Role of seipin in lipid droplet morphology and hepatitis C virus life cycle.

Infectious hepatitis C virus (HCV) particle assembly starts at the surface of lipid droplets, cytoplasmic organelles responsible for neutral fat storage. We analysed the relationship between HCV and seipin, a protein involved in lipid droplet maturation. Although seipin overexpression did not affect the total mean volume occupied by lipid droplets nor the total triglyceride and cholesterol ester levels per cell, it caused an increase in the mean diameter of lipid droplets by 60 %, while decreasing their total number per cell. The latter two effects combined resulted in a 34 % reduction of the total outer surface area of lipid droplets per cell, with a proportional decrease in infectious viral particle production, probably due to a defect in particle assembly. These results suggest that the available outer surface of lipid droplets is a critical factor for HCV release, independent of the neutral lipid content of the cell.

The Interaction of the Calcium Sensitiser Levosimendan with Cardiac Troponin C

Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increase. Effective treatments including the use of calcium sensitisers are being sought. They cause a positive inodilatory effect on cardio-myocytes without deleterious effects (arrhythmias) resulting from increases in intracellular calcium concentration. Levosimendan is a novel calcium sensitiser that hasbeen proved to be a welltolerated and effective treatment for patients with severe decompensated heart failure. Cardiac troponin C (cTnC) is its target protein. However, there have been controversies about the interactions between levosimendan and cTnC. Some of these controversies have been addressed in this dissertation. Furthermore, studies on the calcium sensitising mechanism based on the interactions between levosimendan and cTnC as followed by nuclear magnetic resonance(NMR) are presented and discussed. Levosimendan was found to interact with bothdomains of the calcium-saturated cTnC in the absence of cardiac troponin I (cTnI). In the presence of cTnI, the C-domain binding site was blocked and levosimendan interacted only with the regulatory domain of cTnC. This interaction may have caused the observed calcium sensitising effect by priming the N-domain for cTnI binding thereby extending the lifetime of that complex. It is suggested that this is achieved by shifting the equilibrium between open and closed conformations.

Warlike outlines of the securitarian state. Life control and the exclusion of people

Present book collects some of the thoughts developed during the 5 years (2004-2009) of work in the frame of the CHALLENGE project, "The Changing Landscape of European Liberty and Security". The project has related academic knowledge and research with the analysis of the policies and practices of the member States of the European Union [EU] around the couple liberty and security

Evaluación de la educación emocional en el ciclo medio de Educación Primaria

El principal propósito de la educación consiste en favorecer el desarrollo integral de la persona, lo cual implica atender el aspecto cognitivo y afectivo. Tradicionalmente, se han priorizado sólo los contenidos cognitivos por este motivo queremos incidir sobre los afectos. El objetivo general de este trabajo de investigación que presentamos consiste en aplicar y evaluar un Programa de Educación Emocional (PEEP), integrado dentro del currículum de Primaria de ciclo medio que ayude a prevenir los efectos nocivos de las emociones negativas y facilite la relación consigo mismo y con los demás. Objetivo general que se constatara a partir de cuatro criterios: conseguir un mejor conocimiento de las propias emociones y de las emociones de los demás, desarrollar estrategias de regulación emocional, mejorar la autoestima, aprender habilidades de vida y socioemocionales. Pues, la finalidad es intervenir en la mejora de la educación emocional de los alumnos entre los 8 y los 10 años, en total 510 alumnos de los cuales 104 formaron la muestra de investigación. Fueron divididos en dos grupos el grupo experimental y el grupo control, ambos constituían una muestra homogénea y estadísticamente comparable por lo que podíamos plantearnos una intervención y valorar su incidencia. Los resultados indican que mejora el nivel de Educación Emocional (EE) de estos alumnos con un nivel de significación de p= 0,001. A partir de este momento, podemos concretar que los resultados conseguidos por los alumnos que han seguido la aplicación del programa mejoran significativamente. Este resultado, nos permite afirmar que el uso intencional del programa de educación emocional para mejorar el ámbito afectivo ha incidido positivamente en el proceso de aprendizaje de los alumnos. Sin embargo consideramos esencial llevar a cabo una formación y posterior evaluación del profesorado en EE, como paso previo necesario para una aplicación óptima del programa.

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.

BACKGROUND: Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. CASE PRESENTATION: We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. CONCLUSIONS: The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

Planning and reporting of quality-of-life outcomes in cancer trials.

BACKGROUND: Information about the impact of cancer treatments on patients' quality of life (QoL) is of paramount importance to patients and treating oncologists. Cancer trials that do not specify QoL as an outcome or fail to report collected QoL data, omit crucial information for decision making. To estimate the magnitude of these problems, we investigated how frequently QoL outcomes were specified in protocols of cancer trials and subsequently reported. DESIGN: Retrospective cohort study of RCT protocols approved by six research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We compared protocols to corresponding publications, which were identified through literature searches and investigator surveys. RESULTS: Of the 173 cancer trials, 90 (52%) specified QoL outcomes in their protocol, 2 (1%) as primary and 88 (51%) as secondary outcome. Of the 173 trials, 35 (20%) reported QoL outcomes in a corresponding publication (4 modified from the protocol), 18 (10%) were published but failed to report QoL outcomes in the primary or a secondary publication, and 37 (21%) were not published at all. Of the 83 (48%) trials that did not specify QoL outcomes in their protocol, none subsequently reported QoL outcomes. Failure to report pre-specified QoL outcomes was not associated with industry sponsorship (versus non-industry), sample size, and multicentre (versus single centre) status but possibly with trial discontinuation. CONCLUSIONS: About half of cancer trials specified QoL outcomes in their protocols. However, only 20% reported any QoL data in associated publications. Highly relevant information for decision making is often unavailable to patients, oncologists, and health policymakers.

The use of cost per life year gained as a measurement of cost-effectiveness in Spain: a systematic review of recent publications

The objective of this study was to evaluate the methodological characteristics of cost-effectiveness evaluations carried out in Spain, since 1990, which include LYG as an outcome to measure the incremental cost-effectiveness ratio. METHODS: A systematic review of published studies was conducted describing their characteristics and methodological quality. We analyse the cost per LYG results in relation with a commonly accepted Spanish cost-effectiveness threshold and the possible relation with the cost per quality adjusted life year (QALY) gained when they both were calculated for the same economic evaluation. RESULTS: A total of 62 economic evaluations fulfilled the selection criteria, 24 of them including the cost per QALY gained result as well. The methodological quality of the studies was good (55%) or very good (26%). A total of 124 cost per LYG results were obtained with a mean ratio of 49,529 and a median of 11,490 (standard deviation of 183,080). Since 2003, a commonly accepted Spanish threshold has been referenced by 66% of studies. A significant correlation was found between the cost per LYG and cost per QALY gained results (0.89 Spearman-Rho, 0.91 Pearson). CONCLUSIONS: There is an increasing interest for economic health care evaluations in Spain, and the quality of the studies is also improving. Although a commonly accepted threshold exists, further information is needed for decision-making as well as to identify the relationship between the costs per LYG and per QALY gained.

Very preterm infants in Finland - Use of health care services and economic consequences during the first five years of life

The aim of this thesis was to study the health, the hospitalisations, and the use of communal health care services in very preterm children during the first five years of life. In addition, the effect of very preterm birth and prematurity-related morbidities on the costs of hospitalisations, other health care services and the cost per quality adjusted life years (QALY) were studied. This population-based study included all very preterm children (gestational age (GA) <32 weeks or birth weight<1501g, N=2 064) and full-term controls (GA 37+0−41+6, N=200 609) born in Finland during 2000-2003. The data sources included national register data, costing data from the participating hospitals and parental questionnaires. This study showed that most very preterm infants born in Finland survived without prematurity-related morbidities diagnosed during the first years of life. They required relatively little hospital care after the initial discharge, which accounted for the vast majority of the total four-year hospitalisation costs. However, a minority of children born very preterm later developing morbidities had a long initial length of stay and more re-admissions and outpatient visits during the five-year follow-up period. In particular, the number and costs of non-emergency outpatient visits were considerable in individuals with prematurity-related morbidities. The need and costs of hospitalisations decreased clearly with each follow-up year, even in individuals with morbidities. The health-care related costs during the fifth year of life in children born very preterm without prematurity-related morbidities were close to the costs in infants born healthy at term. The cost per QALY of 19,245 € was at an acceptable level already by four years of age in the very preterm population as a whole. Prematurity-related later morbidities and decreasing GA increased the costs per QALY. As the initial hospital stay accounted for a great majority of the total four-year costs, and the costs of hospitalisation decreased with each follow-up year, the cost per QALY is likely to decrease with age. In conclusion, the majority of costs arising after the initial hospitalisation were associated with morbidities related to prematurity. Therefore offering high-quality neonatal care to prevent later morbidities in very preterm survivors has a long-term impact on the cost per QALY. In addition, this study indicates that when estimating the costs of prematurity after the first year of life, one should calculate not only the hospitalisation costs, but also other costs for social welfare services, primary care, and therapies, as these exceed the hospitalisation costs in very preterm infants during the fifth year of life.

Integration in project business : mechanisms for integrating customers and the project network during the life-cycle of industrial projects

This thesis focuses on integration in project business, i.e. how projectbased companies organize their product and process structures when they deliver industrial solutions to their customers. The customers that invest in these solutions run their businesses in different geographical, political and economical environments, which should be acknowledged by the supplier when providing solutions comprising of larger and more complex scopes than previously supplied to these customers. This means that the suppliers are increasing their supply range by taking over some of the activities in the value chain that have traditionally been handled by the customer. In order to be able to provide the functioning solutions, including more engineering hours, technical equipment and a wider project network, a change is needed in the mindset in order to be able to carry out and take the required responsibility that these new approaches bring. For the supplier it is important to be able to integrate technical products, systems and services, but the supplier also needs to have the capabilities to integrate the cross-functional organizations and departments in the project network, the knowledge and information between and within these organizations and departments, along with inputs from the customer into the product and process structures during the lifecycle of the project under development. Hence, the main objective of this thesis is to explore the challenges of integration that industrial projects meet, and based on that, to suggest a concept of how to manage integration in project business by making use of integration mechanisms. Integration is considered the essential process for accomplishing an industrial project, whereas the accomplishment of the industrial project is considered to be the result of the integration. The thesis consists of an extended summary and four papers, that are based on three studies in which integration mechanisms for value creation in industrial project networks and the management of integration in project business have been explored. The research is based on an inductive approach where in particular the design, commissioning and operations functions of industrial projects have been studied, addressing entire project life-cycles. The studies have been conducted in the shipbuilding and power generation industries where the scopes of supply consist of stand-alone equipment, equipment and engineering, and turnkey solutions. These industrial solutions include demanding efforts in engineering and organization. Addressing the calls for more studies on the evolving value chains of integrated solutions, mechanisms for inter- and intra-organizational integration and subsequent value creation in project networks have been explored. The research results in thirteen integration mechanisms and a typology for integration is proposed. Managing integration consists of integrating the project network (the supplier and the sub-suppliers) and the customer (the customer’s business purpose, operations environment and the end-user) into the project by making use of integration mechanisms. The findings bring new insight into research on industrial project business by proposing integration of technology and engineering related elements with elements related to customer oriented business performance in contemporary project environments. Thirteen mechanisms for combining products and the processes needed to deliver projects are described and categorized according to the impact that they have on the management of knowledge and information. These mechanisms directly relate to the performance of the supplier, and consequently to the functioning of the solution that the project provides. This thesis offers ways to promote integration of knowledge and information during the lifecycle of industrial projects, enhancing the development towards innovative solutions in project business.

Lujien hitsattavien terästen käyttäytyminen -60 °C:ssa

Opinnäytetyö on osa Arctic Materials Technologies Development -projektia, jonka tavoitteena on kehittää perusteita arktisten alueiden sovelluksiin suunnittelun ja valmistuksen kannalta. Arktisella alueella sijaitsee useita potentiaalisia öljy- ja maakaasuesiintymiä, joiden hyödyn-täminen tulee vuosi vuodelta kannattavammaksi ilmaston lämpenemisestä johtuvan merijään heikkenemisen vuoksi. Alin suunnittelulämpötila arktisilla alueilla on -60 °C, mikä aiheuttaa haasteita sekä materiaalinvalinnalle että hitsaukselle. Ferriittisillä teräksillä esiintyy lämpötilasta riippuvaa sitkeyden vaihtelua, jota kutsutaan transi-tiokäyttäytymiseksi. Lämpötilan laskiessa teräksen iskusitkeys sekä murtumissitkeys laske-vat. Arktisissa sovelluskohteissa käytetään yleisesti niukkaseosteisia, mikroseostettuja hie-noraeteräksiä, joille on ominaista erinomaiset sitkeys-, lujuus- sekä hitsattavuusominaisuudet vaativissakin olosuhteissa. Lujat termomekaanisesti valssatut ja nuorrutetut hienoraeteräkset kattavat myötölujuusluokat 355…700 MPa. Tutkimuksissa on saatu vaihtelevia tuloksia ma-teriaalien isku- ja murtumissitkeydestä -60 °C:ssa. Erityisesti sitkeysominaisuudet hitsiaineen ja muutosvyöhykkeen alueiden välillä ovat vaihtelevia. Pienemmällä lämmöntuonnilla ja seostetuilla lisäaineilla saavutetaan kuitenkin pääsääntöisesti parempia sitkeysarvoja. Asiku-laarinen ferriitti sekä alabainiitti ovat toivottavia mikrorakenteita liitoksessa, niiden pienen raekoon johdosta.

Weight of preterm newborns during the first twelve weeks of life

A longitudinal and prospective study was carried out at two state-operated maternity hospitals in Belo Horizonte during 1996 in order to assess the weight of preterm appropriate-for-gestational-age newborns during the first twelve weeks of life. Two hundred and sixty appropriate-for-gestational-age preterm infants with birth weight <2500 g were evaluated weekly. The infants were divided into groups based on birth weight at 250-g intervals. Using weight means, somatic growth curves were constructed and adjusted to Count's model. Absolute (g/day) and relative (g kg-1 day-1) velocity curves were obtained from a derivative of this model. The growth curve was characterized by weight loss during the 1st week (4-6 days) ranging from 5.9 to 13.3% (the greater the percentage, the lower the birth weight), recovery of birth weight within 17 and 21 days, and increasingly higher rates of weight gain after the 3rd week. These rates were proportional to birth weight when expressed as g/day (the lowest and the highest birth weight neonates gained 15.9 and 30.1 g/day, respectively). However, if expressed as g kg-1 day-1, the rates were inversely proportional to birth weight (during the 3rd week, the lowest and the highest weight newborns gained 18.0 and 11.5 g kg-1 day-1, respectively). During the 12th week the rates were similar for all groups (7.5 to 10.2 g kg-1 day-1). The relative velocity accurately reflects weight gain of preterm infants who are appropriate for gestational age and, in the present study, it was inversely proportional to birth weight, with a peak during the 3rd week of life, and a homogeneous behavior during the 12th week for all weight groups.

Absence-like seizures in adult rats following pilocarpine-induced status epilepticus early in life

Administration of pilocarpine causes epilepsy in rats if status epilepticus (SE) is induced at an early age. To determine in detail the electrophysiological patterns of the epileptogenic activity in these animals, 46 Wistar rats, 7-17 days old, were subjected to SE induced by pilocarpine and electro-oscillograms from the cortex, hippocampus, amygdala, thalamus and hypothalamus, as well as head, rostrum and vibrissa, eye, ear and forelimb movements, were recorded 120 days later. Six control animals of the same age range did not show any signs of epilepsy. In all the rats subjected to SE, iterative spike-wave complexes (8.1 ± 0.5 Hz in frequency, 18.9 ± 9.1 s in duration) were recorded from the frontal cortex during absence fits. However, similar spike-wave discharges were always found also in the hippocampus and, less frequently, in the amygdala and in thalamic nuclei. Repetitive or single spikes were also detected in these same central structures. Clonic movements and single jerks were recorded from all the rats, either concomitantly with or independently of the spike-wave complexes and spikes. We conclude that rats made epileptic with pilocarpine develop absence seizures also occurring during paradoxical sleep, showing the characteristic spike-wave bursts in neocortical areas and also in the hippocampus. This is in contrast to the well-accepted statement that one of the main characteristics of absence-like fits in the rat is that spike-wave discharges are never recorded from the hippocampal fields.