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Risk stratification of patients with chronic kidney disease and atherosclerotic heart disease is crucial. Microalbuminuria (MA) is associated with an increased risk of kidney and cardiovascular (CV) death, especially in patients with diabetes. However, MA in many instances is not sensitive for disease outcome; for instance, not all diabetic patients with albuminuria progress to kidney failure, and not all patients with diabetic kidney disease (DKD) have albuminuria. Furthermore, albuminuria is not essentially associated with endothelial dysfunction or glomerular lesions in non-diabetic patients. Urinary excretion of larger proteins, such as IgM and IgG would better reflect glomerular dysfunction and vascular endothelial damage. In this thesis we aimed to evaluate the value of IgG-uria and IgM-uria in predicting kidney and CV outcome in patients with diabetes, glomerulonephritis and atherosclerotic heart disease. In study I, 139 patients with type-1 diabetes, and in study II, 106 patients with type-2 diabetes, were followed at the diabetes outpatient clinic, for an average of 18 and 5 years, respectively. Type-1 & -2 diabetic patients had about a 3-fold increase in CV and renal mortality (HR = 2.7, p = 0.004, and HR = 3.6, p < 0.001, respectively) if they had an increased urine IgM excretion, even when adjusted to the degree of albuminuria. In study III, 178 consecutive patients who presented with acute chest pain to the emergency department of Lund University Hospital were followed for up to 2 years. Patients with acute coronary syndrome had significantly higher baseline IgM-uria than those with non-specific chest pain. Chest pain patients with IgM-uria at time of presentation had a 3-fold higher risk for the occurrence of subsequent major CV event (HR = 3.3, p = 0.001). In study IV, 189 patients with proteinuric primary glomerulonephritis were followed at the nephrology outpatient clinic for an average of 8 years. Patients with an increased urine IgG excretion had an increased risk for end-stage kidney disease (ESKD), even when adjusted for the degree of albuminuria and kidney function (HR = 5.9, p = 0.001). In conclusion, IgM-uria could be a useful biomarker for kidney and cardiovascular risk assessment of patients with diabetes and atherosclerotic heart disease. IgM- uria could imply an extensive atherosclerotic vascular disease. IgG-uria is helpful in identifying patients with glomerulonephritis at increased risk for disease progression to ESKD. Diabetes mellitus, kronisk njursjukdom samt aterosklerotisk hjärtsjukdom utgör de vanligaste orsakerna till hjärt-kärlsjukdom och för tidig dödlighet. Dessa sjukdomar har blivit ett stort världsomfattande hälsoproblem med ökande prevalens och incidens. Tidig identifiering av patienter som ligger i riskzonen for komplikationer, framförallt hjärt-kärl komplikationer, torde vara av stort värde for både patienter och samhälle. Därför är behovet av att finna nya markörer för hjärt- kärlsjukdom ytterst angeläget. Det är sedan tidigare känt att även en lätt förhöjd utsöndring av äggvita i urinen, s.k. mikroalbuminuri, är en oberoende riskfaktor för njursjukdom, ateroskleros och dödlighet i hjärt-kärlsjukdom. Dock, mikroalbuminuri kan förekomma vid såväl olika sjukdomstillstånd (såsom diabetes, högt blodtryck, övervikt, etc.), som en rad olika icke sjukliga tillstånd (såsom vid fysisk ansträngning, trauma, graviditet, etc.). Dessutom, en stor del av patienterna med diabetisk njursjukdom, trots befintlig diabetisk njurskada, har ingen uttalad albuminuri. Senaste experimentella och epidemiologiska studier har visat ett samband mellan utsöndringen av mycket stora proteiner, som IgG och IgM, i urinen med ökad risk för njursjukdom. I denna avhandling har vi studerat betydelsen av utsöndringen av dessa stora proteiner (IgG och IgM) i urinen vid vanligt förekommande sjukdomstillstånd, såsom diabetes, glomerulonefrit och ischemic hjärtsjukdom, och dess samband med hjärt- kärl dödlighet och njursvikt. I studie I och II har vi undersökt 139 patienter med typ-1, respektive 106 patienter med typ-2 diabetes som har början till njurskada, vid njurmottagningen på universitetssjukhuset i Lund. Medianuppföljningstiden var 18 år respektive 5år. De som hade en hög grad av IgM-uri vid studiestart, oavsett grad av albuminuri, hade en signifikant högre risk (ca 3-4 gånger högre) att avlida av komplikationer som hjärtinfarkt, hjärtstillestånd samt att utveckla njursvikt under uppföljningstiden. 55 I studie III, undersöktes sambandet mellan urin-IgM och förekomsten av större hjärt-kärl händelser, såsom akut hjärtinfarkt, angina pectoris, akut hjärtsvikt och stroke. Vi inkluderade 178 patienter som sökte akutmottagningen vid universitetssjukhuset i Lund för akut bröstsmärta. Vid ankomsten till akutmottagningen, efter patientens samtycke, togs urin- och blodprover samt EKG. Proverna analyserades för urinproteiner (albumin och IgM) samt plasma troponin T (hjärtinfarkt markör) och högsensitiv snabbsänka (hsCRP). Studien visade att patienter som hade akut kranskärlssjukdom vid ankomsten till akutmottagningen hade signifikant högre grad av IgM-uri jämfört med de som hade icke-specifik bröstsmärta. Dessutom, dem med hög IgM-uri vid ankomsten, oavsett grad av albuminuri, hade 3 gånger högre risk inom ca 2 år för att dö i hjärtsjukdom eller utveckla en större hjärt-kärl händelse. I studie IV, studerades 189 patienter med biopsi-verifierad primär glomerulonefrit (kronisk inflammation i njurnefroner, som kan leda till njursvikt och dialys). Patienterna utgjorde en del av en större kohort som genomgått ett utredningsprogram för glomerulär sjukdom på njurmottagningen vid universitetssjukhuset i Lund. Medianuppföljningstiden var 8år. Patienter med hög grad av IgG-uri vid studiestart hade en signifikant högre risk att utveckla njursvikt, oberoende av grad av albuminuri. Resultatet visade att urin-IgG på > 5 mg/mmol var det bästa cut-off värdet för att identifiera glomerulonefrit-patienter med risk för njursvikt. Njurens minsta funktionella enhet nefronet, består av ett kärlnystan (glomerulus) som producerar urin genom filtration av blodplasma genom kapillärväggen (den glomerulära filtrationsbarriären). Den glomerulära filtrationsbarriären består av 3 lager: endotelcellerna (finns närmast blodet), det glomerulära basalmembranet samt podocytcellerna med sina fotutskott (omsluter kapillärerna). Alla tre lager samspelar för att filtret ska vara tätt. För stora proteiner, som albumin (radie 36 Å), är det endast mycket små mängder som passerar ut (1 av 10 000 albuminmolekyler). Ännu större proteiner, som IgM (radius 120 Å), kan passera filtret endast via mycket stora hål (läckor), som föreligger vid en svår skada i filtret. Därför kan en skada i ett eller flera av dessa lager (som till exempel vid kärlförkalkningar eller inflammation) leda till att stora proteiner kan komma att filtreras ut i urinen. Förekomst av IgG/IgM i urinen i stora mängder speglar således en betydligt större skada i glomerulära filtret. Då våra studieresultat har visat att IgM i urinen hos diabetiker och kranskärlsjuka är starkt förknippat med ökad risk för njur- och hjärt-kärlsjukdomar, torde urin-IgM vara en markör för en underliggande ateroskleros och kronisk kärlinflammation. Ateroskleros och inflammation i sin tur orsakar minskat blodflöde, så kallad ischemi, som medför ökat antal mycket stora hål (läckor) i det glomerulära filtret och därmed IgM-uri. Svåra glomerulonefriter 56 orsakar också stora skador i det glomerulära filtret vilket leder till ökat antal mycket stora porer. Vi tror att graden av IgG-uri (och med all sannolikhet IgM-uri) kan reflektera svår glomerulärskada, och därmed njursvikt. Dessa fynd ger oss en möjlighet att hitta patienter som riskerar att utveckla komplikationer tidigare än vad som är möjligt idag. Konklusion: Högriskpatienter som vi kan identifiera med hjälp av IgG och IgM i urinen, bör genomgå intensivare uppföljning och behandling, för att på så sätt minska risken för framtida skador på hjärta, blodkärl och njurar. I praktiken innebär detta en ny approach för omhändertagandet av denna patientgrupp.

Urological problems can be caused by diseases that affect the bladder wall and its innervation. Contraction and relaxation of smooth muscle cells (SMCs) is essential for maintaining detrusor function and for emptying the bladder. It is well established that a family of regulatory proteins called Myocardin Related Transcription Factors (MRTFs) controls the property of SMCs. SMCs have a number of unique ultrastructural features, including caveolae in the membrane and “dense bodies” in the cytoplasm. An overarching aim of the work presented here was to investigate the regulatory mechanism of the key proteins in caveolae and dense bodies. The generation of caveolae depends on caveolins and cavins. We found that most caveolae proteins are regulated by MRTFs via proximal promoter sequences. MRTFs thus likely represent major drivers of formation of caveolae in SMCs. We also found that Cavin3 (Prkcdbp) is preferentially expressed in SMCs compared to other cells. Knockout of Cavin3 reduced the number of caveolae in the SMC membrane, but not elsewhere, and at the same time reduced Caveolin-1, Caveolin-3 and Cavin1. This suggests that Cavin3 contributes to the generation of caveolae in SMCs. Dense bodies in smooth muscle may be regarded as equivalents of Z-discs in striated muscle. The protein Nexilin (NEXN) was previously identified as a Z-disc-localized protein that controls mechanical stability. We found that Nexilin (NEXN) is highly expressed in SMCs and regulated by MRTF- and YAP/TAZ-coactivators. Nexilin was moreover found to be a dense body-associated protein in SMCs that promotes actin polymerization, differentiation and motility. Bladder wall remodelling in pathological situations is accompanied by reduced innervation. A second aim of this work was to define changes in gene expression after denervation. We show that numerous mRNAs and miRNAs are differentially expressed in the denervated bladder. Pathway analysis indicates that many of the differentially expressed genes are related to proliferation (60%). This is no surprise because the bladder weight increases 5-fold following denervation. Cthrc1 is upregulated at both the mRNA and protein levels, correlating with bladder weight, and overexpression and knockdown of this protein influences SMC proliferation in vitro. Neural plasticity is influenced by neurotrophic factors released from the target organs. We addressed if the bladder may influence its own nerve supply by such a mechanism. We demonstrate that neurotrophic factors, including NGF, BDNF, and NT-3, are synthesized in the bladder wall, and promote outgrowth of neurites from the pelvic ganglia in vitro, presumably via Trk-receptors. In conclusion, the studies summarized here provide understanding of the transcriptional control of key proteins and ultrastructural features of SMCs. They also unveil molecular mechanisms of bladder remodelling following denervation. Manipulation of some of the genes identified here represents promising strategies for recovering bladder function in disease.

Amputation of a hand is a life-changing event, and the loss of motor and sensory functions leads to disability and has devastating effects on the individual. What is normally performed using two hands must be solved with only one, and the loss also affects body balance and body posture. In addition, amputation of a hand has psychological effects, and has an influence on social life, participation, and identity. A hand prosthesis has an important role in reducing the negative effects of an amputation. However, rejection of the prosthesis is common, due to expectations that are too high to be fulfilled and limitations in technical solutions, with possible overuse of the existing hand as a consequence. The overall aim of this work has been to further develop and implement a non-invasive concept for sensory feedback in hand prostheses. Specific aims were to explore forearm amputees’ views of prosthesis use and perception of sensory feedback, to investigate the sensory qualities of phantom hand maps (PHMs) in amputees, to determine whether it is possible to learn to associate sensory stimuli on the skin of the forearm to specific fingers in healthy non-amputee volunteers, and lastly to evaluate a non-invasive sensory feedback system for a prosthetic hand in the everyday lives of forearm amputees.Initial findings indicated that today’s myoelectric hand prostheses allow the wearer to experience agency―the experience of controlling one’s own motor acts―but the lack of sensory feedback appears to limit achievement of a sense of body ownership of the prosthesis. A PHM on the residual limb is a phenomenon seen in many amputees, and when it is touched it generates a perception of touch on the hand that no longer exists. The neurobiological basis of the phenomenon is not fully understood, but it probably originates from plastic changes within the brain following amputation and also changes in peripheral nerves. We have demonstrated that the PHM has better discriminative sensibility than the corresponding skin area on the uninjured arm. Thus, the PHM is an ideal target for a non-invasive concept to achieve sensory feedback in prostheses. Given that not all amputees have a PHM, it was also found that it is possible to learn to associate stimuli on the skin of the forearm with specific fingers, i.e. it is possible to create a PHM. An evaluation of the non-invasive sensory feedback system based on the PHM in a prototype prosthesis during four weeks of use at home was also performed. The participants experienced the sensory feedback as being real, which gave a strong feeling of being complete, linked to body ownership. However, this was not verified by the quantitative measurements. This thesis shows that the PHM may be a possible target for non-invasive somatotopically matched sensory feedback systems in hand prostheses. The fact that it is possible to learn to associate sensory stimuli on the skin of the forearm to specific fingers is also promising for future development of sensory feedback systems, e.g. for congenital amputees or amputees who do not experience a PHM. The long-term goal is that this non-invasive concept for sensory feedback will be applicable to several types of hand prostheses, for various levels of amputation.

The 2010 population and housing census in Ghana revealed that more than half of the Ghanaian population lived in urban centers. Critical to the phenomenon of urbanization is the question of how to sustainably feed the urban population especially the urban poor as rapid urbanization has the tendency to urbanize poverty. This has led to renewed policy debate about the implications of farming in cities to the food security of urban residents.This thesis aims at contributing to the debate by delineating the non-market sources of food and analyze their implications for urban households in terms of food security. In doing this, the thesis analyzes the interplay that exist between the various agricultural engagements by urban households in both urban and rural areas as well as food transfer receipts to urban households and how they contribute to household food security in small and medium sized cities in Ghana. The thesis employs a mixed methods approach-quantitative and qualitative methods- to investigate the concept of urban food security. The analytical framework employed is grounded on the access pillar to household food security.The findings of the thesis are presented in three articles preceded by a ‘kappa’. I argue that the debate on the contribution of urban agriculture to urban household food security seems to over concentrate on urban agriculture alone without accounting for the other food provisioning opportunities available to the household including food production in peri-urban and rural spaces. Expanding the scope also helps to account for other non-market food sources such as food transfer receipts that are found to play important roles in the food security of urban households. The thesis establishes that, households with multiple food provisioning opportunities, especially those who engage in both urban and rural agriculture have better food security outlook than those who do not.The implications from the findings is that policies aimed at addressing urban food security through own food provisioning should not be treated in isolation. Rather, such policies should account for the active rural-urban interactions characteristic of many countries in sub-Saharan Africa and how they could be harnessed to complement each other for better food security and livelihood outcomes.

This dissertation investigates the use of religious terms and symbols in politics. More specifically, it investigates Muslim politics. Its aim is to analyze the role of religious terms and symbols within a non-fundamentalist political party, namely the Sri Lanka Muslim Congress (SLMC), a Muslim political party that has been part of the democratic process in Sri Lanka since the 1980s. I thereby hope to broaden the range of research concerning political parties founded on religious ideologies. The empirical focus of the dissertation is on the official documents of the SLMC, such as internal documents to members, online publications from their official website and social media. The empirical data also includes parliamentary speeches made by the late leader M.H.M. Ashraff during the years from 1989 to 1992 and parliamentary speeches made by the current leader Rauff Hakkem during the years from 2006 to 2011. I have also conducted interviews with 33 leading members of the party on three different occasions. In 2006, 2011 and 2013 I visited Sri Lanka and had Colombo as my base. This thesis also contains an introduction to the history of Muslims in Sri Lanka and thereafter the structure of this thesis follows the different empirical data that I have collected. The first of my empirical chapters focuses on official documents written by the SLMC. The second presents and examines interviews with leading members of the SLMC. The third and fourth empirical chapters concern the parliamentary speeches of the two party leaders mentioned above, M.H.M. Ashraff (1989–1992) and Rauff Hakeem (2006–2011). The final chapter discusses the conclusions drawn from the empirical chapters in relation to the theoretical framework presented in Chapter 2. In sum, “Pragmatic Muslim politics” can be seen as the complete opposite of a politics that is ideology driven and utopian. This fits well with what has been observed in the case of the SLMC. The main use of references to Islam as a religious tradition in the party has been to delimitate Muslims as a specific group in a political situation in post-colonial Sri Lanka. While there have been some initial attempts made, particularly during the 1990s, to put forward specific “Islamic” solutions to social problems, with direct references made to the scriptures particularly in the field of economics, few if any such attempts can be seen today.

In the age of museomics, the ability to sequence the genetic material from old museum specimens provides an invaluable and often untapped molecular resource. The application of the latest Next-Generation sequencing (NGS) technologies to such specimens allows us to utilise the diverse biobank that is natural history museums. These approaches provide the opportunity to study both extinct or difficult to collect taxa. The aim of this thesis is to apply NGS techniques to museum specimens of Lepidoptera, to better investigate the types of data generated and their uses.In the first chapter, we use a targeted enrichment (TE) approach to sequence nuclear loci from museum specimens dating back to 1892 for 35 taxa across the order Lepidoptera. Loci recovery ranged from 500-1,747. The success of this technique across the specimens highlights the usefulness of such a kit to study the entire order, thereby enabling the potential to resolve both shallow and deeper nodes in the phylogeny.In the second chapter, we applied the TE approach to three moth families belonging to the superfamily Geometroidea. Thirty-three museum specimens collected between 2001 and 1892 were sequenced from the families Epicopeiidae, Sematuridae and Pseudobistonidae. We recovered up to 1,383 raw loci per individual. Loci recovered in 20 or more specimens were carried forward for phylogenetic analysis, with a final data set consisting of 378 loci. These loci from another 19 publically available genomes and transcriptomes were combined to complete our dataset. We find strong support for the hypothesis that Sematuridae is the sister group to Epicopeiidae + Pseudobistonidae.Further expanding on our results from the TE approach, in the third chapter we apply whole genome sequencing (WGS) to expand our dataset. We sequenced whole genomes of 30 museum specimens of Epicopeiidae and Sematuridae. Recovery of the 387 loci from the TE experiment ranged from 20 - 94%. The resulting phylogeny confirms the phylogenetic relationships within these families. Additionally, we compared the data generated between the two approaches, presenting the advantages and disadvantages of each approach.In the final chapter, we investigated the usefulness of museum specimen WGS for population genomics studies. Data was generated for 13 specimens of Pieris napi, a common butterfly in Sweden. The availability of a recently published genome allows us to demonstrate that ~81% of the recovered DNA is from the target specimen. Average genomic coverage was 15.6X for nuclear DNA, and 1,963X for the mitochondria. We found that individuals originating from Abisko are genetically distinct from the remaining P. napi populations. This study highlights the potential of museum specimens for looking at changes in population genetic dynamics through time.In summary, we show the usefulness of various museomics applications. In particular, we focus on the use of TE and WGS for phylogenomic studies. Additionally, we highlight that WGS sequencing can also be utilized for population genetic-based studies, opening a window to the past.

It is well-known that dietary fibre can have a positive effect on the development of lifestyle-dependent diseases such as cardiovascular disease and type 2 diabetes. However, the effect may be different for different kinds of fibre and different sub-populations at risk. Therefore, the effects of three different kinds of fibre on postprandial and long-term response in healthy subjects were investigated. Consumption of rye bran, oat powder, sugar beet fibre or a mixture of all three in a meal study, led to lower postprandial glucose levels for all meals except oat powder, although the difference was only significant for rye bran. The outcome seemed to be determined not only by the amount of soluble fibre, but also by the total dietary fibre content. The combined effect of an intake of oat bran, rye bran and sugar beet fibre was also investigated in a 5-week randomised cross-over intervention study in healthy, mildly hypercholesterolaemic subjects. Subjects were given a high-fibre (HF) diet (48 g) and a low-fibre (LF) diet (30 g). Despite the high fibre intake, no significant effects were observed on glucose, insulin, or lipid metabolism. However, low-grade inflammatory response was reduced by the HF diet, as reflected by decreased C-reactive protein and fibrinogen levels. Moreover, markers from the high intake of oat, rye and sugar beet fibre were observed in plasma and 24-h urine samples using an untargeted metabolomic profiling approach. After the HF diet, different benzoxazinoids and their metabolites 2-aminophenol sulphate, HPAA (N-(2-hydroxyphenyl)acetamide) and HHPAA (2-hydroxy-N-(2-hydroxyphenyl)acetamide), together with the alkylresorcinol metabolite DHPPA (3-(3,5-dihydroxyphenyl)-1-propanoic acid), were found to be specific for the rye intake, whereas enterolactone was related to rye and oat fibre intake. Some specific markers for oat intake were found, however, their identity needs further validation. One identified marker, 2,6-DHBA (dihydroxybenzoic acid), has not previously been reported as a marker related to dietary fibre intake. Whether there is a specific marker for sugar beet fibre intake remains unclear. These markers of the intake of specific dietary fibre sources could, if validated, serve as markers in intervention studies and larger observational studies, to provide more accurate data on general dietary fibre intake, apart from the subjects’ self-reported values, which are normally used. The effect of a healthy Nordic diet based on the Nordic Nutrition Recommendations, including a high dietary fibre intake, was investigated in obese subjects with metabolic syndrome. This was a randomised, parallel multi-centre study in which the Nordic diet was compared to a control diet. No effects were observed on the glucose and insulin metabolism, however, reductions in lipoproteins were found together with an indication of reduction in the inflammatory response after the intake of the Nordic diet. In conclusion, these studies confirm that a high dietary fibre intake has a beneficial effect on glucose and lipid metabolism. The intervention studies also indicated a reduction in low-grade inflammation markers that are associated with overweight and type 2 diabetes. Kostfiber visar på gynnsamma effekter på blodsockersvar, inflammationsmarkörer och blodfetter utifrån tre humanstudier som genomfördes i detta arbete. I en av studierna analyserades blod och urin med metabolomik. Det är en metod där man analyserar alla små molekyler (metaboliter) som finns i provet med hjälp av vätskekromatografi kopplat till masspektrometri. Med hjälp av denna analys identifierades flera markörer för kostfiberintag, dels nya markörer men även en bekräftelse av markörer som identifierats i tidigare kostfiberstudier. Kostfiber är växtmaterial som inte kan brytas ner av vårt matspjälkningssystem men som i varierande grad bryts ner av bakterier i tjocktarmen. Kostfiber påskyndar matens transport genom tarmen vilket minskar risken för förstoppning. Sänkning av blodsocker, blodfettnivåer samt den antiinflammatoriska effekten tillskrivs bland annat en långsammare magsäckstömning och upptag av näringsämnen i tarmen efter intag av kostfiber. Kostfiberintaget i Sverige är idag ca 20 g per dag vilket är lägre än de 25-35 g som rekommenderas i de svenska näringsrekommendationerna för att minska risken att drabbas av hjärt- och kärlsjukdomar, övervikt och diabetes typ 2. I en måltidsstudie undersöktes blodsocker, insulin och triglycerider (blodfett) hos friska försökspersoner efter intag av olika frukostar med tillsatta kostfiber från spraytorkad havredryck, rågkli, sockerbetsfiber eller en blandning av de tre kostfibrerna. Blodprov togs före och sedan varje halvtimme under tre timmar efter måltiden. Alla måltider, förutom den spraytorkade havredrycken, gav en sänkning av blodsockret men endast för måltiden med rågkli var den signifikant. Denna effekt berodde inte bara på andelen lösliga kostfiber i måltiden utan även på totala mängden kostfiber som måltiden innehöll. Kvinnor hade ett lägre blodsockersvar än män när de intog de olika kostfibermåltiderna. Insulin- och triglyceridnivåerna påverkades inte signifikant av kostfiberintaget i denna studien. I en långtidsstudie undersöktes hur ett högt kostfiberintag påverkade blodsocker, insulin, olika blodfetter och inflammationsmarkörer hos friska försökspersoner med något förhöjt blodkolesterol. Kostfiber från rågkli, havrekli och sockerbetsfiber sattes till en brödbulle, två drycker och en färdigrätt som intogs dagligen under fem veckor. I kontrolldieten användes samma livsmedel men utan tillsatta kostfibrer. Blodprover togs fastande och en sänkning av inflammationsmarkörerna C-reaktivt protein (CRP) och fibrinogen kunde konstateras efter högfiberkosten. Inga skillnader i blodsocker, insulin eller blodfetter uppmättes mellan hög- och lågfiberdieten. Eftersom försökspersonerna fick äta fritt utöver testprodukterna så resulterade det i att kostfiberintaget under lågfiberkosten blev relativt högt, vilket kan vara en anledning till utebliven effekt i dessa markörer. Urin och blodprover från långtidsstudien analyserades med metabolomik med syftet att hitta och identifiera vilka metaboliter som påverkas av ett högt kostfiberintag samt att bekräfta kända och hitta nya markörer relaterat till kostfiberintag från råg, havre och sockerbetsfiber. En ny markör relaterad till det höga kostfiberintaget identifierades både i urin och blod; 2,6-dihydroxybensoesyra. Ytterligare metaboliter relaterade till råg- och havreintag ökade signifikant både i blod och urin efter det höga kostfiberintaget. I en nordisk multicenter-studie undersöktes hur intag av en hälsosam nordisk kost under sex månader påverkade blodsockret, insulin, blodfetter och inflammationsmarkörer hos överviktiga försökspersoner med metabolt syndrom. Den hälsosamma nordiska kosten ställdes mot en kontrollkost som återspeglade en typisk kost hos den nordiska befolkningen. Blodfetterna förbättrades signifikant hos de som intog den hälsosamma nordiska kosten. En markör för inflammation ökade successivt och signifikant under hela studien för de som åt kontrollkosten. Ingen effekt på blodsockret eller insulin kunde påvisas. Sammanfattningsvis bekräftar studierna tidigare visade hälsoeffekter för kostfiber på blodsocker och blodfetter. Interventionsstudierna indikerade också att ett högt kostfiberintag kan ha positiv effekt på låggradig inflammation, ett tillstånd som är associerat med övervikt och diabetes typ 2. Ett flertal potentiella markörer för kostfiberintag från råg och havre kunde påvisas i blod och urin med metabolomik. En del markörer behöver undersökas mer för att se från vilken typ av kostfiber de kommer ifrån. Detta kan utföras genom att undersöka respektive kostfiber i separata studier och även genom att karakterisera de ämnen som finns närvarande i respektive kostfiber. Om de är robusta markörer för en specifik typ av kostfiber kan dessa användas som kontrollmarkörer för att kvantifiera det generella kostfiberintaget i framtida studier.

Neuroblastoma is a childhood tumor of the sympathetic nervous system and the most common tumor form diagnosed in infants. Patients with aggressive tumors are treated intensely with multi-modal therapy including chemotherapy, surgery, radiotherapy and immunotherapy. Despite this, many children suffer from incurable relapses and long-term side effects are common. Novel treatments are thus necessary for these patients. The aim of this thesis was to identify and test novel therapies against neuroblastoma. For this work, I have used patient-derived xenograft mouse models and neuroblastoma cells grown as 3D tumor organoids.In paper I, we identified and tested novel inhibitors targeting the PIM, PI3K, and mTOR pathways. The inhibitors demonstrated promising effects in vitro with reduced viability, increased differentiation and cell death of neuroblastoma cells. Combinatory treatment of the inhibitors with chemotherapeutic agent cisplatin showed synergistic effects. In vivo, combination treatment resulted in slower tumor growth and increased survival of neuroblastoma PDX models.In paper II, we performed a high-throughput drug screen to identify drugs that target neuroblastoma. We identified several drugs with previously unknown activity in neuroblastoma, among them the KSP inhibitor ARRY-520. Analysis of KSP expression across multiple tumor types demonstrated that neuroblastoma is highly dependent on this protein. Treatment of neuroblastoma PDX cells with ARRY-520 resulted in mitotic arrest and subsequent cell death. KSP inhibition caused tumor regression in vivo and resulted in increased survival of multiple PDX models. In paper III, we investigated the effects of inhibitor rigosertib against neuroblastoma. Rigosertib reduced cell viability of neuroblastoma cells and caused cell cycle arrest in the G2/M phase. In vivo, rigosertib treatment resulted in decreased tumor growth and increased survival of PDX mice.In paper IV, we performed a high-throughput combination drug screen with the aim of finding drugs that work synergistically with KSP inhibition. Using in silico synergy prediction tools, we identified drugs with synergistic activity against neuroblastoma. Our results suggest that Ras pathway inhibitors in combination with KSP inhibition represent a promising treatment strategy against neuroblastoma.In summary, we identified and tested drugs which represent novel therapeutic opportunities against children with high-risk neuroblastoma.

Mild to moderate renal impairment affects 10% of the general population. Renal impairment is difficult to detect because of the lack of symptoms, but it can be estimated by calculating the estimated glomerular filtration rate (eGFR) on the basis of plasma creatinine and/or cystatin C concentrations. Chronic kidney disease (CKD) is associated with an increased risk of development of cardiovascular disease and an increase in the mortality rate. As kidney function decreases, structural and functional changes in the heart increase. Cardiovascular disease also affects renal function, leading to CKD. This pathophysiological association between the two organs is referred to as cardiorenal syndrome (CRS). Mortality and morbidity rates are increased in patients with CRS, and early detection of this syndrome can lead to a reduction in the disease burden. To more accurately stage CKD and calculate the mortality risk, the eGFR based on creatinine (eGFRCR) and cystatin C (eGFRCYS) is recommended for use in clinical practice. The eGFRCYS and eGFRCR usually correspond well with each other. In some individuals, the eGFRCYS/eGFRCR ratio is < 0.7, and it is associated with increased morbidity and mortality. A selective decrease in renal filtration of cystatin C is thought to cause the difference between eGFRCYS and eGFRCR, and this condition is called shrunken pore syndrome (SPS). This thesis presents studies on the early detection of CRS and the association of SPS with mortality and morbidity in patients with heart failure (HF) and in individuals who were randomly chosen from a population-based cohort. In Paper I, data from 1504 individuals without HF from the Malmö Prevention Project, which is a population-based cohort, showed significant associations between mild to moderate impairment of renal function and echocardiographic markers of cardiac structure and diastolic function. These findings support the hypothesis that there is an interaction between the kidney and heart, even at eGFR 45–60 mL/min/1.73 m2. In Papers II and III, data from approximately 300 hospitalized patients with HF from the HeARt and brain failure inVESTigation trial showed an association between SPS and a doubled risk of all-cause mortality, higher risk of 30-day rehospitalization, and impaired quality of life. Proteomic analyses showed that in patients with HF, SPS was associated with proteins related to atherosclerosis and cell proliferation. These findings may help identify pathophysiological pathways involved in the known adverse effects of SPS. In Paper IV, data from 5061 individuals from the Malmö Diet and Cancer cardiovascular cohort, which is a population-based cohort, showed that SPS affected as much as 8% of the general middle-aged population, and that individuals with SPS had a 38% higher risk of all-cause mortality. In conclusion, structural changes in the heart can develop already at mild to moderate impairment of renal function. SPS is an important predictor of mortality in patients with HF and in individuals in the general population. Further studies are required to investigate the pathophysiology of SPS and the mechanism behind the association between SPS and mortality.