1. |
- Thomas, HS, et al.
(author)
-
- 2019
-
swepub:Mat__t
|
|
2. |
- Ademuyiwa, Adesoji O., et al.
(author)
-
Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
-
In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
-
Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
|
|
3. |
- Kvitne, K. E., et al.
(author)
-
Correlations between 4 beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range
- 2022
-
In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:8, s. 1289-1299
-
Journal article (peer-reviewed)abstract
- Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4 beta-hydroxycholesterol (4 beta OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4 beta OHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4 beta OHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4 beta OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (rho = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (rho = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (rho = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (rho = 0.15, p = 0.53). 4 beta OHC concentrations correlated weakly with midazolam absolute bioavailability (rho = - 0.23, p = 0.027) and apparent oral clearance (rho = 0.28, p = 0.008), but not with systemic clearance (rho = - 0.03, p = 0.81). Conclusion These findings suggest that 4 beta OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4 beta OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.
|
|
4. |
- Kvitne, K. E., et al.
(author)
-
Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity
- 2022
-
In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 88:9, s. 4121-4133
-
Journal article (peer-reviewed)abstract
- Aim Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean +/- SD weight loss from baseline was similar in the RYGB-group (13 +/- 2.4%) and the diet group (10.5 +/- 3.9%) at week 9, but differed at year 2 (RYGB -30 +/- 6.9%, diet -3.1 +/- 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference -0.30 [-0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.
|
|
5. |
- Sampson, Joshua N., et al.
(author)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
6. |
- Andersson, C, et al.
(author)
-
The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
-
In: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
-
Journal article (peer-reviewed)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
|
|
7. |
- Kvitne, K. E., et al.
(author)
-
Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity - a non-randomized three-armed controlled trial
- 2022
-
In: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:1, s. 221-233
-
Journal article (peer-reviewed)abstract
- It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet-induced (n = 41) weight-loss, and controls (n = 18). Both weight-loss groups underwent a 3-week low-energy-diet (<1200 kcal/day) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight-loss at week 9 (13 +/- 2.4% vs. 11 +/- 3.6%), but differed substantially after 2 years (-30 +/- 7.0% vs. -3.1 +/- 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 +/- 7.5% in the RYGB group and 32 +/- 6.1% in the diet group at year 2 compared with baseline, with no between-group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A-activity is not only dependent on weight-loss through RYGB.
|
|
8. |
- Båth, Petra, 1988, et al.
(author)
-
Lipidic cubic phase serial femtosecond crystallography structure of a photosynthetic reaction centre
- 2022
-
In: Acta Crystallographica Section D-Structural Biology. - : International Union of Crystallography (IUCr). - 2059-7983. ; 78, s. 698-708
-
Journal article (peer-reviewed)abstract
- Serial crystallography is a rapidly growing method that can yield structural insights from microcrystals that were previously considered to be too small to be useful in conventional X-ray crystallography. Here, conditions for growing microcrystals of the photosynthetic reaction centre of Blastochloris viridis within a lipidic cubic phase (LCP) crystallization matrix that employ a seeding protocol utilizing detergent-grown crystals with a different crystal packing are described. LCP microcrystals diffracted to 2.25 angstrom resolution when exposed to XFEL radiation, which is an improvement of 0.15 angstrom over previous microcrystal forms. Ubiquinone was incorporated into the LCP crystallization media and the resulting electron density within the mobile Q(B) pocket is comparable to that of other cofactors within the structure. As such, LCP microcrystallization conditions will facilitate time-resolved diffraction studies of electron-transfer reactions to the mobile quinone, potentially allowing the observation of structural changes associated with the two electron-transfer reactions leading to complete reduction of the ubiquinone ligand.
|
|
9. |
- Hjelmesaeth, J., et al.
(author)
-
Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)
- 2018
-
In: Bmj Open. - 2044-6055. ; 8:5
-
Journal article (peer-reviewed)abstract
- Introduction Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups. Methods and analysis This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUC(oral)/AUC(iv)) of midazolam (CYP3A4 probe), systemic exposure (AUC(oral)) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers. Ethics and dissemination The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK serest A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants.
|
|
10. |
- Hovd, M., et al.
(author)
-
Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance
- 2023
-
In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 62:5, s. 725-735
-
Journal article (peer-reviewed)abstract
- IntroductionRosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity.MethodsPatients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day).ResultsA total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant.ConclusionsNeither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.
|
|
11. |
- Kanatsuna, N, et al.
(author)
-
Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
- 2015
-
In: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 82:4, s. 361-369
-
Journal article (peer-reviewed)abstract
- The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
|
|
12. |
- Krogstad, V., et al.
(author)
-
Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes
- 2021
-
In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 432-437
-
Journal article (peer-reviewed)abstract
- Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m(2) were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (C-Lint,C-u) values for CYP3A correlated negatively with body weight (r = -0.43, p < 0.01), waist circumference (r = -0.47, p < 0.01), hip circumference (r = -0.51, p < 0.01), fat percent (r = -0.41, p < 0.05), fat mass (r = -0.48, p < 0.01) and BMI (r = -0.46, p < 0.01). Linear regression analysis showed that C-Lint,C-u values for CYP3A decreased with 5% with each 10% increase in body weight (r(2) = 0.12, beta = -0.558, p < 0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight. (C) 2020 The Authors. Published by Elsevier Inc.
|
|
13. |
- Kvitne, K. E., et al.
(author)
-
Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity
- 2022
-
In: Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:11, s. 2685-2696
-
Journal article (peer-reviewed)abstract
- Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
|
|
14. |
- Nilsson, Anna-Lena, et al.
(author)
-
Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children
- 2013
-
In: Viral immunology. - : Mary Ann Liebert, Inc.. - 0882-8245 .- 1557-8976. ; 26:3, s. 207-215
-
Journal article (peer-reviewed)abstract
- Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.
|
|
15. |
- Tanner, Lloyd, et al.
(author)
-
Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation
- 2021
-
In: Journal of Cystic Fibrosis. - : Elsevier BV. - 1873-5010 .- 1569-1993. ; 20:2, s. 346-355
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination.METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial activity towards P. aeruginosa. Next, the effect of neutrophil elastase (NE)-mediated proteolysis of histone H3.1 was investigated. Finally, PADI4, H3.1, and citrullinated H3.1 were examined in healthy control and CF patient lung tissues.RESULTS: Full-length histone H3.1 and sections of the histone H3.1 tail, displayed bactericidal activity towards P. aeruginosa. These antibacterial effects were reduced following citrullination by PADI4 or proteolysis by NE. Interestingly, citrullination of histone H3.1 exacerbated NE-mediated degradation. In CF lung tissue, citrullinated histone H3.1 and PADI4 immunoreactivity was abundant. Degraded histone H3.1 was detected in the sputum of CF patients but was absent in the sputum of healthy controls.CONCLUSIONS: Citrullination impairs the antibacterial activity of histone H3.1 and exacerbates its proteolytic degradation by NE. Citrullination is likely to play an important role during resolution of acute inflammation. However, in chronic inflammation akin to CF, citrullination may dampen host defense and promote pathogen survival, as exemplified by P. aeruginosa.
|
|
16. |
- Wang, Zhaoming, et al.
(author)
-
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
|
|
17. |
- Andersson, Cecilia K, et al.
(author)
-
Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
- 2011
-
In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139
-
Journal article (peer-reviewed)abstract
- Background: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. Methods: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-beta. Results: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-beta. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-beta, correlated negatively with patient lung function. Conclusions: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
|
|
18. |
- Hober, Sophia, Professor, 1965-, et al.
(author)
-
Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay
- 2021
-
In: Clinical & Translational Immunology. - : Wiley. - 2050-0068. ; 10:7
-
Journal article (peer-reviewed)abstract
- Objective. The COVID-19 pandemic poses an immense need for accurate, sensitive and high-throughput clinical tests, and serological assays are needed for both overarching epidemiological studies and evaluating vaccines. Here, we present the development and validation of a high-throughput multiplex bead-based serological assay. Methods. More than 100 representations of SARS-CoV-2 proteins were included for initial evaluation, including antigens produced in bacterial and mammalian hosts as well as synthetic peptides. The five best-performing antigens, three representing the spike glycoprotein and two representing the nucleocapsid protein, were further evaluated for detection of IgG antibodies in samples from 331 COVID-19 patients and convalescents, and in 2090 negative controls sampled before 2020. Results. Three antigens were finally selected, represented by a soluble trimeric form and the S1-domain of the spike glycoprotein as well as by the C-terminal domain of the nucleocapsid. The sensitivity for these three antigens individually was found to be 99.7%, 99.1% and 99.7%, and the specificity was found to be 98.1%, 98.7% and 95.7%. The best assay performance was although achieved when utilising two antigens in combination, enabling a sensitivity of up to 99.7% combined with a specificity of 100%. Requiring any two of the three antigens resulted in a sensitivity of 99.7% and a specificity of 99.4%. Conclusion. These observations demonstrate that a serological test based on a combination of several SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay.
|
|
19. |
|
|
20. |
- Kvitne, K. E., et al.
(author)
-
Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals
- 2024
-
In: Clinical Pharmacokinetics. - 0312-5963. ; 63:1, s. 109-120
-
Journal article (peer-reviewed)abstract
- Background and Objective Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. Methods This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. Results The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 +/- 2.3% and 11 +/- 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 mu g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 mu g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 +/- 0.33 hours at week 3 to 0.77 +/- 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 mu g h/L [-0.94, 3.2]) or the diet group (0.94 mu g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 +/- 7%, diet: 3 +/- 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 mu g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/mu g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.
|
|
21. |
- Nango, E., et al.
(author)
-
A three-dimensional movie of structural changes in bacteriorhodopsin
- 2016
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6319, s. 1552-1557
-
Journal article (peer-reviewed)abstract
- Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side. The resulting cascade of structural changes throughout the protein shows how motions are choreographed as bR transports protons uphill against a transmembrane concentration gradient.
|
|
22. |
- Andersson, Annica, 1983, et al.
(author)
-
Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis
- 2015
-
In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 17:32
-
Journal article (peer-reviewed)abstract
- Introduction: The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis. Methods: Ovariectomized DBA/1 mice treated with 17 beta-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor a-knockout mice (ERa-/-) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis. Results: E2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ER alpha. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes. Conclusions: This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.
|
|
23. |
- Andersson, Annica, 1983, et al.
(author)
-
IL-17-producing γδT cells are regulated by estrogen during development of experimental arthritis.
- 2015
-
In: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-7035 .- 1521-6616. ; 161:2, s. 324-32
-
Journal article (peer-reviewed)abstract
- Interleukin-17 (IL-17) drives inflammation and destruction of joints in rheumatoid arthritis (RA). The female sex hormone 17β-estradiol (E2) inhibits experimental arthritis. γδT cells are significant producers of IL-17, thus the aim of this study was to investigate if E2 influenced IL-17(+) γδT cells during arthritis development using a variety of experimental RA models: collagen-induced arthritis (CIA); antigen-induced arthritis (AIA); and collagen antibody-induced arthritis (CAIA). We demonstrate that E2 treatment decreases IL-17(+) γδT cell number in joints, but increases IL-17(+) γδT cells in draining lymph nodes, suggesting an E2-mediated prevention of IL-17(+) γδT cell migration from lymph nodes to joints, in concert with our recently reported effects of E2 on Th17 cells (Andersson et al., 2015). E2 did neither influence the general γδT cell population nor IFNγ(+) γδT cells, implying a selective regulation of IL-17-producing cells. In conclusion, this study contributes to the understanding of estrogen's role in autoimmune disease.
|
|
24. |
- Andersson, Cecilia K, et al.
(author)
-
Alterations in Lung Mast Cell Populations in Patients with COPD.
- 2010
-
In: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 181:3, s. 206-217
-
Journal article (peer-reviewed)abstract
- RATIONALE: Mast cells have important roles in innate immunity and tissue remodeling but have remained poorly studied in inflammatory airway diseases like COPD. OBJECTIVES: To perform a detailed histological characterization of human lung mast cell popu-lations at different severities of COPD, comparing with smoking and never-smoking controls. METHODS: Mast cells were analyzed in lung tissues from patients with mild to very severe COPD, GOLD IâIV (n = 25, 10 of whom were treated with corticosteroids). Never-smokers and smokers served as controls. The density, morphology and molecular characteristics of mucosal and connective tissue mast cells (MCT and MCTC, respectively) were analyzed in several lung regions. MEASUREMENTS AND MAIN RESULTS: In all compartments of COPD lungs, especially at severe stages, the MCTC population increased in density while the MCT population decreased. The net result was a reduction in total mast cell density. This phenomenon was paralleled by in-creased numbers of luminal mast cells whereas the numbers of TUNEL(+) apoptotic mast cells remained unchanged. In COPD lungs, the MCT and MCTC populations showed alterations in morphology and expression of CD88 (C5a-R), TGF-beta, and renin. Statistically significant cor-relations were found between several COPD-related mast cell alterations and lung function parameters. CONCLUSIONS: As COPD progresses to its severe stages, the mast cell population in the lung undergoes changes in density, distribution, and molecular expression. In COPD lungs, these novel histopathological features were found to be correlated to lung function and they may thus have clinical consequences.
|
|
25. |
- Andersson, Cecilia K
(author)
-
Aspects of ZnT8 autoimmunity in childhood type 1 diabetes
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- Type 1 diabetes is one of the most common chronic diseases in childhood and adolescence with an increasing incidence worldwide. It is an autoimmune disease with many autoimmune markers, where the zinc transporter 8 autoantibody (ZnT8A) is the most recent autoantibody discovered. The most important genetic susceptibility towards type 1 diabetes is found within the HLA-region on chromosome 6. We showed that all three ZnT8A are common among children and adolescents at type 1 diabetes diagnosis and that 3.4% of the children in Sweden displayed only ZnT8A at diagnosis. Only 7% of the Swedish children were autoantibody negative at diagnosis. Additionally, 0.3% of type 1 diabetes patients in Sweden had an isolated positivity for the islet cell cytoplasm autoantibodies (ICA). This is an autoantibody with an unspecified reaction pattern to most of the other antigens involved in autoantibody formation in type 1 diabetes. The fact that children can still be diagnosed with ICA as the only autoantibody suggests that another yet unidentified autoantigen or autoantigens may contribute to ICA and the search for additional autoantigens should continue. We propose that the glutamine variant of the ZnT8A (ZnT8QA) is not cost effective as a diagnostic marker, as it was found as a single islet autoantibody only in one patient among 3851 analyzed children. However, comparing young healthy children with multiple autoantibodies with normal and impaired glucose metabolism we found that significantly more children with impaired glucose metabolism were positive for ZnT8QA compared to children with normal glucose metabolism. Hence, the ZnT8QA analysis is important in screening of populations for type 1 diabetes risk and for secondary prevention studies. All variants of ZnT8A were positively associated with either HLA DQA1-B1*X-0604 (DQ6.4) or HLA DQA1*0301-DQB1*0302 (DQ8) but dominantly negative with HLA DQA1*0501-DQB1*0201 (DQ2). The association between DQ 6.4 and all three ZnT8A may be related to ZnT8 antigen-presentation by the DQ6.4 heterodimer.
|
|
26. |
- Andersson, Cecilia K, et al.
(author)
-
Distal respiratory tract viral infections in young children trigger a marked increase in alveolar mast cells
- 2018
-
In: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 4:4
-
Journal article (peer-reviewed)abstract
- Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood. Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection. Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0-78) MCs per mm2) compared to controls (0.63 (0-4) MCs per mm2, p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34+ tryptase+ progenitors (controls: 0% (0-1%); LRTIs: 0.9% (0-3%) CD34+ MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07-0.3); LRTIs: 0.3 (0.02-2) VCAM-1 per mm2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3-0.5); HDM: 0.6 (0.4-0.9); H1N1: 1.4 (0.4-2.0); HDM+H1N1: 2.2 (1.2-4.4) MCs per mm2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2-4.4); day 57: 4.6 (1.6-15) MCs per mm2 (p=0.01)) but not when infected with H1N1 alone. Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development.
|
|
27. |
- Andersson, Cecilia K, et al.
(author)
-
Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study.
- 2013
-
In: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 14:5, s. 341-349
-
Journal article (peer-reviewed)abstract
- AIMS: Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. METHODS: In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. RESULTS: All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤30 μU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤30 μU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). CONCLUSION: Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.
|
|
28. |
- Andersson, Cecilia K., et al.
(author)
-
Impaired airway epithelial cell wound-healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze
- 2020
-
In: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538. ; 75:12, s. 3195-3207
-
Journal article (peer-reviewed)abstract
- Background: Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Methods: Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. Results: PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Conclusions: Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.
|
|
29. |
|
|
30. |
- Andersson, Cecilia K, et al.
(author)
-
Novel Site-Specific Mast Cell Subpopulations in the Human Lung.
- 2009
-
In: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 64, s. 297-305
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Lung mast cells are stereotypically divided into connective tissue (MCTC) and mucosal (MCT) mast cells. This study tests the hypothesis that each of these subtypes can be divided further into site-specific populations created by the microenvironment within each anatomic lung compartment. METHODS: To study mast cells under non-inflamed conditions surgical resections and bronchial and transbronchial biopsies from non-smoking individuals were obtained to investigate morphometric and molecular characteristics of mast cell populations in multiple lung structures by immunohistochemistry and electron microscopy. RESULTS: MCT and MCTC coexisted at all compartments with MCT being the prevailing type in bronchi, bronchioles and the alveolar parenchyma. MCTC were more abundant in pulmonary vessels and the pleura. Each of the MCTC and MCT phenotypes could be further differentiated into site-specific populations. MCTC was of significantly larger size in pulmonary vessels than in small airway walls (p<0.001) while a reversed pattern was observed for MCT (p<0.001). Within each MCTC and MCT population there was also distinct site-specific expression pattern of the IgE-receptor, IL-9 receptor, renin, histidine decarboxylase, VEGF, FGF, 5-Lipoxygense, and LTC4-synthase; e.g. bronchial MCT consistently expressed more histidine decarboxylase than alveolar MCT (p<0.004). Renin content was high among vascular MCTC but markedly reduced among MCTC in other compartments (p<0.0002). Notably, for both MCTC and MCT IgE-receptor was highly expressed in conducting airways but virtually absent in alveolar parenchyma. CONCLUSION: Our findings demonstrate novel site-specific sub-populations of lung MCTC and MCT. This observation is suggested to have important implications in unravelling the recently proposed role of mast cells in a variety of pulmonary diseases.
|
|
31. |
- Andersson, Cecilia K, et al.
(author)
-
The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.
- 2011
-
In: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44, s. 394-405
-
Journal article (peer-reviewed)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. Methods: A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
|
|
32. |
- Andersson, Evelyn, et al.
(author)
-
Genetics of response to cognitive behavior therapy in adults with major depression : a preliminary report
- 2019
-
In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 24:4, s. 484-490
-
Journal article (peer-reviewed)abstract
- Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Asberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Asberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
|
|
33. |
- Bengtsson, Calle, 1934, et al.
(author)
-
The Prospective Population Study of Women in Gothenburg, Sweden, 1968-69 to 1992-93. A 24-year follow-up study with special reference to participation, representativeness, and mortality
- 1997
-
In: Scandinavian Journal of Primary Health Care. ; 15, s. 214-219
-
Journal article (peer-reviewed)abstract
- Department of Primary Health Care, Göteborg University, Sweden. OBJECTIVE: To describe the fourth phase of the Prospective Population Study of Women in Gothenburg, Sweden, with special reference to participation and survival. DESIGN: Prospective population study. SETTING: City of Gothenburg with about 430,000 inhabitants. PARTICIPANTS: 1462 participants and 128 refusers aged 38-60 years at the time of the initial study in 1968-69, 282 women who were sampled but not invited to the study in 1968-69, and 266 women participating since 1980-81 and 32 women for the first time in 1992-93. MAIN OUTCOME MEASURES: Participation rate, survival, anthropometric and metabolic characteristics. RESULTS: The participation rate throughout the study period was high. The participants were mainly characteristic of women of the same ages in the general population even after 24 years. The mortality after 24 years was higher in non-participants than in participants, while there was no difference in survival between women who were invited and women who were not invited to the study. CONCLUSIONS: The initial participants were mainly characteristic of the general population, also after a long follow-up period. The long-term survival was lower in initial refusers than in initial participants. PMID: 9444727 [PubMed - indexed for MEDLINE]
|
|
34. |
|
|
35. |
- Berlin, Frida, et al.
(author)
-
Mast Cell Tryptase Promotes Airway Remodeling by Inducing Anti-Apoptotic and Cell Growth Properties in Human Alveolar and Bronchial Epithelial Cells
- 2023
-
In: Cells. - 2073-4409. ; 12:10
-
Journal article (peer-reviewed)abstract
- Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth–death regulation.
|
|
36. |
- Boke Olén, Niklas, et al.
(author)
-
Effects of farm type on food production, landscape openness, grassland biodiversity, and greenhouse gas emissions in mixed agricultural-forestry regions
- 2021
-
In: Agricultural Systems. - : Elsevier BV. - 0308-521X .- 1873-2267. ; 189
-
Journal article (peer-reviewed)abstract
- Context: The global demand for food is expected to continue increasing for decades, which may drive both agricultural expansion and intensification. The associated environmental impacts are potentially considerable but will depend on how the agricultural sector develops. Currently, there are contrasting regional developments in agriculture; expansion and/or intensification in some regions and abandonment in others, as well as changes in the type of farming. However, the environmental consequences of changes in farm type are not well understood. Objective: We have evaluated the impacts of farm type on food production and three key environmental variables—landscape openness, grassland biodiversity and greenhouse gas (GHG) emissions—in three marginal agricultural regions in Sweden. Methods: We do this by first dividing the population of farms in each region into types, based on their land-use and livestock holdings using an innovative clustering method. Thereafter we analysed changes in production activities for farm types over time and evaluated the environmental and food-production impacts, where landscape openness is quantified using a novel indicator. Results and conclusion: Our results show that there is not one single farm type that would simultaneously maximize food production, grassland biodiversity, and landscape openness, whilst minimizing GHG emissions. However, there exists considerable potential to manage the trade-offs between food production and these environmental variables. For example, by reducing land use for dairying and instead increasing both cropping for food production and extensive livestock grazing to maintain landscape openness and biodiversity-rich semi-natural pastures, it would keep food production at similar levels. Significance: Our farm typology allows us to assess the multifunctionality of farming, by relating contrasting production activities to multiple ecosystem services, grassland biodiversity and GHG emissions for informing policy towards more sustainable agriculture. We have demonstrated this with examples under Swedish conditions, but it should to a large extent also be applicable for other countries.
|
|
37. |
- Callesen, Katrine T., et al.
(author)
-
Characterization of Mast Cells from Healthy and Varicose Human Saphenous Vein
- 2022
-
In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
-
Journal article (peer-reviewed)abstract
- Mast cells (MCs) are distributed in tissues throughout the body and are highly involved in many physiological and pathophysiological processes. The potential and involvement of different MC phenotypes are still not well understood. MCs are present in blood vessel walls, but their specific phenotypic features are unknown. We aimed at characterizing MCs from human saphenous veins for localization, mediator content, and receptor expression. This was done in MCs from both healthy and varicose human saphenous veins (hSV and vSV, respectively). For both vSV and hSV, we found that vein MCs are mainly present in the tunica adventitia (99% MCs in adventitia) and that the population consists of both MCT and MCTC phenotypes (vSV: 55% MCT, hSV: 64% MCT). The vein MCs contained high levels of histamine (vSV: 27 pg/MC, hSV: 55 pg/MC) and tryptase (vSV: 98 pg/MC, hSV: 111 pg/MC), indicating a strong potential for regulatory effects on blood vessels. The receptor expression of FcɛRI, MRGPRX2, PTAFR, C3aR, and C5aR was found, even though the percentage of positive cells differed between vSV and hSV MCs. We conclude that vein MCs from the blood vessel wall have a high potential to affect the tissue around them.
|
|
38. |
- Dillner, Joakim, et al.
(author)
-
Antibodies to SARS-CoV-2 and risk of past or future sick leave
- 2021
-
In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n=15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43-1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98-3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures.Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.
|
|
39. |
- Engdahl, Cecilia, 1983, et al.
(author)
-
Role of Androgen and Estrogen Receptors for the Action of Dehydroepiandrosterone (DHEA)
- 2014
-
In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 155:3, s. 889-896
-
Journal article (peer-reviewed)abstract
- Dehydroepiandrosterone (DHEA) is an abundant steroid hormone, and its mechanism of action is yet to be determined. The aim of this study was to elucidate the importance of androgen receptors (ARs) and estrogen receptors (ERs) for DHEA function. Orchidectomized C57BL/6 mice were treated with DHEA, DHT, 17 beta-estradiol-3-benzoate (E2), or vehicle. Orchidectomized AR-deficient (ARKO) mice and wild-type (WT) littermates were treated with DHEA or vehicle for 2.5 weeks. At termination, bone mineral density (BMD) was evaluated, thymus and seminal vesicles were weighted, and submandibular glands (SMGs) were histologically examined. To evaluate the in vivo ER activation of the classical estrogen signaling pathway, estrogen response element reporter mice were treated with DHEA, DHT, E2, or vehicle, and a reporter gene was investigated in different sex steroid-sensitive organs after 24 hours. DHEA treatment increased trabecular BMD and thymic atrophy in both WT and ARKO mice. In WT mice, DHEA induced enlargement of glands in the SMGs, whereas this effect was absent in ARKO mice. Furthermore, DHEA was able to induce activation of classical estrogen signaling in bone, thymus, and seminal vesicles but not in the SMGs. In summary, the DHEA effects on trabecular BMD and thymus do not require signaling via AR and DHEA can activate the classical estrogen signaling in these organs. In contrast, DHEA induction of gland size in the SMGs is dependent on AR and does not involve classical estrogen signaling. Thus, both ERs and ARs are involved in mediating the effects of DHEA in an organ-dependent manner.
|
|
40. |
|
|
41. |
- Garcia-Ryde, Martin, et al.
(author)
-
Expression of Stress-Induced Genes in Bronchoalveolar Lavage Cells and Lung Fibroblasts from Healthy and COPD Subjects
- 2024
-
In: International Journal of Molecular Sciences. - 1422-0067. ; 25:12, s. 1-16
-
Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized endoplasmic reticulum (ER) in fibroblasts from COPD with different responses to chemical stressors compared to healthy subjects. Here, we aimed to investigate differences in stress-related gene expressions within lung cells from COPD and healthy subjects. Bronchoalveolar lavage (BAL) cells were collected from seven COPD and 35 healthy subjects. Lung fibroblasts were derived from 19 COPD and 24 healthy subjects and exposed to cigarette smoke extract (CSE). Gene and protein expression and cell proliferation were investigated. Compared to healthy subjects, we found lower gene expression of CHOP in lung fibroblasts from COPD subjects. Exposure to CSE caused inhibition of lung fibroblast proliferation in both groups, though the changes in ER stress-related gene expressions (ATF6, IRE1, PERK, ATF4, CHOP, BCL2L1) and genes relating to proteasomal subunits mostly occurred in healthy lung fibroblasts. No differences were found in BAL cells. In this study, we have found that lung fibroblasts from COPD subjects have an atypical ER stress gene response to CSE, particularly in genes related to apoptosis. This difference in response to CSE may be a contributing factor to COPD progression.
|
|
42. |
- Jin, Y. K., et al.
(author)
-
A Dual-Promoter Gene Orchestrates the Sucrose-Coordinated Synthesis of Starch and Fructan in Barley
- 2017
-
In: Molecular Plant. - : Elsevier BV. - 1674-2052 .- 1752-9867. ; 10:12, s. 1556-1570
-
Journal article (peer-reviewed)abstract
- Sequential carbohydrate synthesis is important for plant survival because it guarantees energy supplies for growth and development during plant ontogeny and reproduction. Starch and fructan are two important carbohydrates in many flowering plants and in human diets. Understanding this coordinated starch and fructan synthesis and unraveling how plants allocate photosynthates and prioritize different carbohydrate synthesis for survival could lead to improvements to cereals in agriculture for the purposes of greater food security and production quality. Here, we report a system from a single gene in barley employing two alternative promoters, one intronic/exonic, to generate two sequence-overlapping but functionally opposing transcription factors, in sensing sucrose, potentially via sucrose/glucose/fructose/trehalose 6-phosphate signaling. The system employs an autoregulatory mechanism in perceiving a sucrose-controlled trans activity on one promoter and orchestrating the coordinated starch and fructan synthesis by competitive transcription factor binding on the other promoter. As a case in point for the physiological roles of the system, we have demonstrated that this multitasking system can be exploited in breeding barley with tailored amounts of fructan to produce healthy food ingredients. The identification of an intron/exon-spanning promoter in a hosting gene, resulting in proteins with distinct functions, adds to the complexity of plant genomes. ERYSTWYTH, WALES, V123, P453
|
|
43. |
- Jonsdottir, Berglind, et al.
(author)
-
Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents
- 2013
-
In: Diabetologia. - : Springer Verlag (Germany). - 0012-186X .- 1432-0428. ; 56:8, s. 1735-1742
-
Journal article (peer-reviewed)abstract
- The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. less thanbrgreater than less thanbrgreater thanBlood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). less thanbrgreater than less thanbrgreater thanAt type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p andlt; 0.0001). GADA was positively associated with TPOAb (p andlt; 0.001) and with TGAb (p andlt; 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p (c)) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p (c) = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. less thanbrgreater than less thanbrgreater thanGADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.
|
|
44. |
- Kanatsuna, Norio, et al.
(author)
-
Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes.
- 2015
-
In: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 82:4, s. 361-369
-
Journal article (peer-reviewed)abstract
- The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ, or both, in newly diagnosed type 1 diabetes patients and controls. Patients (n=676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n=363) were analyzed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA, and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than controls (p<0.001). Irrespective of age at diagnosis, 19 % (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (p<0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR=1.509; 95th CI 1.011, 2.252; p=0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans, rather than cis heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes. This article is protected by copyright. All rights reserved.
|
|
45. |
- Kolbeck, Roland, et al.
(author)
-
MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function
- 2010
-
In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 125:6, s. 1344-1353
-
Journal article (peer-reviewed)abstract
- Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma. Objective: We sought to develop a novel humanized anti IL-5 receptor alpha (IL-5R alpha) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue. resident eosinophils and basophils for the treatment of asthma. Methods: We used surface plasmon resonance to determine the binding affinity of MEDI-563 to Fc gamma RIII alpha. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5R alpha was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates. Results: MEDI-563 binds to an epitope on IL-5R alpha that is in close proximity to the IL-5 binding site, and it inhibits IL-5 mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow. Conclusions: MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5. (J Allergy Clin Immunol 2010;125:1344-53.)
|
|
46. |
- Lindqvist, Peter, 1945, et al.
(author)
-
Concurrent and separate effects of body mass index and waist-to-hip ratio on 24-year mortality in the Population Study of Women in Gothenburg: evidence of age-dependency
- 2006
-
In: European Journal of Epidemiology. ; 21, s. 789-794
-
Journal article (peer-reviewed)abstract
- Department of Public Health and Community Medicine/Primary Health Care, The Sahlgrenska Academy at Göteborg University, P.O. Box 454, SE 405 30, Göteborg, Sweden. peter.lindqvist@allmed.gu.se Obesity is generally assumed to be an important risk factor for death and morbidity. However, the association between excess body weight and all-cause mortality among younger and older women and the impact of body mass index (BMI) and waist-to-hip ratio (WHR) concurrently is not fully understood. In 1968-1969 we initiated a prospective study comprising a population sample of 1,462 women from Gothenburg, Sweden. During a 24 year period, until 1992-1993, 265 women had died. A multivariable Cox Proportional Hazards Regression model was used to estimate the relative risk of death in relation to BMI and WHR, with age and other covariates of age-specific interest as smoking, physical activity at work and leisure time and serum triglyceride concentration, at start of the study. BMI and WHR were analyzed as independent variables. Younger women (38 and 46 years at baseline) presented a statistically significant non-linear (U-shaped) relation between BMI and mortality. Among older women (50, 54 and 60 years at baseline), a significant negative linear relationship with decreasing mortality in relation to increasing BMI values was seen. For all women a higher WHR was related to an increased risk of death. The lowest risk of death among younger women corresponded to a low WHR and a BMI within the middle range. For older women the highest survival was observed for those with lowest WHR and highest BMI. Thus, in older women a high BMI seems not to be an increased risk as long as adiposity is not centrally located. PMID: 17111249 [PubMed - indexed for MEDLINE]
|
|
47. |
- Lissner, Lauren, 1956, et al.
(author)
-
Participation bias in longitudinal studies: experience from the Population Study of Women in Gothenburg, Sweden
- 2003
-
In: Scandinavian Journal of Primary Health Care. ; 21, s. 242-247
-
Journal article (peer-reviewed)abstract
- Department of Primary Health Care, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. lauren.lissner@medfak.gu.se OBJECTIVE: To describe a cohort study of women receiving a series of comprehensive health examinations over 32 years. DESIGN: Longitudinal population study based on a randomised sample of the female population from defined age cohorts. SETTING: City of Göteborg, Sweden. SUBJECTS: Subjects were 38, 46, 50, 54 or 60 years old at the start of the study in 1968. Re-examinations were performed in 1974, 1982 and 1992. Non-participants in the most recent examination, initiated in 2000, were offered home visits. MAIN OUTCOME MEASURES: Participation, anthropometric and blood pressure changes. RESULTS: At the end of the 32-year follow-up, 64% of the original participants were alive, and low participation among survivors was a problem. An acceptable participation rate (71% of those alive) was obtained after home visits were offered. Surviving non-participants already had elevated cardiovascular risk factors at onset of the study in 1968, along with lower educational level and lower socioeconomic status. Home visited subjects were similar to non-participants with regard to anthropometry and blood pressure, but did not differ from participants with regard to social indicators. Thirty-two-year longitudinal data demonstrate clear ageing effects for several important variables, which should, however, be considered in the context of documented differences with non-participants at the baseline examination. CONCLUSIONS: Longitudinal studies in elderly populations provide important data on changes during the ageing process. However, participation rates decline for a number of reasons and generalisations should be made with care. Moreover, including home visits in the protocol can both increase participation and reduce participation bias in elderly cohorts. PMID: 14695076 [PubMed - indexed for MEDLINE]
|
|
48. |
- Lobell, Anna, et al.
(author)
-
Vaccination with DNA encoding an immunodominant myelin basic protein peptide targeted to Fc of immunoglobulin G suppresses experimental autoimmune encephalomyelitis
- 1998
-
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 187:9, s. 1543-1548
-
Journal article (peer-reviewed)abstract
- We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68-85 (MBP68-85), before induction of EAE with MBP68-85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon gamma production after challenge with MBP68-85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.
|
|
49. |
- Mogren, Sofia, et al.
(author)
-
Mast Cell Proteases Promote Diverse Effects on the Plasminogen Activation System and Wound Healing in A549 Alveolar Epithelial Cells
- 2022
-
In: Cells. - : MDPI AG. - 2073-4409. ; 11:18
-
Journal article (peer-reviewed)abstract
- Tissue damage, epithelial alterations, and intraepithelial presence of mast cells (MCs) are characteristics of asthma pathogenesis. Increased alveolar infiltration of MC populations has also been identified as a feature of asthma and other chronic respiratory diseases. The asthma associated receptor, urokinase plasminogen activator receptor (uPAR), has been shown to regulate bronchial epithelial repair responses. However, the impact of MC tryptase and chymase on functional properties and expression of uPAR in alveolar epithelial cells have not been fully investigated. Alveolar epithelial cell migration and wound healing were investigated using holographic live cell imaging of A549 cells in a wound scratch model post stimulation with tryptase or chymase. The expression of uPAR was investigated on the protein and gene level from cellular supernatants and in bronchoalveolar lavage fluid fractions from allergic asthmatics. We found that tryptase improved wound healing capacity, cellular migration and membrane bound uPAR expression. Chymase reduced gap closure capacity, cellular migration and membrane bound uPAR expression but increased soluble uPAR release. Our data suggest a dual regulatory response from the MC proteases in events related to uPAR expression and wound healing which could be important features in asthmatic disease.
|
|
50. |
- Mori, Michiko, et al.
(author)
-
Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease
- 2013
-
In: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:6, s. 521-531
-
Journal article (peer-reviewed)abstract
- Rationale The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. Objectives To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. Methods Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. Results Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)+ dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin+ dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. Conclusions Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.
|
|