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1.	Klionsky, Daniel J, et al. (författare) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). 2016 Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 12:1, s. 1-222 Tidskriftsartikel (refereegranskat)
2.	Abdellah, Tebani, et al. (författare) Integration of molecular profiles in a longitudinal wellness profiling cohort. 2020 Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Tidskriftsartikel (refereegranskat)abstract An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
3.	Ahlin, Sofie, 1985, et al. (författare) Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity. 2013 Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:12 Tidskriftsartikel (refereegranskat)abstract Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
4.	Bellman, Jakob, et al. (författare) Loading enhances glucose uptake in muscles, bones, and bone marrow of lower extremities in humans. 2024 Ingår i: The Journal of clinical endocrinology and metabolism. - 1945-7197. Tidskriftsartikel (refereegranskat)abstract Increased standing time has been associated with improved health, but the underlying mechanism is unclear.We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities.In this single-center clinical trial with randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index (BMI) between 30 and 35kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography (PET/CT) imaging. The primary endpoint was the change in GU ratio between loaded bones (i.e. femur and tibia) and non-loaded bones (i.e. humerus).High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (e.g. femur/humerus ratio increased by 19%, p=0.029), muscles (e.g. m. quadriceps femoris/m. triceps brachii ratio increased by 28%, p=0.014) and in certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, p=0.041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load.Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.
5.	Bergkvist, Bo, et al. (författare) Pools and fluxes of carbon in three Norway spruce ecosystems along a climatic gradient in Sweden 2008 Ingår i: Biogeochemistry. - : Springer Science and Business Media LLC. - 0168-2563 .- 1573-515X. ; 89:1, s. 7-25 Tidskriftsartikel (refereegranskat)abstract This paper presents an integrated analysis of organic carbon (C) pools in soils and vegetation, within-ecosystem fluxes and net ecosystem exchange (NEE) in three 40-year old Norway spruce stands along a north-south climatic gradient in Sweden, measured 2001-2004. A process-orientated ecosystem model (CoupModel), previously parameterised on a regional dataset, was used for the analysis. Pools of soil organic carbon (SOC) and tree growth rates were highest at the southernmost site (1.6 and 2.0-fold, respectively). Tree litter production (litterfall and root litter) was also highest in the south, with about half coming from fine roots (< 1 mm) at all sites. However, when the litter input from the forest floor vegetation was included, the difference in total litter input rate between the sites almost disappeared (190-233 g C m(-2) year(-1)). We propose that a higher N deposition and N availability in the south result in a slower turnover of soil organic matter than in the north. This effect seems to overshadow the effect of temperature. At the southern site, 19% of the total litter input to the O horizon was leached to the mineral soil as dissolved organic carbon, while at the two northern sites the corresponding figure was approx. 9%. The CoupModel accurately described general C cycling behaviour in these ecosystems, reproducing the differences between north and south. The simulated changes in SOC pools during the measurement period were small, ranging from -8 g C m(-2) year(-1) in the north to +9 g C m(-2) year(-1) in the south. In contrast, NEE and tree growth measurements at the northernmost site suggest that the soil lost about 90 g C m(-2) year(-1).
6.	Carlsson, Per-Anders, 1972, et al. (författare) A transient in situ FTIR and XANES study of CO oxidation over Pt/Al2O3 catalysts 2004 Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 226:2, s. 422-434 Tidskriftsartikel (refereegranskat)abstract We report experimental results for the oxidation of CO over supported Pt/Al2O3 catalysts operating in oxygen excess at atmospheric pressure. To study the reaction kinetics under transient conditions we have employed step changes of the O2 concentration by intermittently switching off the O2 supply at various temperatures ranging from 523 to 623 K. Detailed in situ FTIR and XANES data for CO coverage and the chemical state of Pt, respectively, are presented together with the CO conversion, which in both cases was monitored by mass spectrometry. A red-shift of the vibrational frequency of linearly bonded CO which correlates with a blue-shift of the Pt LIII binding energy indicates that the Pt catalyst initially is partially oxidised and gradually reduced when the O2 supply is switched off. Control experiments with a NO2 oxidised Pt/Al2O3 catalyst support these findings. A hysteresis in the catalytic activity due to the different rates whereby Pt is oxidised and reduced as a function of gas-phase composition is observed. The activation energy for the Pt oxide reduction (decomposition) process is estimated to be about 50 kJ/mol. The results further emphasise that the conventional three-step Langmuir-Hinshelwood (LH) scheme used to interpret CO oxidation on Pt surfaces must be complemented by a Pt oxidation and reduction mechanism during transient conditions. Moreover, FTIR data suggest that during the extinction, the partially oxidised platinum surface is reduced by chemisorbed CO which should be explicitly accounted for in the modeling of the reaction mechanism.
7.	Carlsson, Per-Anders, 1972, et al. (författare) CO oxidation over Pt/Al2O3 - A transient in-situ FTIR and XANES study 2005 Ingår i: Proceedings of the 19th North American Catalysis Society Meeting, Philadelphia, USA, May 21-28. Konferensbidrag (refereegranskat)
8.	Carlsson, Per-Anders, 1972, et al. (författare) CO oxidation over Pt/Al2O3 - A transient in-situ FTIR and XANES study 2004 Ingår i: Proceedings of the Third International Taylor Conference, Belfast, UK, September 5-9. Konferensbidrag (refereegranskat)
9.	Carlsson, Per-Anders, 1972, et al. (författare) Oxidation of CO over Pt/Al2O3 catalysts - A transient in-situ FTIR and XANES study 2005 Ingår i: Proceedings of the 4th International Conference on Environmental Catalysis, Heidelberg, Germany, June 5-8. Konferensbidrag (refereegranskat)
10.	Carlsson, Per, 1951-, et al. (författare) Prioriteringar inom hälso- och sjukvård - erfarenheter från andra länder 2005 Rapport (övrigt vetenskapligt/konstnärligt)abstract Under de senaste femton åren kan man notera ett uppvaknande hos politiker i flera länder när det gäller behovet av att göra prioriteringar i hälso- och sjukvården. I själva verket har ransonering skett i alla tider. Sådan kan dock föregås av mer eller mindre medvetna och systematiska prioriteringar. När svenska politiker i likhet med sina kollegor i andra länder började prata om behovet av att göra prioriteringar handlade det om att göra dem mer öppet än vad som gällt tidigare. Det har dock visat sig svårt att agera öppet på grund av mängd orsaker. Avsaknaden av enhetliga begrepp, svårt att bestämma vilka kriterier för rättvisa som skall användas och en oförståelse från allmänheten att hälso- och sjukvård ska begränsas på något sätt är exempel på sådana svårigheter. För att övervinna dessa svårigheter har man valt olika strategier i de länder som på allvar försökt göra sina prioriteringar mer öppna. I några länder har man valt att fokusera på att utveckla en gemensam värdegrund medan andra valt att utveckla medborgardialogen. I ytterligare andra länder väljer man att undvika att tala öppet om prioriteringar.I den internationella debatten är det framförallt de amerikanska etikerna Norman Daniels och James Sabin teorier om diskursiv rättvisa som fått ett stort genomslag. De menar att vi aldrig kommer att kunna nå en fullständig enighet om vilka principer som skall gälla vid nödvändiga prioriteringar. Istället anser de att det borde vara möjligt att nå större acceptans om ett prioriteringsbeslut fattats på ett sätt som flertalet anser som legitimt och rättvist. Förutom kravet på öppenhet är det enligt Daniels och Sabin viktigt att grunderna för besluten uppfattas som relevanta. Ett sätt för beslutsfattare att uppnå detta är att alliera sig med andra grupper som åtnjuter viss legitimitet t ex att politiker och vårdpersonal samarbetar. Ett annat sätt kan vara att rationalisera svåra beslut; d v s ge dem karaktär av att vara rationella. Här spelar tillgången på fakta om olika hälso- och sjukvårdsinsatsers effekter och patientnytta en stor roll.Andra forskare menar att prioriteringar av sjukvård alltid innehåller ett stort mått av värderingar och individuella variationer mellan olika patienter. Därför kan man inte grunda sina ställningstaganden på vetenskapliga studier och utarbeta riktlinjer utan istället låta sig styras av vedertagna etiska principer. I Sverige gäller sedan 1997 principen att de med stora behov av vård i första hand skall garanteras vård. Denna princip liksom principen om människors lika värde och kostnadseffektivitet som Riksdagen tagit ställning till är ett försök få igång en bred dialog kring prioriteringar men även att bidra med en plattform för mer öppna och legitima prioriteringar i hälso- och sjukvården. I praktiken visar det sig svårt att omsätta allmänna principer i det dagliga beslutsfattandet.I Sverige efterlyser läkare och andra vårdgrupper tydligare riktlinjer för att kunna ta sitt ansvar för prioriteringar. Den aktuella genomgången visar att man nått olika långt när det gäller öppenheten i de länder som ingår i vår undersökning.Norge var tidigt ute med att utarbeta riktlinjer för prioriteringar inom hälso- och sjukvården. Redan år 1987 avlämnade regeringen en offentlig utredning (NOU 1987:23) i ämnet (Lönning I). Tio år senare återkom regeringen med ytterligare tankar och förslag i NOU 1997:18 (Lönning II). Liksom i alla västländer har den norska hälso- och sjukvårdssektorn haft kostnadsproblem. I synnerhet under 1990-talet tycks kostnaderna ha vuxit i en snabbare takt än vad tillgängliga resurser har tillåtit. En öppen prioritering i enlighet med Lönning-utredningarna tycks dock inte ha varit lösningen på detta dilemma. Genomgången av den norska hälso- och sjukvården ger inget stöd för att dessa tankar fått genomslag i vården. I Norge har man istället försökt lösa problemen med en omfattande strukturförändring som i korthet inneburit att staten genom de regionala hälsoföretagen tagit ett än fastare grepp om den specialiserade sjukhusvården. I de dokument som ligger till grund för den nya ordningen finns dock klara viljeyttringar om att de principer och diskussioner om öppna prioriteringar som finns i både Lönning I och Lönning II ska genomsyra vården framöver. Särskilt omfattande konkret och praktiskt prioriteringsarbete tycks emellertid inte pågå inom ramen för det nya statliga huvudmannaskapet. Införande av en rättighetslag för slutenvård på sjukhus ställer dock krav på en tydligare avgränsning av det offentliga åtagandet. Inte heller inom andra hälso- och sjukvårdssektorer tycks aktiviteterna vara särskilt omfattande.Förändringar av detta slag tar dock lång tid. Det Nationella rådet för prioriteringar inom hälso- och sjukvården som har till uppgift att vara regeringens rådgivande organ ska utveckla principer och metoder för prioriteringar inom hela hälso- och sjukvårdsområdet, både det statliga och det kommunala. Genom rådet har prioriteringsarbetet kommit alltmer i fokus i den omfattande strukturförändring som norsk hälso- och sjukvård genomgår.Nya Zeeland var liksom Norge tidigt med att diskutera prioriteringar inom hälso- och sjukvården på ett öppet och medvetet sätt. I samband med en genomgripande förändring av sjukvårdssystemet i början av 1990-talet påbörjade regeringen ett samtal om gränserna för det offentliga åtagandet och behovet av prioriteringar. Man valde metoder som involverade både sjukvårdspersonal och medborgare. Drygt tio år senare kan man konstatera att det nya zeeländska försöket bara delvis realiserats. Prioriteringar som var tänkta att göras genom att definiera en kärna av sjukvårdstjänster som skulle finansieras offentligt utifrån fastställda kriterier kom aldrig riktigt till stånd.Ekonomin vände, en regering med en annan majoritet tillträdde år 1999 och hälso- och sjukvårdssektorn tillfördes ytterligare medel. Under de första åren på 2000-talet har sjukvården blivit tillförsäkrad resurser motsvarande en utgiftsökning för staten med 21 procent på tre år. Intresset för att diskutera prioriteringar och rättvisefrågor har därmed falnat.Samtidigt kan man konstatera att diskussionen och det arbete som lades ner från början av 1990-talet och framåt har haft viss effekt. Det finns idag en medvetenhet om att det är nödvändigt att se över hur åtminstone tillskottet av resurser som sektorn tilldelas ska fördelas. Arbete pågår både centralt i Ministry of Health och regionalt i de nytillskapade District Health Boards att finna metoder och fördelningsnycklar för hur nytillskottet av pengar ska användas på bästa sätt med de fyra prioriteringskriterierna som formulerades redan i början av 90-talet som grund. Samtalet med befolkningen fortsätter i nya former i första hand genom de nya distriktsstyrelserna.Storbritannien uppvisar relativt låga ambitioner när det gäller att utveckla former för öppna prioriteringar. Det beror dels på att majoriteten av sjukvård fördelas genom en politiskt styrd organisation och dels på den starka symboliska roll som National Health Service (NHS) intar i det brittiska samhället. NHS är en av få organisationer i ett ganska ojämlikt samhälle som alltid har stått för principen om jämlikhet – vård efter behov och inte betalningsförmåga. Det har därför varit särskilt känsligt för politikerna på den nationella nivån att öppet diskutera att utesluta vissa vårdåtgärder.På den lokala nivån inom den offentliga sjukvården har dock beslutsfattare prövat olika former för en mer öppen prioritering. Det finns ingen klar linje utan det förekommer stora lokala variationer, där vissa sjukvårdsområden försökt gå i riktning mot en tydlig process där motiven bakom prioriteringar tydliggörs för allmänheten. Hur framtiden kommer att te sig i detta avseende är svårt att uttala sig om då den lokala beställarorganisationen befinner sig i en period av omställning, där de läkardominerade Primary Care Trusts håller på att ta över ansvaret från de traditionella ”health authorities”.Den nuvarande brittiska regeringen har valt en strategi för att lösa brister i NHS med mer pengar och effektivisering. I fallet med prioriteringar har politikerna lämnat över ansvaret till allehanda expertorgan, helt i linje med uppfattningen att god evidens ska leda till mer självklara avvägningar inom den lokala sjukvården. I vilken utsträckning den verksamhet som bedrivs inom expertorganet NICE kommer att underlätta prioriteringar är dock oklart. En effekt blir också att den lokala sjukvården måste implementera de nya medicinska metoder som av NICE bedöms vara kostnadseffektiva. Att detta leder till att nya prioriteringar aktualiseras är givet.NICE löser inte det grundläggande dilemma som en heltäckande offentlig sjukvårdsorganisation, som brittiska NHS, står inför, nämligen att kraven på organisationen tenderar att hela tiden öka. Trots en del försök med konsultation av medborgare i frågor om prioritering finns dock inget som tyder på att den brittiska allmänheten stöder uppfattningen att den offentliga hälso- och sjukvården måste begränsa sitt åtagande.Liksom i flera andra länder väcktes frågan om öppna prioriteringar i Nederländerna under en tid av dålig offentlig ekonomi. På samma sätt som i Sverige mynnade diskussionen ut i ett politiskt dokument med höga ambitioner rörande öppenhet och prioriteringsprinciper (den s k Dunningkommitténs slutrapport). Trots vissa försök att begränsa det samhälleliga åtagandet inom hälso- och sjukvården har de flesta tjänster som genom politiska beslut lyfts ut ur förmånssystemet lyfts tillbaka igen efter påtryckningar. Kostnadskontrollen har följd
11.	Chantzichristos, Dimitrios, 1976, et al. (författare) Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. 2021 Ingår i: eLife. - 2050-084X. ; 10 Tidskriftsartikel (refereegranskat)abstract Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.NCT02152553.
12.	Drake, Isabel, et al. (författare) The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses 2022 Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65, s. 128-139 Tidskriftsartikel (refereegranskat)abstract Aims/hypothesis Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. Methods Participants (n = 4022; 58.6% women) in the Malmo Diet and Cancer Study-Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 +/- 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 +/- 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 x 10(-11)). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. Results Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 x 10(-89)) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 x 10(-3)). Conclusions/interpretation Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.
13.	Eriksson, Jan W., et al. (författare) Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study 2018 Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:9, s. 1923-1934 Tidskriftsartikel (refereegranskat)abstract Aims/hypothesis The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA). individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21). 4 g OM3-CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). Results Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m(2) (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%,p = 0.037) in comparison with placebo. There was an interaction between the PNPLA31148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transfcrase (gamma-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in gamma-GT correlated with changes in liver PDFF (rho = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. Conclusions/interpretation Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD.
14.	Eriksson, Jan W., et al. (författare) Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation : the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study 2008 Ingår i: Hypertension. - : American Heart Association. - 0194-911X .- 1524-4563. ; 52:6, s. 1030-1037 Tidskriftsartikel (refereegranskat)abstract Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P
15.	Fryk, Emanuel, et al. (författare) Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients 2016 Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006 Tidskriftsartikel (refereegranskat)abstract Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
16.	Gummesson, Anders, 1973, et al. (författare) Longitudinal plasma protein profiling of newly diagnosed type 2 diabetes 2021 Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 63 Tidskriftsartikel (refereegranskat)abstract Background: Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status. Methods: To elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes. Findings: Early stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM. Interpretation: The results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments. Funding: This work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
17.	Gärdenäs, Annemieke, et al. (författare) Tracey - a simulation model of trace element fluxes in soil-plant system for long-term assessment of a radioactive groundwater contamination 2009 Rapport (övrigt vetenskapligt/konstnärligt)
18.	Hergens, Maria-Pia, et al. (författare) Use of Scandinavian Moist Smokeless Tobacco (Snus) and the Risk of Atrial Fibrillation 2014 Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 25:6, s. 872-876 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Snus is a smokeless tobacco product, widely used among Swedish men and increasingly so elsewhere. There is debate as to whether snus is an acceptable "harm-reduction" tobacco product. Since snus use delivers a dose of nicotine equivalent to cigarettes, and has been implicated in cardiac arrhythmia because of associations with sudden cardiovascular death, a relation with atrial fibrillation is plausible and important to investigate.METHODS:: To assess the relation between use of snus and risk of atrial fibrillation, we carried out a pooled analysis of 7 prospective Swedish cohort studies. In total, 274,882 men, recruited between 1978 and 2004, were followed via the National Patient Register for atrial fibrillation. Primary analyses were restricted to 127,907 never-smokers. Relative risks were estimated using Cox proportional hazard regression.RESULTS:: The prevalence of snus use was 25% among never-smokers. During follow-up, 3,069 cases of atrial fibrillation were identified. The pooled relative risk of atrial fibrillation was 1.07 (95% confidence interval = 0.97-1.19) in current snus users, compared with nonusers.CONCLUSION:: Findings from this large national pooling project indicate that snus use is unlikely to confer any important increase in risk of atrial fibrillation.
19.	Hägg, Daniel, 1974, et al. (författare) Osteoblast-lineage cells regulate metabolism and fat mass 2023 Ingår i: Current Opinion in Endocrine and Metabolic Research. - 2451-9650. ; 31 Forskningsöversikt (refereegranskat)abstract As energy depots in many circumstances have been limited during evolution, it is necessary to prioritize how to manage energy resources. In this review we summarize data from the last 15 years indicating that osteoblast-lineage cells are regulators of whole-body energy metabolism and fat mass. We focus mainly on three factors, osteocalcin, lipocalin-2 and sclerostin, that are released by osteoblast-lineage cells and proposed to exert endocrine effects on metabolism. In addition, we present a hypothesis on why osteoblast-lineage cells during evolution have developed a function to regulate metabolism and fat mass. We propose that osteoblast-lineage cells through the osteocyte network in bone are sensors of gravitational forces induced by body mass and gravity on land-living species. By sensing the body weight, the osteoblastlineage cells may then feed-back this information on the whole-body nutritional status via osteoblast-derived endocrine factors or via the nervous system to regulate energy metabolism and fat mass.
20.	Jansson, John-Olov, 1954, et al. (författare) The dual hypothesis of homeostatic body weight regulation, including gravity-dependent and leptin-dependent actions. 2023 Ingår i: Philosophical transactions of the Royal Society of London. Series B, Biological sciences. - 1471-2970. ; 378:1888 Forskningsöversikt (refereegranskat)abstract Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the gravitostat and proposed that there are two components of the gravitostat. First, an obvious mechanism involves increased energy consumption in relation to body weight when working against gravity on land. In addition, we propose that there exists a component, involving sensing of the body weight by osteocytes in the weight-bearing bones, resulting in a feedback regulation of energy metabolism and body weight. The gravity-dependent homeostatic regulation is mainly active in obese mice. We, herein, propose the dual hypothesis of body weight regulation, including gravity-dependent actions (= gravitostat) at the upper end and leptin-dependent actions at the lower end of the body weight spectrum. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
21.	Klemedtsson, Leif, 1953, et al. (författare) Bayesian calibration method used to elucidate carbon turnover in forest on drained organic soil 2008 Ingår i: Biogeochemistry. - : Springer Science and Business Media LLC. - 0168-2563 .- 1573-515X. ; 89:1, s. 61-79 Tidskriftsartikel (refereegranskat)abstract Depending on the balance between sink and source processes for C, drained organic forest soil ecosystems can be in balance or act as net sinks or sources of CO2 to the atmosphere. In order to study the effect of groundwater level and soil temperature on C-flux, the CoupModel was calibrated (climate data, groundwater levels, soil CO2 flux, net ecosystem fluxes of CO2-exchange, sensible heat flux and latent heat flux, forest production etc.) for a drained forest in Sweden. Bayesian calibration techniques were used to elucidate how different parameters and variables were interlinked in C-circulation. The calibrated model reproduced abiotic and biotic variables reasonably well except for root respiration, which was largely underestimated. Bayesian calibration reduced the uncertainties in the model and highlighted the fact that calibrations should be performed with a high number of parameters instead of specific parameter values.
22.	Klemedtsson, Leif, 1953, et al. (författare) Skogaryd – Integration of terrestrial and freshwater greenhouse gas sources and sinks 2010 Ingår i: 1st COST meeting ‘Belowground carbon in Europeanforest’, Birmensdorf, Switzerland, 26–28 January 2010.. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Forests play an important role in the global carbon (C) cycle, and management as well as climate can cause major effects on the balance of C between the atmosphere and the plant/soil system. With re-gard to our commitments to the Kyoto and post-Kyoto actions on climate change, we need reliable predictions on how this balance is affected by management and climate. In 2006 the Skogaryd Research Forest was established in the southwest of Sweden (58°23’N, 12°09’E). The overall goal is to quantify net greenhouse gas (GHG) fluxes from drained spruce forest, by determining the individual fluxes and pools of C and nitrogen and elucidating their connection to site fertility, drainage status and abiotic parameters and then use the generated data in GHG models, for model validations and ultimately emissions predictions. During 2006-2009 the research has fo-cused on two sites, mineral and organic, dominated by Norway spruce (Picea abies). Both sites are drained fertile soils but with different land-use history that have affected their physical properties. Measurements includes: net ecosystem exchange of CO2, Shoot photosynthesis and respiration at different locations within the canopy, stem respiration, emissions of N2O and CH4 using manual cham-bers, soil respiration with automatic chambers including a trenching experiment where root-, mycelia-, and heterotrophic respiration are separated, fine root production using minirhizotrons, and mycelia production. The organic site also includes a wood ash experiment. From 2010 the research will be expanded to the whole watershed, from the mire system via streams, riparian zones, forests, to lakes and the subsequent exchange between the atmosphere and surface waters. Different terrestrial and limnic ecosystems will be linked holistically, using site specific tech-niques at different scales, from aircraft (km2) to chambers (m2) to create integrated models that can be used to quantify net GHG flux for management strategies.
23.	Ohlsson, Claes, 1965, et al. (författare) Increased weight loading reduces body weight and body fat in obese subjects – A proof of concept randomized clinical trial 2020 Ingår i: EClinicalMedicine. - : Elsevier BV. - 2589-5370. ; 22 Tidskriftsartikel (refereegranskat)abstract Background: Recently we provided evidence for a leptin-independent homeostatic regulation, the gravitostat, of body weight in rodents. The aim of the present translational proof of concept study was to test the gravitostat hypothesis in humans. Methods: We conducted a randomized controlled single center trial (ClinicalTrial.gov number, NCT03672903), to evaluate the efficacy of artificially increased weight loading on body weight in subjects with mild obesity (BMI 30–35 kg/m2). Subjects were either treated with a heavy (=high load; 11% of body weight) or light (=low load; 1% of body weight) weight vest for eight hours per day for three weeks. The primary outcome was change in body weight. Secondary outcomes included change in body fat mass and fat-free mass as measured using bioelectrical impedance analysis. Findings: In total 72 participants underwent randomization and 69 (36 high load and 33 low load) completed the study for the primary outcome. High load treatment resulted in a more pronounced relative body weight loss compared to low load treatment (mean difference -1.37%, 95% confidence interval (CI), -1.96 to -0.79; p = 1.5 × 10−5). High load treatment reduced fat mass (-4.04%, 95% CI, -6,53 to -1.55; p = 1.9 × 10−3) but not fat free mass (0.43%, 95% CI, -1.47 to 2.34; p = 0.65) compared to low load treatment. Interpretation: Increased weight loading reduces body weight and fat mass in obese subjects in a similar way as previously shown in obese rodents. These findings demonstrate that there is weight loading dependent homeostatic regulation of body weight, the gravitostat, also in humans. Funding: Funded by Jane and Dan Olsson (JADO) Foundation, the Torsten Söderberg Foundation, The Knut and Alice Wallenberg's Foundation and the Novo Nordisk Foundation. © 2020 The Author(s)
24.	Oscarsson, Jan, et al. (författare) Effects of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, and free omega-3 carboxylic acids on liver steatosis and hepatocyte damage biomarkers in Type 2 diabetes patients with non-alcoholic fatty liver disease 2016 Ingår i: Hepatology. - 0270-9139 .- 1527-3350. ; 64:1 SUPP, s. 554A-554A Tidskriftsartikel (refereegranskat)
25.	Paul-Visse, Gesine, et al. (författare) Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients 2015 Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:3, s. 1339-1346 Tidskriftsartikel (refereegranskat)abstract BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.
26.	Pournaras, N., et al. (författare) Glucose Homeostasis in Relation to Neutrophil Mobilization in Smokers with COPD 2022 Ingår i: International Journal of Chronic Obstructive Pulmonary Disease. - 1178-2005. ; 17, s. 1179-1194 Tidskriftsartikel (refereegranskat)abstract Purpose: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are common comorbidities in chronic obstructive pulmonary disease (COPD), but the underlying pathogenic mechanisms are poorly understood. Given that these morbidities all display increased neutrophil mobilization, the current study aimed to address whether glucose homeostasis relates to signs of neutrophil mobilization in COPD. Methods: The study population included healthy non-smokers (HNS) and long-term smokers without (LTS) and with COPD (LTS +COPD). No subject had T2DM or MetS. Serum cotinine was quantified to evaluate current smoking. Capillary blood glucose was measured after overnight fasting and during an oral glucose tolerance test (OGTT). Neutrophils were quantified in blood and bronchoalveolar lavage samples (BAL). The neutrophil-related cytokines IL-36 alpha, -beta and -gamma were quantified (ELISA) along with IL-6, IL-8, INF-gamma and CXCL10 (U-Plex (R)) in plasma and cell-free BAL fluid (BALF). In addition, we quantified neutrophil elastase (ELISA) and net proteinase activity (substrate assay) in BALF. Results: The LTS+COPD group had lower fasting glucose, greater change in glucose during OGTT and higher neutrophil concentrations in BAL and blood compared with HNS. Fasting glucose correlated in a positive manner with blood neutrophil concentration, forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) and FEV1 (% of predicted) in LTS+COPD. In this group, the concentration of IL-36 alpha in BALF correlated in a negative manner with fasting glucose, blood neutrophil concentration and FEV1, while the CXCL10 concentration in BALF correlated in a negative manner with glucose at the end of OGTT (120 min). We observed no corresponding correlations for neutrophil elastase, net proteinase or gelatinase activity. Conclusion: In smokers with COPD, altered glucose homeostasis is associated with local and systemic signs of increased neutrophil mobilization, but not with local proteinases. This suggests that other specific aspects of neutrophil mobilization constitute pathogenic factors that affect glucose homeostasis in COPD.
27.	Sjögren, Lovisa, et al. (författare) Postprandial effects of the phosphodiesterase-5 inhibitor tadalafil in people with well-controlled Type 2 diabetes mellitus: a randomized controlled trial. 2016 Ingår i: Diabetic medicine : a journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 33:9, s. 1299-1301 Tidskriftsartikel (refereegranskat)abstract Type 2 diabetes mellitus is a serious global health problem that is hard to treat in the long term, prompting great efforts to find new drug targets. Little attention has been paid, however, to the metabolic significance of the microcirculation in insulin-sensitive tissues, despite the fact that microvascular insulin resistance and endothelial dysfunction are closely associated and have been shown to precede Type 2 diabetes [1]. Endothelial nitric oxide plays a major role in mediating the beneficial effects of insulin on capillary recruitment and muscle glucose uptake [2] and in suppression of inflammatory pathways, including those activated by a high-fat diet [3]. This article is protected by copyright. All rights reserved.
28.	Volkov, Petr, et al. (författare) A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits 2016 Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6 Tidskriftsartikel (refereegranskat)abstract Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, highdensity lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys) metabolic traits associated with the development of obesity and diabetes.
29.	Abrahamsson, Gun, 1947, et al. (författare) Ovarian cyst formation in women of reproductive age receiving mitotane as part of the treatment of adrenocortical carcinoma: Clinical and experimental observations 2020 Ingår i: Acta Obstetricia Et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 99:10, s. 1297-1302 Tidskriftsartikel (refereegranskat)abstract Introduction Mitotane is an adrenolytic drug that is used as an adjuvant to treat adrenocortical carcinoma. This study aimed to evaluate the clinical course and pathogenetic mechanisms underlying ovarian cyst formation in women of reproductive age diagnosed with adrenocortical carcinoma and being treated with mitotane as an adjuvant to surgery. Material and methods Five women presented with stage III-IV adrenocortical carcinoma and ovarian cyst formation during mitotane treatment. The clinical course of the disease was followed during and after treatment. The effects of mitotane on progesterone production and cell proliferation were studied in cultured human ovarian granulosa cells. Results Computed tomography and vaginal ultrasonography during mitotane treatment repeatedly demonstrated ovarian cysts of varying size without solid intralocular structures. Two women became amenorrheic during the treatment period. After mitotane cessation, the ovarian cysts disappeared and normal menstrual cycles resumed. One woman had an uncomplicated pregnancy two years after mitotane treatment. In one woman, who underwent salpingo-oophorectomy, histological analysis demonstrated benign ovarian cysts. Mitotane impeded the synthesis of progesterone, reduced the stimulatory effect of gonadotropins on progesterone formation, and reduced labeling with [H-3]thymidine in cultured granulosa cells. Conclusions Therapeutic concentrations of mitotane are associated with the formation of benign ovarian cysts and amenorrhea. Mitotane-induced suppression of ovarian steroidogenesis and impediment of the proliferative capacity of steroid-producing cells are suggested potential pathogenetic mechanisms underlying mitotane-induced ovarian dysfunction and cyst development. Mitotane treatment does not compromise future ovarian function.
30.	Ahlberg, Erik, et al. (författare) "Vi klimatforskare stödjer Greta och skolungdomarna" 2019 Ingår i: Dagens nyheter (DN debatt). - 1101-2447. Tidskriftsartikel (populärvet., debatt m.m.)abstract DN DEBATT 15/3. Sedan industrialiseringens början har vi använt omkring fyra femtedelar av den mängd fossilt kol som får förbrännas för att vi ska klara Parisavtalet. Vi har bara en femtedel kvar och det är bråttom att kraftigt reducera utsläppen. Det har Greta Thunberg och de strejkande ungdomarna förstått. Därför stödjer vi deras krav, skriver 270 klimatforskare.
31.	Ahrén, Bo, et al. (författare) Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. 2004 Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 89:5, s. 2078-84 Tidskriftsartikel (refereegranskat)
32.	Ahrén, Bo, et al. (författare) Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. 2002 Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 25:5, s. 869-75 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study.RESEARCH DESIGN AND METHODS: A total of 93 patients (61 men and 32 women), aged 64 +/- 9 years (means +/- SD) and with BMI 27.3 +/- 2.7 kg/m(2), entered the study. Fasting blood glucose was 8.5 +/- 1.5 mmol/l, and HbA(1c) was 7.4 +/- 0.7%. Before and after treatment with NVP DPP728 at 100 mg x 3 (n = 31) or 150 mg x 5 (n = 32) or placebo (n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal).RESULTS: Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA(1c) was reduced to 6.9 +/- 0.7% in the combined active treatment groups (P < 0.001). Laboratory safety and tolerability was good in all groups.CONCLUSIONS: We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease.
33.	Arnell, Anders, et al. (författare) Naturvägledning i Sverige - en översikt 2009 Rapport (övrigt vetenskapligt/konstnärligt)abstract Naturvägledning handlar om att förmedla kunskap om och väcka känslor för naturen och kulturlandskapet. Naturvägledare finns i många verksamheter och kallas ofta för något annat i sin vardag: naturguide, museipedagog, ekoturismföretagare, naturinformatör. Centrum för naturvägledning presenterar i rapporten Naturvägledning i Sverige en bred översikt över begrepp, historik, och pågående aktiviteter inom svensk naturvägledning, med en internationell utblick. Rapporten bygger bland annat på intervjuer och enkäter med cirka 100 personer, som ger sin bilder av mål, glädjeämnen och utmaningar med arbetet som naturvägledare.
34.	Arvidsson, Daniel, et al. (författare) Cardiorespiratory fitness and the association with galectin-1 in middle-aged individuals. 2024 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:4 Tidskriftsartikel (refereegranskat)abstract Galectin-1 plays a functional role in human metabolism and the levels are altered in obesity and type 2 diabetes (T2D). This study investigates the association of cardiorespiratory fitness (CRF) with galectin-1 and the interconnection with body fatness. Cross-sectional data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot was analyzed, including a sample of 774 middle-aged individuals. A submaximal cycle ergometer test was used to estimate CRF as an indirect measure of the physical activity (PA) level. Serum-galectin-1 concentration was determined from venous blood collected after an overnight fast. Body mass index (BMI) was used as an indirect measure of body fatness. CRF was significantly associated with galectin-1, when controlled for age and sex (regression coefficient (regr coeff) = -0.29, p<0.001). The strength of the association was attenuated when BMI was added to the regression model (regr coeff = -0.09, p = 0.07), while the association between BMI and galectin-1 remained strong (regr coeff = 0.40, p<0.001). CRF was associated with BMI (regr coeff = -0.50, p<0.001). The indirect association between CRF and galectin-1 through BMI (-0.50 x 0.40) contributed to 69% of total association (mediation analysis). In group comparisons, individuals with low CRF-high BMI had the highest mean galectin-1 level (25 ng/ml), while individuals with high CRF-low BMI had the lowest level (21 ng/ml). Intermediate levels of galectin-1 were found in the low CRF-low BMI and high CRF-high BMI groups (both 22 ng/ml). The galectin-1 level in the low CRF-high BMI group was significantly different from the other three groups (P<0.001). In conclusion, galectin-1 is associated with CRF as an indirect measure of the PA level through interconnection with body fatness. The size of the association is of clinical relevance.
35.	Axelsen, Mette, 1965, et al. (författare) Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes. 1999 Ingår i: Annals of internal medicine. - 0003-4819 .- 1539-3704. ; 131:1, s. 27-31 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.
36.	Axelsson, T., et al. (författare) Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects 2001 Ingår i: J Intern Med. - 0954-6820. ; 249:6, s. 539-44 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: The aim of this study was to examine if an acute nicotine infusion alters insulin sensitivity to a similar degree in type 2 diabetic patients as in healthy control subjects. DESIGN: . Double-blind, cross-over, placebo-controlled, randomized experimental study. Nicotine 0.3 microg kg-1 min(-1) or NaCl was infused (2 h) during a euglycaemic hyperinsulinaemic clamp (4 h) to assess insulin sensitivity. SETTING: University research laboratory. SUBJECTS: Six male and female type 2 diabetic patients [DM2; age 54 +/- 10 (mean +/- SD) years; body mass index (BMI) 25.6 +/- 2.9 kg m(-2)] treated with diet or one oral hypoglycaemic agent and six age- and BMI-matched control subjects (Ctr). MAIN OUTCOME MEASURE: Insulin sensitivity (rate of glucose infusion per kg fat free body mass and minute), nicotine and free fatty acid (FFA) levels, pulse rate and blood pressure. RESULTS: The infusions produced similar nicotine levels in both groups. In the absence of nicotine, DM2 were more insulin resistant than Ctr (6.7 +/- 0.4 vs. 10.9 +/- 0.3 mg kg-1 LBM min(-1), respectively; P < 0.0001). This insulin resistance was further aggravated by the nicotine infusion in DM2 but not in Ctr (4.6 +/- 0.3 vs. 10.9 +/- 0.3 mg kg(-1) LBM min(-1); P < 0.0001). Only minor differences were seen in FFA levels, pulse rates and blood pressure. CONCLUSIONS: At this low infusion rate, nicotine aggravated the insulin resistance in DM2 but not in Ctr. This finding may be because of the (dysmetabolic) diabetic state per se or to an increased sensitivity to environmental factors associated with a genetic predisposition for type 2 diabetes. These results show that diabetic subjects are particularly susceptible to the detrimental effects of nicotine.
37.	Berndt, Sonja I., et al. (författare) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 2013 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69 Tidskriftsartikel (refereegranskat)abstract Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
38.	Boesgaard, T. W., et al. (författare) The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study 2008 Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:5, s. 816-20 Tidskriftsartikel (refereegranskat)abstract AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients. METHODS: We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/INTERPRETATION: Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
39.	Boesgaard, T. W., et al. (författare) Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study 2009 Ingår i: PLoS One. - 1932-6203. ; 4:9 Tidskriftsartikel (refereegranskat)abstract BACKROUND: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. METHODOLOGY/RESULTS: Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. CONCLUSION: The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.
40.	Boström, Anders E, 1951, et al. (författare) Antiplane elastic wave scattering from a curved randomly rough crack 1994 Ingår i: Journal of Applied Mechanics. ; 61, s. 835-842 Tidskriftsartikel (refereegranskat)
41.	Boström, Anders E, 1951, et al. (författare) Ultrasound in an anisotropic cladding with wavy interface 2005 Ingår i: Review of progress in Quantitative Nondestructive Evaluation. - 0735402450 ; 24A, s. 150-155 Konferensbidrag (refereegranskat)
42.	Boström, Pontus, 1982, et al. (författare) The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes. 2010 Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
43.	Brekke, Hilde Kristin, 1972, et al. (författare) Lifestyle changes can be achieved through counseling and follow-up in first-degree relatives of patients with type 2 diabetes. 2003 Ingår i: Journal of the American Dietetic Association. - 0002-8223. ; 103:7, s. 835-43 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To describe two lifestyle prevention strategies tested in first-degree relatives of patients with type 2 diabetes and to present the short-term effects of these strategies on nutrient intake, physical activity pattern, and body weight. DESIGN: In this 16-week controlled intervention trial, subjects were assigned to one of three treatment conditions: diet group (D) (n=25), diet and exercise group (DE) (n=30), or control group (C) (n=22). Subjects/setting Non-diabetic relatives of individuals with diabetes were recruited (n=77; men and women; age 25 to 55 years). INTERVENTION: Intervention groups received group counseling on two occasions and follow-up through unannounced telephone interviews every 10 days. Counseling regarding diet and physical activity was based on the Nordic Nutrition Recommendations. In addition, increased intake of fatty fish and low glycemic index foods were recommended. Main outcome measures Changes in diet (assessed by food frequency questionnaires), leisure time physical activity (assessed through interviews), fatty acid composition of erythrocyte membrane, and body weight. Statistical analysis One-way analysis of variance and Mann-Whitney U test were used to compare changes among groups. RESULTS: Compared with the control group, both intervention groups decreased intake of saturated fatty acids (percent of energy), increased intake of dietary fiber, and reduced average glycemic index of the diet. The ratio of n-6:n-3 fatty acids of the erythrocyte membranes decreased, confirming increased intake of fatty fish. Body weight decreased 1.7 kg (2.1%, P=.030) in group DE, and physical activity increased in the least-active subjects (+70 min/week, P<.01 within group). Applications/Conclusions Healthy individuals with heredity for type 2 diabetes can achieve desired changes in lifestyle factors associated with increased risk for the disease.
44.	Brekke, Hilde Kristin, 1972, et al. (författare) Lifestyle modification improves risk factors in type 2 diabetes relatives. 2005 Ingår i: Diabetes research and clinical practice. - : Elsevier BV. - 0168-8227. ; 68:1, s. 18-28 Tidskriftsartikel (refereegranskat)abstract AIMS: To investigate the short-term (16 weeks) effect of lifestyle intervention on insulin sensitivity, anthropometric and metabolic variables in non-diabetic first-degree relatives of type 2 diabetic patients (FDR). METHODS: Seventy-seven (49 male, 28 female) FDR were allocated to one of three groups, diet (D-group; n = 25), diet and exercise (DE-group; n = 30) or control group (C-group; n = 22). Lifestyle counselling was based on current nutrition recommendations, including increased intake of fatty fish and low glycaemic index foods. Group counselling was given on two occasions with follow-up through telephone interviews every 10 days. Assessments included insulin sensitivity index (Si), anthropometry, lipid parameters, circulating leptin and adiponectin levels. RESULTS: The D-group reduced total cholesterol (-0.31 mmol/l, P = 0.024), LDL cholesterol (-0.22 mmol/l, P = 0.021) and apolipoprotein B (-9.5 mg/dl, P = 0.009) levels, whereas the DE-group decreased body weight (-2.1%, P = 0.030) and waist circumference (-3.0 cm, P < 0.001) versus controls. A 13% reduction in fasting insulin was observed in the DE-group, but no significant improvement in Si in D-group or DE-group was observed. A subgroup, adherent to diet and who increased exercise, significantly improved Si and lipid profile. CONCLUSIONS: The improved metabolic risk profile in FDR suggests that lifestyle changes can be effective in individuals at high risk to develop type 2 diabetes and cardiovascular disease.
45.	Brekke, Hilde Kristin, 1972, et al. (författare) Long-term (1- and 2-year) effects of lifestyle intervention in type 2 diabetes relatives. 2005 Ingår i: Diabetes research and clinical practice. - : Elsevier BV. - 0168-8227. ; 70:3, s. 225-34 Tidskriftsartikel (refereegranskat)abstract AIMS: To study the long-term (1- and 2-year) effect of a lifestyle intervention on non-diabetic first-degree relatives of type 2 diabetic patients, i.e., the 1-year effect of diet versus diet and exercise in relation to a control group and the 2-year sustainability of these treatment effects. METHOD: Seventy-seven healthy first-degree relatives (men and women) between the ages of 25 and 55 were allocated to one of three groups: diet group (D), diet and exercise group (DE) and control group (C). For ethical reasons, after 1 year the control group began the intervention and were followed for another 2 years. Diet and physical activity counselling was based on current nutrition recommendations, including increased intake of fatty fish and low glycaemic index foods. The fatty acid composition of the erythrocyte membrane was studied as an objective measure of dietary change. Assessments included fasting insulin, 2-h insulin, oral glucose tolerance test (OGTT), anthropometry and blood lipid measurements. Groups D and DE received intensive follow-up through unannounced telephone interviews during the first 4 months. RESULTS: Dietary changes were significant at 1 year, and to a large degree sustained at 2 years. Adherence to advice regarding fat quality was confirmed through changes in the fatty acid composition of the erythrocyte membrane. The least active subjects in DE increased their physical activity (PA). At 1 year, group D showed a reduction in the ratio of LDL to HDL cholesterol (p=0.028) while group DE decreased their body weight by 2.7% (p<0.029) and increased HDL (p<0.037) versus controls. At 2 years, cholesterol levels (total, LDL and the ratio LDL/HDL) were reduced within group D and when compared to DE (p=0.022, 0.009, 0.035, respectively). Fasting insulin was reduced within group DE and when compared to group D (p=0.025). CONCLUSIONS: Positive changes in lifestyle, blood lipids and fasting insulin can be achieved and maintained in a non-diabetic population at risk of type 2 diabetes after 2 years.
46.	Bresell, Anders, et al. (författare) Bioinformatic and enzymatic characterization of the MAPEG superfamily 2005 Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 272:7, s. 1688-1703 Tidskriftsartikel (refereegranskat)abstract The membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily includes structurally related membrane proteins with diverse functions of widespread origin. A total of 136 proteins belonging to the MAPEG superfamily were found in database and genome screenings. The members were found in prokaryotes and eukaryotes, but not in any archaeal organism. Multiple sequence alignments and calculations of evolutionary trees revealed a clear subdivision of the eukaryotic MAPEG members, corresponding to the six families of microsomal glutathione transferases (MGST) 1, 2 and 3, leukotriene C4 synthase (LTC4), 5-lipoxygenase activating protein (FLAP), and prostaglandin E synthase. Prokaryotes contain at least two distinct potential ancestral subfamilies, of which one is unique, whereas the other most closely resembles enzymes that belong to the MGST2/FLAP/LTC4 synthase families. The insect members are most similar to MGST1/prostaglandin E synthase. With the new data available, we observe that fish enzymes are present in all six families, showing an early origin for MAPEG family differentiation. Thus, the evolutionary origins and relationships of the MAPEG superfamily can be defined, including distinct sequence patterns characteristic for each of the subfamilies. We have further investigated and functionally characterized representative gene products from Escherichia coli, Synechocystis sp., Arabidopsis thaliana and Drosophila melanogaster, and the fish liver enzyme, purified from pike (Esox lucius). Protein overexpression and enzyme activity analysis demonstrated that all proteins catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione. The E. coli protein displayed glutathione transferase activity of 0.11 µmol·min−1·mg−1 in the membrane fraction from bacteria overexpressing the protein. Partial purification of the Synechocystis sp. protein yielded an enzyme of the expected molecular mass and an N-terminal amino acid sequence that was at least 50% pure, with a specific activity towards 1-chloro-2,4-dinitrobenzene of 11 µmol·min−1·mg−1. Yeast microsomes expressing the Arabidopsis enzyme showed an activity of 0.02 µmol·min−1·mg−1, whereas the Drosophila enzyme expressed in E. coli was highly active at 3.6 µmol·min−1·mg−1. The purified pike enzyme is the most active MGST described so far with a specific activity of 285 µmol·min−1·mg−1. Drosophila and pike enzymes also displayed glutathione peroxidase activity towards cumene hydroperoxide (0.4 and 2.2 µmol·min−1·mg−1, respectively). Glutathione transferase activity can thus be regarded as a common denominator for a majority of MAPEG members throughout the kingdoms of life whereas glutathione peroxidase activity occurs in representatives from the MGST1, 2 and 3 and PGES subfamilies.
47.	Bäck, Marcus, et al. (författare) Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease : use of cyclopentane and cyclopentene P2-motifs 2007 Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7184-7202 Tidskriftsartikel (refereegranskat)abstract Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
48.	Bäck, Marcus, et al. (författare) Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs 2007 Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896. ; 15:22, s. 7184-7202 Tidskriftsartikel (refereegranskat)
49.	Carvalho, Eugénia, 1967, et al. (författare) Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. 1999 Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 13:15, s. 2173-8 Tidskriftsartikel (refereegranskat)abstract We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two first-degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1 (
50.	Ceder, Jens, et al. (författare) Delta-Like 1 (Dlk-1), a Novel Marker of Prostate Basal and Candidate Epithelial Stem Cells, Is Downregulated by Notch Signalling in Intermediate/Transit Amplifying Cells of the Human Prostate. 2008 Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 54, s. 1344-1353 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: There is a lack of understanding of the processes that regulate differentiation in the prostate. OBJECTIVE: To determine localisation, activity, and regulation of cytodifferentiation-modulatory proteins in the human adult prostate. DESIGN, SETTINGS, AND PARTICIPANTS: Eighteen volunteering patients with organ-confined prostate cancer were prospectively enrolled at a single university hospital. INTERVENTION: All patients underwent radical prostatectomy, and normal/benign tissue was excised and obtained from the transition zone. MEASUREMENTS: Expression and activity of Notch-protein family members, including the Notch-homologous protein Delta-like 1 (Dlk-1/Pref1), were investigated immunohistochemically in normal/benign tissue and explant cultures. The effect of the Notch inhibitor L-685,458 on Dlk-1 expression and cell number was investigated in primary cell cultures, and data were analysed with Student t test. RESULTS AND LIMITATIONS: Mature luminal cells were found to co-express Notch-1 and its ligand Jagged1, but epithelia in normal/benign tissue showed no active Notch signalling. The basal cell layer, rare candidate epithelial stem cells, and a subpopulation of neuroendocrine cells expressed the differentiation protein Dlk-1. In explant cultures, luminal cells and Jagged1 expression were lost, whereas intermediate cells downregulated Dlk-1 concomitant with Notch-1 upregulation and activation. Notch inhibition in primary cell cultures led to lower cell densities (p<0.001) and suppressed downregulation of Dlk-1. This is a small study; current results need to be confirmed in larger investigations. CONCLUSIONS: We demonstrate that Notch-1 is upregulated in differentiation of prostate epithelia, and that the novel prostate progenitor marker Dlk-1 is downregulated by Notch signalling in intermediate cells. The identification of Dlk-1-expressing candidate stem and neuroendocrine cells suggests a hierarchical relationship.

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