Epidemiology of physician interventions in maritime environment by the Marseille Fire Brigade (BMPM) from 2005 to 2017

Background: Marseille is the second largest city in France. The Marseille Fire Brigade (BMPM) is the largest unity of the French Navy. This organization is in charge of rescue operations and medical intervention in the Marseille area. The aim of the study was to describe the epidemiology of interventions that required a physician to be present that were performed by the BMPM between the years of 2005 to 2017.  Materials and methods: The statistical office database of the BMPM and the medical interventions forms (FIM) acquired from the BMPM medical ambulances (SMUR) archives were analysed from the years 2005 to 2017.  Results: The BMPM performed a total of 2,375 interventions in the maritime environment between 2005 and 2017. A physician was necessary for intervention a total of 186 times. The extraction and analysis reports of 107 medical intervention forms found the BMPM archives revealed a significant number of interventions (67%) in the southern bay of Marseille and Frioul, specifically from the If and Planier islands. The majority of interventions (77%) took place within the 300m band. The most common cause of medical intervention was due to an accidental fall into the water, followed by boating (sailing and motor), and swimming. Drowning was the most common cause of mortality, consisting of 34% of all interventions. Diving accidents represented 14% of interventions. Trauma affected 22% of the study population and 83% of trauma patients were transported to the hospital under the supervision of a physician.  Conclusions: Potential areas for improvement in the management of drowning victims are the use of Szpilman’s classification, sonography, and non-invasive ventilation. A recertification course for medical education training of BMPM doctors on the management of diving accidents could help to optimize the information recorded on FIM. Accident prevention training should be continued and reinforced when it comes to maritime activities.

Pathophysiology and treatment of acute intermittent porphyria

La porphyrie aiguë intermittente (PAI) est la plus fréquente des porphyries hépatiques aiguës. Elle est décrite comme une maladie autosomique dominante dont le trait génétique est estimé à 1/1675 en France avec une pénétrance faible et variable allant de 10% à 50% dans les familles connues de PAI. La PAI est due à des mutations réduisant le niveau d’activité de l’hydroxyméthylbilane-synthase (HMBS). Son déficit entraîne l’accumulation de précurseurs neurotoxiques responsables de la symptomatologie clinique. Dans le foie, la synthèse d’hème est contrôlée par l’enzyme ALA-Synthétase 1 (ALAS1) dont l’activité est régulée par un rétrocontrôle négatif par le produit final : l’hème. Le traitement consiste à freiner l’induction d’ALAS1 induit par la carence en hème, par l’administration d’hème exogène. Ce traitement de la crise aiguë est très efficace mais génère rapidement une dépendance physique avec apparition de crises récurrentes nécessitant l’administration chronique d’hème exogène. L’objectif principal de ce projet a été d’étudier les mécanismes physiopathologiques et génétiques liés à cette pathologie afin de traiter et conseiller au mieux les patients. Une partie du projet a consisté à explorer les facteurs génétiques modulateurs de la pénétrance de la maladie. Tout d’abord, une prévalence minimale du trait génétique dans la population générale a été estimée à 1/1299 permettant d’en déduire une pénétrance de l’ordre de 1% alors que celle dans les familles PAI suivies par le CFP est estimée à 22,9 %. Ensuite, concernant les facteurs pouvant expliquer cette différence, la présence d’une mutation type non-sens est plus fréquemment associée aux formes sévères et à une pénétrance plus élevée. De plus, les études de corrélation et d’héritabilité suggèrent plutôt une transmission de type oligogénique associée à des facteurs épigénétiques modulateurs de la pénétrance dont le facteur environnemental. Une autre partie a consisté à explorer les effets de l’administration d’hème exogène sur les patients et un modèle murin de PAI créé génétiquement. Chez l’homme, le traitement est associé à une augmentation des formes chroniques (1,7 % avant vs 7,5 % après l’introduction du celui-ci). Dans le modèle murin de PAI, les injections intrapéritonéales répétées induisent une augmentation paradoxale d’ALAS1 (3 fois), une augmentation de l’hème oxygénase 1 qui catabolise l’hème (HMOX1, 9 fois) ainsi que des voies de l’inflammation (analyse transcriptomique et protéomique hépatique) et une surcharge en fer. De plus, cette administration induit une altération des complexes de la chaine respiratoire mitochondriale responsable d’anomalies du métabolisme énergétique au niveau hépatique, cérébral et musculaire pouvant expliquer la symptomatologie neuroviscérale. En conclusion, ce travail a permis d’explorer les caractéristiques génétiques de la maladie (prévalence, pénétrance) en remettant en cause le mode de transmission autosomique dominant jusqu’ici admis, et d’explorer les mécanismes physiopathologiques associées à l’administration d’hème exogène faisant de cette thérapeutique un pharmakonThe biosynthesis of porphyrins is one of the most conserved pathways known. By associating different metals, porphyrins give rise to the "pigments of life". The formation of haem is accomplished by a sequence of eight dedicated enzymes encoded by different genes, some being active in ubiquitous as well as in erythroid isoforms. In humans, the genes for each of the haem synthetic enzymes may become the target of mutations that give rise to an impaired cellular enzyme activity called porphyrias. The acute porphyrias are characterized by attacks of neuropsychiatric symptoms, which may be due to a toxic surplus of the porphyrin precursor 5-aminolevulinic acid, or a consequence of a deficit of vital hemoproteins. Mutations of the gene encoding the third enzyme: hydroxymethylbilane synthase, are associated with the most frequent type of acute hepatic porphyria, acute intermittent porphyria. AIP is thought to display autosomal dominant inheritance with incomplete penetrance. In the classical form of AIP, HMBS activity is about 50% lower than normal in all tissues. These levels of activity in basal conditions are not sufficiently low to cause symptoms. However, factors increasing hepatic heme demand, resulting in an upregulation of hepatic aminolevulinate synthase (ALAS1, the first enzyme of the heme biosynthesis pathway), precipitate acute attacks. The treatment of the attack of AIP consists to repress ALAS1 and restores metabolic equilibrium. But this treatment leads side effects and dependency. The pathophysiological mechanism of the disease is partially known and difficult to explore because there is not an AIP model or prediction model of porphyrogenicity. We aimed to obtain further insight into the pathophysiological mechanism of AIP and into the genetic (prevalence and penetrance) of AIP, and the contribution of genetic factors to the variable clinical expression of HMBS mutations.We first calculated the penetrance of HMBS mutations in AIP patients seen at the French reference center for porphyria: 22.9%. We then used the Exome Variant Server (EVS) to estimate the prevalence of deleterious HMBS mutations in the general population: 1/1299; and the penetrance of the AIP genetic trait in France: 1%. Finally, we investigated further the genetic factors underlying the penetrance of AIP by analyzing genotype/phenotype correlations, and the pattern of familial correlations for the symptoms of the acute crises of AIP. Intrafamily correlation studies showed correlations to be strong overall and modulated by kinship and the era in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance suggesting that AIP inheritance does not follow the classical autosomal dominant model. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant alleles.On the other hand, we explored the effect of heme administration. In human, the introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. We show that repeated hemin infusions in mice trigger a high level heme oxygenase 1 response, induce a pro-oxidative iron accumulation, a complex pattern of liver inflammation with macrophage infiltration and an alteration of oxidative phosphorylatio

Usage d'internet (étude descriptive et critères d'addiction chez des collégiens des Hauts-de-Seine)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude sur le traitement de fond des patients en décompensation cardiaque hospitalisés dans le service de cardiologie de l'hôpital de Langon

Les patients hospitalisés pour décompensation cardiaque ont un traitement insuffisant comparativement aux recommandations. Un traitement optimal permettrait de réduire le nombre d'hospitalisation et la morbi-mortalité des patients. Cette thèse étudie les raisons qui limitent cette optimisation du traitement. Méthode : Les patients sélectionné ont été hospitalisés à Langon en service Médecine A à orientation cardiologique à partir des registres du DMI, sur l'année civile 2012. Un questionnaire a recueilli les données de traitement à l'entrée et à la sortie, ainsi que les informations sur les comorbidités, les informations sociales et les causes retrouvées dans les dossiers limitant l'adaptation de traitement. Les patients retirés de l'étude sont les patients décédés pendant l'hospitalisation, transférés, ou dont le dossier est incomplet au niveau des traitements d'entrée et de sortie. Résultats : les résultats sur 140 patients ont été analysés et ont permis de comprendre les limitations de la trithérapie recommandée. Les différences de traitements entre l'entrée et la sortie du service sont limitées aux patients ayant fait des hypotension ou des bradycardies, par la baisse des traitements, ou aux patients hospitalisés pour une découverte de la maladie ou qui étaient en échappement thérapeutique, par l'introduction ou l'augmentation des traitements. Par ailleurs, la plupart des comorbidités limitant l'augmentation ou l'introduction de traitement (comme le RAo, l'insuffisance rénale, ou la BPCO) sont respectées et justifiées. Conclusion : Les traitements prescrits en ambulatoire par les généralistes ou les cardiologues sont tout à faits cohérents vis à vis des recommandations dans le sens où elles sont limitées par le terrain du patient. Il est difficile d'améliorer les traitements dans le cadre actuel. La création d'un réseau autour de ces patients permettrait une amélioration limitée, uniquement sur la dose moyenne prescrite à ces patients.BORDEAUX2-Bib. électronique (335229905) / SudocBORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria

International audienc

From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria

International audienceAcute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused by mutations of the hydroxymethylbilane synthase (HMBS) gene. AIP is thought to display autosomal dominant inheritance with incomplete penetrance. We evaluated the prevalence, penetrance and heritability of AIP, in families with the disease from the French reference center for porphyria (CFP) (602 overt patients; 1968 relatives) and the general population, using Exome Variant Server (EVS; 12 990 alleles) data. The pathogenicity of the 42 missense variants identified was assessed in silico, and in vitro, by measuring residual HMBS activity of the recombinant protein. The minimal estimated prevalence of AIP in the general population was 1/1299. Thus, 50 000 subjects would be expected to carry the AIP genetic trait in France. Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population. Intrafamily correlation studies showed correlations to be strong overall and modulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant alleles. In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS. An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability

Adhesive bond testing between composite laminates by laser shockwave loading

"Assembling materials by adhesive bonding has several advantages compared to other joining methods such as the use of fasteners or welding. Fasteners require drilling holes in the parts to be joined and both fastening and welding require significant investment in machinery. For metals, welded joints also generally produce a mechanically weaker heat affected zone. Adhesive bonding also has significant advantages for polymer-matrix composites. Drilling through composites has the drawback of cutting load-bearing fibers with adverse effects of possible delamination and excessive tool wear. It may also be economically advantageous to bond several small parts to make a large structure instead of having it co-cured. However, for all materials, the use of adhesive bonding for loadbearing structures is impeded by the absence of reliable nondestructive methods that can guarantee the strength of the joint, and in particular are able to very reliably identify the presence of near zerostrength \u201ckissing bonds\u201d [1]. Kissing bonds are undetectable by conventional ultrasonic inspection since the return echo from the interface in the pulse-echo technique does not depend upon the bond strength and only requires mechanical contact between the adherends. This is also the case for the transmitted echo. Although there have been many attempts to develop other ultrasonic approaches, such as using waves that propagate essentially along the bond line, none of these approaches has succeeded in detecting a weak bond other than those that are weakened by defects such disbonds or porosity [1-3]. These defects can be detected by the well established ultrasonic inspection technique and in the case of porosity, also by x-ray radiography. Among possible causes of weak bonds are contamination of surfaces prior to bonding, inadequate surface preparation, degradation of the adhesive from improper storage, and inadequate mixing ratio for two-part adhesives. In all these cases, there can be good mechanical contact without defects, combined with poor mechanical strength, undetectable by established ultrasonic inspection techniques. Ultrasonic techniques only apply weak stresses to the bond line and such weak stresses cannot reveal characteristics that are only apparent by applying significant stresses, like in destructive tests. Therefore, a reliable technique to identify such weak bonds requires application of a strong tensile stress across the bond line. A convenient approach that has been previously studied for evaluating the dhesion of coatings to their substrate and fibers to their matrix uses a pulsed laser to generate a large amplitude wave (shockwave) that propagates throughout the material [4-9]. This wave, being initially in compression, is converted by reflection on the back surface of the sample into a strong tensile wave that can pry apart the sample and disbond the assembly. This approach has been more recently extended to proof testing of adhesive bonds between carbon-epoxy laminates [10,11]. To probe bond strength, higher and higher tensile stress loading is applied by increasing the laser pulse energy step by step. A \u201cgood\u201d joint will be unaffected under a given stress level whereas a weaker one will be damaged, allowing this method to evaluate the bond strength. The principle of the method is described next in more detail. We then describe how the ethod is implemented, the instrumentation that has been developed and the fabrication of weak bond test specimens. Finally we present some results and indicate erspectives and future developments.Peer reviewed: YesNRC publication: Ye

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

Background: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. Objective: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. Methods: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs−/− mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. Results: The introduction of hemin into the pharmacopeia has coincided with a 4.4‐fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. Conclusion: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti‐inflammatory therapies should be considered in patients with recurrent AIP