Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer’s Disease Diagnosis

Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD

Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype

Abstract The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands

Results of a cosmetovigilance survey in The Netherlands

Background. Cosmetic products contribute considerably to the incidence of contact dermatitis. In response to a resolution of the Council of Europe, the National Institute for Public Health and the Environment (RIVM) in The Netherlands set up a pilot project to report undesirable effects attributed to cosmetic products. Objectives. To provide an overview of undesirable effects attributed to cosmetic products and to identify the ingredients involved. The information could contribute to the assessment of whether current EU legislation on cosmetics provides adequate protection. Patients/methods. General practitioners, dermatologists and consumers in The Netherlands completed questionnaires on reported undesirable effects of cosmetics. Dermatologists also carried out patch tests and, where necessary, tests with specific batch ingredients of the associated cosmetic product. A website and a public awareness campaign were launched to encourage consumers to report undesirable effects. Results. Between July 2009 and May 2011, the RIVM received more than 1600 reports. Severe undesirable effects were claimed in 14% of the cases. The most frequently reported cosmetic products were make-up and moisturisers, and the most frequently identified allergens were isothiazolinones and fragrance ingredients. Three patients tested positive for co-polymers/cross-polymers. Conclusions. Further investigations are recommended on the prevalence of isothiazolinone-induced allergic contact dermatitis and the allergenic potential of co-polymers/cross-polymers

Malformations veineuses unifocales sporadiques : prise en charge dans un centre tertiaire

Introduction: Venous malformations (VM) are rare, benign and present at birth; they grow over the life course leading to functional and esthetic impairment. Objective and methods: Retrospective study of a cohort of patients suffering from unifocal and sporadic VM, managed in the muldisciplinary consultation for vascular anomalies at the CHU of CAEN between august 2016 and august 2019. Results: 68 patients were included, 64.7% of whom were women. Pain was present in 70.6% of cases and 34.5% presented a localized consumption coagulopathy. 58.8% of patients were treated with sclerotherapy and 8.8% by surgery. Medical treatment alone was performed in 22% of cases. Recurrences after sclerotherapy were observed in 35% of patients. Conclusion: This study enabled us to confirm the chronicity and the need of a long-term follow-up of these benign malformations. The treatment is discussed according to functional impairment, mainly pain. Localized Intravascular Coagulopathy with elevated D Dimer levels is an important biomarker for the diagnosis and also for the management of these slow flow vascular malformations. Considering the chronicity of these malformations, sclerotherapy is the first-line treatment. The discovery of somatic mutations currently allows to propose a targeted therapy (sirolimus). The place of this treatment in the medical and interventional therapeutic approach has to be defined. We have proposed diagnostic and therapeutic algorithm, but these will evolve according to the European collaborative clinical studies currently in progress.Introduction : les malformations veineuses (MV) sont rares, bénignes et présentes dès la naissance ; elles se développent au cours de la vie entrainant un préjudice fonctionnel et esthétique. Objectif et méthodes : étude rétrospective d’une cohorte de patients atteints d’une MV unifocale et sporadique, pris en charge au sein de la consultation multidisciplinaire des anomalies vasculaires du CHU de Caen entre août 2016 et août 2019. Résultats : 68 patients ont été inclus dont 64,7% de femmes. Une douleur était présente dans 70,6% des cas et 34,5% présentaient une coagulopathie de consommation localisée. 58,8% des patients ont été traités par sclérothérapie et 8,8% par chirurgie. Un traitement médical seul était réalisé dans 22% des cas. Des récidives après sclérothérapie ont été observées chez 35% des patients. Conclusion : cette étude nous a permis de confirmer le caractère chronique et le suivi indispensable de ces malformations bénignes. Le traitement est adapté à la gêne fonctionnelle, essentiellement la douleur. La recherche d’une coagulopathie de consommation est essentielle à la fois pour le diagnostic et la prise en charge. Compte tenu de la chronicité de ces malformations, la sclérothérapie est le traitement de première intention. La découverte de mutations somatiques tissulaires permet actuellement de proposer une thérapie ciblée (sirolimus) dont la place dans l’arsenal thérapeutique médical et interventionnel est à définir. Nous avons proposé des arbres diagnostique et thérapeutique mais ceux-ci évolueront en fonction des études cliniques collaboratives européennes actuellement en cours