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Central response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.HighlightsCirculating insulin activates brain insulin receptors in microvessels.BBB INSR contribute to cerebral insulin resistance in AD.Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.Loss of isoform INSRα-B is associated with increased BACE1 activity.SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.

Severe climate changes culminating in at least three major glacial events have been recognized in the Neoproterozoic sedimentary record from many parts of the world. Supportive to the global nature of these climatic shifts, a considerable amount of data have been acquired from deposits exposed in PanAfrican orogenic belts in southwestern and western Africa. By comparison, published data from the Pan-African belts in Central Africa are scarce. We report here evidence of possibly two glacial events recorded in the Mintom Formation that is located on the margin of the Pan-African orogenic Yaounde belt in South-East Cameroon. In the absence of reliable radiometric data, only maximum and minimum age limits of 640 and 580 Ma, respectively, can at present be applied to the Mintom Formation. The formation consists of two lithostratigraphic ensembles, each subdivided in two members (i.e., in ascending stratigraphic order the Kol, Metou, Momibole, and Atog Adjap Members). The basal ensemble exhibits a typical glacial to post-glacial succession. It includes diamictites comprising cobbles and boulders in a massive argillaceous siltstone matrix, and laminated siltstones followed by, in sharp contact, a 2 m-thick massive dolostone that yielded negative d 13 C values (

In this paper, we show the possibility of forming amorphous molecular trehalose/mannitol alloys by two independent routes: the usual thermal quenching of the mixed melts, and the co-milling of the stable crystalline forms at room temperature. However, by quenching the melt, molecular alloys can be obtained for the whole range of mannitol concentration, while by co-milling the possibility of forming the alloy ceases when the glass transition temperature of the alloy approaches the milling temperature. The fraction of mannitol not involved in the alloy then undergoes a polymorphic transformation toward a metastable polymorph which coexists with the alloy. The detailed analysis of all these transformations indicates clearly that the glass transition temperature is a key parameter which drives the “amorphization/polymorphic transformation” duality often detected during the milling of molecular materials.

In this paper we compare the solid-state transformations upon room temperature milling of four sugars: lactose, trehalose, mannitol and sorbitol. The two disaccharides (lactose and trehalose) are found to undergo a direct transformation from crystal to glass while the two sugar alcohols (mannitol and sorbitol) are found to undergo polymorphic transformations. The origin of these different behaviors is discussed and ascribed to the relative position of the glass transition temperature (T g) of the amorphous states with respect to the milling temperature. This point was also finely studied through co-milling experiments of lactose and mannitol. These two compounds having their glass transition respectively above and below room temperature the T g of the mixture can be conveniently tuned on either side of the milling temperature by varying the concentrations.

In this paper, we report the possibility to form glassy molecular alloys (α-lactose)1−x(mannitol)x for x

Introduction Cutaneous arterio-venous malformations (AVM) are high-flow vascular malformations made up of a direct link between arteries and veins without intermediary capillary space. ‘Distal limb's AVM’, which mean involving hands or feet, are rare and their functional prognosis is often poor. Little is known about their early clinical symptoms. The objectives of this study were to identify early clinical symptoms of distal limb's cutaneous AVMs and to determine their long-term clinical outcome. Methods A retrospective study was carried out including adult patients who had distal limb's AVM, who were followed up between January 2000 and November 2013 in two regional tertiary care centres. The information was collected from patients' clinical records and completed by a structured telephone questionnaire. Results Nineteen patients were included in the study: four (21%) with foot AVM and 15 (79%) with hand AVM. The first clinical symptoms were as follows: swelling (47%), pain (47%), one or several venous dilatations (37%) and rarely abnormal skin colour, hyperthermia and pulsating sensation. The median diagnosis delay was 9 years after the onset of first manifestations. Amongst the 17 patients who underwent a treatment, 53% had embolotherapy session(s), 12% surgery and 35% had both. After an average follow-up of 57.6 months, 31% of the 13 patients contacted who were receiving treatment were in complete remission; 31% had partial remission; 15% had relapse after initial improvement and 23% had treatment failure. Overall, 74% of patients had a serious development of the AVM: 37% had digital or hand amputation, and 42% remained symptomatic and/or unstable. Conclusion This study suggests that initial manifestations of distal limb's AVMs are discreet and non-specific, leading to a diagnosis delay of about 10 years, with poor prognosis. Doctors should evoke the diagnosis earlier, when these symptoms are shown: pain and/or swelling, sometimes with a large vein.

Introduction Les malformations arterio-veineuses (MAV) cutanees sont des malformations vasculaires a flux rapide composees d’arteres et de veines connectees entre-elles sans lit capillaire intermediaire. Les « MAV distales des membres », c’est-a-dire atteignant les mains ou les pieds sont rares et souvent de mauvais pronostic. Leurs manifestations cliniques precoces sont mal connues. Les objectifs de notre etude etaient d’identifier les manifestations cliniques precoces des MAV cutanees distales des membres et d’evaluer leur pronostic a long terme. Patients et methodes Notre etude retrospective a inclus les patients adultes atteints d’une MAV distale de membre suivis dans deux centres specialises entre janvier 2000 et novembre 2013. Observations Les informations etaient recueillies dans les dossiers des patients et lors d’un questionnaire telephonique standardise. Resultats L’etude a inclus 19 patients : 4 (21 %) avaient une MAV du pied et 15 (79 %) de la main, dont 8 sur 15 (53 %) avec une atteinte digitale. Aux dernieres nouvelles, un tiers des MAV etaient compliquees, avec deux MAV de stade 1 (11 %), onze de stade 2 (58 %), cinq de stade 3 et une de stade 4. Les premieres manifestations cliniques etaient : une tumefaction localisee (47 %), des douleurs (47 %), une/des veine(s) dilatee(s) (37 %), et plus rarement : une coloration anormale, une hyperthermie locale et une sensation de battement. Le delai diagnostique etait de 10,4 ans apres l’apparition des premieres manifestations cliniques. Sur le plan therapeutique, 47 % des patients avaient ete traites par embolisation(s), 10,5 % par chirurgie, et 32 % par embolisation(s) et chirurgie. Des complications severes du traitement etaient observees dans 32 % des cas et une amputation avait ete realisee dans 37 % des cas. Apres un suivi moyen de 57,6 mois, parmi les 13 patients traites que nous avons pu contacter, 31 % etaient en remission complete, 31 % en remission partielle, 15 % en recidive apres amelioration, et 23 % etaient en echec therapeutique. Discussion Notre etude est la premiere a s’interesser aux manifestations inaugurales des MAV distales de membres. Elle suggere que les signes cliniques sont longtemps discrets et aspecifiques, entrainant un retard diagnostique de plus de 10 ans, et que le pronostic de ces MAV est globalement pejoratif. Conclusion Le clinicien doit donc evoquer precocement le diagnostic de MAV distale de membre, devant des douleurs et/ou une tumefaction parfois associee a une veine dilatee pour ne pas retarder la prise en charge.

Les endotoxines sont des molecules (lipopolysaccharides ou LPS) constituant la paroi de certaines bacteries, dites « Gram negatif ». Ces molecules peuvent entrainer des effets sur la sante, dans des milieux professionnels varies tels que l’assainissement ou encore le transport, le stockage et la transformation des produits animaux et vegetaux. Une exposition massive par inhalation a des poussieres organiques contaminees par des endotoxines est associee au syndrome toxique des poussieres organiques (Organic dust toxic syndrom [ODTS]), qui se traduit par une reaction generale (fievre, malaises, douleurs diffuses) et respiratoire (gene thoracique, toux). Ces signes sont attribues a une reaction inflammatoire intense survenant a la fois dans le tissu pulmonaire et dans l’organisme entier. La guerison est rapide et sans sequelles. La repetition des expositions et des phenomenes inflammatoires qu’elles provoquent sont a l’origine de troubles respiratoires plus marques de type bronchite. En cas d’exposition prolongee, ces affections prennent la forme d’une bronchopneumopathie chronique obstructive (BPCO). De plus, la co-exposition a des agents biologiques et chimiques (situation la plus frequemment rencontree en milieu professionnel) est susceptible de renforcer les effets des endotoxines sur la sante. De facon generale, il est difficile de relier des concentrations d’endotoxines a des symptomes definis. Les endotoxines peuvent etre mesurees dans l’atmosphere de travail, selon la procedure decrite dans la fiche MetroPol M-154 de l’INRS. Toutefois, il n’existe a ce jour aucune valeur limite d’exposition professionnelle aux endotoxines. En l’absence de reglementation, il est indispensable de faciliter et d’harmoniser l’interpretation des resultats de mesure des endotoxines. C’est dans cet objectif, que l’INRS, la Cramif et les Carsat ont defini, pour la premiere fois en France, deux valeurs guides de concentration d’endotoxines dans l’air. Ces valeurs de 200 UE/m3 et 1000 UE/m3 ont ete fixees apres analyse des resultats de campagnes de prelevements dans divers milieux de travail. Les valeurs guides definissent trois niveaux d’exposition, permettant de determiner les actions de prevention a engager.

Les anticorps monoclonaux (Acm) constituent une classe de medicaments en plein essor. Or le developpement des applications therapeutiques des Acm multiplie les situations de manipulations professionnelles et pose la question des mesures de prevention a mettre en place. L’objectif du travail presente est de realiser un etat des lieux des pratiques et des mesures de prevention mises en place en milieu de soins lors de la manipulation des Acm, afin d’en degager des enseignements pratiques en termes de prevention. Pour remplir ces objectifs, une recherche documentaire et une enquete de terrain ont ete realisees. L’etude de la litterature met en evidence le peu de donnees publiees sur ce sujet : absence de recommandation consensuelle sur la prevention a mettre en place et meconnaissance de la toxicite professionnelle des Acm. Certaines proprietes toxicologiques sont communes a l’ensemble des Acm comme le potentiel sensibilisant, d’autres sont propres a certains Acm comme la reprotoxicite. Cependant, l’extrapolation de ces donnees aux consequences pour la sante lors d’une exposition professionnelle est difficile. Cette enquete a ete realisee de mars a juin 2015 par questionnaires aupres de travailleurs manipulant des Acm : personnels infirmiers (n = 18), personnels de pharmacie (n = 20) et aupres de medecins du travail ou de prevention d’etablissements de soins (n = 22). Une variete de pratiques est observee entre etablissements, voire au sein d’un meme etablissement, ce qui est a l’origine de scenarios d’exposition divers. De plus, le suivi medical du personnel expose varie selon les medecins interroges. Cette heterogeneite des pratiques en termes de prevention et la divergence des avis obtenus, soulignent une meconnaissance du sujet. Une prevention pertinente passerait par un renforcement de l’information du personnel manipulant des Acm et des professionnels en sante au travail, ainsi que par une evaluation des risques permettant de guider la prevention. Si les donnees sur certains Acm sont insuffisantes pour evaluer leur dangerosite, compte tenu des donnees de toxicite connues pour d’autres, une approche dite de precaution est conseillee afin de limiter au maximum l’exposition. Enfin, l’elaboration de procedures institutionnelles permettrait d’homogeneiser les pratiques. A notre connaissance, il s’agit de la premiere etude de ce genre menee en France. L’essor des Acm ouvre un large eventail d’etudes utiles a mener en sante au travail pour completer ces resultats et impose de rester vigilant sur ce sujet.

In this paper, we present a short review of the different solid state vitrification routes of trehalose recently identified by our group. Three routes are investigated: the mechanical milling of the stable crystalline anhydrous form, the rapid dehydration of the dihydrate form, and the sub Tg annealing of the polymorphic form α. The investigations have been performed by powder x‐ray diffraction and differential scanning calorimetry.

High-speed cinephotography was used to investigate the mechanical characteristics of the free translational motion of molten metal drops as it occurs within the column of a mild steel-argon arc. The drops were found to undergo considerable acceleration across the arc gap before reaching a terminal velocity at the weld pool. The current intensity had a controlling effect on both quantities. The experimental results are analyzed on the basis of the existing drag theory whereby the high-velocity plasma jet exerts an entraining force on the metal drops. Reasonable correlation is obtained between the experimental values and the drag equation as adapted from hydromechanics. Resume Les caracteristiques mecaniques du mouvement libre de translation des gouttes de metal liquide tel qu'il se produit dans un arc avec de l'acier doux sous argon, a ete etudie par cinematographie rapide. Les goutellettes subissent une acceleration considerable dans l'intervalle de l'arc avant d'atteindre une vitesse limite dans...