Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease

International audienceAbstractBackgroundIncreasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer’s disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice.ResultsTranscriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals.ConclusionsThis study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way

Optimal decay for solutions of the Teukolsky equation on the Kerr metric for the full subextremal range |a| < M

We derive the large time asymptotics of initially regular and localized solutions of the Teukolsky equation on the exterior of a subextremal Kerr black hole for any half integer spin. More precisely, we obtain the leading order term (predicted by Price's law) in the large time regime assuming that the initial data have compact support and have enough (but finite) Sobolev regularity. For initial data with less spatial decay (typically decaying like r^{--1--$\alpha$} with $\alpha$ $\in$ (0, 1)), we prove that the solution has a pointwise decay of order t^{--1--$\alpha$--s--|s|+} on spatially compact regions. In the proof, we adopt the spectral point of view and make use of recent advances in microlocal analysis and non elliptic Fredholm theory which provide a robust framework to study linear operators on black hole type spacetimes

Age-related differences on event-related potentials and brain rhythm oscillations during working memory activation

Previous functional imaging studies have pointed to the compensatory recruitment of cortical circuits in old age in order to counterbalance the loss of neural efficiency and preserve cognitive performance. Recent electroencephalographic (EEG) analyses reported age-related deficits in the amplitude of an early positive-negative working memory (PNwm) component as well as changes in working memory (WM)-load related brain oscillations during the successful performance of the n-back task. To explore the age-related differences of EEG activation in the face of increasing WM demands, we assessed the PNwm component area, parietal alpha event-related synchronization (ERS) as well as frontal theta ERS in 32 young and 32 elderly healthy individuals who successfully performed a highly WM demanding 3-back task. PNwm area increased with higher memory loads (3- and 2-back>0-back tasks) in younger subjects. Older subjects reached the maximal values for this EEG parameter during the less WM demanding 0-back task. They showed a rapid development of an alpha ERS that reached its maximal amplitude at around 800ms after stimulus onset. In younger subjects, the late alpha ERS occurred between 1,200 and 2,000ms and its amplitude was significantly higher compared with elders. Frontal theta ERS culmination peak decreased in a task-independent manner in older compared with younger cases. Only in younger individuals, there was a significant decrease in the phasic frontal theta ERS amplitude in the 2- and 3-back tasks compared with the detection and 0-back tasks. These observations suggest that older adults display a rapid mobilization of their neural generators within the parietal cortex to manage very low demanding WM tasks. Moreover, they are less able to activate frontal theta generators during attentional tasks compared with younger person

Nouvelles approches thérapeutiques anti-inflammatoires et antiparasitaires dans les trypanosomoses

La trypanosomose humaine africaine (THA) et les trypanosomoses animales sont causees par l'inoculation vectorielle de trypanosomes. Différentes espèces de glossines sont vectrices des deux trypanosomes pathogènes pour l'Homme, Trypanosoma brucei gambiense en Afrique de l'Ouest et du Centre, et Trypanosoma brucei rhodesiense en Afrique de l'Est. Au point de piqure, se développe un chancre d'inoculation, puis le parasite envahit le sang et le tissu lymphatique (stade I), enfin, le franchissement de la barrière hémato-méningée définit la phase neurologique de l'affection (stade II). En raison du caractère fatal de l'évolution, le traitement est indispensable, bien que non dénué de toxicité. La suramine et la pentamidine, médicaments du stade I sont plus ou moins bien tolérés, et responsables de réactions médicamenteuses diverses. Le traitement de la phase II fait appel a un dérivé de l'arsenic, l'Arsobal®, qui est responsable, dans 5 a 10% des cas, d'encéphalopathies arsenicales mortelles. De plus, dans les trypanosomoses, de profondes modifications du système immunitaire sont observées. Une hypergammaglobulinemie, de nombreux auto-anticorps, et un syndrome inflammatoire intense sont observes tout au long de la maladie. Ce syndrome inflammatoire, lie a une production exagérée et persistante de cytokines pro-inflammatoires comme le TNF-[alpha], est également responsable d'une partie de la symptomatologie. En effet, il existe une corrélation entre la sévérité de la maladie et le taux de TNF-[alpha] circulant. Par ailleurs, dans les trypanosomoses animales, le role des radicaux libres a également été mis en évidence. C'est dire l'importance de la découverte de nouvelles approches thérapeutiques et cibles moléculaires dans les trypanosomoses. Les polyphenols végétaux possèdent de nombreuses propriétés, en particulier anti-infectieuses et anti-inflammatoires. Parmi les molécules testées, le quercetol s'est révélé très intéressant car il agit sur les deux versants de la pathologie, d'une part en possédant une activité trypanocide et, d'autre part, en inhibant la réponse inflammatoire induite par le parasite. Des études in vitro (cocultures parasites-cellules humaines) ont montre que l'activité trypanocide du quercetol s'exerce a des doses non toxiques pour les cellules humaines. Celle-ci est perçue pour des doses 300 fois plus élevées. L'étude de l'effet trypanocide du quercetol a révélé un nouveau mécanisme de destruction du parasite, l'apoptose, pouvant être visualisée par cryométrie de flux. Le quercetol et des molécules de structure voisine représentent donc une nouvelle approche thérapeutique très intéressante car peu toxique, peu onéreuse, et disponible dans les pays où sévissent les trypanosomoses. Différents polyphenols sont en cours d'étude, pour trouver une molécule active, susceptible de franchir la barrière hémato-méningée, et utilisable en phase neurologique de la THA. (Texte intégral

A public private partnership to fight against malaria along the Chad-Cameroon pipeline corridor: I. Baseline data on socio-anthropological aspects, knowledge, attitudes and practices of the population concerning malaria

BACKGROUND: Malaria is ranked as the major public health problem in Cameroon, representing 50% of illness in less than five year old children, 40-45% of medical consultation and 40% of the annual home income spent on health. The Cameroon Oil Transportation Company (COTCO) that exploits the Chad-Cameroon pipeline in Cameroon territory, initiated in 2010, a public private partnership project to control malaria along the pipeline corridor. A research component was included in the project so as to guide and evaluate the control measures applied in this pipeline corridor. This study presents the baseline socio-anthropological data as well as the knowledge, attitudes and practices of the local population concerning malaria, its transmission, management and prevention. METHODS: A descriptive cross-sectional survey was undertaken in four sentinel sites (one site per ecological zone) along the Chad-Cameroon pipeline corridor. Three structured questionnaires were used for the survey. Two of them were addressed to the heads of households (one for census and the other to collect information concerning the characteristics of houses and living conditions in households as well as their knowledge, attitudes and practices concerning malaria). The last questionnaire was used to collect information on malaria management and prevention. It was addressed to women who had delivered a living child within the past three years. Interviewers were recruited from each village and trained for two consecutive days on how to fill the different questionnaires. All data were analysed at 5% significant level using Epi-Info, SPSS and Cs PRO 4.0 STATA. Values of p ≤ 0.05 were considered statistically significant. RESULTS: Interviews were conducted in 2597 households (Bipindi 399, Bélabo 835, in Meidougou 820 and Dompta 543). Whatever the study site, 50% of the heads of household were workers of the agro-pastoral sector. Most of the heads of household were men (average 77.4% for men and 22.6% for females). The walls of households were mostly made-up of earth blocks and access to media was low. There were significant differences between mean ages and educational level of the heads of household. Significant differences were also observed between the characteristics of houses and the sites located in the southern regions (Bipindi and Bélabo) and those located in the northern regions (Meidougou and Dompta). The later household heads were younger and less educated than those in the other regions. In most of the study sites, paracetamol was cited as the first intention drug for malaria treatment, followed by chloroquine, a banned drug. More than half of the households studied had a correct knowledge of malaria and its mode of transmission: 120/155 (77.1%) in Bipindi, 244/323 (74.5%) in Bélabo, 171/235 (72.8%) in Meidougou and 118/218 (54.1%) in Dompta. Fever and headache were the malaria signs/symptoms most often cited by the households. An important percentage of pregnant women did not take any malaria prophylaxis during their last pregnancy (up to 43.4% in Bélabo). CONCLUSION: In all the study sites, there were conditions that indicated the all year round transmission of malaria (characteristics of houses and limited access to media making sensitization campaigns difficult). In general, most households had a good knowledge of malaria and its mode of transmission. However, malaria treatment drugs were most often inappropriate. In this study, recommendations were made in order to guide the implementation of control measures

Impact of Periodic Current Pulses on Li-Ion Battery Performance

International audiencePulse charging and pulse discharging have been reported by many authors in the literature to improve the performance of various secondary electrochemical cells. Only a few authors mentioned the effects of such charge and discharge method on lithium-ion batteries. The overall objective of this work is to experimentally investigate the impact of certain current pulse profiles on the electrical performance of Li-ion batteries. The results highlight a detrimental impact of periodic pulses on the cell performance compared to profiles with constant current

Availability of Antimalarial Drugs and Evaluation of the Attitude and Practices for the Treatment of Uncomplicated Malaria in Bangui, Central African Republic

National malaria management policy is based upon the availability of effective and affordable antimalarial drugs. This study was undertaken to evaluate the quality of the treatment of uncomplicated malaria cases in Bangui, an area with multidrug-resistant parasites, at a time preceding implementation of a new therapeutic policy relying on the artemisinin derivative combined treatment artemether-lumefantrine. A cross-sectional study was carried out in Bangui city to assess availability of antimalarial drugs and the performances of health workers in the management of uncomplicated malaria. Availability of drugs was recorded in all drugs wholesalers (n = 3), all pharmacies in health facilities (n = 14), private drugstores (n = 15), and in 60 non-official drug shops randomly chosen in the city. Despite a limited efficacy at the time of the survey, chloroquine remained widely available in the official and nonofficial markets. Artemisinin derivatives used in monotherapy or in combination were commonly sold. In health care facilities, 93% of the uncomplicated malaria cases were treated in the absence of any laboratory confirmation and the officially recommended treatment, amodiaquine-sulfadoxine/pyrimethamine, was seldom prescribed. Thus, the national guidelines for the treatment of uncomplicated malaria are not followed by health professionals in Bangui. Its use should be implemented while a control of importation of drug has to be reinforced

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in urban health facilities in Yaoundé, central province, Cameroon

<p>Abstract</p> <p>Background</p> <p>After adoption of artesunate-amodiaquine (AS/AQ) as first-line therapy for the treatment of uncomplicated malaria by the malaria control programme, this study was designed to assess the availability of anti-malarial drugs, treatment practices and acceptability of the new protocol by health professionals, in the urban health facilities and drugstores of Yaoundé city, Cameroon.</p> <p>Methods</p> <p>Between April and August 2005, retrospective and current information was collected by consulting registers and interviewing health practitioners in urban health facilities using a structured questionnaire.</p> <p>Results</p> <p>In 2005, twenty-seven trade-named drugs have been identified in drugstores; quinine tablets (300 mg) were the most affordable anti-malarial drugs. Chloroquine was restricted to food market places and no generic artemisinin derivative was available in public health centres. In public health facilities, 13.6% of health professionals were informed about the new guidelines; 73.5% supported the use of AS-AQ as first-line therapy. However, 38.6% apprehended its use due to adverse events attributed to amodiaquine. Malaria treatment was mainly based on the diagnosis of fever. Quinine (300 mg tablets) was the most commonly prescribed first-line anti-malarial drug in adults (44.5%) and pregnant women (52.5%). Artequin^®was the most cited artemsinin-based combination therapy (ACT) (9.9%). Medical sales representatives were the main sources of information on anti-malarials.</p> <p>Conclusion</p> <p>The use of AS/AQ was not implemented in 2005 in Yaoundé, despite the wide range of anti-malarials and trade-named artemisinin derivatives available. Nevertheless, medical practitioners will support the use of this combination, when it is available in a paediatric formulation, at an affordable price. Training, information and participation of health professionals in decision-making is one of the key elements to improve adherence to new protocol guidelines. This baseline information will be useful to monitor progress in ACT implementation in Cameroon.</p

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

<p>Abstract</p> <p>Background</p> <p>One year after the adoption of artesunate-amodiaquine (AS/AQ) as first-line therapy for the treatment of uncomplicated malaria, this study was designed to assess the treatment practices regarding anti-malarial drugs at health facilities in four rural areas in southern Cameroon.</p> <p>Methods</p> <p>Between April and August 2005, information was collected by interviewing fifty-two health professionals from twelve rural health facilities, using a structured questionnaire.</p> <p>Results</p> <p>In 2005, only three anti-malarial drugs were used in rural health facilities, including: amodiaquine, quinine and sulphadoxine-pyrimethamine. Only 2.0% of the health professionals prescribed the recommended AS/AQ combination. After reading the treatment guidelines, 75.0% were in favour of the treatment protocol with the following limitations: lack of paediatric formulations, high cost and large number of tablets per day. Up to 21.0% of professionals did not prescribe AS/AQ because of the level of adverse events attributed to the use of amodiaquine as monotherapy.</p> <p>Conclusion</p> <p>The present study indicates that AS/AQ was not available in the public health facilities at the time of the study, and health practitioners were not informed about the new treatment guidelines. Results of qualitative analysis suggest that prescribers should be involved as soon as possible in projects related to the optimization of treatment guidelines and comply with new drugs. Adapted formulations should be made available at the international level and implemented locally before new drugs and treatments are proposed through a national control programme. This baseline information will be useful to monitor progresses in the implementation of artemisinin-based combination therapy in Cameroon.</p

From the Adour valley to the Gelise valley (western part of the Gers department): an important occurrence of siliceous raw material of Senonian origin.

This study refers the western part of the “Gers department” which covers the Adour valley, its tributaries (Izaute, Midour and Douze) and the Gélise valley. A geological study was carried out from 2010 to 2012. It allowed us to collect 290 alluvial siliceous pebbles from the Plio-Pleistocene sediments. At the same time, 132 flint artefacts from prehistoric sources in the Gers (Upper Palaeolithic) were collected. Petrographic, sedimentological and palaeontological studies were carried out. They allowed us to distinguish 19 lithological types:- 1 related to the Cenozoic formation;- 2 associated with Flysch deposits from the Pyrenean orogenic belt;- 10 attributed to the Senonian age (from the Coniacian to the Campanian);- 6 imputed to the Upper Maastrichtian with Lepidorbitoides.Then these types were brought together into six groups that show their stratigraphic positions and their palaeogeographic environments at different time periods.- 0.2 % of the alluvial pebbles were related to the Pyrenean Flysch;- 45 % were of Upper Maastrichtian age (Lepidorbitoides);- 54 % were of Senonian age (Coniacian to Middle Maastrichtian).The artefacts collected in the same region show a very similar proportion of siliceous pebbles (49 % of Maastrichtian with Lepidorbitoides).The result of this study is that, up to now, the western part of the Lannemezan Plateau includes alluvial areas of Plio-Pleistocene age, containing a large amount of flint pebbles of Upper Cretaceous age (Senonian and Maastrichtian). The gathering of this siliceous raw material by Palaeolithic communities is obvious. The identification of a new lithic raw material located in the southern Aquitaine Basin will have to be taken into account, while former interpretations probably have to be amended