| 1. |
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| 2. |
- Solinas, Giovanni, et al.
(författare)
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An adipoincretin effect links adipostasis with insulin secretion.
- 2024
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Ingår i: Trends in endocrinology and metabolism: TEM. - 1879-3061. ; 35:6, s. 466-477
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Forskningsöversikt (refereegranskat)abstract
- The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
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| 3. |
- Lind, Marcus, et al.
(författare)
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Thrombomodulin as a marker for bleeding complications during warfarin treatment
- 2009
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Ingår i: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 169:13, s. 1210-1215
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The major adverse effect of warfarin treatment is hemorrhage. Several risk factors for bleeding complications are also risk factors for thromboembolic events, making the clinical decision to initiate or withhold anticoagulant treatment difficult. Specific markers that solely identify patients at high risk of bleeding would have great clinical impact. This study aimed to test if thrombomodulin (TM) concentrations were associated with bleeding complications, cardiovascular events, or mortality in long-term anticoagulant-treated patients. METHODS: In a longitudinal cohort study we followed up 719 patients receiving warfarin treatment for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified. Soluble TM antigen (sTM) concentration in plasma was measured with an enzyme-linked immunosorbent assay method. RESULTS: During the follow-up time, 113 clinically relevant bleeding events and 73 major bleeding events occurred. Increased concentration of sTM was associated with both clinically relevant bleeding and major bleeding events after adjustment for age. In the multivariable models, hazard ratios for the highest tertiles compared with the lowest were 2.29 (95% confidence interval, 1.35-3.89) and 2.33 (95% confidence interval, 1.21-4.48), respectively. No association between sTM concentration and nonfatal ischemic cardiovascular events or all-cause mortality was found. CONCLUSIONS: Increased levels of sTM are associated with bleeding complications during warfarin treatment but not with cardiovascular events or all-cause mortality. Soluble TM antigen concentration has potential as a new specific marker to identify patients at high risk of bleeding during warfarin treatment.
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| 4. |
- Bauzá-Thorbrügge, Marco, et al.
(författare)
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NRF2 is essential for adaptative browning of white adipocytes.
- 2023
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Ingår i: Redox biology. - : Elsevier. - 2213-2317. ; 68
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Tidskriftsartikel (refereegranskat)abstract
- White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.
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| 5. |
- Khoshnood, Ardavan
(författare)
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Prehospital Diagnosis and Oxygen Treatment in ST Elevation Myocardial Infarction
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionPaper I: An Artificial Neural Network (ANN) was constructed to identify ST Elevation Myocardial Infarction (STEMI) and predict the need for Percutaneous Coronary Intervention (PCI). Paper II, III and IV: Studies suggest that O2 therapy may be harmful in STEMI patients. We therefore conducted the SOCCER study to evaluate the effects of O2 therapy in STEMI patients.MethodsPaper I: 560 ambulance ECGs sent to the Cardiac Care Unit (CCU), was together with the CCU physicians interpretation and decision of conducting an acute PCI or not collected, and compared with the interpretation and PCI decision of the ANN. Paper II, III, IV: Normoxic (≥94%) STEMI patients accepted for acute PCI were in the ambulance randomized to standard care with 10 L/min O2 or room air. A subset of the patients underwent echocardiography for determination of the Left Ventricular Ejection Fraction (LVEF) and the Wall Motion Score Index (WMSI). All patients had a Cardiac Magnetic Resonance Imaging (CMRI) to evaluate Myocardial area at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI).ResultsPaper I: The area under the ANN’s receiver operating characteristics curve for STEMI detection as well as predicting the need of acute PCI were very good.Paper II, III, IV: No significant differences could be shown in discussing MaR, MSI or IS between the O2 group (n=46) and the air group (n=49). Neither could any differences be shown for LVEF and WMSI at the index visit as well after six months between the O2 group (n=46) and the air group (n=41)ConclusionsPaper I: The results indicate that the number of ECGs sent to the CCU could be reduced with 2/3 as the ANN would safely identify ECGs not being STEMI.Paper II, III, IV: The results suggest that it is safe to withhold O2 therapy in normoxic, stable STEMI patients.
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| 6. |
- Magnusson, Marie, et al.
(författare)
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A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans
- 2006
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 61:2, s. 138-147
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.
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| 7. |
- Abbas, Abdul-Karim, 1959, et al.
(författare)
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Long-term potentiation and insult conditioning in hippocampal slices from young rats: a role for protein synthesis under chemical stress?
- 2010
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Ingår i: The 10th Biennial Meeting of the Asia-Pacific Society for Neurochemistry (APSN), October 17-20, 2010, Phuket, Thailand.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We have previously demonstrated that in young rats (12-20-day-old) a sustained long-term potentiation (LTP) can still be induced under conditions of protein synthesis inhibition. It was therefore suggested that sufficient and necessary proteins were already available at the induction time to accomplish LTP maintenance for several hours. Against this background, we have questioned whether hippocampal slices subjected to certain insult conditions might be more sensitive to protein synthesis inhibitors. High K+ concentration has previously been reported to cause an amnesic effect in vivo as well as increasing protein turnover in vitro. We have here employed a K+ insult model under conditions when protein synthesis was inhibited. Recordings were obtained from hippocampal slices for up to 9 h, with or without a cocktail of protein synthesis inhibitors, containing cycloheximide (60 µM) and anisomycin (25 µM). High potassium (50 mM) was transiently applied (5-15 min) shortly after inducing LTP in one of two separate pathways stimulated alternatively. Additionally, an NMDA-receptor antagonist AP5 was supplied after LTP induction to minimize effects related to depolarization-induced glutamate release. Following elimination of all responses for about 30 min, both test and control responses partly recovered. The degree of remaining LTP, defined as test/control ratio, was reduced in both groups of slices (NMDA-independent depotentiation) but was significantly smaller in the drug-treated ones. We are also running an insult model based on oxidative stress, applying hydrogen peroxide (4-5 mM) before or after LTP induction; however, the results are still insufficient for a final conclusion. The potency of cycloheximide, anisomycin or cocktail of the drugs was verified by measurement of incorporation of [3H]-leucine into trichloracetic acid (TCA) precipitable macromolecules. Cycloheximide, anisomycin or cocktail, at concentrations used here caused 95%, 97% and 95% blocking effect, respectively. Our data confirm the idea that sufficient and necessary constitutive proteins are available in the young hippocampus to maintain LTP under conditions of protein synthesis inhibition. They also reveal that LTP in slices subjected to certain insult conditions early after the induction is sensitive to protein synthesis inhibition, probably due to increase in constitutive proteins turnover.
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| 8. |
- Ruiz, Jonatan R., et al.
(författare)
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Homocysteine levels in children and adolescents are associated with the methylenetetrahydrofolate reductase 677C>T genotype, but not with physical activity, fitness or fatness : the European Youth Heart Study
- 2007
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Ingår i: British Journal of Nutrition. - Cambridge : Cambridge university press. - 0007-1145 .- 1475-2662. ; 97:2, s. 255-262
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Tidskriftsartikel (refereegranskat)abstract
- To examine the associations of total plasma homocysteine (tHcy) with physical activity, cardiorespiratory fitness and fatness in children and adolescents, a cross-sectional study of 301 children (9–10 years old) and 379 adolescents (15–16 years old) was conducted. Physical activity was measured by accelerometry. Cardiorespiratory fitness was measured with a maximal ergometer bike test. Body fat was derived from the sum of five skinfold thicknesses. Genotyping for the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism was done by DNA sequencing. Fasting tHcy level was the outcome variable. Multiple regressions were used to determine the degree to which variance in tHcy was explained by physical activity, cardiorespiratory fitness and body fat, after controlling for potential confounders including MTHFR 677C>T genotype. tHcy levels were neither associated with any measure of level and pattern of physical activity nor with data on cardiorespiratory fitness, or body fat, in any age group after controlling for potential confounders including MTHFR 677C>T and even when subgroups 677TT and 677CC+CT were analysed separately. Mean values of tHcy were significantly higher in the TT subgroup compared with CC and CT subgroups in children (TT 7·4 μmol/l, CC 6·3 μmol/l, CT 6·6 μmol/l, P < 0·001 and P = 0·019, respectively) and adolescents (TT 16·9 μmol/l, CC 8·3 μmol/l, CT 9·0 μmol/l, both P < 0·001). The results suggest that physical activity, fitness and body fat are not associated with tHcy levels in children and adolescents, even after controlling for presence of the MTHFR 677C>T genotype, the main influence on tHcy levels in these subjects.
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| 9. |
- Saulo, Eleonor C., et al.
(författare)
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Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania
- 2008
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Ingår i: Malaria Journal. - London : BioMed Central. - 1475-2875. ; 7, s. 227-
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyse willingness to pay (WTP) and ability to pay (ATP) for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored.MethodsStructured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM) was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors.ResultsAmong 265 mothers and household heads, 244 (92%, CI = 88%–95%) were willing to pay Tanzanian Shillings (TSh) 500 (US$ 0.46) for a child's dose of ACT, but only 55% (49%–61%) were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6). Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care."Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug.ConclusionWTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision taken in Tanzania to subsidize Coartem® fully at governmental health care facilities and at a consumer price of TSh 300–500 (US$ 0.28–0.46) at special designated shops through the programme of Accredited Drug Dispensing Outlets (ADDOs) appears to be well founded.
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| 10. |
- Labayen, Idoia, et al.
(författare)
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Association of common variants of UCP2 gene with low-grade inflammation in Swedish children and adolescents : the European Youth Heart Study
- 2009
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Ingår i: Pediatric Research. - : Nature Publishing Group. - 0031-3998 .- 1530-0447. ; 66:3, s. 350-354
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Tidskriftsartikel (refereegranskat)abstract
- We examined the associations of two functional variants 866G>A and DEL/INS polymorphisms of UCP2 gene with low-grade inflammatory proteins (C-reactive protein, fibrinogen, complement C3 [C3], and complement C4 [C4]) in 131 children (52.7% boys, aged 9.5 +/- 0.4 y) and 118 adolescents (44.1% males, aged 15.5 +/- 0.4 y) selected from the European Youth Heart Study. Differences in inflammatory markers among the genotype variants of the two UCP2 gene polymorphisms were analyzed after adjusting for sex, age, pubertal stage, fitness, and fatness. The results showed that fibrinogen, C3, and C4 were higher in GG carriers than in subjects carrying the A allele of the 866G>A polymorphism of the UCP2 gene (UCP2 -866G>A) polymorphism (all p < 0.05). The DEL/DEL genotype of 45nt deletion/insertion variant polymorphism of the UCP2 gene (UCP2 DEL/INS) was associated with higher C3 (p < 0.05) than DEL/INS and INS/INS genotypes. This study provides evidence of a role of UCP2 -866G>A in modifying low-grade inflammatory state in apparently healthy children and adolescents. Given the implication of complement factors on atherosclerosis process, these results contribute to explain the reduced cardiovascular risk associated with the A allele of the UCP2 -866G>A polymorphism.
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| 11. |
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| 12. |
- Olsson, G. M., et al.
(författare)
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Family conditions and dietary control in phenylketonuria
- 2007
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Ingår i: Journal of Inherited Metabolic Disease. - Berlin : Springer. - 0141-8955 .- 1573-2665. ; 30:5, s. 708-715
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Tidskriftsartikel (refereegranskat)abstract
- Objective This investigation is an attempt to describe coping with phenylketonuria (PKU) in order to understand some aspects underlying good compliance. Methods The coping concept was applied to PKU in two questionnaires. Self- and parental ratings were combined with assessments of phenylalanine levels and the severity of the disease. All Swedish patients with PKU born in 1980–91, a total of 53 children and youths with their parents, were invited to participate in the study and 41 (77%) of them did so. Results The patients turned out to have good compliance with the diet. The main result was that patients with separated or divorced parents were more likely to have higher phenylalanine levels and this association was not diminished by adjustment for the potential confounding factors. Conclusion Patients’ need for support must be judged individually according to different family conditions.
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| 13. |
- Zhu, Changlian, 1964, et al.
(författare)
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X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants.
- 2007
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Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 26:12, s. 3402-10
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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| 14. |
- Håkansson, Samuel, 1996, et al.
(författare)
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Potential for improved retention rate by personalized antiseizure medication selection: A register-based analysis
- 2021
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 62:9, s. 2123-2132
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Tidskriftsartikel (refereegranskat)abstract
- Objective The first antiseizure medication (ASM) is ineffective or intolerable in 50% of epilepsy cases. Selection between more than 25 available ASMs is guided by epilepsy factors, but also age and comorbidities. Randomized evidence for particular patient subgroups is seldom available. We asked whether register data could be used for retention rate calculations based on demographics, comorbidities, and ASM history, and quantified the potential improvement in retention rates of the first ASM in several large epilepsy cohorts. We also describe retention rates in patients with epilepsy after traumatic brain injury and dementia, patient groups with little available evidence. Methods We used medical, demographic, and drug prescription data from epilepsy cohorts from comprehensive Swedish registers, containing 6380 observations. By analyzing 381 840 prescriptions, we studied retention rates of first- and second-line ASMs for patients with epilepsy in multiple sclerosis (MS), brain infection, dementia, traumatic brain injury, or stroke. The rank of retention rates of ASMs was validated by comparison to published randomized control trials. We identified the optimal stratification for each brain disease, and quantified the potential improvement if all patients had received the optimal ASM. Results Using optimal stratification for each brain disease, the potential improvement in retention rate (percentage points) was MS, 20%; brain infection, 21%; dementia, 14%; trauma, 21%; and stroke, 14%. In epilepsy after trauma, levetiracetam had the highest retention rate at 80% (95% confidence interval [CI] = 65-89), exceeding that of the most commonly prescribed ASM, carbamazepine (p = .04). In epilepsy after dementia, lamotrigine (77%, 95% CI = 68-84) and levetiracetam (74%, 95% CI = 68-79) had higher retention rates than carbamazepine (p = .006 and p = .01, respectively). Significance We conclude that personalized ASM selection could improve retention rates and that national registers have potential as big data sources for personalized medicine in epilepsy.
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| 15. |
- Lindberg, Frida A., et al.
(författare)
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SLC38A10 knockout mice display a decreased body weight and an increased risk-taking behavior in the open field test
- 2022
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- The solute carrier 38 family (SLC38) is a family of 11 members. The most commonsubstrate among these are alanine and glutamine, and members are present in a widerange of tissues with important functions for several biological processes, such as liverand brain function. Some of these transporters are better characterized than others and,in this paper, a behavioral characterization of SLC38A10−/− mice was carried out. Abattery of tests for general activity, emotionality, motor function, and spatial memorywere used. Among these tests, the elevated plus maze, Y-maze, marble burying, andchallenging beamwalk have not been tested on the SLC38A10−/− mice previously, whilethe open field and the rotarod tests have been performed by the International MousePhenotyping Consortium (IMPC). Unlike the results from IMPC, the results from this studyshowed that SLC38A10−/− mice spend less time in the wall zone in the open field testthan WT mice, implying that SLC38A10-deficient mice have an increased explorativebehavior, which suggests an important function of SLC38A10 in brain. The present studyalso confirmed IMPC’s data regarding rotarod performance and weight, showing thatSLC38A10−/− mice do not have an affected motor coordination impairment and havea lower body weight than both SLC38A10+/− and SLC38A10+/+ mice. These resultsimply that a complete deficiency of the SLC38A10 protein might affect body weighthomeostasis, but the underlying mechanisms needs to be studied further.
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| 16. |
- Andersson, Ingemar, 1950-
(författare)
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Rehabilitering vid långvarig smärta
- 2010. - 2
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Ingår i: Smärta och smärtbehandling. - Stockholm : Liber. - 9789147084135 ; , s. 401-409
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 17. |
- Di Gennaro, A., et al.
(författare)
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Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm
- 2018
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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. - 0027-8424 .- 1091-6490. ; 115:8, s. 1907-1912
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Tidskriftsartikel (refereegranskat)abstract
- Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
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| 18. |
- Forsberg, Anna, et al.
(författare)
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Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy
- 2013
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Ingår i: Clinical and Experimental Allergy. - : Wiley-Blackwell. - 0954-7894 .- 1365-2222. ; 43:4, s. 434-442
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWe have previously shown that Lactobacillus reuteri supplementation from pregnancy week 36 and to the infant through the first year of life decreased the prevalence of IgE-associated eczema at 2 years. The underlying immunological mechanisms are unknown, however.ObjectiveTo investigate the immunomodulatory effect of probiotic supplementation on allergen- and mitogen-induced immune responses in children until 2 years of age.MethodsBlood mononuclear cells were collected at birth, 6, 12 and 24 months from 61 children (29 probiotic and 32 placebo treated) and cultured with ovalbumin, birch and cat extract and Phytohaemagglutinin (PHA). Cytokine and chemokine secretion was determined using an in-house multiplexed Luminex assay and ELISA. Real-time PCR was performed to investigate the Ebi3, Foxp3, GATA-3 and T-bet mRNA expression.ResultsProbiotic treatment was associated with low cat-induced Th2-like responses at 6 months (IL-5, P = 0.01, and IL-13, P = 0.009), with a similar trend for IL-5 at 12 months (P = 0.09). Cat-induced IFN-γ responses were also lower after probiotic than after placebo treatment at 24 months (P = 0.007), with similar findings for the anti-inflammatory IL-10 at birth (P = 0.001) and at 12 months (P = 0.009). At 24 months, Th2-associated CCL22 levels were lower in the probiotic than in the placebo group after birch stimulation (P = 0.02), with a similar trend after ovalbumin stimulation (P = 0.07). Lower CCL22 levels were recorded at 12 and 24 months (P = 0.03 and P = 0.01) after PHA stimulation.Conclusion and Clinical RelevanceLactobacillus reuteri supplementation decreases allergen responsiveness and may enhance immunoregulatory capacity during infancy. L. reuteri supplementation from week 36 and during the first year of life significantly decreases IgE-associated eczema and lowers allergen and mitogen responsiveness.
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| 19. |
- Johansson, Åsa, et al.
(författare)
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Precision medicine in complex diseases - : Molecular subgrouping for improved prediction and treatment stratification
- 2023
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 1365-2796 .- 0954-6820. ; 294:4, s. 378-396
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Forskningsöversikt (refereegranskat)abstract
- Complex diseases are caused by a combination of genetic, lifestyle, and environmental factors and comprise common noncommunicable diseases, including allergies, cardiovascular disease, and psychiatric and metabolic disorders. More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease-both with regards to symptoms and underlying causal mechanisms-and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic-based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases-including psychiatric disorders and allergies-available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high-throughput molecular technologies, together with large collections of health data and novel data-driven approaches, offers promise toward improved individual health through precision medicine.
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| 20. |
- Kuemmel, Andreas, et al.
(författare)
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TA-MUC1 epitope in non-small cell lung cancer
- 2009
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 63:1, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- MUC1 (CD227), an established tumor marker, is expressed on glandular epithelia and on epithelial tumors. Tumor MUC1 differs from normal MUC1 by modified glycan side chains. Recently, a novel carbohydrate-induced conformational tumor-associated MUC1 epitope (TA-MUC1) was described, whose clinical relevance in lung cancer is not known. Eighty-five paraffin embedded tissue sections of non-small cell lung cancer (NSCLC) patients (73% male; mean age 64+/-9 years) were stained with the monoclonal antibody PankoMab (against TA-MUC1) and compared with the established antibodies E29 and 214D4 regarding prognostic relevance. TA-MUC1 is virtually absent in bronchial epithelium. As shown by multivariate analysis, only staining with PankoMab, but not with E29 or 214D4, was correlated with patients' survival (p=0.029). Moreover, when regarding interactions of MUC1 antibody staining results and clinico-pathological parameters, patients with lymph node metastasis lacking PankoMab staining were attributed the highest risk by far (Hazard ratio=4.6, 95% CI: 2.1-9.7, p=0.000). In summary, the presence of TA-MUC1 is a favorable prognostic factor in this cohort of NSCLC patients, in particular if lymph node metastases are present. This is in contrast to the results for E29 and 214D4, which recognize less or not glycosylation dependent epitopes. As this is the first report on a well-defined MUC1 epitope associated with improved survival in NSCLC, a more differentiated view on MUC1 may be mandatory.
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| 21. |
- Stener-Victorin, Elisabet, et al.
(författare)
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Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
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| 22. |
- Abrahamsson, Thomas, et al.
(författare)
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No effect of probiotics on respiratory allergies : a seven-year follow-up of a randomized controlled trial in infancy
- 2013
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 24:6, s. 556-561
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Tidskriftsartikel (refereegranskat)abstract
- Background: Supplementation with the probioticLactobacillus reuteri reduced the incidence of IgE-associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhinoconjunctivitis in school age.Objective: To evaluate whether perinatal and infant supplementation withL.reuteri reduced the prevalence of respiratory allergic disease in school age and to explore whether this supplementation was associated with any long-term side effects.Methods: A randomized, placebo-controlled trial with oral supplementation withL.reuteriATCC 55730 (1x10(8)CFU) during the last month of gestation and through the first year of life comprising 232 families with allergic disease, of whom 184 completed a 7-yr follow-up. The primary outcomes at 7yr of age were allergic disease and skin prick test reactivity (ClinicalTrials.govID NCT01285830).Results: The prevalence of asthma (15% in the probiotic vs. 16% in placebo group), allergic rhinoconjunctivitis (27% vs. 20%), eczema (21% vs. 19%) and skin prick test reactivity (29% vs. 26%) was similar in the probiotic and placebo group. Growth indices and gastrointestinal symptoms were similar in the two groups. No severe adverse events were reported.Conclusion: The effect ofL.reuteri on sensitization andIgE-associated eczema in infancy did not lead to a lower prevalence of respiratory allergic disease in school age. Thus, the effect ofL.reuteri on the immune system seems to be transient. Administration ofL.reuteri during the last weeks of gestation and in infancy was not associated with any long-term side effects.
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| 23. |
- Brundin, Peik M. A., 1975-
(författare)
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Sex differences in immune response and sex hormone receptor expression in healthy individuals and during viral infection
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is sex-bias in morbidity and mortality from infectious diseases. Infections kill more men than women and several studies have pointed out differences in the immune system as a reason. The sex hormones estrogen, progesterone and testosterone all shape the effect of the immune response on multiple levels. Women at fertile age have been suggested to have higher proinflammatory responses from inflammatory stimuli compared to men and post-menopausal women, which has been ascribed to their higher estrogen levels. This could possibly lead to a more active pathogen response but may also result in a detrimental immunopathology to infections or development of autoimmune reaction.The overall aim of this thesis is to study the contribution of sex hormones and sex hormone receptors (SHR) to sex differences in immune response. We focus on peripheral blood mononuclear cells (PBMCs) to study such relationships in healthy individuals, as well as in individuals with asymptomatic Torque Teno Virus infection, and individuals with acute Puumala virus infection.In Paper I, we investigated expression of SHR and immune response genes in PBMC from healthy premenopausal (pre-MP) women during the menstrual cycle. The expression levels were estimated using a qPCR Array (Taqman low-density array, TLDA). SHR expression did not change significantly during the menstrual cycle, but several key immune regulatory genes were significantly more expressed during the ovulatory and mid luteal phase. Further, we separated PBMC into cell subsets (CD4+ T-cells, CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) and analyzed the expression through qPCR of estrogen receptors (ERs), ERα, ERβ1 (wildtype) and the isoform ERβ2. For the first time and unexpectedly, we demonstrate that the isoform ERβ2 was more abundant than wildtype ERβ1. The data from this paper provides new knowledge on the contribution of the menstrual cycle on immune response.In Paper II, we explored the use of Torque Teno Virus as a secondary functional immune marker in men and women. Expression of viral TTV DNA in PBMCs was estimated using a qPCR kit from Argene (R-gene) and analyzed in relation to serum sex hormone levels. The results showed that 50% of the men, 25% the post-MP women, and 18% of the pre-MP women were TTV+. Interestingly, all pre-MP women that were TTV+ had hormonal aberrances and were either anovulatory and/or hypothyroid. TTV+ pre-MP women also had significantly lower progesterone levels than TTV- pre-MP women. This paper indicates that the prevalence of TTV in PBMC differs between men, pre-MP and post-MP women. Furthermore, hormonal aberrances (at least in pre-MP women) will lead to increased prevalence of TTV.In Paper III we investigated the expression of ERα, ERβ1 and ERβ2 in PBMC from patients with Nephropathia epidemica, the viral zoonotic disease caused by Puumala virus, a Hanta virus known to affect more men than women. Expression of ERs in PBMCs and clinical laboratory results during the acute and convalescent phases were analyzed using a principal component analysis (PCA). The results show differences in ER expression and support previous findings that men and women have a different clinical pictureIn conclusion, the results in this thesis reveal distinct patterns of immune response related to sex hormone levels, SHR expression and the phases of the menstrual cycle supporting that there a link between sex hormone levels and immune responses. Further, we show that the ER isoform ERβ2 is more abundant in PBMCs than what was previously described. The data in this thesis adds to the knowledge to the sex differences in immune response and exemplifies the importance of taking these differences into account in the clinic.
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| 24. |
- Mohammadi, Elyas, et al.
(författare)
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Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9, s. 1-24
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Forskningsöversikt (refereegranskat)abstract
- Simple Summary Drug repurposing is an accelerated route for drug development and a promising approach for finding medications for orphan and common diseases. Here, we compiled databases that comprise both computationally- or experimentally-derived data, and categorized them based on quiddity and origin of data, further focusing on those that present high throughput omic data or drug screens. These databases were then contextualized with genome-wide screening methods such as CRISPR/Cas9 and RNA interference, as well as state of art systems biology approaches that enable systematic characterizations of multi-omic data to find new indications for approved drugs or those that reached the latest phases of clinical trials. Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
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| 25. |
- Ali, Magdi M. M., et al.
(författare)
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Fc gamma RIIa (CD32) polymorphism and onchocercal skin disease : implications for the development of severe reactive onchodermatitis (ROD)
- 2007
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Ingår i: American Journal of Tropical Medicine and Hygiene. - Lawrence, Kans. : American society of tropical medicine and hygiene. - 0002-9637 .- 1476-1645. ; 77:6, s. 1074-8
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Tidskriftsartikel (refereegranskat)abstract
- The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.
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