Familial hypercholesterolemia is a genetic disease affecting about 10 million people around the world. Those who carry the disease have a very high risk of developing cardiovascular diseases and commonly encounter myocardial infarction at the early age of 40. Therefore, a diagnosis and immediate treatment are very important for these patients. Despite many combinations of available drugs, there are many patients who still cannot reach the desired cholesterol levels. Mipomersen is a new lipid-lowering drug which inhibits the synthesis of apolipoprotein B, a common component of lipoproteins such as low-density lipoprotein. Inhibition of this protein leads to reduced production of these lipoproteins and reduces the risk of cardiovascular diseases. The drug is currently only indicated for treating patients with homozygous familial hypercholesterolemia.  Unfortunately, there have been many reports of adverse events in patients using mipomersen which has proven problematic.         The aim of this thesis is to analyze the efficacy and safety of mipomersen when treating patients with familial hypercholesterolemia. This has been done by searching for five clinical trials in the database Web of Science. The studies were required to include patients with familial hypercholesterolemia, use mipomersen as the study drug and analyze its effect and safety.   The studies showed that mipomersen has a very good effect in decreasing low-density lipoproteins as well as other lipoproteins in comparison to placebo. Many of the patients who were treated with mipomersen displayed several adverse events and the most common were injection-site reaction and influenza-like symptoms. Elevated levels of aminotransaminase and increased fat deposit in the liver were also common. Based on the five clinical trials analyzed in this thesis, mipomersen is an effective lipid-lowering drug which reduces low density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a) in patients with familial hypercholesterolemia. Elevations in alanine aminotransferase and aspartate aminotransferase are common in patients treated with mipomersen. This could indicate a negative impact on the liver. To be more certain of its safety profile, more research could be needed. There are however, new treatments that combines statins and a proprotein convertase subtilisin/kexin 9 inhibitor, which could be the future of lipid-lowering treatments and mipomersen would then likely be substituted.

Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor. Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy. In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury. Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.

The toxicity of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) was measured. When Caco-2 cells from human adenocarcinoma are cultivated on a filter a monolayer is formed with properties similar to human duodenum epithelium. The Caco-2 cells grown on filter were exposed to the environmental contaminants PFOS and PFOA. The effects on the Caco-2 epithelium were examined by four different methods: trans-epithelial resistance (TEER), leakage of the intracellular protein lactate dehydrogenase (LDH), 14C-mannitol passage through the epithelium and protein content of the epithelium. TEER and C-mannitol passage show the Caco-2 cellmonolayer integrity, LDH leakage gives information of cytotoxicity and protein content of the epithelium shows cell adhension to the filter. In the first study TEER decreased at the highest concentrations of PFOS and PFOA (1Mm). The 14C-mannitol passage increased at the highest PFOS concentration. No cytotoxicity was shown and protein-loss was not observed. The second study with PFOS doses of 0, 1, 10, 100 and 500µM and 1 and 10mM showed that the effect of PFOS on TEER was dose-dependent. The 14C-mannitol passage was very high at the highest PFOS-concentration (10mM) and a dose-response was indicated. No cytotoxicity was demonstrated and protein-quantity was not affected. In the third study it was demonstrated that the toxicity of PFOS did not depend on the different concentrations of the oil-emulsion used to dissolve PFOS and PFOA.

The resistance of established medicines is rapidly increasing while the rate of discovery of new drugs and treatments have not increases during the last decades (Spiro et al. 2008). Systems pharmacology can be used to find new combinations or concentrations of established drugs to find new treatments faster (Borisy et al. 2003). A recent study aimed to use high resolution Liquid chromatography–mass spectrometry (LC-MS) for in vitro systems pharmacology, but encountered problems with unwanted variability and batch effects(Herman et al. 2017). This thesis builds on this work by improving the pipeline and comparing alternative methods and evaluating used methods. The evaluation of methods indicated that the data quality was often not improved substantially by complex methods and pipelines. Instead simpler methods such as binning for feature extraction performed best. In-fact many of the preprocessing method commonly used proved to have negative or neglect-able effects on resulting data quality. Finally the recently introduced Optimal Orthonormal System for Discriminant Analysis (OOS-DA) for batch removal was found to be a good alternative to the more complex Combat method.

Prostate cancer is the leading male cancer form i Sweden and maybe worldwide as well. Vitamin D is synthesized in the skin following the exposure to sunlight. Researcers have long been aware of the positive effect that vitamin D3 has on prostate tumour growth. 1,25(OH)2D3 have for a long time been the target of these studies and have shown good results. The steroid hormone induces cAMP accumulation and activiates the cAMP dependent protein kinaseA (PKA). PKA is then able to activate a transcription regulating protein. 1,25(OH)2D3 is known to cause LNCaP cells to accumulate in the G1 phase ofthe cell cycle. It has also been shown that 1,25(OH)2D3 is under negativefeedback control via 24-hydroxylase. In this study, PKA activity was observed by transfecting LNCaP cells with a viral vector carrying firefly and Renillaluciferase genes. The successfully transfected LNCaP cells would then express luciferase as a response to PKA gene expression. The LNCaP cells were then treated with 1,25(OH)2D3 and GDP-β-S (100μM), a G-protein coupled receptorinhibitor, in order to examine if 1,25(OH)2D3 regulate PKA dependent gene expression through a G-protein coupled receptor. The study could show that 1,25(OH)2D3 regulate gene expression in LNCaP cells through a PKAdependent pathway. Furthermore, the PKA dependent gene expression was demonstrated to be independent of G-protein coupled recpetor activation.

Introduction: Significant changes in the global ecosystem, together with a potential shortfall in oil resources, have stimulated intense interest in the development of other sources of energy, and most particularly biofuels since these are basically considered to be less harmful to human health than petroleum-based fuels. However, information about the impact of biofuel-derived vehicle emissions on human health is limited and incomplete.   Aim of the study: To identify those biofuels that are less detrimental to human health on the basis of published results from toxicological and chemical studies of vehicle emission products.   Tasks of the study: To review systematically all conventional and alternative fuels used in internal combustion engines, to identify all known toxic emission products formed by such fuels, to review their toxic effects on human health, and to analyse the data collected in order to develop conclusions concerning the possible health benefits deriving from the use of alternative fuels.   Materials and methods: In order to fulfil the requirements of a complete, comprehensive and up-to-date review of the toxic effects of automotive exhaust, an extensive search of official scientific data sources has been performed. Relevant publications were retrieved from public domain databases with a toxicological focus such as Toxcenter and CAplus, as well as from the websites of the US Environmental Protection Agency and the US Agency for Toxic Substances and Disease Registry. Keywords employed in the literature search were: petrol, gasoline, diesel exhaust, emission, biofuel, biogas, biodiesel, bioethanol, bioalcohol, toxicity, methanol and ethanol. A total of 295 references were initially selected relating to the period 1962 to 2008, and 142 of these presented titles and abstracts that met the main inclusion criteria, i.e. describing toxicological and epidemiological studies in humans. In cases where eligible studies relating to the goals and tasks of the review were limited or not available, some in vitro or in vivo toxicological studies involving animal models were included.   Results: In comparison with petroleum diesel, the emissions derived from biodiesel contain less particulate matter, carbon monoxide, total hydrocarbons and other toxic compounds including vapour-phase C1-C12 hydrocarbons, aldehydes and ketones (up to C8), selected semi-volatile and particle-phase polycyclic aromatic hydrocarbons (PAHs). Whilst sulphur-containing compounds appear to be undetectable in biodiesel, nitrogen oxide and a soluble organic fraction comprising unregulated pollutants including the “aggregated toxics” (i.e., formaldehyde, acetaldehyde, acrolein, benzene, 1,3-butadiene, ethylbenzene, n-hexane, naphthalene, styrene, toluene and xylene) are present at elevated levels. Toxicological studies have shown that the mutagenicity of exhaust particles from biodiesel is normally lower than those obtained from petroleum diesel, however, rapeseed oil-derived biodiesel exhibits toxic effects that are 4-fold greater than petroleum diesel. Such enhanced toxicity is probably caused by the presence of carbonyl compounds and unburnt fuel. The toxicity of highly volatile components of biofuel exhaust has not yet been evaluated accurately. A substantial portion of these compounds was apparently lost in the process of preparing the test samples used for the assays (during the evaporation). The overall recoveries of these compounds have not been evaluated and the accuracy of the sample preparation method has not been validated. Hence, it could be that the cytotoxic effect of biodiesel exhaust is higher than that reported. Moreover, compared with fossil diesel, fuel derived from rapeseed oil emits particulate matter with increased mutagenic effects. Epidemiological investigations of the effects of biofuels on humans are very sparse but have revealed dose-dependent respiratory symptoms following exposure to rapeseed oil biodiesel, although the observed differences between this fuel and petroleum diesel are not significant. Such data, however, give rise to serious concerns about the future usage of this plant material as a replacement for established diesel fuels. Combustion of alcohol-based fuels leads to a reduced formation of photochemical smog in comparison with gasoline or diesel, however, the emission of aldehydes (officially classified as carcinogenic or potentially carcinogenic) is several times higher. The toxicity of the exhaust emissions of gasoline-fuelled engines is generally significantly greater than that of alcohol-burning engines. However, some harmful effects from ethanol blends might be expected, such as enhanced emissions of carcinogenic PAHs and increased ozone-related toxicity associated with the high level of aldehydes emitted. The use of ethanol–diesel fuel blends gives rise to increases in regulated exhaust emissions and, possibly, to greater emissions of aldehydes and unburnt hydrocarbons. The most promising fuels, in terms of reduced toxicity and genotoxicity of exhaust emissions, are methanol-containing blends. However, the emission from these fuels still contains formaldehyde, which is a carcinogen. The use of biogas can significantly reduce emissions of total PAHs and formaldehyde and, consequently, the risk of lung toxicity. On the other hand, the emissions of particulate matter by compressed natural gas, and the mutagenic potencies of the exhaust, are similar to those associated with gasoline and diesel fuels.   Conclusions: The use of biofuel is currently viewed very favourably and there are suggestions that the exhaust emissions from such fuel are less likely to present risks to human health in comparison with gasoline and diesel emissions. However, the expectation of a reduction in health effects based on the chemical composition of biodiesel exhaust is far from reality. Thus, although toxicological evidence relating to the effects of biofuels on humans is sparse, it is already apparent that emissions from the combustion of biofuel and blends thereof with petroleum-based fuels are toxic. In addition to the regulated toxic compounds, such as total hydrocarbons, carbon monoxide, nitrogen oxides, particulate matter and polycyclic aromatic hydrocarbons, biofuel emissions contain significant amounts of various other harmful substances that are not regulated, e.g. carbonyls (including formaldehyde, acetaldehyde, benzene, 3-butadiene, acrolein, etc.). Whilst biofuels may be potentially less damaging to human health than petroleum fuels, considerable harmful effects must still be expected. Substitution of conventional fuel by biofuel decreases the concentration of regulated toxic pollutants in vehicle exhaust, but increases the concentration of some unregulated toxic pollutants emitted from on-road engines. Generally, the toxicity of biofuels decreases in the order biodiesel>biogas>ethanol>=methanol. In this respect, methanol produced by the oxidation of biogas appears to represent an alternative fuel that exhibits the least potential for damage to human health, however, this alcohol represents a source of formaldehyde pollution and is carcinogenic. .

Nästan 15 000 långtidssjukskrivna personer utförsäkrades sista december 2009! Arbetslinjen -att ta till vara människors arbetsförmåga och allas bidrag till välfärden - har präglat reformerandetav den svenska socialförsäkringen. Metoden blev en övergång från sjukskrivning tillarbetssökande genom en ny arbetsmarknadspolitisk åtgärd; Arbetslivsintroduktion. Programmetstartade januari 2010 vid Arbetsförmedlingen.Syftet med denna studie var att undersöka sex deltagares upplevelser av programmet Arbetslivsintroduktion.Urvalet hämtades från den population som tidigare haft sjukpenningeller tillfällig sjukersättning och som utförsäkrats 31 december 2009 samt deltagit i Arbetslivsintroduktionen2 januari – 31 mars 2010 vid en lokal Arbetsförmedling. Urvalsmetodenvar 1) självselektion och 2) bekvämlighetsurval. Sex kvalitativa intervjuer genomfördes. Dessaanalyserades med en kvalitativ innehållsanalys.Resultatet gav två teman; Deltagaren upplevde Arbetslivsintroduktionen som 1) påtvingadförändring och/eller innehållande 2) underlättande faktorer. I diskussionen relaterades resultatettill aktuell forskning om långtidssjukskrivna respektive arbetsmarknadsåtgärder, till regeringensintentioner med Arbetslivsintroduktionen samt till teorin KASAM. Studien påvisadeatt upplevelsen av Arbetslivsintroduktionen påverkades av många faktorer samt att resultatetstvå teman kunde relateras till deltagarens känsla av sammanhang (KASAM).Studien gav implikationer om upplevda brister under Arbetslivsintroduktionen vad gällerdialogen mellan olika rehabiliteringsaktörer, i synnerhet mellan sjukvård och Arbetsförmedling,men lyfte också frågor om samarbetet mellan Arbetsförmedlingen och Försäkringskassan. Nyckelord: Arbetsmarknadsåtgärd, KASAM, Långtidssjukskriven, Samverkan,Återgång till arbete.

Antalet äldre har ökat i hela världen och fortsätter att öka. I takt med stigande ålder ökar risken för sjukdomar och därmed även läkemedelsanvändningen. Personer över 80 år konsumerar i genomsnitt 5,8 läkemedel per person och äldre på sjukhem tio läkemedel per person vilket är en ökning med 60 % sedan slutet av 1980-talet. Anledningen till denna ökning är att det idag finns stora möjligheter att förebygga och behandla många sjukdomar eftersom det hela tiden utvecklas nya läkemedel och behandlingsmetoder. Polyfarmaci och olämplig förskrivning av läkemedel till äldre över 65 år enligt Beers kriterier (se bilaga I) är ett växande och världsomspännande hälsoproblem. Vid polyfarmaci används i genomsnitt fem eller flera olika läkemedel. Polyfarmaci ökar i takt med stigande ålder och är vanligast hos kvinnor samt hos lågutbildade individer. Med ökat antal läkemedel ökar också risken för biverkningar samt interaktioner eftersom äldre är känsligare på grund av åldersförändringar och sjukdom. Syftet med studien var att belysa förekomsten av polyfarmaci och olämplig förskrivning av läkemedel till äldre samt dess konsekvenser. Studien utfördes som en litteraturstudie där 17 vetenskapliga artiklar analyserades. Resultatet visar att en tredjedel av de äldre patienterna konsumerar olämpliga läkemedel, enligt Beers kriterier, vilket leder till onödigt lidande och ökad sjukhusvistelse. Det är därför viktigt att all vårdpersonal är väl insatta i de åldersförändringarna som sker hos den äldre individen samt har god kunskap inom farmakologi. Sjuksköterskor och läkare bör även förbättra samarbetet med farmaceuterna för att öka patientsäkerheten. / The elderly population is increasing all over the world. Aging is associated with diseases resulting in increased medical consumption. Elderly over 80 years consume in average 5,8 different drugs. Nursing home residents consume ten drugs which represents an increase of 60 % within the last two decades. This development is based on the increasing progress within the field medical treatment. Polypharmacy and inappropriate prescribing in elderly over 65 years, according to Beer´s criteria (annex I), results in a growing and worldwide health problem. Polypharmacy comprises use of multiple drugs (mostly five or more per day). Polypharmacy is associated with increased age and is most common in women and low educated individuals. Multiple medications increase the risk of adverse drug reactions and drug-drug interactions especially in old and frail persons with comorbidity. The aim of the study was to elucidate the prevalence and the consequences of polypharmacy and inappropriate prescribing in elderly. The study was based on a literature study in which 17 articles were analyzed. The result shows that one third of the elderly patients consume inappropriate medications, according to Beer´s criteria, which are associated with unnecessary suffering and increased hospital admission. It´s important that health care personnel gains understanding about the pharmacological consequences of body composition changes in older adults. Nurses and physicians should also improve their cooperation with pharmacists to increase knowledge leading to better patient safety.

Bakgrund: I dagens vårdarbete är behandling av venösa bensår en vanlig omvårdnadsåtgärd. Smärta, immobilitet samt social isolering relaterat till venösa bensår, är några av de faktorer som påverkar patientens livskvalitet. Syfte: Syftet med litteraturstudien var att beskriva hur sjuksköterskan på bästa sätt kan främja läkningen av venösa bensår. Metod: Beskrivande litteraturstudie sammanställd utifrån 14 kvantitativa samt sju kvalitativa studier publicerade mellan åren 2001 till 2009. Databaserna Cinahl och PubMed användes i sökningen av vetenskapliga artiklar. Sökorden som användes var Leg Ulcer, Nursing, Activity, Pain, Venous leg ulcer, Treatment, Management, Exercise, Bandages samt Psychological. Resultat: De omvårdnadsåtgärder som visade sig ha stor betydelse för sårläkning var kompression/sårvård, fysisk aktivitet, psykologiskt stöd samt eftervård. Sjuksköterskans kunskap och förmåga att kunna se patienten som en helhet var av stor vikt för god omvårdnad och förbättrad sårläkning. Slutsats: Sjuksköterskor behöver förbättra sina kunskaper angående sårvårdsbehandling. Sjuksköterskan bör ha en holistisk syn på patienten.

Platelets are important for the healing of damaged blood vessels since they have an importantpart to play in the coagulation process. At the same time, the blood must be kept fluid and notcoagulate at the wrong time. Therefore there are factors that effect the aggregation of plateletsin a positive or a negative way. Previous investigations have shown that platelets during stirring conditions produce reactiveoxygen species (ROS) that weaken the inhibiting effect of nitric oxides (NO) on platelets andthat the drug Dexamethasone (Dex) can reduce the ROS-production. The aim of this project was to investigate if glucocorticoids, in this case Dexamethasone,could restore the inhibiting effect of NO on platelets and if there was any decrease in ROS-production. The result of the ROS-measurements showed a great variance and it was difficult to draw anyconclusions from them, but a clear decrease in ROS, as previous reported, was not shown. In the aggregation experiments the inhibiting effect of NO was observed through the drug S-nitroso-N-acetylpenicillamine (SNAP), a NO-donator. From the aggregation experiments, the result seemed to be that SNAP during longerincubation time lost its inhibiting effect, probably because the cells become desensitized.With superoxid dismutase (SOD), the effect of SNAP increased, both in the experiment withlonger and shorter incubation times. Dex seemed to reinforce the aggregation in relation toboth SOD and SNAP. To understand this relation further, more investigations must be done.Another interesting experiment would be to do combinations of experiments monitoring bothaggregation and ROS-production at the same time. / Trombocyterna, blodplättarna i blodet, är livsviktiga för att människor inte ska förblöda vid enskada. Samtidigt måste blodet hållas flytande och inte koagulera i onödan och därför finns deti kroppen en mängd faktorer som verkar pro- eller antiaggregerande. Tidigare undersökningar har visat på att trombocyter har en omrörningsberoendesyreradikalproduktion (ROS) som försvagar kväveoxids (NO) antiaggregerande effekt och attläkemedlet Dexametason (Dex) kan minska denna produktion. Detta projekt syftade till att ytterligare studera om glukokortikoider, i detta fall Dexametason,kunde återställa NO:s effekt på trombocyterna och om de i någon grad minskaderadikalproduktionen. Resultatet av ROS-mätningarna blev väldigt varierande och svårtolkade och några säkraslutsatser kunde inte dras, men en tydlig minskning i produktionen som tidigare observeratskunde inte upptäckas. I aggregationsförsöken observerades NO:s inhibitoriska verkan genomS-nitroso-N-acetylpenicillamine (SNAP), en NO-donator.Resultaten tyder på att SNAP under en längre inkuberingstid tappar sin inhiberande förmågapå trombocyterna, vilket förmodligen beror på att cellerna desensibiliseras.Superoxiddismutas (SOD) verkar ha en förstärkande effekt på SNAP oavsett ominkuberingstiden innan dosresponstillsats av trombin är lång eller kort, medan Dex tenderaratt förstärka aggregeringen både i förhållande till SNAP och SOD. För att få mer klarhet omdessa resultat är korrekta måste fler upprepningar göras och dessutom borde man genomförakombinationsförsök där man samtidigt övervakar ROS-produktion och aggregering.