Suchergebnisse

Since the global economic and financial crisis of 2008, Serbia has struggled with a weak economy and a deteriorating fiscal position. Until 2008, fiscal deficits were moderate and public debt declined significantly. Since the start of the global economic and financial crisis in 2008, however, Serbia has struggled with the interlinked problems of minimal growth and unfavorable fiscal dynamics. As economic activity has stagnated, revenues have fallen and expenditures, particularly mandatory spending on pensions and wages, have remained high. At the same time, structural fiscal issues, such as continued state support to state-owned enterprises (SOEs) and tax administration inefficiencies, have been a drag on growth. As a result of these pressures, general government fiscal deficits averaged 5.6 percent of GDP a year between 2009 and 2014. Reflecting the high fiscal deficits and poor economic growth, Serbia's public debt has more than doubled, from 34 percent of GDP in 2008 to 71 percent at yearend-2014. The objective of this report is therefore two-fold: (i) policy options and recommendations (beyond those built into the current program) that would help solidify the ongoing fiscal consolidation program and help achieve public debt sustainability over the medium term; and (ii) given near-term fiscal constraints, identify opportunities for enhancing the efficiency, quality, and equity of current public spending on health, education, and social protection over the medium term

Since the global economic and financial crisis of 2008, Serbia has struggled with a weak economy and a deteriorating fiscal position. Until 2008, fiscal deficits were moderate and public debt declined significantly. Since the start of the global economic and financial crisis in 2008, however, Serbia has struggled with the interlinked problems of minimal growth and unfavorable fiscal dynamics. As economic activity has stagnated, revenues have fallen and expenditures, particularly mandatory spending on pensions and wages, have remained high. At the same time, structural fiscal issues, such as continued state support to state-owned enterprises (SOEs) and tax administration inefficiencies, have been a drag on growth. As a result of these pressures, general government fiscal deficits averaged 5.6 percent of GDP a year between 2009 and 2014. Reflecting the high fiscal deficits and poor economic growth, Serbia's public debt has more than doubled, from 34 percent of GDP in 2008 to 71 percent at yearend-2014. The objective of this report is therefore two-fold: (i) policy options and recommendations (beyond those built into the current program) that would help solidify the ongoing fiscal consolidation program and help achieve public debt sustainability over the medium term; and (ii) given near-term fiscal constraints, identify opportunities for enhancing the efficiency, quality, and equity of current public spending on health, education, and social protection over the medium term

The Kyrgyz Republic has made some progress in improving its poverty and social indicators but the gains have been fragile and significant disparities remain within the country. The slowdown in economic growth in 2009 and the resulting uptick in poverty underscored the susceptibility of the economy to external shocks. In this report, author's tackle the issue of inequality in the Kyrgyz Republic by framing it along the notion of equity as opposed to equality. The reason for doing so is that it is easier to galvanize social consensus and policy action when the overarching principle guiding policy is fairness in the allocation and access to opportunities as opposed to equality of outcomes. A girl born in a remote village in the oblast of Naryn to a single, uneducated mother with four other siblings ought to have the same shot at becoming a doctor or an engineer as a boy with one sibling, born in an educated, two-parent household in Bishkek. Basic opportunities are defined as subset of goods and services for children, such as access to education, safe water on site, or reliable electricity that are critical in determining opportunities for economic advancement in life. These are either already affordable by society at large or could be in the near future, given the available technology. Opportunities among children are measured in this report by the Human Opportunity Index (HOI), which is the coverage rate of a particular basic service adjusted by how equitably the service is distributed among groups differentiated by circumstances. In discounting inequitable access, the HOI reflects how personal circumstances- for which the children cannot be held accountable-affect their basic opportunities. The key finding of this report is that the goal of equal opportunity remains distant in the Kyrgyz Republic: a child's circumstances such as her parents' socioeconomic status, region of residence, whether it is urban and rural etc. have a substantial bearing on the extent to which certain services are available to her. Similarly, opportunities pertaining to a healthy start in life adequate access to household infrastructure and amenities that ensure a stable, safe and stimulating childhood also have strong regional dimensions with entire regions being underserved. Finally, what this report has done is taken a snapshot of the distribution of opportunities in the Kyrgyz Republic for a particular year.

España es líder Europea en la producción piscícola de rodaballo (Scophthalmus maximus) y, concretamente en Galicia supone una importante actividad económica y social, representando más del 60% de la producción de la Unión Europea. Debido a que uno de los mayores problemas en la acuicultura es el impacto negativo que tienen las enfermedades, en los últimos años se ha realizado un considerable esfuerzo en estudiar el sistema inmune de los peces cultivados, para poder desarrollar herramientas de lucha y prevención frente a estas. Incluso cuando enfermedades víricas, (como la causada por el virus de la septicemia hemorrágica viral (VHSV) (Tafalla et al., 1998)), bacterianas (como la causada por bacterias como Aeromonas sp (Toranzo et al., 1993)) o parasitarias (como la causada por Philasterides dicentrarchi (Iglesias et al., 2001)) han sido investigadas y se sabe que afectan a estos cultivos, poco se conoce sobre los mecanismos de defensa de estos animales contra los patógenos. Aunque se han llevado a cabo considerables esfuerzos para desarrollar vacunas convencionales o subunidades para muchos de estos patógenos de peces, su éxito ha sido muy limitado. Es conveniente que se introduzcan nuevos enfoques en la investigación concerniente a las vacunas, que proporcionen seguridad y eficacia frente a las enfermedades más importantes de los peces comerciales. Se conoce que en los peces el peso de la respuesta inmune no específica o innata es mayor que el que parece tener en mamíferos y por lo tanto, se confía más en su respuesta inmune innata que en la adaptativa para combatir las infecciones. Recientemente se ha descrito en vertebrados la existencia de mecanismos inmunes independientes de células B/T o "trained immunity" (TI), que previamente ya habían sido descritos en plantas e invertebrados. Sin embargo, la TI y su contribución a la protección frente agentes infecciosos en peces aún no ha sido explorada, aunque existen muchas evidencias que sugieren que es así. En este proyecto emplearemos dos especies de peces; el rodaballo (Scophthalmus maximus) y el pez cebra (Danio rerio), que emplearemos como herramienta de laboratorio para poder profundizar en el estudio de procesos básicos en los que sea difícil trabajar con especies comerciales. El pez cebra se ha empleado como modelo, tanto para el estudio de la respuesta inmune frente a enfermedades de los peces cultivados (Novoa et al., 2006; Rodríguez et al., 2008; Encinas et al., 2010; Novoa y Figueras, 2012), como para el estudio de procesos inflamatorios de gran interés para la salud humana, como el choque séptico y la tolerancia al lipopolisacárido bacteriano (LPS) (Novoa et al., 2009). Además, nos ha servido para estudiar la ontogenia del sistema inmune en peces (Dios et al., 2010; Varela et al., 2012 ). En este proyecto pretendemos profundizar en la modulación de la respuesta inflamatoria o innata frente a patógenos virales como el virus de la septicemia hemorrágica viral (VHSV), asociado con mortalidades de rodaballo o el SVCV, que se emplea como patógeno del pez cebra (Varela et al, 2014). - Dios S, Romero A, Chamorro R, Figueras A, Novoa B. 2010. Fish Shellfish Immunol, 29(6):1019-27. - Encinas P, Rodriguez-Milla MA, Novoa B, Estepa A, Figueras A, Coll J. 2010. BMC Genomics, 27;11:518. - Iglesias R, Paramá A, Alvarez MF, Leiro J, Fernández J, Sanmartín ML. 2001. Dis Aquat Organ, 22;46:47-55. - Novoa B, Romero A, Mulero V, Rodríguez I, Fernández I, Figueras A. 2006. Vaccine, 24 (31-32):5806-16. - Novoa B, Bowman TV, Zon L, Figueras A. 2009. Fish Shellfish Immunol, 26(2):326-31 - Novoa B. and Figueras A. 2012. Adv Exp Med Biol, 946:253-75 - Rodríguez I, Novoa B, Figueras A. 2008. Fish Shellfish Immunol; 25(3):239-49. - Tafalla, A. Figueras & Novoa, B. 1998. Veterinary Immunology and Immunopathology, 62: 359-366. - Varela M, Dios S, Novoa B, Figueras A. 2012. Dev Comp Immunol, 37:97-106. - Varela M, Dios S, Novoa B, Figueras A. 2014. J.Virol, 88(20):12026-12040. ; España é líder Europea na produción piscícola de rodaballo (Scophthalmus maximus) e, concretamente en Galicia supón unha importante actividade económica e social, representando máis do 60% da produción da Unión Europea. Debido a que un dos maiores problemas na acuicultura é o impacto negativo que teñen as enfermidades, nos últimos anos realizouse un considerable esforzo en estudar o sistema inmune dos peixes cultivados, para poder desenvolver ferramentas de loita e prevención fronte a estas. Mesmo cando enfermidades víricas, (como a causada polo virus da septicemia hemorrágica viral (VHSV) (Tafalla et al., 1998)), bacterianas (como a causada por bacterias como Aeromonas sp (Toranzo et al., 1993)) ou parasitarias (como a causada por Philasterides dicentrarchi (Iglesias et al., 2001)) foron investigadas e sábese que afectan a estes cultivos, pouco coñécese sobre os mecanismos de defensa destes animais contra os patógenos. Aínda que se levaron a cabo considerables esforzos para desenvolver vacinas convencionais ou subunidades para moitos destes patógenos de peixes, o seu éxito foi moi limitado. É conveniente que se introduzan novos enfoques na investigación concernente ás vacinas, que proporcionen seguridade e eficacia fronte ás enfermidades máis importantes dos peixes comerciais. Coñécese que nos peixes o peso da resposta inmune non específica ou innata é maior que o que parece ter en mamíferos e por tanto, se confia máis na súa resposta inmune innata que na adaptativa para combater as infeccións. Recentemente describiuse en vertebrados a existencia de mecanismos inmunes independentes de células B/T ou "trained immunity" (TI), que previamente xa foran descritos en plantas e invertebrados. Con todo, a TI e a súa contribución á protección fronte axentes infecciosos en peces aínda non foi explorada, aínda que existen moitas evidencias que suxiren que é así. Neste proxecto empregaremos dúas especies de peces; o rodaballo (Scophthalmus maximus) e o peixe cebra (Danio rerio), que empregaremos como ferramenta de laboratorio para poder profundar no estudo de procesos básicos nos que sexa difícil traballar con especies comerciais. O peixe cebra empregouse como modelo, tanto para o estudo da resposta inmune fronte a enfermidades dos peixes cultivados (Novoa et al., 2006; Rodríguez et al., 2008;Encinas et al., 2010; Novoa e Figueras, 2012), como para o estudo de procesos inflamatorios de gran interese para a saúde humana, como o choque séptico e a tolerancia ao lipopolisacárido bacteriano (LPS) (Novoa et al., 2009). Ademais, serviunos para estudar a ontogenia do sistema inmune en peces (Dios et al., 2010; Varela et ao., 2012 ). Neste proxecto pretendemos profundar na modulación da resposta inflamatoria ou innata fronte a patógenos virales como o virus da septicemia hemorrágica viral (VHSV), asociado con mortalidades de rodaballo ou o SVCV, que se emprega como patógeno do peixe cebra (Varela et al, 2014). - Dios S, Romero A, Chamorro R, Figueras A, Novoa B. 2010. Fish Shellfish Immunol, 29(6):1019-27. - Encinas P, Rodriguez-Milla MA, Novoa B, Estepa A, Figueras A, Coll J. 2010. BMC Genomics, 27;11:518. - Iglesias R, Paramá A, Alvarez MF, Leiro J, Fernández J, Sanmartín ML. 2001. Dis Aquat Organ, 22;46:47-55. - Novoa B, Romero A, Mulero V, Rodríguez I, Fernández I, Figueras A. 2006. Vaccine, 24 (31-32):5806-16. - Novoa B, Bowman TV, Zon L, Figueras A. 2009. Fish Shellfish Immunol, 26(2):326-31 - Novoa B. and Figueras A. 2012. Adv Exp Med Biol, 946:253-75 - Rodríguez I, Novoa B, Figueras A. 2008. Fish Shellfish Immunol; 25(3):239-49. - Tafalla, A. Figueras & Novoa, B. 1998. Veterinary Immunology and Immunopathology, 62: 359-366. - Varela M, Dios S, Novoa B, Figueras A. 2012. Dev Comp Immunol, 37:97-106. - Varela M, Dios S, Novoa B, Figueras A. 2014. J.Virol, 88(20):12026-12040. ; Spain is the European leader in the production of turbot (Scophthalmus maximus). This is an important economic and social activity in Galicia. The turbot production represents more than 60% of the production of the European Union. One of the major problems in aquaculture is the negative impact of disease. For this reason, considerable efforts have been made in recent years to study the immune system of cultured fish. The target is to develop prevention and control tools for aquaculture. Even when viral diseases (such as that caused by viral hemorrhagic septicemia virus (VHSV) (Tafalla et al., 1998)), or bacterial diseases (such as that caused by bacteria such as Aeromonas sp (Toranzo et al., 1993)), or parasitic diseases (such as that caused by Philasterides dicentrarchi (Iglesias et al., 2001)) have been investigated and are known to affect these crops, little is known about the defense mechanisms of these animals against pathogens. Although considerable efforts have been made to develop conventional vaccines or subunits for many of these fish pathogens, their success has been very limited. DNA vaccines are the only prophylactic means that have shown promising results as an effective strategy to fight viral diseases in fish. New approaches to vaccine research should be introduced to provide safety and efficacy against the major diseases of commercial fish. It is known that in fish the weight of the nonspecific or innate immune response is greater than to have in mammals. Because of this, it relies more on its innate immune response than on the adaptive one to combat infections. Recently there have been described in vertebrates the existence of independent immune mechanisms of B / T cells or "trained immunity" (TI). This was previously described in plants and invertebrates. However, TI and its contribution to protection against infectious agents in fish has not yet been explored. There is much evidence to suggest that this is so. In this project we will use two species of fish. The turbot (Scophthalmus maximus) of great commercial interest and cultivated mainly in Galicia, and the zebrafish (Danio rerio), which we will use as a laboratory tool. Zebrafish be able let us deepen into the study of basic processes in which it is difficult to work with commercial species. Zebrafish has been used as a model for the study of the immune response to diseases of cultured fish (Novoa et al., 2006, Novoa et Figueras, 2012), and for the study of inflammatory processes of great interest for human health (such as septic shock and tolerance to bacterial lipopolysaccharide (LPS) (Novoa et al., 2009)). In addition, it has served to study the ontogeny of the immune system in fish (Dios et al., 2010; Varela et al., 2012). In this project, we intend to deepen in the modulation of the inflammatory or innate response to viral pathogens such as viral haemorrhagic septicemia virus (VHSV), associated with mortality of turbot or SVCV, which is used as a zebrafish pathogen (Varela et al. Al, 2014). - Dios S, Romero A, Chamorro R, Figueras A, Novoa B. 2010. Fish Shellfish Immunol, 29(6):1019-27. - Encinas P, Rodriguez-Milla MA, Novoa B, Estepa A, Figueras A, Coll J. 2010. BMC Genomics, 27;11:518. - Iglesias R, Paramá A, Alvarez MF, Leiro J, Fernández J, Sanmartín ML. 2001. Dis Aquat Organ, 22;46:47-55. - Novoa B, Romero A, Mulero V, Rodríguez I, Fernández I, Figueras A. 2006. Vaccine, 24 (31-32):5806-16. - Novoa B, Bowman TV, Zon L, Figueras A. 2009. Fish Shellfish Immunol, 26(2):326-31 - Novoa B. and Figueras A. 2012. Adv Exp Med Biol, 946:253-75 - Rodríguez I, Novoa B, Figueras A. 2008. Fish Shellfish Immunol; 25(3):239-49. - Tafalla, A. Figueras & Novoa, B. 1998. Veterinary Immunology and Immunopathology, 62: 359-366. - Varela M, Dios S, Novoa B, Figueras A. 2012. Dev Comp Immunol, 37:97-106. - Varela M, Dios S, Novoa B, Figueras A. 2014. J.Virol, 88(20):12026-12040.

Aim of investigation. This article describes the origins and key principles for Canada's healthcare system effectiveness. The focus revolves around the general principles of the sphere of medical care; namely, the orderly process of defining health problems, identifying unmet needs and surveying the resources to meet them, establishing priority goals that are realistic and feasible, and projecting administrative action, concerned with the adequacy, efficacy and efficiency of health services in Canada. The author outlines the dominant principle of the Canadian healthcare system; while complying with the international standards, it provides a highlyqualified medical care, furthermore, both high life expectancy and low infant mortality rates testify to this reality. Noteworthy, the bases of social organization and healthcare system in Canada were grounded in late twentieth century. The fact that the Second World War hardly ever devastated both country's economy and the nation testifies to the public health system, being established in quite favorable conditions. In addition, the demography of Canadian population, being quite stable and favorable, prompted the economy to rapidly develop as well as the government political decisionmaking to push to review its existing healthcare law principles and start reforming it, so that the country can respond better to its health and health system challenges. It should be emphasized that the Medical Care Act (1966), which, along with the Hospital and Diagnostic Services Act (1957), established the basis for Canada's universal, publicly financed health insurance system, known as Medicare, effectively enshrined private fee-for-service practice as the dominant mode of practice organization and physician payment in Canada. Canadian Healthcare system establishment fell into several stages: the first stage (in early 40's of the 20th century), the provision of targeted subsidies for special programs of health care and for the construction of hospitals were legally approved, since a growing number of Canadian citizens were able to obtain a level of decent health care through Canadian hospitals. The second step was taken in 1957, the Hospital Insurance and Diagnostic Services Act (HIDS) were passed with all-party approval; it paid approximately half the cost of provincial insurance plans for hospitalbased care, as long as the plans complied with specified national conditions. Medical Care Act of 1966 extended health insurance to cover doctors' services. While the basic principles of Medicare are determined by federal legislation, responsibility for health under the Constitution falls under provincial jurisdiction. Therefore, there are certain variations in the plan from province to province. It is not surprising that the first breakthrough of the legal framework contributed to the development of hospitals network in the country; at the same time, medical care qualitative indicators were complied with the national requirements. The third stage (1968-1979) covered the adoption of the legislative documents that formed the Canadian system of medical insurance for Medicare and established the allocation of funds for hospital and community-based medical care. In 1984, a Health Care Act was adopted in Canada, which consolidated the basic principles of Medicare. Medical care had always been a centerpiece of Canada's welfare state program, since it expected the provincial and territorial governments to be responsible for the management, organization and delivery of health care services for their residents. The specifics of the theme predisposed application of comprehensive approach to the research methodologies, among which there should be mentioned such as: structural-functional analysis, which includes the study of functional dependencies of all elements of the social state. Adhering to the problematic principle of presentation of the material, the author used the institutional method, focused on the study of institutes through which the activities of the health protection system are implemented. At the same time a number of such special methods were used as statistical retrospective and prognostic. Scientific novelty: the mutual precondition of socio-economic, demographic, socio- political factors on the process of formation of the Canadian system of medical services was substantiated , the reasons and the4 main stages of the formation of free medicine in Canada were determined, as well as advantages and disadvantages of the modern Canadian health system. Conclusions An important conclusion of this review is that the Canadian healthcare system also has a spectrum of drawbacks that require bridging the gaps. Currently Canada's healthcare system faces challenges of staff shortage and access to health care. Nonetheless, it should be emphasized that Canada's Medicare is a source of pride, funded by the state and provides universal health care coverage care to all residents of Canada. ; Le but de l'étude. Cet article présente les caractéristiques de la formation et du développement du système de santé canadien et se concentre également sur les caractéristiques et les principes généraux du développement de l'industrie des soins médicaux. Le système de soins de santé canadien fournit un niveau assez élevé de soins médicaux. L'espérance de vie élevée et la faible mortalité infantile en sont la preuve. Les principes d'organisation sociale de la société et du système de soins de santé au Canada ont été créés au cours de la seconde moitié du vingtième siècle. Le système de santé canadien repose sur une base législative solide. Sa formation s'est déroulée en plusieurs étapes: dès la première étape (début des années 40 du XXe siècle), l'octroi de subventions ciblées à des programmes spéciaux de santé et à la construction d'hôpitaux était légalement fixé. Un tel cadre réglementaire a contribué au développement d'un réseau d'hôpitaux dans le pays; lors de la deuxième étape (en 1957), la loi sur l'assurance maladie a été adoptée, qui garantit la répartition fédérale-provinciale des ressources financières pour les soins médicaux. En 1984, le Canada a adopté la Loi sur les soins de santé, qui consacre les principes de base de l'assurance-maladie. Ce système fournit des soins médicaux et des services médicaux gratuits ou presque gratuits à tous les citoyens canadiens. Une telle structure a été mise au point car les soins médicaux relèvent de la compétence des autorités locales et provinciales et non du gouvernement fédéral. La spécificité du sujet prédéfinit une approche intégrée de l'application des méthodes de recherche, notamment: l'analyse structurelle-fonctionnelle, qui comprend l'étude des dépendances fonctionnelles de tous les éléments de l'état social. En adhérant au principe problématique de présentation du matériel, l'auteur a utilisé la méthode institutionnelle, axée sur l'étude des institutions par lesquelles les activités du système de santé sont mises en œuvre. En même temps, des méthodes spéciales telles que statistique, rétrospective et pronostique sont appliquées. Nouveauté scientifique. La dépendance mutuelle de facteurs socio-économiques, démographiques et socio-politiques sur le processus de formation du système de soins de santé canadien est discutée, les causes et les principales étapes de la formation de médicaments gratuits au Canada sont identifiées, ainsi que les avantages et les inconvénients du système de soins de santé canadien moderne. Conclusions. Il est prouvé que le système de santé canadien présente également certains inconvénients, car à l'heure actuelle, la médecine canadienne a cruellement besoin de médecins expérimentés. L'un des principaux problèmes est la longueur des files d'attente dans les établissements médicaux et l'attente prolongée pour pouvoir recevoir des soins médicaux. En même temps, malgré les problèmes décrits, le système de santé canadien appelé Medicare est la fierté du pays, car il est financé par l'État et fournit des soins médicaux pratiquement gratuits à tous les Canadiens. ; Мета дослідження. Дана стаття розкриває особливості формування і розвитку системи охорони здоров'я Канади, а також акцентується увага на характерні риси і загальні принципи побудови сфери медичного обслуговування. Канадська система охорони здоров'я забезпечує досить високий рівень медичного обслуговування і свідченням цьому є висока тривалість життя і низький рівень дитячої смертності. Принципи соціальної організації суспільства і система охорони здоров'я в Канаді сформувалися у другій половині ХХ століття. Система охорони здоров'я Канади має обґрунтовану законодавчу базу, її формування відбувалося в кілька етапів: на першому етапі (початок 40-х років XX ст.) Законодавчо закріплено надання цільових субсидій для спеціальних програм охорони здоров'я і для будівництва лікарняних закладів. Така нормативно-правова база сприяла розвитку мережі лікарняних закладів в країні; на другому етапі (1957 р) був прийнятий Закон про медичне страхування, який закріпив федерально-провінційна розподіл фінансових ресурсів на медичну допомогу. У 1984 р в Канаді був прийнятий Закон про охорону здоров'я, який закріпив основні принципи Medicare. Ця система забезпечує безкоштовне або практично безкоштовне медичне обслуговування і медичні послуги всім громадянам Канади. Така структура була розроблена тому, що медичне обслуговування знаходиться у відомстві місцевих, провінційних властей, а не федерального уряду. Специфікою теми зумовлений комплексний підхід до застосування методів дослідження, серед яких: структурно-функціональний аналіз, який включає вивчення функціональних залежностей всіх елементів соціальної держави. Дотримуючись проблемного принципу викладу матеріалу, автор використовував інституційний метод, орієнтований на вивчення інститутів, через які реалізується діяльність системи охорони здоров'я. У той же час застосовані такі спеціальні методи як статистичний, ретроспективний і прогностичний. Наукова новизна. Аргументовано взаємна обумовленість соціально-економічних, демографічних, суспільно-політичних чинників на процес формування канадської системи медичного обслуговування, визначені причини та основні етапи формування безкоштовної медицини в Канаді, а також відзначено переваги і недоліки сучасної канадської системи охорони здоров'я. Висновки. Доведено, що канадська система охорони здоров'я має також і певні недоліки, адже на сучасному етапі канадська медицина відчуває гостру потребу в досвідчених лікарів, а також однією з основних проблем є великі черги в медичних установах і тривале очікування можливості отримати медичну допомогу. У той же час, незважаючи на окреслені проблеми, канадська система медицини під назвою Medicare є гордістю країни, оскільки фінансується державою і забезпечує практично безкоштовне медичне обслуговування всім громадянам Канади. ; Цель исследования. Данная статья раскрывает особенности формирования и развития системы здравоохранения Канады, а также акцентируется внимание на характерных чертах и общих принципах построения сферы медицинского обслуживания. Канадская система здравоохранения обеспечивает достаточно высокий уровень медицинского обслуживания и свидетельством этому есть высокая продолжительность жизни и низкий уровень детской смертности. Принципы социальной организации общества и система здравоохранения в Канаде сформировались во второй половине ХХ века. Система здравоохранения Канады имеет обоснованную законодательную базу, ее формирование происходило в несколько этапов: на первом этапе (начало 40-х годов XX ст.) законодательно закреплено предоставление целевых субсидий для специальных программ здравоохранения и для строительства больничных заведений. Такая нормативно-правовая база содействовала развитию сети больничных заведений в стране; на втором этапе (в 1957 г.) был принят Закон о медицинском страховании, который закрепил федерально-провинциальное распределение финансовых ресурсов на медицинскую помощь. В 1984 г. в Канаде был принят Закон о здравоохранении, который закрепил основные принципы Medicare. Эта система обеспечивает бесплатное или практически бесплатное медицинское обслуживание и медицинские услуги всем гражданам Канады. Такая структура была разработана потому, что медицинское обслуживание находится в ведомстве местных, провинциальных властей, а не федерального правительства. Спецификой темы предопределен комплексный подход к применению методов исследования, среди которых: структурно-функциональный анализ, который включает изучение функциональных зависимостей всех элементов социального государства. Придерживаясь проблемного принципа изложения материала, автор использовал институционный метод, ориентированный на изучения институтов, через которые реализуется деятельность системы здравоохранения. В то же время применены такие специальные методы как статистический, ретроспективный и прогностический. Научная новизна. Аргументирована взаимная обусловленность социально-экономических, демографических, общественно-политических факторов на процесс формирования канадской системы медицинского обслуживания, определены причины и основные этапы формирования бесплатной медицины в Канаде, а также отмечено преимущества и недостатки современной канадской системы здравоохранения. Выводы. Доказано, что канадская система здравоохранения имеет также и определенные недостатки, ведь на современном этапе канадская медицина испытывает острую потребность в опытных врачах, а также одной из основных проблем есть большие очереди в медицинских учреждениях и длительное ожидание возможности получить медицинскую помощь. В тоже время, невзирая на очерченные проблемы, канадская система медицины под названием Medicare является гордостью страны, поскольку финансируется государством и обеспечивает практически бесплатное медицинское обслуживание всем гражданам Канады.

Aim of investigation. This article describes the origins and key principles for Canada's healthcare system effectiveness. The focus revolves around the general principles of the sphere of medical care; namely, the orderly process of defining health problems, identifying unmet needs and surveying the resources to meet them, establishing priority goals that are realistic and feasible, and projecting administrative action, concerned with the adequacy, efficacy and efficiency of health services in Canada. The author outlines the dominant principle of the Canadian healthcare system; while complying with the international standards, it provides a highlyqualified medical care, furthermore, both high life expectancy and low infant mortality rates testify to this reality. Noteworthy, the bases of social organization and healthcare system in Canada were grounded in late twentieth century. The fact that the Second World War hardly ever devastated both country's economy and the nation testifies to the public health system, being established in quite favorable conditions. In addition, the demography of Canadian population, being quite stable and favorable, prompted the economy to rapidly develop as well as the government political decisionmaking to push to review its existing healthcare law principles and start reforming it, so that the country can respond better to its health and health system challenges. It should be emphasized that the Medical Care Act (1966), which, along with the Hospital and Diagnostic Services Act (1957), established the basis for Canada's universal, publicly financed health insurance system, known as Medicare, effectively enshrined private fee-for-service practice as the dominant mode of practice organization and physician payment in Canada. Canadian Healthcare system establishment fell into several stages: the first stage (in early 40's of the 20th century), the provision of targeted subsidies for special programs of health care and for the construction of hospitals were legally approved, since a growing number of Canadian citizens were able to obtain a level of decent health care through Canadian hospitals. The second step was taken in 1957, the Hospital Insurance and Diagnostic Services Act (HIDS) were passed with all-party approval; it paid approximately half the cost of provincial insurance plans for hospitalbased care, as long as the plans complied with specified national conditions. Medical Care Act of 1966 extended health insurance to cover doctors' services. While the basic principles of Medicare are determined by federal legislation, responsibility for health under the Constitution falls under provincial jurisdiction. Therefore, there are certain variations in the plan from province to province. It is not surprising that the first breakthrough of the legal framework contributed to the development of hospitals network in the country; at the same time, medical care qualitative indicators were complied with the national requirements. The third stage (1968-1979) covered the adoption of the legislative documents that formed the Canadian system of medical insurance for Medicare and established the allocation of funds for hospital and community-based medical care. In 1984, a Health Care Act was adopted in Canada, which consolidated the basic principles of Medicare. Medical care had always been a centerpiece of Canada's welfare state program, since it expected the provincial and territorial governments to be responsible for the management, organization and delivery of health care services for their residents. The specifics of the theme predisposed application of comprehensive approach to the research methodologies, among which there should be mentioned such as: structural-functional analysis, which includes the study of functional dependencies of all elements of the social state. Adhering to the problematic principle of presentation of the material, the author used the institutional method, focused on the study of institutes through which the activities of the health protection system are implemented. At the same time a number of such special methods were used as statistical retrospective and prognostic. Scientific novelty: the mutual precondition of socio-economic, demographic, socio- political factors on the process of formation of the Canadian system of medical services was substantiated , the reasons and the4 main stages of the formation of free medicine in Canada were determined, as well as advantages and disadvantages of the modern Canadian health system. Conclusions An important conclusion of this review is that the Canadian healthcare system also has a spectrum of drawbacks that require bridging the gaps. Currently Canada's healthcare system faces challenges of staff shortage and access to health care. Nonetheless, it should be emphasized that Canada's Medicare is a source of pride, funded by the state and provides universal health care coverage care to all residents of Canada. ; Le but de l'étude. Cet article présente les caractéristiques de la formation et du développement du système de santé canadien et se concentre également sur les caractéristiques et les principes généraux du développement de l'industrie des soins médicaux. Le système de soins de santé canadien fournit un niveau assez élevé de soins médicaux. L'espérance de vie élevée et la faible mortalité infantile en sont la preuve. Les principes d'organisation sociale de la société et du système de soins de santé au Canada ont été créés au cours de la seconde moitié du vingtième siècle. Le système de santé canadien repose sur une base législative solide. Sa formation s'est déroulée en plusieurs étapes: dès la première étape (début des années 40 du XXe siècle), l'octroi de subventions ciblées à des programmes spéciaux de santé et à la construction d'hôpitaux était légalement fixé. Un tel cadre réglementaire a contribué au développement d'un réseau d'hôpitaux dans le pays; lors de la deuxième étape (en 1957), la loi sur l'assurance maladie a été adoptée, qui garantit la répartition fédérale-provinciale des ressources financières pour les soins médicaux. En 1984, le Canada a adopté la Loi sur les soins de santé, qui consacre les principes de base de l'assurance-maladie. Ce système fournit des soins médicaux et des services médicaux gratuits ou presque gratuits à tous les citoyens canadiens. Une telle structure a été mise au point car les soins médicaux relèvent de la compétence des autorités locales et provinciales et non du gouvernement fédéral. La spécificité du sujet prédéfinit une approche intégrée de l'application des méthodes de recherche, notamment: l'analyse structurelle-fonctionnelle, qui comprend l'étude des dépendances fonctionnelles de tous les éléments de l'état social. En adhérant au principe problématique de présentation du matériel, l'auteur a utilisé la méthode institutionnelle, axée sur l'étude des institutions par lesquelles les activités du système de santé sont mises en œuvre. En même temps, des méthodes spéciales telles que statistique, rétrospective et pronostique sont appliquées. Nouveauté scientifique. La dépendance mutuelle de facteurs socio-économiques, démographiques et socio-politiques sur le processus de formation du système de soins de santé canadien est discutée, les causes et les principales étapes de la formation de médicaments gratuits au Canada sont identifiées, ainsi que les avantages et les inconvénients du système de soins de santé canadien moderne. Conclusions. Il est prouvé que le système de santé canadien présente également certains inconvénients, car à l'heure actuelle, la médecine canadienne a cruellement besoin de médecins expérimentés. L'un des principaux problèmes est la longueur des files d'attente dans les établissements médicaux et l'attente prolongée pour pouvoir recevoir des soins médicaux. En même temps, malgré les problèmes décrits, le système de santé canadien appelé Medicare est la fierté du pays, car il est financé par l'État et fournit des soins médicaux pratiquement gratuits à tous les Canadiens. ; Цель исследования. Данная статья раскрывает особенности формирования и развития системы здравоохранения Канады, а также акцентируется внимание на характерных чертах и общих принципах построения сферы медицинского обслуживания. Канадская система здравоохранения обеспечивает достаточно высокий уровень медицинского обслуживания и свидетельством этому есть высокая продолжительность жизни и низкий уровень детской смертности. Принципы социальной организации общества и система здравоохранения в Канаде сформировались во второй половине ХХ века. Система здравоохранения Канады имеет обоснованную законодательную базу, ее формирование происходило в несколько этапов: на первом этапе (начало 40-х годов XX ст.) законодательно закреплено предоставление целевых субсидий для специальных программ здравоохранения и для строительства больничных заведений. Такая нормативно-правовая база содействовала развитию сети больничных заведений в стране; на втором этапе (в 1957 г.) был принят Закон о медицинском страховании, который закрепил федерально-провинциальное распределение финансовых ресурсов на медицинскую помощь. В 1984 г. в Канаде был принят Закон о здравоохранении, который закрепил основные принципы Medicare. Эта система обеспечивает бесплатное или практически бесплатное медицинское обслуживание и медицинские услуги всем гражданам Канады. Такая структура была разработана потому, что медицинское обслуживание находится в ведомстве местных, провинциальных властей, а не федерального правительства. Спецификой темы предопределен комплексный подход к применению методов исследования, среди которых: структурно-функциональный анализ, который включает изучение функциональных зависимостей всех элементов социального государства. Придерживаясь проблемного принципа изложения материала, автор использовал институционный метод, ориентированный на изучения институтов, через которые реализуется деятельность системы здравоохранения. В то же время применены такие специальные методы как статистический, ретроспективный и прогностический. Научная новизна. Аргументирована взаимная обусловленность социально-экономических, демографических, общественно-политических факторов на процесс формирования канадской системы медицинского обслуживания, определены причины и основные этапы формирования бесплатной медицины в Канаде, а также отмечено преимущества и недостатки современной канадской системы здравоохранения. Выводы. Доказано, что канадская система здравоохранения имеет также и определенные недостатки, ведь на современном этапе канадская медицина испытывает острую потребность в опытных врачах, а также одной из основных проблем есть большие очереди в медицинских учреждениях и длительное ожидание возможности получить медицинскую помощь. В тоже время, невзирая на очерченные проблемы, канадская система медицины под названием Medicare является гордостью страны, поскольку финансируется государством и обеспечивает практически бесплатное медицинское обслуживание всем гражданам Канады. ; Мета дослідження. Дана стаття розкриває особливості формування і розвитку системи охорони здоров'я Канади, а також акцентується увага на характерні риси і загальні принципи побудови сфери медичного обслуговування. Канадська система охорони здоров'я забезпечує досить високий рівень медичного обслуговування і свідченням цьому є висока тривалість життя і низький рівень дитячої смертності. Принципи соціальної організації суспільства і система охорони здоров'я в Канаді сформувалися у другій половині ХХ століття. Система охорони здоров'я Канади має обґрунтовану законодавчу базу, її формування відбувалося в кілька етапів: на першому етапі (початок 40-х років XX ст.) Законодавчо закріплено надання цільових субсидій для спеціальних програм охорони здоров'я і для будівництва лікарняних закладів. Така нормативно-правова база сприяла розвитку мережі лікарняних закладів в країні; на другому етапі (1957 р) був прийнятий Закон про медичне страхування, який закріпив федерально-провінційна розподіл фінансових ресурсів на медичну допомогу. У 1984 р в Канаді був прийнятий Закон про охорону здоров'я, який закріпив основні принципи Medicare. Ця система забезпечує безкоштовне або практично безкоштовне медичне обслуговування і медичні послуги всім громадянам Канади. Така структура була розроблена тому, що медичне обслуговування знаходиться у відомстві місцевих, провінційних властей, а не федерального уряду. Специфікою теми зумовлений комплексний підхід до застосування методів дослідження, серед яких: структурно-функціональний аналіз, який включає вивчення функціональних залежностей всіх елементів соціальної держави. Дотримуючись проблемного принципу викладу матеріалу, автор використовував інституційний метод, орієнтований на вивчення інститутів, через які реалізується діяльність системи охорони здоров'я. У той же час застосовані такі спеціальні методи як статистичний, ретроспективний і прогностичний. Наукова новизна. Аргументовано взаємна обумовленість соціально-економічних, демографічних, суспільно-політичних чинників на процес формування канадської системи медичного обслуговування, визначені причини та основні етапи формування безкоштовної медицини в Канаді, а також відзначено переваги і недоліки сучасної канадської системи охорони здоров'я. Висновки. Доведено, що канадська система охорони здоров'я має також і певні недоліки, адже на сучасному етапі канадська медицина відчуває гостру потребу в досвідчених лікарів, а також однією з основних проблем є великі черги в медичних установах і тривале очікування можливості отримати медичну допомогу. У той же час, незважаючи на окреслені проблеми, канадська система медицини під назвою Medicare є гордістю країни, оскільки фінансується державою і забезпечує практично безкоштовне медичне обслуговування всім громадянам Канади.

Background: Schizophrenia is a chronic serious mental disorder with prevalence close to 0.7%. Early symptoms of schizophrenia generally appear in late adolescence or the early twenties. The prognosis is usually worse in cases of early onset. The symptomatology of schizophrenia is complex and can vary a lot between individuals. The two main symptom dimensions are referred to as positive symptoms and negative symptoms. The most common positive symptoms are: hallucinations, particularly auditory hallucinations, delusions, disturbances of thought and persecutory ideation. The most common negative symptoms are: lack of social interest, loss of personal hygiene, reduced motivation, loss of insight and blunting of affect. Over 100 variants are now known in the genome that increase the risk of schizophrenia and the genetic pathogenesis is therefore very complex. Environmental risk factors are believed to play a role in the pathogenesis of schizophrenia, especially cannabis use in adolescence. The socioeconomic cost of schizophrenia is very high because the disease often causes disability among young sufferers. Patients with schizophrenia have a reduced life expectancy of 22.5-25 years. The main reasons are unhealthy lifestyle (most patients smoke, take little exercise, use alcohol or illicit substances and are on a poor diet), cardiovascular disease and suicide. About 20-30% of patients do not respond to conventional antipsychotic treatment and are said to have treatment-resistant schizophrenia (TRS). The only approved treatment that has proven to be efficacious in TRS and been shown to improve overall mortality as well as reduce suicide attempts and probably the odds of suicide is the antipsychotic clozapine. Despite this clozapine is often used rather late in the disease course, most probably due to many side effects and some rare adverse drug reactions (ADR) which can be life-threatening for a very small proportion of TRS patients. A much greater number of patients with TRS lose years of life because they commit suicide or die prematurely due to an unhealthy lifestyle than those who pass away as a result of these rare ADRs. Despite this the proportion of TRS patients with schizophrenia that have ever had clozapine prescribed is much less than the expected 20-30% in most countries. Fewer still remain on the treatment long term for various reasons. Clozapine is not available in a depot injectable preparation and that limits its effectiveness in the treatment of patients with lack of insight or who have difficulty in taking tablets daily. Objective: To study the use of clozapine in the treatment of schizophrenia in Iceland and to assess serious side effects of antipsychotics, focusing on clozapine. Assess neutropenia and the progression to agranulocytosis and compare the prevalence for patients on clozapine versus those that have never been on clozapine. Examine the proportion of patients who had developed diabetes or dyslipidemia and compare it to a standard Icelandic population. Finally, to contribute to Evidence-Based as well as Value-Based Practice and shared decision-making in the often challenging treatment and long term care of patients with TRS. Method: The study population consisted of patients who had participated in an ongoing joint research project of Landspitali University Hospital and deCODE genetics on psychotic disorders. Patients were recruited to the study between 1986-2014. A total of 611 patients with schizophrenia took part in the study. Patients' health records were searched electronically to identify patients who had used clozapine. The health records were then reviewed to confirm use of clozapine. Patients´ health records were searched electronically to seek information on side effects and ADRs as well as the blood test database at Landspitali. Statistical analyses were performed using STATA. Results: The use of clozapine in Iceland is described in paper I. Two hundred and one patients took clozapine at some point during the study. The mean age at the start of clozapine use was 37.8 years. Some 71.2% of patients who began treatment with clozapine remained on clozapine treatment 20 years later. It was estimated that 11.4% of patients with schizophrenia in Iceland were using clozapine and that 16% had ever tried clozapine treatment. Antipsychotic polypharmacy was common since two out of every three patients, 65.6%, also used other antipsychotics alongside treatment with clozapine. Paper II focuses on neutropenia and agranulocytosis in the course of treatment of TRS with clozapine versus other antipsychotics. After the first 18 weeks of clozapine treatment the median number of days between neutrophil measurements was 124 days. Neutropenia was observed in 34 patients out of 188 on clozapine and of those 24 developed mild neutropenia (granulocytes between 1500-1900/mm3). One year after the neutropenia 28 patients out of 34 were still on clozapine. No difference was observed in the proportion of patients who developed moderate to severe neutropenia (granulocytes in the range 0-1400/mm3) between patients on clozapine versus TRS patients who had never been on clozapine. In paper III it was presented that women on clozapine were 4.4 times more likely to have been diagnosed with type 2 diabetes (T2D) than women in the general population. Males on clozapine were 2.3 times more likely to have been diagnosed with T2D than males in the general population. Triglycerides were higher both among those with schizophrenia who had been on clozapine as well as among patients with schizophrenia who had never received clozapine compared to the general population. One case of ketoacidosis was identified in a patient with type 1 diabetes. Conclusions: More patients with TRS in Iceland and other countries should get the opportunity to be offered treatment with clozapine. A large proportion of neutropenia developing during clozapine treatment is probably not caused by clozapine. If clozapine treatment proves to be effective a decision to stop clozapine should only be taken following careful consideration of all possible options in cases of moderate neutropenia, because there are usually no other alternative treatment options available that offer comparable effectiveness available. Doctors must be well aware of the risk of metabolic syndrome during clozapine treatment, especially the high risk of T2D developing in women. ; Bakgrunnur: Geðklofi er langvinnur alvarlegur geðsjúkdómur með algengi nálægt 0,7%. Fyrstu einkenni geðklofa koma oftast fram seint á unglingsárum eða á þrítugsaldri, en þeim mun fyrr sem sjúkdómurinn kemur fram eru horfurnar að jafnaði verri. Einkennaróf geðklofa er margþætt og birtingarform veikindanna getur því verið talsvert mismunandi milli einstaklinga. Tvær helstu víddir sjúkdómsins eru svokölluð jákvæð einkenni og neikvæð einkenni (brottfallseinkenni). Algengustu jákvæðu einkennin eru: ofskynjanir og þá einkum ofheyrnir, ranghugmyndir, truflun á hugsun og aðsóknarkennd. Algengustu neikvæðu einkennin eru: félagsleg einangrun, skert persónuhirða, minni áhugahvöt, innsæisleysi og skert tilfinningaleg viðbrögð. Nú eru þekktir yfir 100 breytileikar í erfðamenginu sem auka líkur á geðklofa og samband erfða og svipgerðar því afar flókið. Talið er að umhverfisþættir komi auk þess við sögu í tilurð geðklofa, ekki síst regluleg notkun unglinga á kannabisefnum. Samfélagslegur kostnaður vegna geðklofa er hár þar sem sjúkdómurinn veldur mjög oft örorku ungs fólks. Sjúklingar með geðklofa lifa að meðaltali 22,5-25 árum skemur en aðrir. Helstu ástæður þess eru óheilbrigður lífstíll (flestir reykja, lítil hreyfing, óheilbrigt mataræði og notkun vímugjafa), hjarta og æðasjúkdómar og loks sjálfsvíg. Um 20-30% sjúklinga svara ekki hefðbundinni meðferð með geðrofslyfjum og eru þeir sagðir vera með meðferðarþráan geðklofa. Eina meðferðin sem hefur sannað sig sem gagnreynd meðferð hjá þeim hópi er geðrofslyfið clozapín, en oft er það notað frekar seint í sjúkdómsferlinu vegna margvíslega aukaverkana, sem sumar hverjar geta verið lífshættulegar. Mun fleiri sjúklingar með meðferðarþráan geðklofa falla þó fyrir eigin hendi en látast vegna þessara sjaldgæfu aukaverkana, en clozapín er það lyf sem helst minnkar líkur á sjálfsvígum og dregur úr dánartíðni í þessum hópi. Þrátt fyrir það eru margir læknar ragir við að bjóða sjúklingum meðferðina og hlutfall sjúklinga sem fær að reyna clozapín meðferð vegna meðferðarþrás geðklofa er hvarvetna mun lægra en 20-30%. Clozapín er ekki til sem forðalyf í sprautuformi. Það takmarkar notagildi þess í tilfellum þar sem sjúklingar hafa mjög skert innsæi eða ráða illa við að taka töflur daglega. Markmið: Að rannsaka notkun clozapíns hér á landi í meðferð geðklofa og alvarlegar aukaverkanir geðrofslyfja með áherslu á clozapín. Skoða kyrningafæð (neutropenia) og tengingu hennar við algjöra kyrningafæð (agranulocytosis) og bera saman tíðnina hjá sjúklingum á clozapín og þeim sem hafa aldrei farið á clozapín. Einnig á að kanna tíðni sykursýki og blóðfituröskunar og bera saman við almennt íslenskt þýði. Síðast en ekki síst að þróa frekar gagnreynda og gildismiðaða meðferð og sameiginlega ákvarðanatöku í langtíma meðferð meðferðarþrás geðklofa. Aðferð: Þýðið í rannsókninni samanstóð af sjúklingum sem hafa tekið þátt í geðrofsrannsókn LSH og Íslenskrar erfðagreiningar. Sjúklingum var safnað í rannsóknina á árunum 1986-2014. Samtals voru upplýsingar um 611 sjúklinga notaðar í rannsókninni. Til að finna sjúklinga sem höfðu notað geðrofslyfið clozapín var leitað að rafrænum skjölum í sjúkraskrá Landspítala sem bentu til clozapín notkunar. Þau skjöl voru lesin til að meta hvort hægt væri að staðfesta clozapín notkun. Til að finna upplýsingar um aukaverkanir var framkvæmd rafræn leit í sjúkraskrám auk þess sem aðgangur fékkst að blóðprufugagnagrunni Landspítala. Tölfræðiúrvinnsla var gerð í STATA. Niðurstöður: Í grein I er fjallað um notkun clozapíns á Íslandi. Tvöhundruð og einn sjúklingur hafði fengið meðferð með clozapíni. Meðalaldur við upphaf clozapíns notkunar reyndist 37,8 ár á tímabilinu. Um 71,2% sjúklinga sem hófu meðferð með clozapíni voru enn á clozapín meðferð 20 árum síðar. Við áætluðum að 11,4% sjúklinga með geðklofa á Íslandi væru að taka clozapín og 16% þeirra hefðu einhvern tíma reynt meðferð með lyfinu. Fjöllyfjanotkun geðrofslyfja var algeng samhliða clozapín meðferð þar sem tveir af hverjum þremur sjúklingum eða 65,6% notuðu önnur geðrofslyf samhliða meðferð með clozapíni. Grein II fjallar um kyrningafæð og algjöra kyrningafæð. Eftir fyrstu 18 vikurnar á clozapín meðferð þá var miðgildi milli mælinga á kyrningum 124 dagar. Kyrningafæð greindist hjá 34 sjúklingum af 188 á clozapín meðferð en oftast var um að ræða væga kyrningafæð (kyrningar milli 1500-1900/mm3 ) eða hjá 24 sjúklingum. Einu ári eftir kyrningarfæð voru 28 af 34 sjúklingum ennþá á clozapíni. Enginn munur kom fram á tíðni alvarlegrar kyrningafæðar (kyrningar á bilinu 0-1400/mm3 ) hjá sjúklingum á clozapíni og sjúklingum með geðklofa sem höfðu aldrei farið á clozapín meðferð. Í grein III kemur fram að konur sem hafa tekið clozapín voru 4,4 sinnum líklegri en konur í almennu þýði til að hafa greinst með sykursýki týpu 2. Karlar á clozapín meðferð voru 2,3 sinnum líklegri til að hafa greinst með sykursýki týpu 2 en karlar í almennu þýði. Þríglýseríð voru einnig hærri bæði hjá þeim sem höfðu tekið clozapín og hjá sjúklingum með geðklofa sem höfðu aldrei tekið clozapín samanborið við almennt þýði. Eitt tilfelli af ketónblóðsýringu greindist hjá sjúklingi með sykursýki af týpu 1. Ályktanir: Hærra hlutfall sjúklinga með meðferðarþráan geðklofa á Íslandi og í öðrum löndum ætti að eiga þess kost að reyna meðferð með clozapíni. Stór hluti af kyrningafæð sem kemur fram hjá sjúklingum á clozapín meðferð stafar líklega ekki af lyfinu. Því þarf að ígrunda vel ákvarðanir um að hætta clozapín meðferð einstaklinga með meðferðarþráan geðklofa á grundvelli miðlungs alvarlegrar kyrningafæðar hafi meðferð skilað góðum árangri og þar sem þá er almennt ekki önnur meðferð með sambærilega virkni í boði. Læknar þurfa að vera vel vakandi fyrir efnaskiptavillu af völdum clozapíns og þá sérstaklega sykursýki týpu 2 hjá konum. ; Landspitali, The National University Hospital European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 279227 (CRESTAR).

El objetivo general consiste en establecer los parámetros que definen la relación entre la calidad del aire y los niveles de emisión de contaminación de origen industrial y proporcionar herramientas que ayuden a la toma de decisiones con el fin de facilitar la localización de impactos ambientales derivados del sector industrial. Los objetivos específicos que se plantean para desarrollar este trabajo se basan en: 1. Realizar una búsqueda bibliográfica de la información relacionada con las emisiones industriales. 2. Recopilar información para identificar los diferentes sectores industriales. 3. Determinar los diferentes parámetros industriales que inciden sobre la calidad del aire. 4. Revisar la legislación vigente internacional y nacional. 5. Realizar un estudio estocástico de las relaciones entre las emisiones industriales y la calidad del aire. 6. Analizar diferentes herramientas de medida de la calidad del aire. 7. Seleccionar los criterios para construir las herramientas. 8. Proponer y aplicar las herramientas de medida a un caso de estudio. ; La calidad del aire es una variable que condiciona la habitabilidad de los sistemas urbanos. La atmósfera es un sistema que, en forma aparente, soporta relativamente bien la influencia que sobre ella ejercen las actividades propias de la ciudad, pero en realidad el aire que respiramos es vulnerable y tiene una capacidad de carga limitada. Es por ello que en las grandes aglomeraciones urbanas el aire respirado está lejos de satisfacer los umbrales recomendados por la Organización Mundial de la Salud (OMS, 2006). Multitud de estudios han puesto de relieve que ciertos contaminantes provocan efectos nocivos sobre la salud humana, sobre la vegetación y sobre el medio, aumentando la morbilidad y la mortalidad de la población, acidificando las aguas continentales, afectando la fauna y la flora de la biosfera, alterando el equilibrio natural existente entre los distintos ecosistemas e incluso provocando cambios catastróficos en el clima terrestre. En la actualidad, la población en general es conocedora de este hecho y por lo tanto exige a los poderes públicos que trabajen al respecto para mejorar la calidad del aire (European Environment Agency, 2009). Por otra parte la industria como motor del modelo de desarrollo actual es uno de los causantes de esta serie de efectos negativos sobre la sociedad y el medio en el que se desarrolla, los cuales se ven reflejados en los diferentes ámbitos de los ecosistemas, donde la misma deposita sus residuos, acción que debe ser tratada y controlada debidamente para evitar la continua degradación de la naturaleza (PASSOLA, 2006). Cabe destacar que el modelo de desarrollo económico de la sociedad actual y su dinámica de crecimiento desmedido está íntimamente ligado al aumento de las emisiones a la atmósfera. Tal disposición del sistema demanda cada vez mayor cantidad de energía para realizar sus funciones, las cuales a su vez son de mayor escala. Dicha provisión energética generada en gran medida a partir de combustibles fósiles, como son el carbón, el fuel-oil y el gas natural, al provenir de fuentes no renovables, poseen una tasa de renovación inferior a nuestra tasa de consumo. Como consecuencia nuestro consumo energético puede y debe ser replanteado en aras de proteger la naturaleza y así planear una convivencia del ser humano no sólo respetuoso sino integrado con la misma. Por su parte, la industria presenta una distribución muy heterogénea en el territorio y la gran variedad de actividades y procesos obliga a un análisis detallado por sectores. Incluso dentro de un mismo sector las tecnologías aplicadas pueden ser muy diversas. Entre los sectores que proporcionan las mayores contribuciones de emisiones se encuentra el de producción de energía, las refinerías de petróleo, las industrias químicas y la siderurgia, como sectores fundamentales de la industria básica. Para afrontar la problemática de la contaminación atmosférica, se vienen tomando medidas, que van en todos los sentidos, desde la modelación de la calidad del aire, pasando por inventarios de emisiones de los diferentes sectores involucrados, creación de índices e indicadores de la calidad del aire para controlar, prevenir y mejorar las medidas que se toman al respecto, con la finalidad de obtener una mejor calidad de vida, que vaya en concordancia con el adecuado funcionamiento de los ecosistemas. El presente trabajo por tanto pretende realizar una caracterización de la calidad del aire debida al sector industrial así como proporcionar un sistema de medidas que sirva como punto de apoyo para las diferentes industrias a la hora de tomar decisiones en las que se impliquen las mejoras ambientales y en este caso específico un cambio en el manejo de las emisiones de contaminantes a la atmósfera. ; Air quality is a variable that affects the habitability of urban systems. The atmosphere is a system that supports relatively well the influence that the activities of the city exerts upon it, but in reality, the air that we breathe is vulnerable and has a limited carrying capacity. Due to this fact, in the built-up urban areas, the breathing air is far away from the satisfactory threshold recommended by the World Health Organization (WHO, 2006) A huge amount of studies have shown that some pollutants have adverse effects on human health, vegetation and on the environment, increasing the morbidity and mortality of the population, the acidification in the inland waters, affecting the flora and the biosphere's flora, altering the existing natural balance between the different ecosystems and even causing catastrophic changes in Earth's climate. Nowadays, the general public is aware of this fact, therefore, requires the government to work in this regard in order to improve the air quality (European Environment Agency, 2009). Moreover, the industry as an engine of the current development model is one of the causes of this series of negative effects on the society and the environment in which it develops, which are reflected in different aspects of the ecosystems, where it deposits its waste; this action must be treated and manage properly to prevent continued degradation of nature. (PASSOLA, 2006) It is to be note, that the current society model of economical development and its sprawl dynamic is closely linked to the increased emission into the atmosphere. This provision of the system increased demand amount of energy to perform their functions, which in turn are larger scale. This energy provision is mostly generated from fossil fuels such as coal, fuel-oil and natural gas, those, coming from not renewable sources, have a turnover rate lower than our rate of consumption. As a consequence, our energy consumption can and should be rethought in order to protect nature and moreover, plan a not only respectful living of the human being but integrated with it. On the other hand, the industry represents a very heterogeneous distribution on the territory and the wide variety of activities and processes requires a detail analysis by sector. Even within the same sector, the applied technologies can be widely. Among the sectors that lead with the highest emission contributions, there are: the energy production, oil refineries, chemical and steel industries as key sectors of basic industry. To deal the air pollution problem, it has been taking steps going in all directions, from modeling air quality, going through emission inventories of the different sectors involved. Besides, creation of indexes and indicators of air's quality in order to control, prevent and improve the measures taken in this regard, with the propose of obtain a better life quality that goes in line with the proper functioning of ecosystems. Therefore, this current investigation seeks to make a characterization of air quality due to the industrial sector as well as provide a measurement system that could be used as a support for the different industries when it comes to make decision which involve environmental improvements and in this specific case, a change in the management of pollutant emissions into the atmosphere. ; La qualitat de l'aire és una variable que condiciona l'habitabilitat dels sistemes urbans. L'atmosfera es un sistema, que aparentment, suporta relativament bé la influencià que sobre ella exerceixen les activitats pròpies d'una ciutat, però en realitat l'aire que respiren és vulnerable i té una capacitat de càrrega limitada. Es per això que les grans aglomeracions urbanes l'aire que respiren està lluny de satisfer els llindars recomanats per l'Organització Mundial de la Salut (OMS, 2006). Multitud d'estudis han posat en relleu que certs contaminants provoquen efectes nocius en la salut humana, en la vegetació i sobre el medi, augmenta la morbiditat i la mortalitat de la població, acidificant les aigües continentals, afectant a la fauna i la flora de la biosfera, alterant l'equilibri natural existent entre els diferents ecosistemes i fins i tot provocant canvis catastròfics en el clima terrestre. En l'actualitat, la població en general és coneixedora d'aquest fet i per tant exigeix als poders públics que treballin al respecte per millorar la qualitat de l'aire (European Environment Agency, 2009). D'altra banda la indústria com a motor del model de desenvolupament actual és una de les causants d'aquesta sèrie d'efectes negatius sobre la societat i el medi en que es desenvolupa, els quals es veuen reflectits en els diferents àmbits del ecosistema,on la mateixa diposita els seus residus, acció que ha de ser tractada i controlada degudament per evitar la continua degradació de la naturalesa (Passola, 2006). Cal destacar que el model de desenvolupament econòmic de la societat actual i la seva dinàmica de creixement desmesurat està íntimament lligat a l'augment de les emissions a l'atmosfera. Tal disposició del sistema demanda cada vegada major qualitat d'energia per realitzar les seves funcions, les quals a la vegada són de major escala. Aquesta provisió energètica generada en gran mesura a partir dels combustibles fòssils, com són el carbó, el fuel-oil i el gas natural, i al ser fonts no renovables, tenen una taxa de renovació inferior a la nostra taxa de consum. Com a conseqüència el nostre consum energètic pot i ha de ser replantejat per tal de protegir la natura i així plantejar una convivència de l'ésser humà no més respectuós sinó integrat amb ella. Per la seva banda, la indústria presenta un distribució molt heterogènia en el territori i la gran varietat d'activitats i processo obliga a un anàlisi detallada per sector. Fins i tot dins d'un mateix sector les tecnologies aplicades poden ser molt diverses. Entre els sectors que donen majors contribucions a les emissions trobem: la producció de energia, les refineries de petroli, les indústries químiques i la siderúrgia, com sectors fonamentals de la indústria bàsica. Per afrontar la problemàtica de la contaminació atmosfèrica, es necessari prenent mesures, en tots els sentits, des de la modelització de l'aire, passant per inventaris d'emissions dels diferents sectors involucrats, creació d'índexs i indicadors de la qualitat de l'aire per controlar, prevenir i millorar les mesures que es prenen al respecte, amb la finalitat de obtenir una millor qualitat de vida, que sigui concordant amb un adequat funcionament dels ecosistemes. Aquest treball per tant pretén realitzar una caracterització de la qualitat de l'aire emesa pel sector industrial així com proporcionar un sistema de mesures que serveixi com a punt de suport per a les diferents indústries a l'hora de prendre decisions en què s'impliquin les millores ambientals i en aquest cas específic un canvi en el maneig de les emissions de contaminats a l'atmosfera.

El objetivo general consiste en establecer los parámetros que definen la relación entre la calidad del aire y los niveles de emisión de contaminación de origen industrial y proporcionar herramientas que ayuden a la toma de decisiones con el fin de facilitar la localización de impactos ambientales derivados del sector industrial. Los objetivos específicos que se plantean para desarrollar este trabajo se basan en: 1. Realizar una búsqueda bibliográfica de la información relacionada con las emisiones industriales. 2. Recopilar información para identificar los diferentes sectores industriales. 3. Determinar los diferentes parámetros industriales que inciden sobre la calidad del aire. 4. Revisar la legislación vigente internacional y nacional. 5. Realizar un estudio estocástico de las relaciones entre las emisiones industriales y la calidad del aire. 6. Analizar diferentes herramientas de medida de la calidad del aire. 7. Seleccionar los criterios para construir las herramientas. 8. Proponer y aplicar las herramientas de medida a un caso de estudio. ; La calidad del aire es una variable que condiciona la habitabilidad de los sistemas urbanos. La atmósfera es un sistema que, en forma aparente, soporta relativamente bien la influencia que sobre ella ejercen las actividades propias de la ciudad, pero en realidad el aire que respiramos es vulnerable y tiene una capacidad de carga limitada. Es por ello que en las grandes aglomeraciones urbanas el aire respirado está lejos de satisfacer los umbrales recomendados por la Organización Mundial de la Salud (OMS, 2006). Multitud de estudios han puesto de relieve que ciertos contaminantes provocan efectos nocivos sobre la salud humana, sobre la vegetación y sobre el medio, aumentando la morbilidad y la mortalidad de la población, acidificando las aguas continentales, afectando la fauna y la flora de la biosfera, alterando el equilibrio natural existente entre los distintos ecosistemas e incluso provocando cambios catastróficos en el clima terrestre. En la actualidad, la población en general es conocedora de este hecho y por lo tanto exige a los poderes públicos que trabajen al respecto para mejorar la calidad del aire (European Environment Agency, 2009). Por otra parte la industria como motor del modelo de desarrollo actual es uno de los causantes de esta serie de efectos negativos sobre la sociedad y el medio en el que se desarrolla, los cuales se ven reflejados en los diferentes ámbitos de los ecosistemas, donde la misma deposita sus residuos, acción que debe ser tratada y controlada debidamente para evitar la continua degradación de la naturaleza (PASSOLA, 2006). Cabe destacar que el modelo de desarrollo económico de la sociedad actual y su dinámica de crecimiento desmedido está íntimamente ligado al aumento de las emisiones a la atmósfera. Tal disposición del sistema demanda cada vez mayor cantidad de energía para realizar sus funciones, las cuales a su vez son de mayor escala. Dicha provisión energética generada en gran medida a partir de combustibles fósiles, como son el carbón, el fuel-oil y el gas natural, al provenir de fuentes no renovables, poseen una tasa de renovación inferior a nuestra tasa de consumo. Como consecuencia nuestro consumo energético puede y debe ser replanteado en aras de proteger la naturaleza y así planear una convivencia del ser humano no sólo respetuoso sino integrado con la misma. Por su parte, la industria presenta una distribución muy heterogénea en el territorio y la gran variedad de actividades y procesos obliga a un análisis detallado por sectores. Incluso dentro de un mismo sector las tecnologías aplicadas pueden ser muy diversas. Entre los sectores que proporcionan las mayores contribuciones de emisiones se encuentra el de producción de energía, las refinerías de petróleo, las industrias químicas y la siderurgia, como sectores fundamentales de la industria básica. Para afrontar la problemática de la contaminación atmosférica, se vienen tomando medidas, que van en todos los sentidos, desde la modelación de la calidad del aire, pasando por inventarios de emisiones de los diferentes sectores involucrados, creación de índices e indicadores de la calidad del aire para controlar, prevenir y mejorar las medidas que se toman al respecto, con la finalidad de obtener una mejor calidad de vida, que vaya en concordancia con el adecuado funcionamiento de los ecosistemas. El presente trabajo por tanto pretende realizar una caracterización de la calidad del aire debida al sector industrial así como proporcionar un sistema de medidas que sirva como punto de apoyo para las diferentes industrias a la hora de tomar decisiones en las que se impliquen las mejoras ambientales y en este caso específico un cambio en el manejo de las emisiones de contaminantes a la atmósfera. ; Air quality is a variable that affects the habitability of urban systems. The atmosphere is a system that supports relatively well the influence that the activities of the city exerts upon it, but in reality, the air that we breathe is vulnerable and has a limited carrying capacity. Due to this fact, in the built-up urban areas, the breathing air is far away from the satisfactory threshold recommended by the World Health Organization (WHO, 2006) A huge amount of studies have shown that some pollutants have adverse effects on human health, vegetation and on the environment, increasing the morbidity and mortality of the population, the acidification in the inland waters, affecting the flora and the biosphere's flora, altering the existing natural balance between the different ecosystems and even causing catastrophic changes in Earth's climate. Nowadays, the general public is aware of this fact, therefore, requires the government to work in this regard in order to improve the air quality (European Environment Agency, 2009). Moreover, the industry as an engine of the current development model is one of the causes of this series of negative effects on the society and the environment in which it develops, which are reflected in different aspects of the ecosystems, where it deposits its waste; this action must be treated and manage properly to prevent continued degradation of nature. (PASSOLA, 2006) It is to be note, that the current society model of economical development and its sprawl dynamic is closely linked to the increased emission into the atmosphere. This provision of the system increased demand amount of energy to perform their functions, which in turn are larger scale. This energy provision is mostly generated from fossil fuels such as coal, fuel-oil and natural gas, those, coming from not renewable sources, have a turnover rate lower than our rate of consumption. As a consequence, our energy consumption can and should be rethought in order to protect nature and moreover, plan a not only respectful living of the human being but integrated with it. On the other hand, the industry represents a very heterogeneous distribution on the territory and the wide variety of activities and processes requires a detail analysis by sector. Even within the same sector, the applied technologies can be widely. Among the sectors that lead with the highest emission contributions, there are: the energy production, oil refineries, chemical and steel industries as key sectors of basic industry. To deal the air pollution problem, it has been taking steps going in all directions, from modeling air quality, going through emission inventories of the different sectors involved. Besides, creation of indexes and indicators of air's quality in order to control, prevent and improve the measures taken in this regard, with the propose of obtain a better life quality that goes in line with the proper functioning of ecosystems. Therefore, this current investigation seeks to make a characterization of air quality due to the industrial sector as well as provide a measurement system that could be used as a support for the different industries when it comes to make decision which involve environmental improvements and in this specific case, a change in the management of pollutant emissions into the atmosphere. ; La qualitat de l'aire és una variable que condiciona l'habitabilitat dels sistemes urbans. L'atmosfera es un sistema, que aparentment, suporta relativament bé la influencià que sobre ella exerceixen les activitats pròpies d'una ciutat, però en realitat l'aire que respiren és vulnerable i té una capacitat de càrrega limitada. Es per això que les grans aglomeracions urbanes l'aire que respiren està lluny de satisfer els llindars recomanats per l'Organització Mundial de la Salut (OMS, 2006). Multitud d'estudis han posat en relleu que certs contaminants provoquen efectes nocius en la salut humana, en la vegetació i sobre el medi, augmenta la morbiditat i la mortalitat de la població, acidificant les aigües continentals, afectant a la fauna i la flora de la biosfera, alterant l'equilibri natural existent entre els diferents ecosistemes i fins i tot provocant canvis catastròfics en el clima terrestre. En l'actualitat, la població en general és coneixedora d'aquest fet i per tant exigeix als poders públics que treballin al respecte per millorar la qualitat de l'aire (European Environment Agency, 2009). D'altra banda la indústria com a motor del model de desenvolupament actual és una de les causants d'aquesta sèrie d'efectes negatius sobre la societat i el medi en que es desenvolupa, els quals es veuen reflectits en els diferents àmbits del ecosistema,on la mateixa diposita els seus residus, acció que ha de ser tractada i controlada degudament per evitar la continua degradació de la naturalesa (Passola, 2006). Cal destacar que el model de desenvolupament econòmic de la societat actual i la seva dinàmica de creixement desmesurat està íntimament lligat a l'augment de les emissions a l'atmosfera. Tal disposició del sistema demanda cada vegada major qualitat d'energia per realitzar les seves funcions, les quals a la vegada són de major escala. Aquesta provisió energètica generada en gran mesura a partir dels combustibles fòssils, com són el carbó, el fuel-oil i el gas natural, i al ser fonts no renovables, tenen una taxa de renovació inferior a la nostra taxa de consum. Com a conseqüència el nostre consum energètic pot i ha de ser replantejat per tal de protegir la natura i així plantejar una convivència de l'ésser humà no més respectuós sinó integrat amb ella. Per la seva banda, la indústria presenta un distribució molt heterogènia en el territori i la gran varietat d'activitats i processo obliga a un anàlisi detallada per sector. Fins i tot dins d'un mateix sector les tecnologies aplicades poden ser molt diverses. Entre els sectors que donen majors contribucions a les emissions trobem: la producció de energia, les refineries de petroli, les indústries químiques i la siderúrgia, com sectors fonamentals de la indústria bàsica. Per afrontar la problemàtica de la contaminació atmosfèrica, es necessari prenent mesures, en tots els sentits, des de la modelització de l'aire, passant per inventaris d'emissions dels diferents sectors involucrats, creació d'índexs i indicadors de la qualitat de l'aire per controlar, prevenir i millorar les mesures que es prenen al respecte, amb la finalitat de obtenir una millor qualitat de vida, que sigui concordant amb un adequat funcionament dels ecosistemes. Aquest treball per tant pretén realitzar una caracterització de la qualitat de l'aire emesa pel sector industrial així com proporcionar un sistema de mesures que serveixi com a punt de suport per a les diferents indústries a l'hora de prendre decisions en què s'impliquin les millores ambientals i en aquest cas específic un canvi en el maneig de les emissions de contaminats a l'atmosfera.

According to the European Parliament and the Council of the European Union (Regulation EC n.141/2000), rare diseases are defined solely on the basis of low prevalence and affect not more than five individuals per 10.000 in the European population. RD are a large and diverse group of disorders; they include more than 6.000 conditions and involve all organs and tissues, often with several clinical subtypes within the same disease. Almost all RD may cause early mortality and/or long-term disability and accurate and timely diagnosis is often of great importance for prevention and treatment. Very often information on many RD are insufficient, concerning either diagnosis and/or prognosis. An integrated approach was set on a very rare and severe liver malignancy of childhood, hepatoblastoma. Although its annual incidence in western countries is 1.5 cases per million of individuals younger than 15 years, HB represents the most common liver cancer of childhood (Reynolds et al., 2004; McLaughlin et al., 2006; Roebuck and Perilongo, 2006). Its prognosis depends on numerous clinical and histological factors. Children with a poor prognosis are usually characterized by abnormal α-fetoprotein levels (1,000,000 ng/ml) and distant metastases (i.e. lung and lymph nodes), whereas patients with good prognosis appear to have, among others, a decline in circulating AFP levels during chemotherapy (Roebuck and Perilongo, 2006; De Ioris et al., 2007). Scientific evidence points out HB as a multi-factorial condition associated with: genetic conditions (i.e. Beckwith-Wiedemann Syndrome and Familial Adenomatous Polyposis) (Roebuck and Perilongo, 2006), non genetic and environmental factors such as the endocrine-metabolic status of the mother (young age, higher body mass index, use of infertility treatments, smoking) and (pre)eclampsia (McLaughlin et al., 2006). An association with occupational paternal exposure to metals, petroleum products and paints/pigments as well the possible involvement of ubiquitous environmental contaminants, such as phthalates, have been suggested (Buckley et al., 1989; Reynolds et al., 2004; McLaughlin et al., 2006). Moreover, epidemiological data indicate low birth weight and increased survival of LBW newborns as consistently associated with increased risk of HB (Reynolds et al., 2004). In the first part of the project, in vitro studies on 4 liver cancer cell lines and 9 matched biopsis collected from HB patients were performed in order to individuate new molecular markers of childhood liver cancers. Special attention was dedicated to the canonical and non canonical WNT pathways and to the IGF-II signalling, since they are involved in the pathogenesis of FAP and BWS, the genetic disorders that predispose to HB onset. FAP patients carry a germline mutation in APC gene, which codifies for a protein that is part, together with Axin and GSK-3β, of the complex that controls the cytoplasmic levels of β-catenin (Orford et al., 1998), the central effector molecule of the canonical WNT pathway (Rubinfeld et al., 1996). BWS patients show a loss of imprinting LOI in the region 11p15, where IGF-II gene is localized. The LOI causes the biallelic expression and therefore, an increase of IGF-II levels, that could lead, as suggested by Veronese and coworkers, to enhanced cellular proliferation, differentiation failure and tumour development (Veronese et al., 2010). An mRNA- and protein-array, performed on the liver cancer cell lines; showed different signatures in the expression levels of genes and proteins, compared to normal human hepatocytes. The mRNA array analyzed the expression of several genes (96) involved in canonical and non canonical WNT signallings and revealed, in liver cancer cell lines compared to normal human hepatocytes, the contemporary upregulation of antagonists genes of the canonical WNT pathway, such as NLK and SOX17, and the downregulation of its agonists genes, such as TCF7L2, TLE1, SLC9A3R1 and WNT10A. These evidences suggest an inactivation of the canonical WNT signalling; at the same time the overexpression of RHOU transcript indicate the activation of the non canonical WNT signalling. The very innovative protein array technology evaluated the epression levels of 224 proteins involved in biological pathways such as apoptosis, cell cycle, and signal transduction, and revealed that Grb-2 is over-expressed in the cell lines investigated, compared to normal human primary hepatocytes. Grb-2 is an ubiquitously expressed adapter induced by IGF (I and II) signallings, in normal conditions; through the interaction with Raf/MAPK, Grb-2 activation leads to the induction of cellular proliferation (Foulstone et al., 2005). In a second step, we approached the study of 3 snap-frozen and 6 paraffin-embedded matched tissues obtained from HB patients. In these rare samples we could evaluate the markers previously evidenced and validated in liver cancer cell lines (NLK, RHOU and WNT10A transcripts; Grb-2 protein). This study showed similar results in HB matched tissues when compared to liver cancer cell lines, suggesting that these markers are reliable also in HB tissue samples. MicroRNAs are small RNA sequences, 20-22 nucleotides long, that can bind to the 3'UTR of specific mRNAs, and regulate their expression by leading to translational repression, mRNA cleavage, and mRNA decay. Since microRNA expression profiles are altered in several tumours compared to their normal counterparts, these molecules are largely used also in the field of cancer classification (Calin and Croce, 2006). A microRNA-array, performed in the three snap-frozen HB tissues, revealed that 51 microRNAs could distinguish tumour from non-tumour samples. By comparing our results with previously published data (Varnholt et al., 2008), we selected 9 microRNAs to be analysed in our 9 matched samples. The comparison between these microRNAs expression in tumour and in non-tumour counterparts, highlighted four up-regulated microRNAs (miR-125a, -150, -199a and -214), and a down-regulated one (miR-148a). It has been demonstrated that miR-214 binds to the PTEN mRNA and downregulates its protein levels (Yang et al., 2008). PTEN is a negative regulator of the PI3K/Akt pathway which is activated by IGF signalling, in normal conditions (Foulstone et al., 2005). In our samples as well, the comparison of tumour and normal counterparts indicated a correlation between high miR-214 levels and low PTEN protein levels in the tumour samples. The study of liver cancer cell lines and HB biopsis revealed the inactivation of the canonical WNT pathway and the contemporary induction of the non canonical one. Furthermore the activation of IGF-signalling is also speculated on the basis of the deregulation of Grb-2 and PTEN protein levels. In the second part of the project the association between HB onset and the exposure to a particular phthalate, DEHP, was investigated. DEHP is the most abundant phthalate in the environment and liver represents one of its main targets. Studies performed on mice and humans demonstrated that DEHP alters the glucose metabolism (Latini et al., 2008). This process involve a family of proteins called PPARs that mediates the IGF-promoted signalling (Feige et al., 2007; Latini et al., 2008), responsible of glycogen storage (Lopez et al., 1999). In utero exposure to phthalates has been shown to be significantly associated with prematurity (Latini et al., 2008), that in turn has been strongly associated with HB (McLaughlin et al., 2006). HB can derive either from developmental disturbances during critical phases of organogenesis or from the interplay of risk factors (e.g. DEHP) during prenatal or early neonatal life (Salvatore et al., 2008). In order to investigate the post-natal effects of DEHP prenatal exposure on liver development, pregnant CD-1 mice were exposed to DEHP (25 and 100 mg/kg BW pro die) during the critical period of liver organogenesis and histogenesis (starting from the 11th day of gestation and till the 19th) (Duncan, 2003). Male and female F1 mice were sacrificed at post natal day 21 and 35, respesenting weaning and puberty, respectively. Histopathological, histochemical and gene expression studies performed on livers of PND35 treated mice did not show significant differences compared to controls, while at PND21 treated mice showed alterations in glucose and lipid metabolism that were absent in controls. The inactivation of GSK-3β was speculated since these mice were characterized by lack of glycogen storage and presence of cytoplasmic β-catenin. Glycogen storage is triggered by IGF-II in fetal life and ensures stable levels of glycaemia at birth when the newborn makes the adjustment to extra-uterine life (Lopez et al., 1999; Hui et al., 2006). The presence of cytoplasmic β-catenin indicates that the canonical WNT pathway is active, and that the transcription of genes involved in cell proliferation is promoted (Rubinfeld et al., 1996). PND21 mice exposed to DEHP showed hepatocytes vacuolization (hepatosteatosis), a feature of an ecess of fatty acid synthesis, as a consequence of glycogen synthesis inhibition (Shimano et al., 2007). AFP levels in mice progressively decrease after birth and are almost completely switched off in the third week of life, when liver accumulates energy as glycogen instead of AFP (Rusyn et al., 2006; Heudorf et al., 2007; Latini et al., 2009) On the basis of the association between AFP expression and embryonal status, this gene is also used as a marker of hepatocytes maturation (Qin and Tang, 2004). Our results showed high levels of AFP gene expression in treated mice compared to controls, suggestable of a role for DEHP exposure in determining both the alteration of post-natal AFP to glycogen switch off, and a delay of hepatocytes maturation. Furthermore the possible role of microRNAs in the DEHP-induced alterations was speculated. IGF-II gene, fundamental in the promotion of glycogen storage during fetal life (Lopez et al., 1999; Hui et al., 2006), harbours a microRNA, miR-483, within its second intron (Fu et al., 2005; www.ensembl.org). The analysis of miR-483 expression showed that this miR can be considered a fetal marker, since its levels progressively decrease after birth. High levels of miR-483 were detected in PND21 mice treated with DEHP 100 mg/kg bw pro die, in confirmation with a role of DEHP exposure in delaying the hepatocytes maturation. We also demonstrated that this miR is able to target and downregulate β-catenin, thus representing a limit in the proliferation stimulus induced by high levels of this protein within the cytoplasm (Rubinfeld et al., 1996). The multidisciplinary approach, performed by using in vivo and in vitro studies, enabled us to identify early and tardive markers of hepatoblastoma. Our studies indicated that the prenatal exposure to DEHP delays liver maturation by affecting carbohydrate and lipid pathways involved in fetal nutrition. The incapability to accumulate glycogen, due to the inactivation of GSK-3β function, is counterbalanced by an enhanced synthesis of lipid, as demonstrated by the presence of hepatocyte vacuolization. Furthermore the improper increased levels of AFP gene expression, suggested that DEHP alters the post-natal AFP-to-glycogen switch and may delay the post natal maturation of hepatocytes, as suggested also by high levels of miR-483, another fetal marker. A biological role for miR-483 in limiting the proliferation activation induced by β-catenin has been also proposed. The characterization of in vitro models (liver cancer cell lines and HB matched tissue samples) has identified new molecular tardive markers of chilhood liver cancers, at mRNA- (WNT10A, NLK and RHOU trascripts), protein- (Grb-2 and PTEN), and at microRNA- (miR-214) level. Gene expression analysis showed an inactivation of the canonical WNT signalling; and the contemporary activation of the non canonical one. At protein level, the upregulation of Grb-2 in tumour compared to non tumour samples, lets speculate the activation of the Raf/MAPK signalling pathway. The upregulation of miR-214 in tumour compared to non tumour samples seemed to affect PTEN protein levels, which resulted to be downregulated in the tumour counterpart. This evidence suggests that the activation of PI3K/Akt pathway could lead to the misregulation of the cellular functions that it controls, such as glucose metabolism, cell proliferation and survival (Foulstone et al., 2005). Even though in in vivo and in vitro models the patterns of deregulation of WNT and IGF-signalling pathways involve different mechanisms, the importance of these pathways and their crosstalks can be considered pivotal in the onset and in the characterization of hepatoblastoma.

Ensuring access to essential medicines is a key objective of all health systems, and is an integral component of the progress towards universal health coverage (UHC). Despite global and national efforts to improve access and affordability of medicines, millions of people – particularly in low- and middle-income countries – still remain without access to quality-assured and affordable medicines. This study aims to contribute to existing knowledge on regulatory systems and harmonization efforts in Southeast Asia. Focusing on five member states of the Association of Southeast Asian Nations (ASEAN) – Indonesia, Malaysia, the Philippines, Thailand, an Vietnam – this study gives an overview of pharmaceutical markets and key pharmaceutical policies in the region, provides a cross-country comparison of medicines regulatory systems, and details harmonization efforts, opportunities, and challenges.

Low export prices and high production costs are contributing to a persistent deficit in the external accounts. Despite narrowing somewhat in recent years, Zimbabwe's current account deficit remains much larger than those of comparable countries in the region, and exports currently amount to just over half of imports. A decline in global prices for gold, platinum and other mineral commodities, coupled with unresolved supply-side constraints, has reduced the value of mining exports. Zimbabwe has also benefited from lower oil prices, but rising import volumes largely offset the impact on import values. Remittances gradually increased during 2010-2015 and are estimated to have reached almost 7 percent of Gross National Income (GNI) in 2015. The domestic financial sector is slowly recovering from a post-dollarization credit boom and interest rates remain elevated. The Central Bank has stabilized the financial sector, a recent growth of broad money looks robust and bank lending has become market-driven. But still only blue-chip borrowers are able to access financing at competitive rates. The authorities are taking measures to update Zimbabwe's credit infrastructure, strengthen oversight and restore the regulatory framework. Zimbabwe is experiencing a deflationary trend in response to these macroeconomic imbalances. The multicurrency regime, adopted in 2009, limits monetary policy instruments available to the authorities but also provides a level of fiscal and economic restraint. As competitive pressures increased, the consumer price index fell -2.5 percent, year-on-years, at end-2015. Declining prices should help to restore competitiveness over time, but should be accompanied by efforts to raise productivity at all levels of the economy.

This study examines the determinants of adolescent sexual behavior and fertility in Nigeria, with a special focus on knowledge, attitudes and behaviors of adolescents aged 10-19 years old in Karu Local Government Authority (LGA), a peri-urban area near the capital city of Abuja. Using the last three waves of Demographic and Health Surveys (2003, 2008, 2013), focus group discussions, stakeholder interviews, and a specialized survey of 643 girls and boys aged 10-19 years old in Karu LGA, the study narrows in on key challenges to and opportunities for improving adolescent sexual and reproductive health outcomes. The national median age at sexual debut for adolescent girls and boys is between 15 and 16 years of age. This is closely emulated in Karu LGA with a median age of 14.8 years for girls and 15.3 years for boys. While data on pregnancies was limited in the Karu sample, DHS data show that for girls, sexual debut is closely associated with marriage or cohabitation, which in turn is a strong predictor of adolescent fertility. Poverty is another strong predictor, with the odds of becoming pregnant being twice as high for adolescents in the lower wealth quintiles compared to their counterparts in the richest quintile in the country. While adolescents' knowledge of contraception has increased from under 10 percent to over 30 percent, use of health services among adolescents for SRH (and contraception) is limited due to factors such as fear of stigma, embarrassment, and poor access to services, something also emphasized in focus group discussions. Challenges for improving adolescent SRH outcomes relate to: (i) the paucity of data, especially on the 10-14 year olds; (ii) availability and access to youth-friendly services and the Family Life and HIV Education (FLHE); (iii) reaching out-of-school adolescents with SRH information; and (iv) addressing ambiguities and gaps in Federal law and customs on age at marriage, and generating support for the legal age at marriage of at least 18 years old. Addressing these barriers at the State and sub-regional levels is going to be critical in improving adolescent well-being.

In 2015, Indonesia stands as an increasingly divided country, unequal in many ways. There is a growing income divide between the richest 10 percent and the rest of the population, and this gap is driven by many other types of inequality in Indonesia.People are divided into haves and have-nots from before birth. Some children are born healthy and grow up well in their early years; many do not. Some children go to school and receive a quality education; many do not. In today's modern and dynamic economy; most do not and are trapped in low-productivity and low-wage jobs. Some families have access to formal safety nets that can protect them from the many shocks that occur in life; many do not. And a fortunate few Indonesians have access to financial and physical assets (such as land and property) that increase their wealth over time. This wealth is passed down from generation to generation, both in the form of money and physical assets, and through greater access to better health and education. As a result, inequalities are being compounded and deepened over time. This report asks why inequality is increasing, why it matters, and what can be done. The first section examines the trend in inequality, which is already relatively high in Indonesia and rising more rapidly than in many neighboring countries. The second section seeks to understand what is driving rising inequality in Indonesia. The final section looks at what can be done to prevent the country from becoming even more divided. This section suggests ways to avoid an Indonesia in which relatively few people are healthy, happy and prosperous, and many more can only aspire to a better life but are unable to attain it.

This report is the result of extensive analytical work on social protection in Chad. During 2014 and 2015, the World Bank's Social Protection and Labor (SPL) Global Practice undertook extensive analytical work in Chad to assess the country's poverty and vulnerability profile, and the characteristics of its social safety nets system. This report, Republic of Chad – Shaping Adaptive Safety Nets to Address Vulnerability, is the result of such work and was prepared in the context of the renewed relationship between the Government of Chad and the World Bank. Such partnership includes the reengagement of the World Bank on the SPL agenda, and programming of World Bank support to Chad as part of the Systematic Country Diagnostic and the Country Partnership Framework.