Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional impact of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing LRRK2 (leucine-rich repeat kinase 2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months

Corneal Transduction by Intra-Stromal Injection of AAV Vectors In Vivo in the Mouse and Ex Vivo in Human Explants

The cornea is a transparent, avascular tissue that acts as the major refractive surface of the eye. Corneal transparency, assured by the inner stroma, is vital for this role. Disruption in stromal transparency can occur in some inherited or acquired diseases. As a consequence, light entering the eye is blocked or distorted, leading to decreased visual acuity. Possible treatment for restoring transparency could be via viral-based gene therapy. The stroma is particularly amenable to this strategy due to its immunoprivileged nature and low turnover rate. We assayed the potential of AAV vectors to transduce keratocytes following intra-stromal injection in vivo in the mouse cornea and ex vivo in human explants. In murine and human corneas, we transduced the entire stroma using a single injection, preferentially targeted keratocytes and achieved long-term gene transfer (up to 17 months in vivo in mice). Of the serotypes tested, AAV2/8 was the most promising for gene transfer in both mouse and man. Furthermore, transgene expression could be transiently increased following aggression to the cornea

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Etude de faisabilité du transfert de gène par un vecteur dérivé de l'adénovirus canin de type 2 dépendant d'un vecteur helper (HD CAV-2) dans l'encéphale du modèle canin de la mucopolysaccharidose de type VII et primate (microcèbe)

Les propriétés des vecteurs CAV-2 démontrées précédemment chez le rongeur, font de ces vecteurs un outil de choix pour le traitement des maladies du cerveau. En effet, les vecteurs CAV-2 transduisent préférentiellement les neurones sur le long-terme et sont transportés efficacement le long des axones in vivo. Comment se comportent ces vecteurs dans un cerveau plus gros voire plus évolué? La réponse à cette question fait l'objet de ce travail de thèse. Pour cela, nous avons testé les vecteurs CAV-2 dans le cerveau du chien chien et du primate. La mucopolysaccharidose de type VII (MPS VII) est une maladie de surcharge lysosomale due au dysfonctionnement de l'enzyme bêta-D-glucuronidase (GUSB). 5 chiens (sains et MPS VII) ont été utilisés dans cette étude. L'injection intra-cérébrale de CAV-2 a permis une expression sur 6 semaines dans différentes structures (cortex, striatum, thalamus et substance noire). Une inflammation transitoire a été notée au niveau des sites d'injection. De plus, nous avons produit et purifié un vecteur CAV-2 qui exprime GUSB. L'efficacité thérapeutique de ce vecteur sera testée prochainement chez les chiens MPS VII. L'organisation du cerveau du microcèbe (Microcebus murinus) est comparable à l'homme. Les propriétés des vecteurs CAV-2 ont été testées chez ce primate. L'injection intra-cérébrale de CAV-2 a permis une expression sur le long-terme (6 mois) dans différentes structures (cortex, striatum, thalamus et substance noire). Aucun des 8 animaux n'a développé de réponse inflammatoire et immunitaire dirigée contre le vecteur. Ces tests confirment le fort potentiel thérapeutique des vecteurs CAV-2 dans le traitement des maladies du cerveauCAV-2 vector properties, previously established in rodents, make them suitable candidates for brain disease treatment. CAV-2 vectors preferentially transduce neurons and were able of efficiently traffic via retrograde transport along axons in vivo. But, how do these vectors behave in a larger or a more evolved brain? This is the aim of this thesis. Do do that, we tested CAV-2 vectors in the brain of dogs and primates. Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disorder due to beta-D-glucuronidase deficiency. Five dogs, healthy and MPS VII, have been used in this study. CAV-2 vector stereotaxical injections permitted transgene expression during 6 weeks in different brain structures (cortex, striatum, thalamus, substantia nigra). Transient inflammation was noted near the injection sites. In parallel, we producted and purified a CAV-2 vector that express GUSB. Vector efficiency will be tested soon in the MPS VII dog model. Microcebe (Microcebus murinus) brain organisation is similar to human. CAV-2 vectors properties were tested in this primate. CAV-2 vector injections permitted long-term transgene expression (6 months) in different brain structures (cortex, striatum, thalamus and substantia nigra). No inflammatory and immune response was detected against the vector on the 8 animals used for this study. In this study, we showed that CAV-2 vectors are able of long-term transgene expression in the brain of dogs and primates. These encouraging preclinical tests demonstrated the potential of CAV-2 vectors for brain diseases treatmentMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Description of a Giant Hypothalamic Hamartoma Associated with an Immature Ruptured Giant Sacrococcygeal Teratoma: A Case Report

International audienc

Etude cinétique de la réaction du complexe 1,4,8,11- tétraazacyclotetradecane-1,4,8,11-tétra(méthylène phosphonato) ferrate (III) avec l'ion cyanure

La cinétique de la réaction d'échange par l'ion cyanure du ligand 1,4,8,11- tétraazacyclotétradécane-1,4,8,11-tétra (méthylènephosphonique acide) (TTMP) complexé à l'ion ferrique Fe (III) a été étudiée dans le domaine de pH 8,6-11,4 par spectrophotométrie classique et écoulement bloqué. Le pH modifie de manière importante le mécanisme réactionnel.A pH 9,5, la réaction comporte trois phases successives ; la première est la formation de Fe(CN)5OH3-, la seconde est sa conversion en présence de l'excès de CN- en Fe(CN)63- et la troisième correspond à la réduction de Fe(CN)63- en Fe(CN)64- par réaction avec le ligand libre formé au cours de la première phase. L'étude cinétique de la formation de Fe(CN)5OH3- montre une relation hyperbolique de la constante de vitesse en fonction de la concentration en CN-. Un mécanisme à trois étapes est proposé, impliquant la formation d'un complexe mixte intermédiaire où le Fer(III) a une coordinence de sept

Determining prognosis in acute exacerbation of COPD.

Acute exacerbations are the leading causes of hospitalization and mortality in patients with COPD. Prognostic tools for patients with chronic COPD exist, but there are scarce data regarding acute exacerbations. We aimed to identify the prognostic factors of death and readmission after exacerbation of COPD

Prognosis of patients eligible for dapagliflozin in acute heart failure

Background: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, was shown in the DAPA-HF study to reduce the risk of worsening heart failure or death in symptomatic patients with left ejection fraction Materials and methods: Analysis of 815 patients recruited in a prospective cohort of acute heart failure at the University Hospitals of Geneva, consisting of consecutive patients admitted with ADHF. Eligibility for dapagliflozin was determined using criteria described DAPA-HF.Results: Of 815 patients, 220 (27%) were eligible for dapagliflozin treatment. In survival analysis, patients who were eligible for dapagliflozin had better clinical outcomes with respect to all-cause mortality and rehospitalization as compared to those who were not eligible. In multivariate analysis, the hazard ratio for all-cause mortality or readmission in patients eligible for dapagliflozin was 0.82 (95% CI 0.68-0.999, P = .049) as compared to the non-eligible.Conclusions: Using DAPA-HF criteria, only 27% of non-selected patients admitted for ADHF are theoretically eligible for dapagliflozin. This eligibility for dapagliflozin is associated with better outcomes. Further evaluation of the benefits of dapagliflozin in selected HF patients may be of interest. This may have implications for selection criteria in future randomized effectiveness studies.</p

Eligibility for sacubitril-valsartan in patients with acute decompensated heart failure

Aims: Large-scale clinical trials have demonstrated clinical benefits of sacubitril-valsartan in symptomatic heart failure with reduced ejection fraction patients (PARADIGM-HF), with potential benefits in patients hospitalized for acute decompensated heart failure (ADHF) (PIONEER-HF) and fewer benefits in patients with heart failure with preserved ejection fraction (PARAGON-HF). The aim of this study was to evaluate eligibility for sacubitril-valsartan using criteria described in PIONNER-HF in non-selected patients hospitalized for ADHF. Methods and results: Between November 2014 and May 2019, 799 patients were recruited in a prospective registry of acute heart failure at the University Hospitals of Geneva (ClinicalTrials.gov: NCT02444416). The cohort consists of consecutive patients admitted to the Department of Medicine with ADHF. Eligibility for sacubitril-valsartan was determined using criteria described in PIONEER-HF, including left ventricular ejection fraction, clinical parameters, and co-morbidities. Of 799 patients, 123 (15.39%) were eligible for sacubitril-valsartan treatment. Clinical outcomes including all-cause mortality and readmission were similar in eligible and non-eligible groups, hazard ratio 1.02 (95% confidence interval 0.81-1.29, P = 083). Conclusions: Using current criteria from randomized controlled trials, only 15% of non-selected patients admitted for ADHF are theoretically eligible for sacubitril-valsartan. Eligibility for sacubitril-valsartan using published criteria is not associated with worse outcome, suggesting that further evaluation of benefits of sacubitril-valsartan in heart failure patients based on parameters other than left ventricular ejection fraction may be of interest.</p

Complexation of the triphosphate anion: tuning the structure of cyclen based macrotricycles with 1,3-dimethylbenzene and 2,6-dimethylpyridine linkers. A potentiometric and NMR study

International audienceThe host–guest interaction between orthophosphate, pyrophosphate and triphosphate anions and three cyclen-based macrotricyclic ligands was investigated by potentiometric measurements and NMR spectroscopy. The ligands differ from one another by the nature of their spacers, which are 1,3-dimethylbenzene (TMC), 2,6-dimethylpyridine (TPyC) or a combination of the two (TMPyC). In aqueous solution, each ligand gave protonated species that further formed ternary complexes after binding with anions; these complexes were analyzed as a result of hydrogen bond formation and coulombic attraction between the organic host and the inorganic guest. The equilibrium constants found for all the detected species are reported and the selectivity, illustrated with species distribution diagrams, is discussed. The results unambiguously showed that the ligand possessing a single supplementary anchoring site (the pyridinyl spacer) exhibited the greatest affinity for the phosphate species in a large p[H] range