| 1. |
- Lundell, Anna-Carin, 1976, et al.
(författare)
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Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naïve CD5+ B cells in boys.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Boys present with higher proportions of immature/naïve CD5+ B cells than girls up to 3 years of age. Boys also have higher fractions of regulatory T cells (Tregs) in early infancy, but the mechanisms for these sex-related differences are unknown. In the prospective FARMFLORA follow-up study of 23 boys and 25 girls, we investigated if these immunological differences remained at 8 years of age. We also examined if testosterone or dihydrotestosterone (DHT) levels at birth and at 8 years of age were associated with immune maturation. Immunological variables and androgen levels were examined and measured in blood samples obtained at birth, 3-5 days and at 8 years of age. Boys had higher proportions of CD5+ and immature/transitional CD24hiCD38hi B cells, whereas girls had higher fractions of B cells with a memory phenotype at 8 years of age. School-aged boys also presented with higher frequencies of Tregs, and a greater capacity to produce T-cell-associated cytokines. Among boys, higher cord blood DHT levels were associated with higher proportions of CD5+ B cells in early infancy and at 8 years of life. These results suggest that DHT actions in utero might be involved in the mechanism for delayed peripheral B-cell maturation in boys.
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| 2. |
- Nilsson, Maria E., et al.
(författare)
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Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry.
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:7, s. 2492-502
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Tidskriftsartikel (refereegranskat)abstract
- Accurate measurement of sex steroid concentrations in rodent serum is essential to evaluate mouse and rat models for sex steroid-related disorders. The aim of the present study was to develop a sensitive and specific gas chromatography-tandem mass spectrometry (GC-MS/MS) method to assess a comprehensive sex steroid profile in rodent serum. A major effort was invested in reaching an exceptionally high sensitivity for measuring serum estradiol concentrations. We established a GC-MS/MS assay with a lower limit of detection for estradiol, estrone, testosterone, dihydrotestosterone, progesterone, androstenedione and dehydroepiandrosterone of 0.3, 0.5, 4, 1.6, 8, 4 and 50 pg/ml, respectively, while the corresponding values for the lower limit of quantification were 0.5, 0.5, 8, 2.5, 74, 12 and 400 pg/ml, respectively. Calibration curves were linear, intra- and inter-assay CVs were low and accuracy was excellent for all analytes. The established assay was used to accurately measure a comprehensive sex steroid profile in female rats and mice according to estrus cycle phase. In addition, we characterized the impact of age, sex, gonadectomy, and estradiol treatment on serum concentrations of these sex hormones in mice. In conclusion, we have established a highly sensitive and specific GC-MS/MS method to assess a comprehensive sex steroid profile in rodent serum in a single run. This GC-MS/MS assay has, to the best of our knowledge, the best detectability reported for estradiol. Our method therefore represents an ideal tool to characterize sex steroid metabolism in a variety of sex steroid-related rodent models and in human samples with low estradiol levels.
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| 3. |
- Wilhelmson, Anna S K, et al.
(författare)
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Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells.
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:4, s. 1228-36
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.
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| 4. |
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| 5. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Tidskriftsartikel (refereegranskat)abstract
- Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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| 6. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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The Bone Sparing Effects of 2-Methoxyestradiol Are Mediated via Estrogen Receptor-α in Male Mice.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:11, s. 4200-4205
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Tidskriftsartikel (refereegranskat)abstract
- 2-Methoxyestradiol (2ME2), a metabolite of 17β-estradiol (E2), exerts bone sparing effects in animal models. We hypothesized that the underlying mechanism is back conversion of 2ME2 to E2, which subsequently acts via estrogen receptor (ER)α. We measured serum E2 levels in orchidectomized wild-type (WT) mice treated with 2ME2 66.6 μg/d or placebo. In placebo-treated animals, E2 was below the detection limit. In 2ME2-treated mice, the serum E2 level was 4.97 ± 0.68 pg/mL. This corresponds to the level found in diesterus in cycling female mice. Next, we investigated bone parameters in orchidectomized WT and ERα knockout mice treated with 2ME2 or placebo for 35 days. 2ME2 (6.66 μg/d) preserved trabecular and cortical bone in WT mice. Trabecular volumetric-bone mineral density was 64 ± 20%, and trabecular bone volume/total volume was 60 ± 20% higher in the metaphyseal region of the femur in the 2ME2 group, compared with placebo (P < .01). Both trabecular number and trabecular thickness were increased (P < .01). Cortical bone mineral content in the diaphyseal region of the femur was 31 ± 3% higher in the 2ME2 group, compared with placebo (P < .001). This was due to larger cortical area (P < .001). Three-point bending showed an increased bone strength in WT 2ME2-treated animals compared with placebo (maximum load [Fmax] +19±5% in the 2ME2 group, P < .05). Importantly, no bone parameter was affected by 2ME2 treatment in ERα knockout mice. In conclusion, 2ME2 treatment of orchidectomized mice results in increased serum E2. ERα mediates the bone sparing effects of 2ME2. The likely mediator of this effect is E2 resulting from back conversion of 2ME2.
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| 7. |
- Kindenberg, Björn, 1972-, et al.
(författare)
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Budskap bortom raderna : Design-baserad forskning om undervisning för tolkande läsning
- 2019
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Konferensbidrag (refereegranskat)abstract
- Tolkande och reflekterande läsning av skönlitteratur är en viktig del av ämnena svenska och svenska som andraspråk, inte minst i fostran av demokratiska medborgare (Svedner, 2012). Detta gör litteraturundervisningen till ett viktigt studieobjekt. Även om det genomförts många klassrumsstudier om litteraturundervisning (t.ex. Hultin, 2006; Bergman, 2007; Langer, 2011), har ganska få involverat lärare i forskningsprocessen. Vår studie utgår ifrån en design-baserad ansats (Cobb et al., 2003), där nio lärare från grundskolans tre stadier tillsammans med forskare planerat och genomfört undervisning i syfte att utveckla elevers tolkande och reflekterade läsning av skönlitterära texters budskap. Texters budskap är ett vanligt, men också omstritt (t.ex. Lundström et al., 2011) begrepp. I studien används begreppet budskap pragmatiskt, som en konkret utgångspunkt för undervisning där begreppet sedan breddas och fördjupas genom en iterativ serie av undervisningsinterventioner. I studien har följande forskningsfrågor formulerats: Vad innebär det att urskilja budskap i skönlitterära texter? Vad hindrar och möjliggör för elever att urskilja budskap i skönlitterära texter? Hur kan elevers förmåga att urskilja texters budskap fördjupas genom undervisning? Langers (2011) läsarpositioner används som ett teoretiskt och metodologiskt ramverk som väglett analys och undervisningsdesign. Det empiriska materialet består av elevtexter, inspelade elevsamtal, inspelade undervisningsavsnitt, lärares undervisningsmaterial och inspelade samtal mellan lärare och forskare. Resultatet visar bland annat att specifika undervisningsaktiviteter, exempelvis att försätta elever i situationer av aktivt budskapsskapande fördjupar elevers tolkning av text. Vidare visar resultaten att lärarens stöttning både kan underlätta och hindra elevers tolkning av text.
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| 8. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 9. |
- Lundell, Anna-Carin, 1976, et al.
(författare)
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Umbilical Cord Blood Androgen Levels in Girls and Boys Assessed by Gas Chromatography-Tandem Mass Spectrometry.
- 2017
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 171, s. 195-200
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Tidskriftsartikel (refereegranskat)abstract
- Androgen exposure of the fetus during gestation plays an important role in human physiology and pathophysiology, but assessment of androgens, in particular dihydrotestosterone (DHT), in human umbilical cord blood is technically challenging. The aim of this study was to assess umbilical cord androgen levels, including DHT, at birth by a highly sensitive assay, and study their association with sex of the infant, sex-hormone-binding globulin (SHBG) levels, and gestational age at delivery. Swedish infants (27 girls, 26 boys) were recruited at maternity care clinics in Southern Sweden. Umbilical cord blood levels of dehydroepiandrosterone (DHEA), androstenedione, testosterone and DHT at delivery were assessed by a gas chromatography-tandem mass spectrometry assay. Cord blood levels of DHT were 2.4-fold higher in boys (median 27.8pg/mL) than in girls (11.5pg/mL), while the sex difference was less pronounced for testosterone (1.3-fold higher in boys) and non-significant for DHEA and androstenedione. Gestational age at delivery associated inversely with DHT levels in boys and with DHEA levels in girls. There was a strong inverse correlation between SHBG and DHEA in both sexes, while there were no associations between SHBG and testosterone or DHT levels. In conclusion, using state of the art technology, we report that there is a pronounced sexual dimorphism in human umbilical cord blood DHT levels. The possibility to assess a complete androgen profile in human cord blood opens up for future increased understanding of the biological impact of the fetal androgen milieu.
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| 10. |
- Poborilova, Zuzana, et al.
(författare)
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DNA hypomethylation concomitant with the overproduction of ROS induced by naphthoquinone juglone on tobacco BY-2 suspension cells
- 2015
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Ingår i: Environmental and Experimental Botany. - : Elsevier BV. - 0098-8472 .- 1873-7307. ; 113, s. 28-39
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Tidskriftsartikel (refereegranskat)abstract
- Juglone, 5-hydroxy-1,4-naphthoquinone, is a naturally occurring plant secondary metabolite with allelopathic and cytotoxic properties. The cytotoxic effect of juglone and changes at the level of DNA methylation were investigated on a plant cell model, tobacco BY-2 cell suspension culture. We found that juglone in a concentration-dependent manner inhibits cell growth and causes creation of reactive oxygen species (ROS) that were visible mainly in nucleus, nucleolus, cytoplasm, and plasma membrane. Analysis of the changes in DNA methylation level using Luminometric Methylation Assay showed that juglone at the concentrations of 60 and 80 mu m causes hypomethylation of DNA. Decrease in DNA methylation was confirmed by the more sensitive technique, confocal immunofluorescence microscopy, already at 30 mu m, and was accompanied by significant overproduction of hydrogen peroxide, hydroxyl radicals, and superoxide anion radicals. The highest percentage of the signs of programed cell death, especially apoptic-like bodies that indicate DNA fragmentation was observed at 30 mu m of juglone. On the basis of results we suggest that overproduction of ROS is the main mechanism that causes hypomethylation of DNA, which may contribute to the initiation of the programmed cell death.
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| 11. |
- Wu, Jianyao, et al.
(författare)
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Enzalutamide Reduces the Bone Mass in the Axial but not the Appendicular Skeleton in Male Mice.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:2, s. 969-977
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone is a crucial regulator of the skeleton but the role of the androgen receptor (AR) for the maintenance of the adult male skeleton is unclear. In the present study, the role of the AR for bone metabolism and skeletal growth after sexual maturation was evaluated by means of the drug enzalutamide, which is a new AR antagonist used in the treatment of prostate cancer patients. Nine-week-old male mice were treated with 10, 30, or 100 mg/kg/day of enzalutamide for 21 days or were surgically castrated, and compared with vehicle-treated gonadal intact mice. Although orchidectomy (orx) reduced the cortical bone thickness and trabecular bone volume fraction in the appendicular skeleton, these parameters were unaffected by enzalutamide. In contrast, both enzalutamide and orx reduced the bone mass in the axial skeleton as demonstrated by reduced lumbar spine areal bone mineral density (p<0.001) and trabecular bone volume fraction in L5 vertebrae (p<0.001) compared with vehicle-treated gonadal intact mice. A compression test of the L5 vertebrae revealed that the mechanical strength in the axial skeleton was significantly reduced by enzalutamide (maximal load at failure, -15.3±3.5%; p<0.01). The effects of enzalutamide in the axial skeleton were associated with a high bone turnover. In conclusion, enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice after sexual maturation. We propose that the effect of testosterone on the axial skeleton in male mice is mainly mediated via the AR.
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| 12. |
- Alt Murphy, Margit, 1970, et al.
(författare)
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Acceleration based Activity Levels during Subacute Inpatient Stroke Rehabilitation
- 2017
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Ingår i: Procedia Technology. - : Elsevier BV. - 2212-0173. ; 27, s. 120-121
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Tidskriftsartikel (refereegranskat)abstract
- People after stroke have difficulties to reach sufficient physical activity level during their rehabilitation and particularly outside the therapy time. We aim to quantify activity levels and investigate differences in motor activity in weekdays and weekends in a subacute stage after stroke. Data from multiple three-axis accelerometers was collected during two 48h sessions in 11 patients. The activity level and symmetry indices were sensitive to variations in weekend and weekdays. This information is valuable in rehabilitation planning and management and enables identification of those in risk of low physical activity and inactivity. (C) 2017 The Authors. Published by Elsevier
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| 13. |
- Alt Murphy, Margit, 1970, et al.
(författare)
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Acceleration based activity metrics during subacute inpatient stroke rehabilitation
- 2016
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Ingår i: Procedia Technology, Biosensors 2016, 25-27 May, Göteborg, Sweden..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- People after stroke have difficulties to reach sufficient physical activity level during their rehabilitation and particularly outside the therapy time. We aim to quantify activity levels and investigate differences in motor activity in weekdays and weekends in a subacute stage after stroke. Data from multiple three-axis accelerometers was collected during two 48h sessions in 11 patients. The activity level and symmetry indices were sensitive to variations in weekend and weekdays. This information is valuable in rehabilitation planning and management and enables identification of those in risk of low physical activity and inactivity.
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| 14. |
- Alt Murphy, Margit, 1970, et al.
(författare)
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Comparison of Accelerometer-Based Arm, Leg and Trunk Activity at Weekdays and Weekends During Subacute Inpatient Rehabilitation After Stroke
- 2019
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Ingår i: Journal of Rehabilitation Medicine. - : Medical Journals Sweden AB. - 1650-1977 .- 1651-2081. ; 51:6, s. 426-433
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether there are differences in arm, leg and trunk activity measured by acceleration between weekdays and weekends in people undergoing rehabilitation in the subacute stage after stroke. Patients: Twenty-eight individuals with stroke (mean age 55.4 years; severe to mild impairment) and 10 healthy controls. Methods: A set of 5 3-axial accelerometers were used on the trunk, wrists and ankles during 2 48-h sessions at weekdays and over a weekend. Day-time acceleration raw data were expressed as the signal magnitude area. Asymmetry between the affected and less-affected limb was calculated as a ratio. Results: Participants with stroke used their both arms and legs less at weekends than on weekdays (p<0.05, effect size 0.3 2-0.5 7). Asymmetry between the affected and less-affected arm was greater at weekends (p < 0.05, effect size 0.32). All activity measures, apart from the less-affected arm on weekdays, were lower in stroke compared with controls (p<0.05, effect size 0.4-0.8). No statistically significant differences were detected between weekday and weekend activity for the control group. One-third of participants perceived the trunk sensor as inconvenient to wear. Conclusion: Increased focus needs to be applied on activities carried out during weekends at rehabilitation wards.
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| 15. |
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| 16. |
- Amzaleg, Y., et al.
(författare)
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Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 183, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.
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| 17. |
- Benyamine, Isak, 1963-
(författare)
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Konstnärliga undervisningspraktiker : Genealogier, diskurser och makt
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation is about art teaching practices at upper secondary schools with a focus on theatre and at university arts programmes with a focus on film. More specifically, it addresses the factors that have contributed to current teaching practices in art education today and how students and teachers in interaction with each other shape, become part of and identify with the norms and values that emerge through these practices.The overarching question concerns how norms and values emerge as power/knowledge processes in the teaching process. The genealogical study presented examines how art education is constructed at a policy level. The study discusses how, in past eras, investigators, researchers and educators described what students needed to do during their education to develop into professional artists, how teaching practices were designed and justified, and how art was distinct from other activities and forms of knowledge in education. The interaction study presented examines the act of teaching. It discusses how, the participants shape each other and establish norms and values in relation to notions of what art “is” and can be.The conditions of possibilities in art teaching practices has been identified in three discourses. The discourse of conversation governs the format and organisation of the teaching practice. It is assumed that through conversation the students can develop their artistic ability. The discourse of freedom identifies how students submit to the vague, flexible and ever-changing notions of what art signifies. The discourse of production describes how the artistic work in the teaching practice takes precedence over an acquisition of established knowledge.The importance of the participants’ own experiences and feelings, therapeutic conversations, the liberation from conventional education discourses, confession practices and the establishment of a production discourse all emerge as important techniques in art teaching practices. Core values and norms are expressed through these techniques.The study shows that participants in art teaching practices develop the skills of self-evaluation, self-analysis and self-governance. The notion of an individualised, exploratory educational experience clashes with a process that directs the students to align themselves with the shared norms and values of the art world, of its content and expression. Students perceive their artistic output as unique while the art produced can be understood as expression of a normalisation process that strives to maintain the values and norms in art teaching practices. In summery the dissertation shows that the participants’ learning process is of an exploratory nature. Rather than acquiring and assimilating established knowledge, the participants learn by finding their own paths in a knowledge-formation process in which they discover the artistic potential of their own experiences and insights.
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| 18. |
- Berglund, Torkel, et al.
(författare)
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Nicotinamide; antioxidative and DNA hypomethylation effects in plant cells
- 2017
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Ingår i: Plant physiology and biochemistry (Paris). - : Elsevier. - 0981-9428 .- 1873-2690. ; 118, s. 551-560
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Tidskriftsartikel (refereegranskat)abstract
- The effects of nicotinamide (NIC) and its natural plant metabolites nicotinic acid (NIA) and trigonelline (TRIG) were studied with respect to defense in plant cell cultures. NIC and NIA could protect against oxidative stress damage caused by 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH), which generates free radicals. Damage was analyzed as DNA strand breaks in cell cultures of Pisum sativum (garden pea), Daucus carota (carrot), Populus tremula L. × P. tremuloides (hybrid aspen) and Catharanthus roseus (Madagascar periwinkle), monitored by single cell gel electrophoresis (comet assay), and assays of cell leakage in C. roseus. The activities of aconitase and fumarase enzymes, which have key roles in energy metabolism, were analyzed in P. sativum cultures after treatment with NIC or NIA. Aconitase activity was increased by NIA, and fumarase activity was increased by both compounds. These compounds were shown to promote glutathione metabolism in P. sativum cultures, and NIC was shown to have a global DNA hypomethylating effect. Neither TRIG nor poly(ADP-ribose) polymerase (PARP) inhibitor 3-aminobenzamide offered any protection against DNA damage or cell leakage, nor did they promote aconitase or fumarase activities, or glutathione metabolism. By this broad approach addressing multiple biochemical factors and different plant species, we demonstrate that NIC and NIA protect plant cells from oxidative stress, and that NIC clearly exerts an epigenetic effect; decreased DNA methylation. This indicates that these compounds have important roles in the regulation of metabolism in plant cells, especially in connection to stress.
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| 19. |
- Berglund, Torkel, et al.
(författare)
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Protection of spruce seedlings against pine weevil attacks by treatment of seeds or seedlings with nicotinamide, nicotinic acid and jasmonic acid
- 2016
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Ingår i: Forestry (London). - : Oxford University Press. - 0015-752X .- 1464-3626. ; 89:2, s. 127-135
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Tidskriftsartikel (refereegranskat)abstract
- Sustainable methods are required to protect newly planted tree seedlings from insect herbivore attack. To this end, here Norway spruce (Picea abies (L.) Karst.) seeds were treated with 2.5 mM nicotinamide (NIC), 2.5 mM nicotinic acid (NIA), 3 mM jasmonic acid (JA) or 0.2 mM 5-azacytidine (5-Aza), and 6-month-old seedlings grown from these seeds were planted at a reforestation area in central Sweden. Attack by pine weevils (Hylobius abietis) was reduced by 50 per cent by NIC treatment, 62.5 per cent by JA treatment and 25 per cent by 5-Aza treatment, when compared with seedlings grown from untreated seeds. Watering 18-month-old spruce seedlings with 2 mM NIC or 2 mM NIA did reduce attack during the first season in the field by 40 and 53 per cent, respectively, compared with untreated plants. Girdling was also reduced by the different treatments. Analysis of conifer seedlings treated with 5-Aza points at a possible involvement of epigenetic mechanisms in this defensive capacity. This is supported by a reduced level of DNA methylation in the needles of young spruce seedlings grown in a greenhouse from NIC-treated seeds. Seed treatment for seedling defense potentiation is simple, inexpensive and also a new approach for forestry with many potential applications.
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| 20. |
- Bonfiglio, F., et al.
(författare)
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 155:1, s. 168-179
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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| 21. |
- Brembeck, Petra, 1977, et al.
(författare)
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Changes in cortical volumetric bone mineral density and thickness, and trabecular thickness in lactating women postpartum.
- 2015
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:2, s. 535-543
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Tidskriftsartikel (refereegranskat)abstract
- Context: Lactation is associated with decreased areal bone mineral density (aBMD). Replenishment occurs especially after ceased lactation. Changes in volumetric BMD (vBMD), microstructure and dimensional parameters are unknown and may clarify the role of lactation for skeletal health. Objective: and main outcomes: To test the hypothesis that lactation is associated with changes in aBMD, vBMD, microstructure and dimensional parameters. Design: At baseline (0.5 months after delivery) and 4, 12 and 18 months thereafter bone was assessed using dual energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT). Participants: and setting: Eighty-one fair-skinned postpartum women and 21 controls aged 25-40 years were recruited. Completion ratio was 73%. Postpartum women were categorized depending on duration of lactation; 0-3.9, 4-8.9 and ≥9 months. Results: During the first 4 months, aBMD decreased at several sites (geometric mean±SE; -0.73±0.21% to -3.98±0.76%) in women lactating at least 4 months. During the same time, cortical vBMD at ultra-distal tibia decreased in women lactating 4-8.9 months (-0.26±0.08%) and ≥9 months (-0.49±0.10%). At 12 months postpartum, also cortical thickness (≥9 months, -2.48±0.41%) and trabecular thickness (4-8.9 months, -2.14±0.92%; ≥9 months, -2.56±1.21%) were lower than baseline. No decreases were found in women lactating less than 4 months or in controls in these parameters. At 18 months postpartum, both cortical vBMD (≥9 months, -0.77±0.17%) and trabecular thickness (4-8.9 months, -2.25±1.25%; ≥9 months, -3.21±1.41%) were lower in women with long lactation. Conclusions: Decreases in cortical vBMD, thickness, and trabecular thickness at ultra-distal tibia were found in women lactating 4 months or longer. Longer follow-up is needed to confirm whether women with extended lactation recover fully, or whether the changes could potentially lead to increased risk of fracture in later life.
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| 22. |
- Brembeck, Petra, 1977, et al.
(författare)
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Determinants of microstructural, dimensional and bone mineral changes postpartum in Swedish women.
- 2016
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Ingår i: The British journal of nutrition. - 1475-2662. ; 116:10, s. 1736-44
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Tidskriftsartikel (refereegranskat)abstract
- During lactation, areal (a) and volumetric (v) bone mineral density (BMD) are known to temporarily decrease. Factors that affect skeletal changes postpartum are not fully elucidated. The aim was to study determinants of the previously observed changes in aBMD at lumbar spine, and cortical vBMD, microstructure and dimensions at ultra-distal tibia postpartum. Women (25-40 years) were studied longitudinally at 2 weeks (baseline) and 4 months (n 81), 12 months (n 79) and 18 months (n 58) postpartum. At each visit, blood samples were collected, body weight and height were measured and information about lactation habits, oestrogen contraceptives and physical activity was obtained. Ca intake was measured using 4-d food diaries at 4 months postpartum. Serum 25-hydroxyvitamin D (25OHD) was analysed by liquid chromatography-tandem MS. Skeletal changes were assessed with dual-energy X-ray absorptiometry and high-resolution peripheral quantitative computed tomography. Mean baseline BMI was 24·8 (sd 3·1) kg/m2. Median (quartiles 1-3) duration of total lactation was 8·1 (6·8-10·4) months. Longer duration of full lactation was associated with larger decreases of lumbar spine aBMD and tibia vBMD and microstructure. Higher baseline body weight was associated with smaller decreases in tibia vBMD and microstructure. Higher Ca intake was associated with smaller decreases in tibia cortical vBMD and thickness. Higher baseline 25OHD was only associated with larger decreases in lumbar spine aBMD. In conclusion, lactation and body weight were the main determinants of skeletal changes during the first 18 months postpartum. Ca intake and serum concentrations of 25OHD appear to have different associations with cortical and trabecular bone.
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| 23. |
- Börjesson, Anna E, et al.
(författare)
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SERMs have substance-specific effects on bone, and these effects are mediated via ER alpha AF-1 in female mice
- 2016
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 310:11
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Tidskriftsartikel (refereegranskat)abstract
- The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)alpha, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ER alpha AF-1 for the estradiol (E-2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ER alpha AF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ER alpha AF-1 (ER alpha AF-1(0)) with E-2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ER alpha AF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ER alpha AF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.
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| 24. |
- Darelid, Anna, et al.
(författare)
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Bone turnover markers predict bone mass development in young adult men: a five-year longitudinal study.
- 2015
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:4, s. 1460-8
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Tidskriftsartikel (refereegranskat)abstract
- Peak bone mass is an important factor for the lifetime risk of developing osteoporosis. Ways to predict bone development in young adulthood are lacking. Objective and Main Outcome Measures: The aim of this study was to investigate whether baseline measurements of bone turnover markers could predict bone development in early adulthood in men.
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| 25. |
- Dias, Joana A., et al.
(författare)
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Inflammatory potential of the diet and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
- 2018
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Ingår i: American Journal of Clinical Nutrition. - : American Society for Nutrition. - 0002-9165 .- 1938-3207. ; 107:4, s. 607-616
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammation plays a critical role in the pathogenesis of the 2 major types of gastric cancer. Several foods, nutrients, and nonnutrient food components seem to be involved in the regulation of chronic inflammation. We assessed the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the 2 major subsites: cardia cancers and noncardia cancers. A total of 476,160 subjects (30% men, 70% women) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 y, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (noncardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated with the use of 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by HRs and 95% CIs calculated by multivariate Cox regression models adjusted for confounders. The inflammatory potential of the diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in 1 SD of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for noncardia cancers. The corresponding values for the highest compared with the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70), respectively. Our results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach. This study is listed on the ISRCTN registry as ISRCTN12136108.
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| 26. |
- Dåderman, Anna Maria, 1953-, et al.
(författare)
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Two in ten feel excluded from social work-related processes by workplace bullying
- 2016
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Ingår i: Proceedings from the 9th GRASP conference, Linköping University, May 2014. - Linköping. - 9789175192178 ; , s. 17-34
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Konferensbidrag (refereegranskat)abstract
- The aim was to investigate (1) the prevalence of workplace bullying experienced by men and women in Swedish workplaces with a high level of stress dominated by one sex, (2) the prevalence of unjust treatment in these workplaces, (3) the relationship between workplace bullying and organizational climate, (4) the variability in bullying in these workplaces, and (5) the variability in organizational climate. These issues were examined using a self-assessment questionnaire in two types of workplace in Sweden: one male-dominated (juvenile detention care) and the other female-dominated (elderly care). About 20% of the participants experienced workplace bullying. There was a positive correlation between bullying and negative communication (strong effect size). There were no differences regarding the type of workplace. The internal consistency of the instrument was high, and we recommend its use in studies of workplace bullying
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| 27. |
- Fages, Anne, et al.
(författare)
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Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.
- 2015
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.
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| 28. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
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| 29. |
- Falkenström, Erica, 1966-, et al.
(författare)
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Developing ethical competence in healthcare management
- 2016
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Ingår i: Journal of Workplace Learning. - 1366-5626 .- 1758-7859. ; 28:1, s. 17-32
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Tidskriftsartikel (refereegranskat)abstract
- Purpose – The purpose of this paper was to explore what kind of ethical competence healthcare managers need in handling conflicts of interest (COI). The aim is also to highlight essential learning processes to develop healthcare managers’ ethical competence.Design/methodology/approach – A qualitative study was performed. Semi-structured interviews with ten Swedish healthcare managers from different care providers were carried out twice and analysed through step-wise categorisation.Findings – Four categories of COI were revealed and two ways (passive and active) in which COI were handled. Ethical guidelines did not help the healthcare managers to handle the COI, and none of the managers made use of any sort of systematic ethical analysis. However, certain ethical competence was of great importance to identify and handle COI, consisting of contextual understanding, rational emotions, some theoretical knowledge and a suitable language. Organising work so that ethical analysis can be carried out is of great importance, and top management needs to clearly express the importance of ethical competence and allocate resources to allow adequate learning processes.Originality/value – This paper highlights the management level and focuses on how work-integrated learning-processes can enable ethical competence. Ethical competence at the management level is essential both to comply with the constitution and legal requirements regarding healthcare, and so that managers are able to analyse COI and justify their decisions.
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| 30. |
- Guilbault, Ryan W.R., et al.
(författare)
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External Validation of Two Classification and Regression Tree Models to Predict the Outcome of Inpatient Cardiopulmonary Resuscitation
- 2017
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Ingår i: Journal of Intensive Care Medicine. - : SAGE Publications. - 0885-0666 .- 1525-1489. ; 32:5, s. 333-338
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To prospectively validate a previously developed classification and regression tree (CART) model that predicts the likelihood of a good outcome among patients undergoing inpatient cardiopulmonary resuscitation. Design: Prospective validation of a clinical decision rule. Setting: Skåne University Hospital in Malmo, Sweden. Patients: All adult patients (N = 287) experiencing in-hospital cardiopulmonary arrest and undergoing cardiopulmonary resuscitation between 2007 and 2010. Interventions: Patients from Skåne University Hospital who underwent CPR (N = 287) were classified using the CART models to predict their likelihood of survival neurologically intact or with minimal deficits, based on a cerebral performance category score of 1. Discrimination and classification accuracy of the score in the Swedish population was compared to that in the original (derivation and internal validation) populations. Measurements and Main Results: For model 1, the area under the receiver-operating characteristic curve (AUROCC) was 0.77, compared with 0.76 and 0.73 in the original derivation and validation populations, respectively. Model 1 classified 71 (2.8%) of 287 patients as being at a very low risk of a good neurologic outcome compared with 157 (26.1%) of 287 patients predicted to be at an above average risk of a good neurologic outcome. Model 2 had a similar AUROCC as the original validation population of 0.71 but lower than the original derivation population. Model 2 performed similarly to Model 1 with regards to its ability to correctly classify patients as very low or higher than average likelihood of a good neurologic outcome. Conclusion: Two CART models validated well in a different population, displaying similar discrimination and classification accuracy compared to the original population. Although additional validation in larger populations is desirable before widespread adoption, these results are very encouraging.
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| 31. |
- Gummeson, Anna, et al.
(författare)
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Automatic Gleason grading of H&E stained microscopic prostate images using deep convolutional neural networks
- 2017
-
Ingår i: Medical Imaging 2017: Digital Pathology. - : SPIE. - 9781510607255 ; 10140
-
Konferensbidrag (refereegranskat)abstract
- Prostate cancer is the most diagnosed cancer in men. The diagnosis is confirmed by pathologists based on ocular inspection of prostate biopsies in order to classify them according to Gleason score. The main goal of this paper is to automate the classification using convolutional neural networks (CNNs). The introduction of CNNs has broadened the field of pattern recognition. It replaces the classical way of designing and extracting hand-made features used for classification with the substantially different strategy of letting the computer itself decide which features are of importance. For automated prostate cancer classification into the classes: Benign, Gleason grade 3, 4 and 5 we propose a CNN with small convolutional filters that has been trained from scratch using stochastic gradient descent with momentum. The input consists of microscopic images of haematoxylin and eosin stained tissue, the output is a coarse segmentation into regions of the four different classes. The dataset used consists of 213 images, each considered to be of one class only. Using four-fold cross-validation we obtained an error rate of 7.3%, which is significantly better than previous state of the art using the same dataset. Although the dataset was rather small, good results were obtained. From this we conclude that CNN is a promising method for this problem. Future work includes obtaining a larger dataset, which potentially could diminish the error margin.
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| 32. |
- Gustafsson, Anna, et al.
(författare)
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Effects of Acute Exercise on Circulating Soluble Form of the Urokinase Receptor in Patients With Major Depressive Disorder
- 2017
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Ingår i: Biomarker Insights. - : Sage Publications. - 1177-2719. ; 12, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation has been proposed to play a role in the generation of depressive symptoms. Previously, we demonstrated that patients with major depressive disorder (MDD) have increased plasma levels of the soluble form of the urokinase receptor (suPAR), a marker for low-grade inflammation. The aim of this study was to test the hypothesis that acute exercise would induce inflammatory response characterized by increased suPAR and elucidate whether patients with MDD display altered levels of suPAR in response to acute exercise. A total of 17 patients with MDD and 17 controls were subjected to an exercise challenge. Plasma suPAR (P-suPAR) was analyzed before, during, and after exercise. There was a significantly higher baseline P-suPAR in the patients with MDD, and the dynamic changes of P-suPAR during the exercise were significantly lower in the patients with MDD, compared with the controls. This study supports the hypothesis that an activation of systemic inflammatory processes, measured as elevated P-suPAR, is involved in the pathophysiology of depression. The study concludes that P-suPAR is influenced by acute exercise, most likely due to release from activated neutrophils.
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| 33. |
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| 34. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 35. |
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| 36. |
- Hu, Min, et al.
(författare)
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Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 112:46, s. 14348-53
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Tidskriftsartikel (refereegranskat)abstract
- During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.
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| 37. |
- Häggström, Jens, et al.
(författare)
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Effect of Body Weight on Echocardiographic Measurements in 19,866 Pure-Bred Cats with or without Heart Disease
- 2016
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Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 30, s. 1601-1611
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEchocardiography is a cost-efficient method to screen cats for presence of heart disease. Current reference intervals for feline cardiac dimensions do not account for body weight (BW).ObjectiveTo study the effect of BW on heart rate (HR), aortic (Ao), left atrial (LA) and ventricular (LV) linear dimensions in cats, and to calculate 95% prediction intervals for these variables in normal adult pure-bred cats.Animals19 866 pure-bred cats.MethodsClinical data from heart screens conducted between 1999 and 2014 were included. Associations between BW, HR, and cardiac dimensions were assessed using univariate linear models and allometric scaling, including all cats, and only those considered normal, respectively. Prediction intervals were created using 95% confidence intervals obtained from regression curves.ResultsAssociations between BW and echocardiographic dimensions were best described by allometric scaling, and all dimensions increased with increasing BW (all P<0.001). Strongest associations were found between BW and Ao, LV end diastolic, LA dimensions, and thickness of LV free wall. Weak linear associations were found between BW and HR and left atrial to aortic ratio (LA:Ao), for which HR decreased with increasing BW (P<0.001), and LA:Ao increased with increasing BW (P<0.001). Marginal differences were found for prediction formulas and prediction intervals when the dataset included all cats versus only those considered normal.Conclusions and ImportanceBW had a clinically relevant effect on echocardiographic dimensions in cats, and BW based 95% prediction intervals may help in screening cats for heart disease.
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| 38. |
- Jansson, John-Olov, 1954, et al.
(författare)
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Body weight homeostat that regulates fat mass independently of leptin in rats and mice.
- 2018
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:2, s. 427-432
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Tidskriftsartikel (refereegranskat)abstract
- Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.
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| 39. |
- Justice, A. E., et al.
(författare)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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| 40. |
- Kokosar, Milana, et al.
(författare)
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A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment-induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPAR gamma and ADIPOR2. Changes in the expression of Nr4 alpha 2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement.
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| 41. |
- Kokosar, Milana, et al.
(författare)
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Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed "gene-CpG" probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.
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| 42. |
- Kokosar, Milana, et al.
(författare)
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Erratum: Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome.
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Scientific Reports 6: Article number: 22883; Published online: 15 March 2016; Updated: 09 May 2016 This Article contains errors. In Table 3, the text in the first row ‘Down-regulated genes’ was incorrectly given as ‘Up-regulated genes’. In addition, Fig. 2E was incorrectly labeled as Fig. 2ES. The correct Fig.
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| 43. |
- Kreutzman, Anna, et al.
(författare)
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Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line
- 2019
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.
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| 44. |
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| 45. |
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| 46. |
- Larsson, Gerry, et al.
(författare)
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Daily hassles, their antecedents and outcomes among professional first responders : a systematic literature review
- 2016
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Ingår i: Scandinavian Journal of Psychology. - : Wiley. - 0036-5564 .- 1467-9450. ; 57:4, s. 359-367
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Tidskriftsartikel (refereegranskat)abstract
- Occupational groups such as firefighters, military officers, paramedics and police officers are exposed to a combination of acute, severe and accumulated everyday stress. Drawing on the daily hassles perspective on stress, the aim was to synthesize existing research on daily hassles in professional first responder settings into a theoretical model. A systematic mixed studies review with an integrated design was undertaken. The selection process resulted in 40 articles meeting the inclusion criteria. The selected papers represented two literature reviews, one qualitative study, eight longitudinal studies and 29 cross-sectional studies. Five superior categories emerged in the analysis: Individual antecedent and continuously framing factors, Environmental antecedent and continuously framing factors, Appraisal and coping processes, Daily hassles and Outcome. Suggestions for future research are presented
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| 47. |
- Larsson, Gerry, Professor, 1952-, et al.
(författare)
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Daily uplifts and adaptive coping as a buffer against daily hassles : relationship with stress reactions over time in military personnel
- 2017
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Ingår i: Scandinavian Psychologist. - : Scandinavian Psychologist. - 1894-5570. ; :4
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this research was to gain a deeper understanding of how daily hassles and uplifts interact with each other and with stress reactions over time in military personnel. Interviews were conducted with 15 Swedish veterans five years after an international peace enforcement mission. The grounded theory method was used and result patterns were generated for six specific time periods distributed before, during, and after the mission. A theoretical model was developed showing that everyday uplifts combined with adaptive coping can be sufficient to limit stress reactions related to daily hassles. The model was supported by the fact that, five years after the mission, none of interviewees had received a PTSD diagnosis or needed professional psychological treatment. The last-mentioned outcome is noteworthy in itself given the severe stress often encountered in peace enforcement missions and previous research observations of high PTSD incidence, suicide rates, criminality, and substance abuse in mission participants.
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| 48. |
- Lauseker, Michael, et al.
(författare)
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Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin
- 2019
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Ingår i: American Journal of Hematology. - : WILEY. - 0361-8609 .- 1096-8652. ; 94:11, s. 1236-1243
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.
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| 49. |
- Lionikaite, Vikte, et al.
(författare)
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Clinically relevant doses of Vitamin A decrease cortical bone mass in mice
- 2018
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Ingår i: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 239:3, s. 389-402
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Tidskriftsartikel (refereegranskat)abstract
- Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone. © 2018 The authors Published by Bioscientifica Ltd.
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| 50. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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