Uusien lääkkeiden markkinoille tulo ja lääkekustannuksiin vaikuttaminen

Lääkekustannukset kasvoivat 2000-luvulla useimmissa teollistuneissa maissa terveydenhuollon kokonaismenoja nopeammin. Lääkkeiden rahoituksesta vastaavat ovatkin etsineet keinoja kustannusten kasvun hillitsemiseksi. Uudet, vanhoja lääkkeitä kalliimmat lääkkeet ovat yksi syy kustannusten kasvuun. Tämän tutkimuksen tarkoitus oli selvittää uusien, avohoidossa käytettävien lääkkeiden käyttöönottoa, hintoja ja kustannuksia sekä analysoida lääkkeen erityiskorvattavuutta edeltävän peruskorvattavuusjakson ja korvauksen rajoittamisen vaikutuksia lääkkeiden kulutukseen ja hoitojen kohdentumiseen. Tutkimusten aineistoina käytettiin muun muassa Lääkelaitoksen ja Kelan tietokantoja ja lääkkeiden tukkumyyntitietoja. Lääkkeiden hintatiedot Euroopan maista kerättiin kyselyllä. Suomen markkinoille tuli vuosina 1996–2005 lähes 300 uutta lääkeainetta. Vuonna 2005 niiden osuus avohoidon lääkemyynnin arvosta oli 38 % ja kulutuksesta 19 %. Avohoidossa uutuuksia tuli erityisesti syöpien, infektioiden ja sydän- ja verisuonisairauksien hoitoon. Osa uutuuksista tarjosi merkittäviä uusia hoitomahdollisuuksia, osan lisähyöty oli vähäinen. Tiukan hintasääntelyn maissa uusien lääkkeiden tukkuhinnat olivat alhaisemmat kuin niissä maissa, joissa ei ollut suoraa sääntelyä. Maan asema tukkuhintojen vertailussa ei kuitenkaan määrittänyt sen asemaa vähittäismyyntihintaisessa vertailussa, sillä apteekkien kate ja verot vaihtelevat maittain. Suomessa uusien lääkkeiden tukkuhinnat olivat eurooppalaista keskitasoa, mutta verolliset vähittäismyyntihinnat keskitasoa korkeammat. Glaukooma-lääkkeillä erityiskorvattavuutta edeltävä peruskorvattavuusjakso hidasti uusien valmisteiden käyttöönottoa. Lääkkeiden tultua erityiskorvattaviksi niiden käyttäjämäärä ja kulutus kasvoivat. Kalleimpien statiinien korvauksen rajoittaminen niille potilaille, joille edullisemmat eivät sovi, lisäsi edullisten statiinien käyttöä. Rajoituksen jälkeen kalleimmat statiinit kanavoituivat sairaammille ja aiemmin muita statiineja käyttäneille. Toimenpiteiden pitkäaikaisvaikutuksista ja terveysvaikutuksista ei ole tietoa.

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve `health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.

Analysis of the Genome and Transcriptome of Cryptococcus neoformans var. grubii Reveals Complex RNA Expression and Microevolution Leading to Virulence Attenuation

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence.

Specificity of the ModA11, ModA12 and ModD1 epigenetic regulator N-6-adenine DNA methyltransferases of Neisseria meningitidis

Phase variation (random ON/OFF switching) of gene expression is a common feature of host-adapted pathogenic bacteria. Phase variably expressed N-6-adenine DNA methyltransferases (Mod) alter global methylation patterns resulting in changes in gene expression. These systems constitute phase variable regulons called phasevarions. Neisseria meningitidis phasevarions regulate genes including virulence factors and vaccine candidates, and alter phenotypes including antibiotic resistance. The target site recognized by these Type III N-6-adenine DNA methyltransferases is not known. Single molecule, real-time (SMRT) methylome analysis was used to identify the recognition site for three key N. meningitidis methyltransferases: ModA11 (exemplified by M.NmeMC58I) (5'-CGY(m6)AG-3'), ModA12 (exemplified by M.Nme77I, M.Nme18I and M.Nme579II) (5'-AC(m6)ACC-3') and ModD1 (exemplified by M.Nme579I) (5'-CC(m6)AGC-3'). Restriction inhibition assays and mutagenesis confirmed the SMRT methylome analysis. The ModA11 site is complex and atypical and is dependent on the type of pyrimidine at the central position, in combination with the bases flanking the core recognition sequence 5'-CGY(m6)AG-3'. The observed efficiency of methylation in the modA11 strain (MC58) genome ranged from 4.6% at 5'-GCGC(m6)AGG-3' sites, to 100% at 5'-ACGT(m6)AGG-3' sites. Analysis of the distribution of modified sites in the respective genomes shows many cases of association with intergenic regions of genes with altered expression due to phasevarion switching.

First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M-tuberculosis

Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38?350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional Delta APSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value.

Neutral red uptake (NRU) entseguaren optimizazioa lur-zizareen sistema immuneko zelulen kultibo primarioetan

Azken urteotan eman diren kutsatzaile desberdinen gehiegizko isurpen edo erabilpena dela eta, lurzoruetan metal astunak metatu dira eta horrek , kate trofikoaren oinarrian dauden organismoen gainean k altea k sorrarazi d itu. Eisenia fetida zizarea espezie zent inela gisa erabili da lur entsegu ekotoxikologi koet an . Esperimentu honetan Eisenia fetida - ren jariakin zelomikoan dauden eta babes funtzioa duten zelomozitoak pH desberdinetara edo Kadmio bezalako metalera esposatzeak Neutral Red (NR) edo gorri neutro tindatzaile kationikoaren harreran eta fagoz itosi ahalmenean , eragina duen aztertu nahi izan da. Esperimentua in vitro egin zen 3R filosofia jarraituz. Alde batetik, pH desberdinen eragin ari dagokio nez gorri neutroaren harrera ( NRU ) entsegua n erantzun bimodal bat behatu zen eta beste alde bate tik, f agozitatzeko ahalmenari dagokiola zelomozitoak Eagle medioan kultibatzean ez zen aldaketa esangarria ikusi kadmioa ren, kontr olaren eta kontrol positi boaren artean. Bai ordea L - 1 5 medioarekin, non kontrol posit iboa k beste biak baino absorbantzia handiagoa erakutsi zuen. Emaitza hauek erakusten dute zelomozitoe n mintza gradualki kaltetzen doala pH neutrotik aldentzen doan heinean eta puntu batetik aurrera NRU emendatzen da zelomozito batzuen (amebozitoen) fagozitosia aktibatzen d el a ko .

Digital-Analog Quantum Simulation of Spin Systems in Trapped Ions

65 p.

Sistema de control y supervisión para una instalación industrial basado en técnicas de computación en la nube.

[ES]Hasta ahora, el control y monitorización de una instalación industrial se realiza desde la sala de control situada en las propias instalaciones de la planta. Cada unidad de control guarda y envía los datos a un ordenador que después se envían a uno central, siguiendo un orden jerárquico, en el que se visualizan ante un operario. Hoy en día, sin embargo, con el auge de los dispositivos móviles inteligentes, se puede conseguir que esa supervisión de la planta industrial se pueda hacer desde cualquier lugar. Podemos visualizar esos datos de control en nuestra mano y mandar órdenes a cada unidad desde nuestro teléfono inteligente. Esto es lo que se ha conseguido hacer con este proyecto, en el que se ha modelizado una instalación industrial basada en una cadena de montaje con tres unidades.

Diseño mecánico de manipulador paralelo XY.

[ES]El proyecto consiste en el desarrollo mecánico de un manipulador paralelo basado en un mecanismo de cadena cerrada y 5 pares de rotación moviéndose en un mismo plano, de modo que cubra un espacio de manipulación previamente definido. Para ello se realizan los diseños en programas de CAD y se realizan los planos de diseño y montaje con el objetivo de posteriormente llevar el diseño a la realidad.

Diseño del sistema de tensor de cadena y acople de pinza de freno trasero para moto de competición.

[ES]En este documento se propone el diseño de dos sistemas imprescindibles en el tren trasero de una moto de competición, el sistema de tensor de cadena y el del acople de pinza de freno trasero. Junto a estos sistemas se diseñará, dada su relevancia, el basculante de la moto. Estos diseños se realizarán de tal manera que cumplan una serie de requisitos geométricos y de resistencia, garantizando en todo momento la estabilidad y seguridad del piloto. Se realizará también el estudio de la fabricación de cada uno de los elementos que componen los sistemas, con el fin de realizar diseños viables, que resulten económicamente factibles y mantengan un alto grado de calidad. En el proyecto se analizarán las diferentes alternativas de los sistemas que se puedan adoptar, sus ventajas y desventajas, para así poder escoger, con un alto grado de seguridad, la opción que mejor cumpla los objetivos y condiciones establecidos. Cabe destacar que este proyecto se encuentra dentro de otro de mayor envergadura consistente en el diseño y la fabricación de una motocicleta de competición para participar en el campeonato internacional llamado “MotoStudent”. Esta competición se realiza entre universidades de todo el mundo y en ella los equipos de estudiantes se enfrentan al desafío de diseñar y desarrollar un prototipo de motocicleta de competición similar a la categoría mundialista de “Moto3”.