| 1. |
|
|
| 2. |
- Fritz, Michael, et al.
(författare)
-
Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
- 2016
-
Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 126:2, s. 695-705
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.
|
|
| 3. |
- Hedberg, Jakob, et al.
(författare)
-
Randomized controlled trial of nasogastric tube use after esophagectomy : study protocol for the kinetic trial
- 2024
-
Ingår i: Diseases of the esophagus. - : John Wiley & Sons. - 1120-8694 .- 1442-2050. ; 37:6
-
Tidskriftsartikel (refereegranskat)abstract
- Esophagectomy is a complex and complication laden procedure. Despite centralization, variations in perioparative strategies reflect a paucity of evidence regarding optimal routines. The use of nasogastric (NG) tubes post esophagectomy is typically associated with significant discomfort for the patients. We hypothesize that immediate postoperative removal of the NG tube is non-inferior to current routines. All Nordic Upper Gastrointestinal Cancer centers were invited to participate in this open-label pragmatic randomized controlled trial (RCT). Inclusion criteria include resection for locally advanced esophageal cancer with gastric tube reconstruction. A pretrial survey was undertaken and was the foundation for a consensus process resulting in the Kinetic trial, an RCT allocating patients to either no use of a NG tube (intervention) or 5 days of postoperative NG tube use (control) with anastomotic leakage as primary endpoint. Secondary endpoints include pulmonary complications, overall complications, length of stay, health related quality of life. A sample size of 450 patients is planned (Kinetic trial: https://www.isrctn.com/ISRCTN39935085). Thirteen Nordic centers with a combined catchment area of 17 million inhabitants have entered the trial and ethical approval was granted in Sweden, Norway, Finland, and Denmark. All centers routinely use NG tube and all but one center use total or hybrid minimally invasive-surgical approach. Inclusion began in January 2022 and the first annual safety board assessment has deemed the trial safe and recommended continuation. We have launched the first adequately powered multi-center pragmatic controlled randomized clinical trial regarding NG tube use after esophagectomy with gastric conduit reconstruction.
|
|
| 4. |
- Klawonn, Anna, 1985-, et al.
(författare)
-
Motivational valence is determined by striatal melanocortin 4 receptors
- 2018
-
Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 128:7, s. 3160-3170
-
Tidskriftsartikel (refereegranskat)abstract
- It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.
|
|
| 5. |
- von Otter, Malin, 1978, et al.
(författare)
-
Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease: a multicenter study
- 2014
-
Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15:1, s. artikel nr 131-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson s disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson s disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson s disease in meta-analyses including all six materials.Methods: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson s disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson s disease were investigated in each material individually and in meta-analyses of the obtained results.Results: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+ 1.1 years per allele, p = 0.048) of Parkinson s disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson s disease (rs7557529 G > A, -1.0 years per allele, p = 0.042; rs35652124 A > G, -1.1 years per allele, p = 0.045; rs2886161 A > G, -1.2 years per allele, p = 0.021; rs1806649 G > A, + 1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson s disease.Conclusion: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson s disease. Functional studies are now needed to explore these results further.
|
|
| 6. |
- Aguilar-Calvo, Patricia, et al.
(författare)
-
Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions
- 2020
-
Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 139:3, s. 527-546
-
Tidskriftsartikel (refereegranskat)abstract
- Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
|
|
| 7. |
- Alm Carlsson, Gudrun, et al.
(författare)
-
Monte Carlo metoden : ett verktyg inom strålningsfysiken
- 1995
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Detta kompendium är tänkt att användas som ett propedeutiskt kursmaterial för kursdeltagare i kursen "Monte Carlo simulering av foton- och elektrontransport vid diagnostiska och radioterapeutiska strålkvaliteter". Först följer en kort repetition av den grundläggande statistik som utnyt1jas i beräkningarna. Därefter följer en beskrivning av slumptal. det fundament som metoden bygger på. Vidare beskrivs val ur olika frekvensfunktioner. Valet kan även göras ur så kallade falska fördelningar för att reducera variansen i den skattade storheten. Metoderna belyses i ett avsnitt om problemlösningsmetodik. först i allmänna termer för att sen gå in på ett specifikt problem (Buffons nålproblem) där en analys och strukturering av problemet görs varefter flödesschema och kodning exemplifieras. Så följer två moment där en beskrivning görs av färderna av fotoner respektive elektroner genom materia. För elektronfärderna gör man en indelning i klass 1- och klass II-färder. Vad detta innebär och hur deltapartiklar tas om hand beskrivs i ett kapitel. Till sist kommer en kort introduktion till de tre laborationerna med laborationshandledningar. Speciell vikt har lagts vid att initiera laboranten att fundera på fysiken i de simulerade experimenten. Detta kompendium har tillkommit som examinationsarbete vid en kurs i "Monte Carlo simulering av foton- och elektrontransport vid diagnostiska och radioterapeutiska strålkvaliteter", med andra ord den kurs du själv nu ämnar studera. Författarna önskar dig lycka till med kursen och hoppas att du kommer att få glädje av den. Speciellt hoppas vi att denna skrift ska underlätta för dig att tillgodogöra dig informationen vid föreläsningarna och under laborationerna.
|
|
| 8. |
- Almon, Ricardo, et al.
(författare)
-
Prevalence and trends in adult-type hypolactasia in different age cohorts in Central Sweden diagnosed by genotyping for the adult-type hypolactasia-linked LCT -13910C > T mutation
- 2007
-
Ingår i: Scandinavian Journal of Gastroenterology. - Oslo : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 42:2, s. 165-170
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or intestinal biopsy. The aims of this study were to estimate the prevalence of AtH by genotyping and to investigate whether AtH prevalence has changed in Sweden during the 20th century. MATERIAL AND METHODS: Schoolchildren (n=690) born in 1983 and 1989, and elderly individuals (n=392) born between 1920 and 1932 were genotyped for AtH using Pyrosequencing technology. RESULTS: The overall prevalence of AtH among children was 14.1%. The majority of children (92%, n=635) were Caucasians with genotype prevalences: CC, 61 (10%); CT, 259 (41%); TT, 307 (49%). The frequency of the mutated allele q was 0.300 in this cohort. The prevalence of AtH estimated from the Hardy-Weinberg equilibrium (HWE) (q 2), was 9.0% (95% CI: 6.7-11.2%). Eight percent (n=55) of the children were non-Caucasian; genotype prevalences were CC, 36 (66%); CT, 15 (27%); TT, 4 (7%). The prevalence of AtH in these children estimated from HWE was 62.5% (95% CI: 49.7-75.3%). The elderly subjects were all Caucasians. Their genotype prevalences were: CC, 20 (5%); CT, 166 (42%); TT, 206 (53%); the frequency of the mutated allele q was 0.262 and their AtH prevalence estimated from HWE was 6.8% (95% CI: 4.3-9.2%). CONCLUSIONS: The overall prevalence of AtH in children (14%) was higher than previously thought. Among Caucasians, higher figures were seen in children than in the elderly (9% versus 6.8%). The prevalence thus seems to be increasing and this may be due to the immigration of both non-Caucasian and Caucasian groups with a higher prevalence of AtH.
|
|
| 9. |
- Andersson, Anna, et al.
(författare)
-
Molecular changes among non-volatile disinfection by-products between drinking water treatment and consumer taps
- 2021
-
Ingår i: Environmental Science. - : Royal Society of Chemistry. - 2053-1400 .- 2053-1419. ; 7:12, s. 2335-2345
-
Tidskriftsartikel (refereegranskat)abstract
- The formation of disinfection by-products (DBPs) during drinking water treatment has been associated with various health concerns but the total DBP exposure is still unknown. In this study, molecular level non-target analysis by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was used to study non-volatile DBPs, and how their composition changes during water distribution in four drinking water treatment plants (DWTPs) in Sweden using different types of raw water and disinfection processes. The largest portion of tap water DBP compositions were detected also at the DWTPs, highlighting that these DBP formulae were rather stable and contribute to human DBP exposure. Yet the number of detected DBPs decreased 14-48% between drinking water treatment and consumer taps in the three plants in which no mixing of water from other DWTPs in the distribution system occurred showing active DBP processing in the water distribution network. While considerable amounts of bromine-containing DBPs were detected upon chemical disinfection in some DWTPs, few of them were detected in the tap water samples, likely due to debromination by hydrolytic reactions. The overall fewer non-volatile DBPs detected in tap waters, along with changed distribution among chlorine and bromine DBPs, demonstrate that DBP mixtures are highly dynamic and that DBP measurements at DWTPs do not adequately reflect exposure at the point-of-use. Clearly, more knowledge about changes of DBP mixtures through the distribution system is needed to improve DBP exposure assessments.
|
|
| 10. |
- Andersson, Anna, et al.
(författare)
-
Waterworks-specific composition of drinking water disinfection by-products
- 2019
-
Ingår i: Environmental Science. - Cambridge : Royal Society of Chemistry. - 2053-1400 .- 2053-1419. ; :5, s. 861-872
-
Tidskriftsartikel (refereegranskat)abstract
- Reactions between chemical disinfectants and natural organic matter (NOM) upon drinking water treatment result in formation of potentially harmful disinfection by-products (DBPs). The diversity of DBPs formed is high and a large portion remains unknown. Previous studies have shown that non-volatile DBPs are important, as much of the total toxicity from DBPs has been related to this fraction. To further understand the composition and variation of DBPs associated with this fraction, non-target analysis with ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was employed to detect DBPs at four Swedish waterworks using different types of raw water and treatments. Samples were collected five times covering a full year. A common group of DBPs formed at all four waterworks was detected, suggesting a similar pool of DBP precursors in all raw waters that might be related to phenolic moieties. However, the largest proportion (64–92%) of the assigned chlorinated and brominated molecular formulae were unique, i.e. were solely found in one of the four waterworks. In contrast, the compositional variations of NOM in the raw waters and samples collected prior to chemical disinfection were rather limited.This indicated that waterworks-specific DBPs presumably originated from matrix effects at the point of disinfection, primarily explained by differences in bromide levels, disinfectants (chlorine versus chloramine) and different relative abundances of isomers among the NOM compositions studied. The large variation of observed DBPs in the toxicologically relevant non-volatile fraction indicates that non-targeted monitoring strategies might be valuable to ensure relevant DBP monitoring in the future.
|
|
