIL deficiency worsens diabetes and that TRAIL delivery, when it is given before disease onset, slows down its development. The present study aimed at evaluating whether TRAIL had the potential not only to prevent, but also to treat type 2 diabetes. Thirty male C57BL/6J mice were randomized to a standard or a high-fat diet (HFD). After 4 weeks of HFD, mice were further randomized to receive either placebo or TRAIL, which was delivered weekly for 8 weeks. Body weight, food intake, fasting glucose, and insulin were measured at baseline and every 4 weeks. Tolerance tests were performed before drug randomization and at the end of the study. Tissues were collected for further analyses. Parallel in vitro studies were conducted on HepG2 cells and mouse primary hepatocytes. TRAIL significantly reduced body weight, adipocyte hypertrophy, free fatty acid levels, and inflammation. Moreover, it significantly improved impaired glucose tolerance, and ameliorated non-alcoholic fatty liver disease (NAFLD). TRAIL treatment reduced liver fat content by 47% in vivo as well as by 45% in HepG2 cells and by 39% in primary hepatocytes. This was associated with a significant increase in liver peroxisome proliferator-activated receptor (PPAR) \u3b3 (PPAR\u3b3) co-activator-1 \u3b1 (PGC-1\u3b1) expression both in vivo and in vitro, pointing to a direct protective effect of TRAIL on the liver. The present study confirms the ability of TRAIL to significantly attenuate diet-induced metabolic abnormalities, and it shows for the first time that TRAIL is effective also when administered after disease onset. In addition, our data shed light on TRAIL therapeutic potential not only against impaired glucose tolerance, but also against NAFLD

PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology

Background: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology

Gamma-Ray Burst observations by the high-energy charged particle detector on board the CSES-01 satellite between 2019 and 2021

In this paper we report the detection of five strong Gamma-Ray Bursts (GRBs) by the High-Energy Particle Detector (HEPD-01) mounted on board the China Seismo-Electromagnetic Satellite (CSES-01), operational since 2018 on a Sun-synchronous polar orbit at a $\sim$ 507 km altitude and 97$^\circ$ inclination. HEPD-01 was designed to detect high-energy electrons in the energy range 3 - 100 MeV, protons in the range 30 - 300 MeV, and light nuclei in the range 30 - 300 MeV/n. Nonetheless, Monte Carlo simulations have shown HEPD-01 is sensitive to gamma-ray photons in the energy range 300 keV - 50 MeV, even if with a moderate effective area above $\sim$ 5 MeV. A dedicated time correlation analysis between GRBs reported in literature and signals from a set of HEPD-01 trigger configuration masks has confirmed the anticipated detector sensitivity to high-energy photons. A comparison between the simultaneous time profiles of HEPD-01 electron fluxes and photons from GRB190114C, GRB190305A, GRB190928A, GRB200826B and GRB211211A has shown a remarkable similarity, in spite of the different energy ranges. The high-energy response, with peak sensitivity at about 2 MeV, and moderate effective area of the detector in the actual flight configuration explain why these five GRBs, characterised by a fluence above $\sim$ 3 $\times$ 10$^{-5}$ erg cm$^{-2}$ in the energy interval 300 keV - 50 MeV, have been detected.Comment: Accepted for publication in The Astrophysical Journal (ApJ