Background: Statins are among the most used drugs in Sweden. There are currently four statins available on the Swedish market; atorvastatin, simvastatin, pravastatin and rosuvastatin. Statins act by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme-A reductase, also known as HMG-CoA-reductase. HMG-CoA-reductase is the rate-limiting enzyme of the cholesterol synthesis. Decreased hepatic cholesterol leads to increased low-density lipoprotein (LDL) clearance from plasma to liver cells. Having a high level of LDL cholesterol is potentially dangerous as it can lead to atherosclerosis and cardiovascular disease. Statins significantly reduce cardiovascular morbidity and mortality in patients with and without coronary heart disease. Purpose: The aim of this work was to investigate if there are any differences between the different statins according to contemporary evidence. Method: This is a literary analysis. Studies included were searched from PubMed. A total of five studies were included. Results: The result of this study indicates rosuvastatin to be most efficacious in lowering LDL cholesterol (LDL-C), triglycerides and total cholesterol. It also improved the high-density lipoprotein cholesterol (HDL-C) better than atorvastatin, simvastatin and pravastatin. Study 1 showed rosuvastatin to lower LDL-C with statistical significance (P<0.001) across dose ranges (10-40 mg) after 12 weeks. Study 2 compared a dose ratio of 1:2 between rosuvastatin and simvastatin in lowering LDL-C with a 3.24% (95% CI 4.10 to 2.38) favor of rosuvastatin. Study 4 compared effects of atorvastatin 80 mg and rosuvastatin 20 mg in patients with ST elevation myocardial infarction in a 4-week therapy. Rosuvastatin 20 resulted in a 35% compared with atorvastatin 80 mg 34% (P=0.59) reduction in LDL-C levels. Study 1 demonstrated rosuvastatin to improve HDL-C levels in daily doses of 40 mg with statistical significance compared with atorvastatin, simvastatin and pravastatin. Study 1 demonstrated rosuvastatin to lower total cholesterol with statistical significance (P<0.002) across doses compared with atorvastatin, simvastatin and pravastatin. Study 1 also demonstrated rosuvastatin to lower triglycerides more. In daily doses of 40 mg rosuvastatin had a statistical significance (P<0.002) versus simvastatin and pravastatin, but not atorvastatin. The P value between rosuvastatin and atorvastatin was not mentioned, neither the P-value between atorvastatin, simvastatin and pravastatin. Conclusion: Statins are not equipotent. Rosuvastatin showed greater results in reducing LDL-C, triglycerides and total cholesterol with no increased risk of adverse events compared with atorvastatin, simvastatin and pravastatin. Rosuvastatin still lacks in clinical experience which makes needs for further studies on this topic.

The aryl hydrocarbon receptor (Ah-receptor) is a member of the bHLH-PAS protein family. The Ah-receptor is a ligand dependent transcription factor, which activates a wide range of genes, most notably the xenobiotica metabolising genes, CYP1A1 and CYP1A2. The biological function of the Ah-receptor is still unknown and an endogenous ligand has yet not been identified. A possible Ah-receptor ligand is 6-formylindolo[3,2-b]carbazole (FICZ). FICZ has a high affinity for the Ah-receptor and is rapidly metabolised by CYP1A1, CYP1A2 and aldehydeoxidase (AOX). To try to trap FICZ or other possible endogenous Ah-receptor ligands, the metabolising enzymes CYP1A1, CYP1A2 and AOX were blocked. This was achieved through chemical blockage of CYP1A1 and CYP1A2 by ellepticin and through silencing with siRNA directed against CYP1A1 and CYP1A2. Successful blockage would be seen as an increase in Ah-receptor dependent XRE-luciferase activity. Chemical blockage of AOX with tungstate did not affect FICZ-dependent XRE-luciferase activation which could indicate that HepG2 cells lack AOX. The chemical blockage of CYP1A1 and CYP1A2 with ellepticin modified the XRE-luciferase response, but did not completely block Ah-receptor activation. In addition it is possible that ellepticin is a ligand for the Ah-receptor. The blockage of CYP1A1 by siRNA was successful; a silencing of CYP1A1 mRNA by at least 50 percent was detected. However due to lack of time it was not tested if the blockage of CYP1A1 and CYP1A2 was sufficient to trap Ah-receptor ligands.

Syftet med studien är att belysa hur barn i åldrarna tre till fem år tänker kring genus. Barnen fick lyssna på sagan ”Prinsessan Papperspåse” (Robert N. Munsch, 1980) och intervjuades sedan med utgångspunkt från sagan. Resultatet visar att barnen tänker relativt lika kring genus oberoende av kön och ålder. Både flickorna och pojkarna hade tydliga föreställningar om vad som är ett acceptabelt uppträdande av det motsatta könet. Framför allt hade de klara tankar om hur en flicka ska se ut om hon ska gifta sig. Att vara smutsig är för barnen inte acceptabelt, vare sig man är flicka eller pojke. Utan undantagsvis lade flickorna fokus på relationen mellan prinsessan och prinsen medan pojkarna lade fokus mer på draken och prinsen.

Breast cancer is one of the deadliest forms of cancers in the world. About 15–30% of all breast cancers are HER2-positive, which involves overexpression of HER2-receptors on the surface of tumor cells. HER2-positive breast cancer is viewed as an aggressive form of cancer because the overexpression of the HER2-receptor causes dimerization with other receptors of the same family; together they bind to ligands and become activated. The activation causes fast, uncontrolled cell proliferation that often results in the formation of a tumor. Cancer can be divided into different stages, at stage 4 the cancer cells from the original tumor breaks away, follows the bloodstream, and forms metastases in other places of the body. When cancer evolves and becomes metastatic the prognosis drastically worsens, and the treatment options are limited. Patients often need several lines of cancer treatment. The first line of treatment is usually trastuzumab in combination with pertuzumab and a taxane, second line is usually trastuzumab emtansine. There is no conclusive third line treatment for HER2-positive metastatic breast cancer (MBC). Due to the development of new anti-HER2 treatments over the last two decades, less patients are dying from breast cancer, however most patients diagnosed with HER2-positive MBC are estimated to face an early death.  The objective of this study was to analyze the pharmaceutical advances that has improved the prognosis for patients diagnosed with HER2-positive MBC. The material, on which this study was based on, was obtained from the Pubmed database via the Linnaeus University Library. Five articles were chosen based on criteria relevant to the topic. The articles were published between 2001 and 2021; all of them were randomized controlled trials (RCT).  The subject of the articles was to compare the efficacy and safety of different forms of anti-HER2 treatments, using patient populations diagnosed with HER2-positive MBC. Mainly the patients' disease progression, treatment response and survival time was analyzed. Pharmaceutical safety was assessed by the rate of adverse events. A total of 2513 patients participated in the studies. Among all the different treatment options that were analyzed in the articles, one treatment combination yielded some of the best results. Pyrotinib in combination with capecitabine increased the disease progression-free time, had the highest proportion of patients who responded to treatment as well as the highest proportion of patients with size-reducing lesions for the longest time. However, the patient group receiving pyrotinib also had the highest incidence of serious adverse events and had the largest percentage of patients who chose to discontinue the study due to adverse events.  Analysis of the five articles concludes that the prognosis for patients diagnosed with HER2-positive MBC has been improved by pharmaceutical advances regarding tyrosine kinase inhibitors, pan-HER inhibitors, combination therapy with monoclonal antibodies (single, mixed, modified or conjugated with other drugs) and chemotherapy with different mechanisms of action. The results from the studies indicated that treatment with a single anti-HER2 drug had the lowest effectiveness, and that some drug combinations had better synergistic effects than others, reflecting on patient survival data. Despite the pharmaceutical advances of the past two decades, the prognosis for HER2-positive MBC can still be considered bleak due to its high death rate. Resistance to anti-HER2 drugs is an ongoing concern that requires more research and development of new treatments.

Introduktion: Läkemedelsbiverkningar delas in i två grupper; typ A och typ B. Typ A-biverkningar är dosberoende medan typ B-biverkningar är idiosynkrasiska och beroende av immunsystemet. Levern är kroppens huvudsakliga metabola organ, och drabbas ofta av läkemedelinducerad toxicitet. Ibland inducerar läkemedelsmetaboliter levertoxicitet, vilket kan medieras av immunsystemet. Karbamazepin är ett antiepileptikum och orsakar levertoxicitet, men den exakta mekanismen är inte klarlagd. Syfte: Syftet med detta arbete är att undersöka om karbamazepins levertoxicitet är beroende av metabolismen av karbamazepin och/eller immunsystemet. Material och metoder: En strukturerad litteraturundersökning utfördes med hjälp av databasen PubMed. 7 artiklar inkluderades i sammanställningen. Resultat: Resultat från in vivo-studier identifierade metaboliter producerade av cytokrom P450-monooxygenaser (CYP450) hos de individer som utvecklade levertoxicitet inducerad av karbamazepin. Samtidigt noterades en ökad nivå CYP3A. Expressionen av en rad immunsystemsmarkörer ökade också vid karbamazepin-inducerad levertoxicitet, exempelvis TNF-α, som leder till apoptos. Slutsats: Utifrån inkluderade studier kan slutsatsen dras att karbamazepins levertoxicitet induceras av dess metaboliter via immunsystemet. Undersökningarna var huvudsakligen associationsstudier, vilket försvårar slutsatser kring kausalitet. Därför behöver ytterligare studier göras så att mekanismen helt kan klargöras.

Neuroblastoma, a neuroendocrine tumor, is the most common cancer in infancy. 75 % of those affected are under the age of 5. The disease is heterogeneous and survival rate is low.   Current treatment of neuroblastoma consists of surgery, radiation and chemotherapy, where the targets for the treatment are the malign cells. Due to the cancer cells instable genome there is a risk for resistance development. This negatively impacts the treatments goal of hindering tumor growth and spread.  Tumor growth is not only determined by malign cells but also the interactions of those tumor cells with tumor vessels and different types of cells in the tumor stroma.   The aim of this paper is to develop a relevant histological method to study the properties of tumor stroma in tumor sections retrieved from human NB tumor xenografts in mice treated with angiogenesis inhibitors SU11657 and Zoledronic acid. The study is a continuation of previous studies with the inhibitors which have shown good effect on tumor growth and angiogenesis on neuroblastoma.   In the short term treatment with SU11657 and Zoledron acid showed that tumor growth declined. In the longer treatment with SU11657 the growth didn’t decline with the same rate compared to the short term treatment. Angiogenesis on the other hand decreased in all the treatments independent of treatment duration. The histological staining with Sirius red revealed that treated tumors had an increased amount of stroma compared to the untreated tumors.   In conclusion the relative increase of tumor volume, decreased number of vessels and expansion of tumor stroma in the longer treatment with SU11657 indicated that tumors might survive the angiogenesis inhibitor treatment through expansion/activation of its stroma. The histological staining with Sirius red in saturated picric acid marked the collagen, i.e. stroma, well and enabled quantification of the stroma.

The purpose of this study was to investigate whether preschool staff who participated in a previous health project retains the good behavior change, and to explore their perceived barriers and opportunities for this. The study was conducted on a "feel good" preschool and the selected population was preschool teachers and/or child minders. The selected method was qualitative, descriptive, and through the interviews the respondents got questions about their behavior changes and their experiences of this. The result of the survey showed that nearly all of the participants in the study had maintained the good behavior changes and most of them had implemented them in their lives. The obstacles that individuals perceived were mainly time constraints and the opportunities they saw were planning, motivation and positive experience. The conclusion was that almost all respondents maintained the previous behavior changes and they have also understood the importance to be physically active and eat a healthy diet. One of the obstacles that individuals considered to be difficult is when there is insufficient time and all of the participants then usually remove the workout. Opportunities that individuals perceived were that planning is important for the success of change unhealthy behaviorsandthat there is a strong motivation. The individuals who participated in the study are driven and well aware of the health benefits they have gained by maintaining their good habits. During the interview it has shown that these people have a very strong will and faith in themselves. They are also motivated to continue their work so that the healthy lifestyle one day will be permanent and a natural part of their lives.

Epilepsi är ingen speciell sjukdom utan ett symtom på en hjärnskada eller störd nervcellsfunktion i hjärnan. Epileptiska anfall beror på abnorm urladdning i hjärnans nervceller. Idag lever omkring 60 000 d.v.s. 0,5-1 % av Sveriges befolkning med epilepsi. Risken att drabbas är störst under det första levnadsåret och efter 65-årsålder då risken att drabbas av stroke är som störst. Behandling av epilepsi används i syfte att hindra uppkomst av anfall och göra det möjligt för den drabbade att leva ett relativt normalt liv. Antiepileptika dämpar aktiviteten i hjärnan och reducerar därmed risken för anfall. Under flera år har man försökt utveckla nya antiepileptika mot andra möjliga targets än de som finns idag, bl.a. GABA-transporthämmare. Det enda förekommande läkemedlet med GABA transporthämmande effekt är tiagabin men detta är inte registrerat som läkemedel i Sverige. Syftet med denna studie var att undersöka om GABA-transporthämmare skulle kunna användas som läkemedel mot epilepsi. Metoden som användes var en litteraturstudie där vetenskapliga artiklar hämtades från PubMed, ELIN, Cochrane och Google Scholar. Arbetet baseras på 4 experimentella originalartiklar och en metaanalys. Artiklarna beskriver antiepileptiska effekter och/eller relaterade egenskaper för olika substanser med hämmande effekter på olika GABA- transportörer. Dessa hämmare, ensamma eller i kombination, visades ge kramplösande effekt i olika djurmodeller av epilepsi. Hämmare av olika GABA-transportörer, till exempel tiagabin och EF1502, gav synergistisk effekt, medan hämmare av samma GABA-transportör, till exempel tiagabin och LU-32-176B, resulterade i additiv effekt. Hämning av olika GABA-transportörer i olika celltyper i och runt synapsklyftan verkar därför kunna ge synergistisk effekt. Ingen synergistisk effekt observerades för toxiska effekter. Det finns anledning att tro att ytterligare läkemedel med effekter på GABA-transportörer kan komma att finnas i framtiden för behandling av epilepsi. / Epilepsy is not a specific disease but a symptom of brain injury or impaired nerve cell function in the brain. Epileptic seizures are symptoms of abnormal activity in the brain neurons. Today, about 60 000 i.e. 0.5-1% of the Swedish population live with epilepsy. The risk of being affected is greatest during the first year of life and after the age of 65 years when the risk for stroke is greatest. The treatment of epilepsy is used in order to prevent the onset of seizures and to allow the patient to live a relatively normal life. Anticonvulsants dampen the activity in the brain and thus reduce the risk of seizures. During many years, attempts have been made to develop new anticonvulsants against other potential targets than those that exist today, for example GABA-transporter inhibitors. The only presently used medicine with GABA-transporter inhibiting effect is tiagabine, but this is not licensed as a pharmaceutical drug in Sweden. The aim of this study was to investigate whether GABA-transport inhibitors could be used as medication for epilepsy. The method that was used was a literature study in which scientific articles were chosen from PubMed, ELIN, Cochrane and Google Scholar. The work is based on 4 original research articles and one meta-analysis. The articles describe antiepileptic effects and/or related properties of various substances with inhibitory actions on different GABA-transporters. These inhibitors, alone or in combination, were shown to have anticonvulsant effects in several different animal models of epilepsy. Inhibitors of different GABA transporters, such as tiagabine and EF1502, resulted in synergistic effects, while inhibitors of the same GABA transporter, such as tiagabine and LU-32-176 B, resulted in additive effects. Inhibition of various GABA transporters in different cell types in and around synapses therefore seems to provide synergistic effects. No synergistic effect was observed for toxic effects. There is reason to believe that additional drugs with effects on GABA transporters may be used in the future for the treatment of epilepsy.

Chronic prenatal hypoxia is associated with intrauterine growth retardation and there is now some evidence that it also induces programmed hypertension in offspring. However these studies are generally confounded as hypoxia is either induced by maternal hypoxia or placental insufficiency. The study described in this thesis is designed to overcome this problem. Pregnant rats were dosed daily with the drug dofetilide (2.5 mg/kg) or water on GD 11-14 and the cardiovascular parameters of the offspring at 8-12 weeks (>300g) were analysed using implanted telemetry blood pressure (BP) transmitters.Dofetilide is a class III antiarrhythmic drug that selectively blocks the Ikr channel which is expressed in the rat embryo but not in the adult rat. When administered to pregnant rats it induces bradycardia (and associated hypoxia) in the embryos without affecting maternal oxygenation or heart rate. Embryo culture studies showed that dofetilide induced a period of embryonic bradycardia for up to 9 hours following each dose. The dofetilide treated-rats had less completed pregnancies, smaller litters and lower weight pups compared to controls. At 8-12 weeks age the dofetilide offspring has increased BP (+10-12%) compared with controls. Postnatal stress in the form of air puffs did not reveal other cardiovascular differences between control and dofetilide offspring. The increased BP was not associated with an increased HR or changes in the autonomic nervous system. Remaining unexplored possibilities include impaired nephrogenesis, vascular dysfunction and microvascular

Niacin som upptäcktes för 70 år sedan är en substans som än i dag studeras mycket kring. Men fortfarande är man inte överens om niacin verkligen har en signifikant effekt på kardiovaskulära sjukdomar. Verkningsmekanismen för niacin är ännu oklar, men forskning pekar på att hämmad syntes av triglycerider resulterar i en minskad LDL-koncentration. HDL-ökningen tros bero på en hämmad nedbrytning av HDL-partiklar, och därmed blir en större mängd HDL kvar i blodet. Nuvarande lipidbehandling består först och främst av en balanserad kost och ökad fysisk aktivitet. Vid otillräcklig effekt sätts läkemedelsbehandling in, som består av statiner, resiner, fibrater och hämmare av kolesterolupptag i tarmen. Syftet med detta arbete är att studera om niacin, både som monoterapi och i kombination med andra lipidsänkande preparat, har en påverkan på blodlipidvärdena HDL, LDL och triglycerider, hos människor. Genom systematisk litteratursökning har artiklar samlats in för att kunna sammanställa resultaten. Alla tio studierna som inkluderades kom fram till att niacin, antingen i kombination med andra lipidsänkande preparat eller som monoterapi, har en signifikant effekt på lipoproteinerna. Resultaten visade en LDL-sänkning upp till 58,5% (i kombination), den högsta HDL-ökning var 50% (monoterapi) och högsta triglycerid-sänkningen var 51,7% (i kombination). Dock är niacins effekt på LDL och triglycerider likartad eller sämre än dagens lipidsänkande preparat. Niacin har däremot en större effekt när det kommer till HDL-ökningen. Därför bör det göras flera och större studier gällande niacins effekt på HDL. Om studierna visar positiva resultat bör det övervägas för användning hos patienter med låg HDL. Dock orsakar biverkningarna en sämre följsamhet, och eventuella analoger till niacin bör utvecklas, detta för att inte gå miste om en eventuellt potent HDL-ökande behandling. Slutsatsen för detta arbete är att i människa har niacin en signifikant effekt på lipoproteinerna LDL och HDL samt lipiden triglycerider. Behandling med niacin leder till en sänkning av LDL och triglycerider samt en markant ökning av HDL.