Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs

How well do Car-Parrinello simulations reproduce the Born-Oppenheimer surface ? Theory and Examples

We derive an analytic expression for the average difference between the forces on the ions in a Car-Parrinello simulation and the forces obtained at the same ionic positions when the electrons are at their ground state. We show that for common values of the fictitious electron mass, a systematic bias may affect the Car-Parrinello forces in systems where the electron-ion coupling is large. We show that in the limit where the electronic orbitals are rigidly dragged by the ions the difference between the two dynamics amounts to a rescaling of the ionic masses, thereby leaving the thermodynamics intact. We study the examples of crystalline magnesium oxide and crystalline and molten silicon. We find that for crystalline silicon the errors are very small. For crystalline MgO the errors are very large but the dynamics can be quite well corrected within the rigid-ion model. We conclude that it is important to control the effect of the electron mass parameter on the quantities extracted from Car-Parrinello simulations.Comment: Submitted to the Journal of Chemical Physic

MSH2 is essential for the preservation of genome integrity and prevents homeologous recombination in the moss Physcomitrella patens

MSH2 is a central component of the mismatch repair pathway that targets mismatches arising during DNA replication, homologous recombination (HR) and in response to genotoxic stresses. Here, we describe the function of MSH2 in the moss Physcomitrella patens, as deciphered by the analysis of loss of function mutants. Ppmsh2 mutants display pleiotropic growth and developmental defects, which reflect genomic instability. Based on loss of function of the APT gene, we estimated this mutator phenotype to be at least 130 times higher in the mutants than in wild type. We also found that MSH2 is involved in some but not all the moss responses to genotoxic stresses we tested. Indeed, the Ppmsh2 mutants were more tolerant to cisplatin and show higher sensitivity to UV-B radiations. PpMSH2 gene involvement in HR was studied by assessing gene targeting (GT) efficiency with homologous and homeologous sequences. GT efficiency with homologous sequences was slightly decreased in the Ppmsh2 mutant compared with wild type. Strikingly GT efficiency with homeologous sequences decreased proportionally to sequence divergence in the wild type whereas it remained unaffected in the mutants. Those results demonstrate the role of PpMSH2 in the maintenance of genome integrity and in homologous and homeologous recombinatio

Drug development for neglected diseases: a deficient market and a public-health policy failure.

There is a lack of effective, safe, and affordable pharmaceuticals to control infectious diseases that cause high mortality and morbidity among poor people in the developing world. We analysed outcomes of pharmaceutical research and development over the past 25 years, and reviewed current public and private initiatives aimed at correcting the imbalance in research and development that leaves diseases that occur predominantly in the developing world largely unaddressed. We compiled data by searches of Medline and databases of the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, and reviewed current public and private initiatives through an analysis of recently published studies. We found that, of 1393 new chemical entities marketed between 1975 and 1999, only 16 were for tropical diseases and tuberculosis. There is a 13-fold greater chance of a drug being brought to market for central-nervous-system disorders or cancer than for a neglected disease. The pharmaceutical industry argues that research and development is too costly and risky to invest in low-return neglected diseases, and public and private initiatives have tried to overcome this market limitation through incentive packages and public-private partnerships. The lack of drug research and development for "non-profitable" infectious diseases will require new strategies. No sustainable solution will result for diseases that predominantly affect poor people in the South without the establishment of an international pharmaceutical policy for all neglected diseases. Private-sector research obligations should be explored, and a public-sector not-for-profit research and development capacity promoted

OPC model error study through mask and SEM measurement error

International audienceMask and metrology errors such as SEM (Scanning Electron Microscopy) measurement errors are currently not accounted for when calibrating OPC models. Nevertheless, they can lead to erroneous model parameters therefore causing inaccuracies in the model prediction if these errors are of the same order of magnitude than targeted modeling accuracy. In this study, we used a dedicated design of hundreds of features exposed through a Focus Exposure Matrix (FEM). We measured the mask bias from target for these structures and investigated its impact on the model accuracy. For the metrology error, we compared the SEM measurements to AFM measurements for as much as 105 features exposed in various process conditions of dose and defocus. These data have then been used in a OPC model calibration procedure. We show that the impact of the metrology error is not negligible and demonstrate the importance of taking into account these errors in order to improve the reliability of the OPC models

Évaluation de l'impact du paludisme et mise en application de la politique nationale de lutte contre le paludisme à Antananarivo, Madagascar (enquêtes réalisées sur le terrain d'après les données de 2012)

Depuis 2000, les engagements politiques accrus et l'augmentation considérable des investissements mondiaux en faveur de la lutte antipaludique ont conduit à des avancées majeures. A Madagascar, la lutte contre le paludisme a commencé à s'organiser efficacement à partir de 1998 avec le lancement du Programme National de Lutte contre le Paludisme (PNLP}, avec pour objectif l'élimination du paludisme pour 2017. Dans le cadre du PNLP, des actions ont été mises en oeuvre, associant la distribution de moustiquaires imprégnées d'insecticides, les campagnes d'aspersion d'insecticides intradomiciliaire et l'utilisation des combinaisons thérapeutiques à base d'artémisinine associé à la confirmation du diagnostic avec les tests de diagnostic rapide. Dans ce travail, deux enquêtes ont été menées sur le terrain pour évaluer l'impact du PNLP. Dans un premier temps, une étude de la prise en charge des patients dans les différentes structures sanitaires de Antananarivo a été faite puis une seconde enquête a été réalisée avec pour but d'estimer le niveau de connaissances et les attitudes pratiques des patients vis-à-vis du paludisme.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Origin of micropores In late jurassic (Oxfordian) micrites of the eastern Paris basin, France

Porous micritic facies, either primary chalks or resulting from secondary destructive micritization, can constitute important hydrocarbon or water reservoirs. Characterization of reservoir properties and the understanding of factors which controlled the distribution of porosity are of primary interest to evaluate the prospective reserves. Middle and late Oxfordian limestones of the eastern Paris Basin show several horizons with porosities higher than 20%. The porosity is mainly microporous and located either within secondary micritized grains or in the micritic matrix. Using SEM, cathodoluminescence, as well as confocal microscopy, stable oxygen and carbon isotope ratios, and petrophysical measurements, a scenario for the evolution of the micropores is proposed. Lime mudstones to packstones constitute the majority of the high-porosity facies (HPFs). Inner lagoonal deposits are more micritized and thus more porous than grainstones, and facies rich in leiolitic oncoids and echinoid clasts are less impacted by micritization. Micritization was responsible for an increase of the intragranular porosity in most grain types. During both eogenesis and shallow burial, mineralogical stabilization dissolved aragonitic particles and allowed precipitation of calcite rhombs. This process was probably enhanced below surfaces of subaerial exposure. During burial, Ostwald ripening allowed the growth of larger micrite crystals at the expense of smaller ones during early Berriasian and late Aptian recharges of deep aquifers when the northern margin of the basin was exposed. Overgrowths on micrite crystals were more important in intervals strongly affected by chemical compaction, which favored oversaturation of waters with respect to calcite. In low-porosity horizons (LPFs), the dense micritic texture of oncoids and the monocrystalline architecture of echinoid clasts prevented an intense micritization, while the strong chemical compaction enhanced poronecrosis. Telogenetic fracturing created new fluid pathways that favored inputs of meteoric fluid in porous micrite and allowed the continuation of Ostwald ripening during Cenozoic times. As a whole, mesogenetic inputs of waters undersaturated with respect to calcite in deep aquifers during exposure of basin margins are a more efficient process than early subaerial exposure for enhancing aggrading neomorphism and appearance of microporous micrites. Initial mineralogical heterogeneities also impact the intensity of chemical compaction and thus the stratigraphical distribution of microporous limestones