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Sökning: WFRF:(Larsson Lena C)

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2.
  • Abe, O, et al. (författare)
  • Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
  • 2005
  • Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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  • Kanatsuna, N, et al. (författare)
  • Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
  • 2015
  • Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 82:4, s. 361-369
  • Tidskriftsartikel (refereegranskat)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.
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5.
  • Andersson, C, et al. (författare)
  • The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
  • 2011
  • Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
  • Tidskriftsartikel (refereegranskat)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.
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  • Ladds, Marcus J. G. W., et al. (författare)
  • A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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  • Fretwurst, T., et al. (författare)
  • Characterization of macrophages infiltrating peri-implantitis lesions
  • 2020
  • Ingår i: Clinical Oral Implants Research. - : Wiley. - 0905-7161 .- 1600-0501. ; 31:3, s. 274-81
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives The mechanisms involved in the initiation and progression of peri-implantitis lesions are poorly understood. It was the aim to determine the content and activation status of macrophages present in human peri-implantitis lesions and compare the current findings with the macrophage polarization associated with periodontitis lesions. Material and Methods A total of 14 patients were studied in this investigation. Seven were soft tissue biopsies from dental implants affected by peri-implantitis that required explantation. Seven biopsies were from chronic periodontal disease. Immunofluorescence stains were performed using biomarkers to identify macrophages (CD68(+)) undergoing M1 polarization (iNOS(+)) and M2 polarization (CD206(+)), along with Hoechst 33,342 to identify DNA content. All samples were stained and photographed, and double-positive cells for CD68 and iNOS or CD68 and CD206 were quantified. Results All peri-implantitis biopsies examined revealed a mixed population of macrophages undergoing M1 polarization and M2 polarization. Further analysis demonstrated the co-expression of iNOS and CD206, which indicates the presence of a heterogenic immune response on peri-implantitis lesions. Macrophage polarization in peri-implantitis lesions presents a distinct pattern than in periodontitis. We observed a significant increase in the population of M1 macrophages on peri-implantitis samples compared to periodontal disease samples. Conclusion Our results demonstrate that peri-implantitis has higher numbers of macrophages displaying a distinct macrophage M1 polarization signature compared to periodontitis lesions. This pattern may explain, in part, the distinct nature of peri-implantitis progression vs. periodontitis in humans.
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  • Garaicoa-Pazmino, C., et al. (författare)
  • Characterization of macrophage polarization in periodontal disease
  • 2019
  • Ingår i: Journal of Clinical Periodontology. - : Wiley. - 0303-6979 .- 1600-051X. ; 46:8, s. 830-839
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim To explore the M1/M2 status of macrophage polarization from healthy, gingivitis, and periodontitis patient samples. Materials and methods Gingival biopsies were collected from 42 individuals (14 gingivitis, 18 periodontitis, and 10 healthy samples) receiving periodontal therapy. Histomorphology analysis was performed with haematoxylin and eosin staining. Immunofluorescence was performed using a combination of CD68 (macrophages), iNOS (M1), and CD206 (M2) in order to acquire changes in macrophage polarization at a single-cell resolution. Macrophages were quantified under microscopy using narrow wavelength filters to detect Alexa 488, Alexa 568, Alexa 633 fluorophores, and Hoechst 33342 to identify cellular DNA content. Results Gingivitis and periodontitis samples showed higher levels of macrophages compared with healthy samples. Unexpectedly, periodontitis samples displayed lower levels of macrophages dispersed in the stromal tissues compared with gingivitis samples; however, it remained higher than healthy tissues. The polarization of macrophages appears to be reduced in periodontitis and showed similar levels to those observed in healthy tissues. Conclusions Our study found that gingivitis and periodontitis differ from each other by the levels of macrophage infiltrate, but not by changes in macrophage polarization.
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  • Larsson, Lena C, et al. (författare)
  • Induction of operational tolerance to discordant dopaminergic porcine xenografts.
  • 2003
  • Ingår i: Transplantation. - 1534-6080 .- 0041-1337. ; 75:9, s. 1448-1454
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and anti-CD40L therapy. METHODS: C57BL/6 mice received intracerebral transplants of ventral mesencephalic tissue from embryonic porcine donors. CTLA4Ig, anti-CD40L, and anti-LFA-1 were administered every other day on days 0 to 8, and the transplants were studied after 4 to 6 weeks. Grafts were histologically analyzed for size, survival of dopaminergic nerve cells, and immune responses. Recipients were challenged with cultured glia cells of donor origin or an allogeneic skin graft to evaluate tolerance induction. RESULTS: Mice treated with all three substances had large grafts containing high amounts of dopamine cells but a low degree of immune response. Grafts in recipients challenged with glial cells showed an increased immunologic activity but were not rejected. Triple-treated mice showed a normal rejection process of the allogeneic skin grafts. CONCLUSION: After a short course of costimulation blocking therapy, discordant neural xenografts demonstrate long-term survival, withstand immunologic challenge, yet maintain host-versus-graft reactivity. Anti-LFA-1 complements CTLA4Ig and anti-CD40L in the induction of operational tolerance to these xenografts.
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  • Martins, M. D., et al. (författare)
  • Epigenetic Modifications of Histones in Periodontal Disease
  • 2016
  • Ingår i: Journal of Dental Research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 95:2, s. 215-222
  • Tidskriftsartikel (refereegranskat)abstract
    • Periodontitis is a chronic infectious disease driven by dysbiosis, an imbalance between commensal bacteria and the host organism. Periodontitis is a leading cause of tooth loss in adults and occurs in about 50% of the US population. In addition to the clinical challenges associated with treating periodontitis, the progression and chronic nature of this disease seriously affect human health. Emerging evidence suggests that periodontitis is associated with mechanisms beyond bacteria-induced protein and tissue degradation. Here, we hypothesize that bacteria are able to induce epigenetic modifications in oral epithelial cells mediated by histone modifications. In this study, we found that dysbiosis in vivo led to epigenetic modifications, including acetylation of histones and downregulation of DNA methyltransferase 1. In addition, in vitro exposure of oral epithelial cells to lipopolysaccharides resulted in histone modifications, activation of transcriptional coactivators, such as p300/CBP, and accumulation of nuclear factor-kappa B (NF-kappa B). Given that oral epithelial cells are the first line of defense for the periodontium against bacteria, we also evaluated whether activation of pathogen recognition receptors induced histone modifications. We found that activation of the Toll-like receptors 1, 2, and 4 and the nucleotide-binding oligomerization domain protein 1 induced histone acetylation in oral epithelial cells. Our findings corroborate the emerging concept that epigenetic modifications play a role in the development of periodontitis.
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  • Pivodic, Aldina, 1978, et al. (författare)
  • Validation of DIGIROP models and decision support tool for prediction of treatment for retinopathy of prematurity on a contemporary Swedish cohort
  • 2023
  • Ingår i: British Journal of Ophthalmology. - : BMJ. - 0007-1161 .- 1468-2079. ; 107:8, s. 1132-1138
  • Tidskriftsartikel (refereegranskat)abstract
    • Background/Aims Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort. Methods Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described. Results For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening. Conclusions DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.
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  • Ahlin, Sofie, 1985, et al. (författare)
  • Fracture risk after three bariatric surgery procedures in Swedish obese subjects : up to 26 years follow-up of a controlled intervention study
  • 2020
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 287:5, s. 546-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous studies have reported an increased fracture risk after bariatric surgery. Objective: To investigate the association between different bariatric surgery procedures and fracture risk. Methods: Incidence rates and hazard ratios for fracture events were analysed in the Swedish Obese Subjects study; an ongoing, nonrandomized, prospective, controlled intervention study. Hazard ratios were adjusted for risk factors for osteoporosis and year of inclusion. Information on fracture events were captured from the Swedish National Patient Register. The current analysis includes 2007 patients treated with bariatric surgery (13.3% gastric bypass, 18.7% gastric banding, and 68.0% vertical banded gastroplasty) and 2040 control patients with obesity matched on group level based on 18 variables. Median follow-up was between 15.1 and 17.9 years for the different treatment groups. Results: During follow-up, the highest incidence rate for first-time fracture was observed in the gastric bypass group (22.9 per 1000 person-years). The corresponding incidence rates were 10.4, 10.7 and 9.3 per 1000 person-years for the vertical banded gastroplasty, gastric banding and control groups, respectively. The risk of fracture was increased in the gastric bypass group compared with the control group (adjusted hazard ratio [adjHR] 2.58; 95% confidence interval [CI] 2.02–3.31; P < 0.001), the gastric banding group (adjHR 1.99; 95%CI 1.41–2.82; P < 0.001), and the vertical banded gastroplasty group (adjHR 2.15; 95% CI 1.66–2.79; P < 0.001). Conclusions: The risk of fracture is increased after gastric bypass surgery. Our findings highlight the need for long-term follow-up of bone health for patients undergoing this treatment.
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  • André, Carl, 1958, et al. (författare)
  • Detecting population structure in a high gene-flow species, Atlantic herring (Clupea harengus) : direct, simultaneous evaluation of neutral vs putatively selected loci
  • 2011
  • Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 106:2, s. 270-280
  • Tidskriftsartikel (refereegranskat)abstract
    • In many marine fish species, genetic population structure is typically weak because populations are large, evolutionarily young and have a high potential for gene flow. We tested whether genetic markers influenced by natural selection are more efficient than the presumed neutral genetic markers to detect population structure in Atlantic herring (Clupea harengus), a migratory pelagic species with large effective population sizes. We compared the spatial and temporal patterns of divergence and statistical power of three traditional genetic marker types, microsatellites, allozymes and mitochondrial DNA, with one microsatellite locus, Cpa112, previously shown to be influenced by divergent selection associated with salinity, and one locus located in the major histocompatibility complex class IIA (MHC-IIA) gene, using the same individuals across analyses. Samples were collected in 2002 and 2003 at two locations in the North Sea, one location in the Skagerrak and one location in the low-saline Baltic Sea. Levels of divergence for putatively neutral markers were generally low, with the exception of single outlier locus/sample combinations; microsatellites were the most statistically powerful markers under neutral expectations. We found no evidence of selection acting on the MHC locus. Cpa112, however, was highly divergent in the Baltic samples. Simulations addressing the statistical power for detecting population divergence showed that when using Cpa112 alone, compared with using eight presumed neutral microsatellite loci, sample sizes could be reduced by up to a tenth while still retaining high statistical power. Our results show that the loci influenced by selection can serve as powerful markers for detecting population structure in high gene-flow marine fish species.
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  • Carlsson, Lena M S, 1957, et al. (författare)
  • Long-term incidence of microvascular disease after bariatric surgery or usual care in patients with obesity, stratified by baseline glycaemic status: a post-hoc analysis of participants from the Swedish Obese Subjects study.
  • 2017
  • Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595. ; 5:4, s. 271-279
  • Tidskriftsartikel (refereegranskat)abstract
    • Bariatric surgery is associated with remission of diabetes and prevention of diabetic complications in patients with obesity and type 2 diabetes. Long-term effects of bariatric surgery on microvascular complications in patients with prediabetes are unknown. The aim of this study was to examine the effects of bariatric surgery on incidence of microvascular complications in patients with obesity stratified by baseline glycaemic status.Patients were recruited to the Swedish Obese Subjects (SOS) study between Sept 1, 1987, and Jan 31, 2001. Inclusion criteria were age 37-60 years and BMI of 34 kg/m(2) or greater in men and 38 kg/m(2) or greater in women. Exclusion criteria were identical in surgery and control groups and designed to exclude patients not suitable for surgery. The surgery group (n=2010) underwent gastric bypass (265 [13%]), gastric banding (376 [19%]), or vertical-banded gastroplasty (1369 [68%]). Participants in the control group (n=2037) received usual care. Bodyweight was measured and questionnaires were completed at baseline and at 0·5 years, 1 year, 2 years, 3 years, 4 years, 6 years, 8 years, 10 years, 15 years, and 20 years. Biochemical variables were measured at baseline and at 2 years, 10 years, and 15 years. We categorised participants into subgroups on the basis of baseline glycaemic status (normal [fasting blood glucose concentration <5·0 mmol/L], prediabetes [5·0-6·0 mmol/L], screen-detected diabetes [≥6·1 mmol/L at baseline visit without previous diagnosis], and established diabetes [diagnosis of diabetes before study inclusion]). We obtained data about first incidence of microvascular disease from nationwide registers and about diabetes incidence at study visits at 2 years, 10 years, and 15 years. We did the main analysis by intention to treat, and subgroup analyses after stratification by baseline glycaemic status and by diabetes status at the 15 year follow-up. The SOS study is registered with ClinicalTrials.gov, NCT01479452.4032 of the 4047 participants in the SOS study were included in this analysis. We excluded four patients with suspected type 1 diabetes, and 11 patients with unknown glycaemic status at baseline. At baseline, 2838 patients had normal blood glucose, 591 had prediabetes, 246 had screen-detected diabetes, and 357 had established diabetes. Median follow-up was 19 years (IQR 16-21). We identified 374 incident cases of microvascular disease in the control group and 224 in the surgery group (hazard ratio [HR] 0·56, 95% CI 0·48-0·66; p<0·0001). Interaction between baseline glycaemic status and effect of treatment on incidence of microvascular disease was significant (p=0·0003). Unadjusted HRs were lowest in the subgroup with prediabetes (0·18, 95% CI 0·11-0·30), followed by subgroups with screen-detected diabetes (0·39, 0·24-0·65), established diabetes (0·54, 0·40-0·72), and normoglycaemia (0·63, 0·48-0·81). Surgery was associated with reduced incidence of microvascular events in people with prediabetes regardless of whether they developed diabetes during follow-up.Bariatric surgery was associated with reduced risk of microvascular complications in all subgroups, but the greatest relative risk reduction was observed in patients with prediabetes at baseline. Our results suggest that prediabetes should be treated aggressively to prevent future microvascular events, and effective non-surgical treatments need to be developed for this purpose.US National Institutes of Health, Swedish Research Council, Sahlgrenska University Hospital Regional Agreement on Medical Education and Research, and Swedish Diabetes Foundation.
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18.
  • Dionigi, Carlotta, et al. (författare)
  • Cellular expression of epigenetic markers and oxidative stress in periodontitis lesions of smokers and non-smokers
  • 2022
  • Ingår i: Journal of Periodontal Research. - : Wiley. - 0022-3484 .- 1600-0765. ; 57:5, s. 952-959
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To evaluate differences in the cellular expression of epigenetic markers and oxidative stress in periodontitis lesions between current smokers and non-smokers. Background Tobacco smoking is recognized as one of the major risk factors for periodontitis. However, the mechanisms by which smoking affects the progression of the disease remain to be determined. Methods Twenty-five current smokers and 21 non-smokers with generalized severe periodontitis were included. From each patient, one soft tissue biopsy from a periodontitis site was harvested and prepared for histological analysis. The infiltrated connective tissue (ICT) was selected as the region of interest to assess the cellular expression of epigenetic markers and reactive oxygen/nitrogen species (RONS) by immunohistochemistry. Results Although the ICT of smokers and non-smokers did not differ in size or in the expression of markers for DNA damage or oxidative stress, current smokers presented with significantly lower area proportions and densities of cells positive for the epigenetic markers DNMT1 and AcH3. In addition, periodontitis lesions in current smokers presented with a diminished antimicrobial activity, as indicated by significantly lower densities and area proportions of NOX2- and iNOS-positive cells. Conclusions Components of the host response and epigenetic mechanisms in periodontitis lesions in smokers are downregulated as opposed to lesions of non-smokers.
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20.
  • Ferndahl, Cecilia, 1975, et al. (författare)
  • Increasing cell biomass in Saccharomyces cerevisiae increases recombinant protein yield: the use of a respiratory strain as a microbial cell factory
  • 2010
  • Ingår i: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Recombinant protein production is universally employed as a solution to obtain the milligram to gram quantities of a given protein required for applications as diverse as structural genomics and biopharmaceutical manufacture. Yeast is a well-established recombinant host cell for these purposes. In this study we wanted to investigate whether our respiratory Saccharomyces cerevisiae strain, TM6*, could be used to enhance the productivity of recombinant proteins over that obtained from corresponding wild type, respiro-fermentative strains when cultured under the same laboratory conditions. Results: Here we demonstrate at least a doubling in productivity over wild-type strains for three recombinant membrane proteins and one recombinant soluble protein produced in TM6* cells. In all cases, this was attributed to the improved biomass properties of the strain. The yield profile across the growth curve was also more stable than in a wild-type strain, and was not further improved by lowering culture temperatures. This has the added benefit that improved yields can be attained rapidly at the yeast's optimal growth conditions. Importantly, improved productivity could not be reproduced in wild-type strains by culturing them under glucose fed-batch conditions: despite having achieved very similar biomass yields to those achieved by TM6* cultures, the total volumetric yields were not concomitantly increased. Furthermore, the productivity of TM6* was unaffected by growing cultures in the presence of ethanol. These findings support the unique properties of TM6* as a microbial cell factory. Conclusions: The accumulation of biomass in yeast cell factories is not necessarily correlated with a proportional increase in the functional yield of the recombinant protein being produced. The respiratory S. cerevisiae strain reported here is therefore a useful addition to the matrix of production hosts currently available as its improved biomass properties do lead to increased volumetric yields without the need to resort to complex control or cultivation schemes. This is anticipated to be of particular value in the production of challenging targets such as membrane proteins.
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21.
  • Fällmar, David, et al. (författare)
  • Arterial spin labeling-based Z-maps have high specificity and positive predictive value for neurodegenerative dementia compared to FDG-PET.
  • 2017
  • Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 27:10, s. 4237-4246
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Cerebral perfusion analysis based on arterial spin labeling (ASL) MRI has been proposed as an alternative to FDG-PET in patients with neurodegenerative disease. Z-maps show normal distribution values relating an image to a database of controls. They are routinely used for FDG-PET to demonstrate disease-specific patterns of hypometabolism at the individual level. This study aimed to compare the performance of Z-maps based on ASL to FDG-PET.METHODS: Data were combined from two separate sites, each cohort consisting of patients with Alzheimer's disease (n = 18 + 7), frontotemporal dementia (n = 12 + 8) and controls (n = 9 + 29). Subjects underwent pseudocontinuous ASL and FDG-PET. Z-maps were created for each subject and modality. Four experienced physicians visually assessed the 166 Z-maps in random order, blinded to modality and diagnosis.RESULTS: Discrimination of patients versus controls using ASL-based Z-maps yielded high specificity (84%) and positive predictive value (80%), but significantly lower sensitivity compared to FDG-PET-based Z-maps (53% vs. 96%, p < 0.001). Among true-positive cases, correct diagnoses were made in 76% (ASL) and 84% (FDG-PET) (p = 0.168).CONCLUSION: ASL-based Z-maps can be used for visual assessment of neurodegenerative dementia with high specificity and positive predictive value, but with inferior sensitivity compared to FDG-PET.KEY POINTS: • ASL-based Z-maps yielded high specificity and positive predictive value in neurodegenerative dementia. • ASL-based Z-maps had significantly lower sensitivity compared to FDG-PET-based Z-maps. • FDG-PET might be reserved for ASL-negative cases where clinical suspicion persists. • Findings were similar at two study sites.
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22.
  • Haglund, Felix, et al. (författare)
  • Inflammatory infiltrates in parathyroid tumors
  • 2017
  • Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 177:6, s. 445-453
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias. Objective: Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism. Design: From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts. Results: Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1-2) infiltrates of predominantly CD8+T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037). Conclusions: No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.
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23.
  • Hao, J., et al. (författare)
  • Multigrowth Factor Delivery via Immobilization of Gene Therapy Vectors
  • 2016
  • Ingår i: Advanced Materials. - : Wiley. - 0935-9648. ; 28:16, s. 3145-3151
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecules can be immobilized onto biomaterials by a chemical vapor deposition (CVD) coating strategy. Pentafluorophenolester groups react with amine side chains on antibodies, which can selectively immobilize adenoviral vectors for gene delivery of growth factors. These vectors can produce functional proteins within defined regions of biomaterials to produce customizable structures for targeted tissue regeneration.
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24.
  • Hellberg, C., et al. (författare)
  • Evidence and evidence gaps in assessments and interventions in areas related to social work research and practice - an overview of four evidence maps
  • 2023
  • Ingår i: European Journal of Social Work. - : Informa UK Limited. - 1369-1457 .- 1468-2664. ; 26:5
  • Tidskriftsartikel (refereegranskat)abstract
    • This overview of four evidence maps is based on systematic reviews of assessment and interventions in social work practice. The aim was to investigate the evidence and evidence gaps within four important areas for social work research and practice. Descriptive data on search strategies and domains were collected from four evidence maps, on Social Assistance, Substance Dependence, Care for older adults respectively for persons with disabilities. The scientific quality and scientific evidence were assessed. Key findings were summarised by analyzing and discussing common and specific elements in the evidence maps. The overview was undertaken in close collaboration between researchers with expertise in the field and a government agency. The overview identified both evidence and evidence gaps with respect to effects and experiences of interventions and assessment methods in four evidence maps. Evidence maps provide a comprehensive picture of the state of social services research and can thereby be of use to both researchers and practitioners, and in the production of evidence based social work.
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25.
  • Jordan, Stanley C, et al. (författare)
  • IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.
  • 2017
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:5, s. 442-453
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).
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26.
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27.
  • Laikre, Linda, et al. (författare)
  • Effekter av spridning av genetiskt främmande populationer : En kartläggning av förutsättningarna för uppföljande studier av utsättningar av djur och växter i Sverige
  • 2008
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Förord Spridning av främmande arter utgör ett av de stora hoten mot biologisk mångfald. En viktig del i arbetet med att verkställa Förenta nationernas konvention om biologisk mångfald (Convention on Biological Diversity – CBD) är därför att öka kunskapen kring, och förhindra fortsatt spridning av, sådana arter. Begreppet ”art” har en vid definition inom konventionsarbetet – även lägre taxonomiska enheter så som underarter och genetiskt särpräglade populationer omfattas. Spridning av genetiskt främmande populationer utgör alltså ett internationellt erkänt hot mot biologisk mångfald. Framför allt är det diversiteten på gennivå som kan drabbas negativt av sådan spridning. Vetenskapliga rådet för biologisk mångfald utses av Sveriges regering och ska bistå regeringen med råd i samband med internationellt och nationellt arbete med frågor som rör biologisk mångfald. Rådet har länge påtalat vikten av att öka kunskapen kring den genetiska nivån av biologisk mångfald och inte minst effekterna på denna mångfald av storskaliga utsättningar av genetiskt främmande populationer. Sådana utsättningar är vanliga inom skogsbruket, fiskevården och viltvården. Från min egen mångåriga erfarenhet av fiskevårdsfrågor har jag praktisk erfarenhet av att introduktion och spridning av främmande arter och populationer kan få högst påtagliga negativa konsekvenser.Vetenskapliga rådet för biologisk mångfald har i samband med konventionens tillämpning tagit upp frågor med koppling till den genetiska variationens betydelse – särskilt de vetenskapliga aspekterna kring detta. Rådet har också arrangerat en workshop som för första gången samlade experter och intressenter från de tre områden inom vilka storskaliga utsättningar bedrivs (skogsbruket, fisk- och viltvården). De intressanta och givande diskussionerna finns refererade i Rapport 5683 i Naturvårdsverkets serie. I den nu föreliggande rapporten fortsätter kartläggningen av vad vi egentligen vet om de storskaliga utsättningarna i Sverige och vilka effekter de har på biologisk mångfald. Ett gediget arbete har gjorts för att försöka bringa reda i detta område där dokumentation till stora delar saknas. Bristen på registrering och uppföljning av dessa stora spridningar, som riskerar att förändra den genetiska sammansättning som under årtusenden mejslats fram hos våra vilda fisk-, träd- och fågelpopulationer, är skrämmande. Här behövs en snabb och påtaglig förändring. Vetenskapliga rådet för biologisk mångfald kommer att fortsätta ägna denna fråga stor uppmärksamhet. Det är angeläget att Sverige bedriver ett starkt och engagerat arbete som ligger i internationell framkant när det gäller att slå vakt om den grundläggande, och för fortsatt evolution nödvändiga, mångfalden på gennivå. Stockholm den 10 september 2008 Per Wramner Professor i tillämpad miljövetenskap Ordförande för Vetenskapliga rådet för biologisk mångfald Förord 2 Utsättning av främmande populationer eller provenienser av växter och djur sker i stor skala i svenska marker och vattendrag. Spridningen av främmande populationer har stora ekonomiska värden men vi vet väldigt lite om vilka effekter den har på biologisk mångfald. Etablering av främmande genotyper kan leda till förlust och förändringar av, i första hand, mångfalden på gennivå hos mottagande naturliga populationer. I förlängningen kan sådana effekter även drabba art- och ekosystemnivåerna negativt. Det är mycket angeläget att öka kunskaperna inom detta område. Regeringen har uppdragit åt naturvårdsverket att ta fram en nationell strategi och handlingsplan för främmande arter och genotyper. Denna rapport utgör ett underlag i detta arbete. Uppdraget gavs med anledning av uppföljningen av miljökvalitetsmålen och implementering av artikel 8 h i Konventionen om biologisk mångfald som särskilt berör främmande arter och populationer och deras effekter på biologisk mångfalden. Rapporten utgör en uppföljning av den första kartläggningen av spridning av genetiskt främmande populationer inom fiske- och viltvården samt skogsbruk i Sverige som genomfördes under 2004–2005. Syftet med rapporten är en fördjupad granskning av den information som är möjlig att få fram när det gäller spridningen av främmande populationer eller genotyper i Sverige, samt i vilken utsträckning effekterna av sådana utsättningar kan kartläggas. Författarna är ensamma ansvariga för rapportens innehåll.Stockholm den 7 oktober 2008Naturvårdsverket
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28.
  • Laikre, Linda, et al. (författare)
  • Potentials for monitoring gene level biodiversity : using Sweden as an example
  • 2008
  • Ingår i: Biodiversity and Conservation. - : Springer Science and Business Media LLC. - 0960-3115 .- 1572-9710. ; 17:4, s. 893-910
  • Tidskriftsartikel (refereegranskat)abstract
    • Programs for monitoring biological diversity over time are needed to detect changes that can constitute threats to biological resources. The convention on biological diversity regards effective monitoring as necessary to halt the ongoing erosion of biological variation, and such programs at the ecosystem and species levels are enforced in several countries. However, at the level of genetic biodiversity, little has been accomplished, and monitoring programs need to be developed. We define “conservation genetic monitoring” to imply the systematic, temporal study of genetic variation within particular species/populations with the aim to detect changes that indicate compromise or loss of such diversity. We also (i) identify basic starting points for conservation genetic monitoring, (ii) review the availability of such information using Sweden as an example, (iii) suggest categories of species for pilot monitoring programs, and (iv) identify some scientific and logistic issues that need to be addressed in the context of conservation genetic monitoring. We suggest that such programs are particularly warranted for species subject to large scale enhancement and harvest—operations that are known to potentially alter the genetic composition and reduce the variability of populations.
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29.
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30.
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31.
  • Larsson, Lena C, et al. (författare)
  • Discordant neural tissue xenografts survive longer in immunoglobulin deficient mice
  • 1999
  • Ingår i: Transplantation. - 0041-1337. ; 68:8, s. 60-1153
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The immune response against discordant xenografts in the brain is incompletely understood and remains a major obstacle for future clinical applications of xenogeneic neural tissue transplants in neurodegenerative disorders. To determine the role of antibodies in the rejection process, we compared graft survival and immune reactions between immunoglobulin deficient (IgKO) and normal mice.METHODS: A cell suspension of embryonic porcine ventral mesencephalon was injected into the striatum of adult normal and IgKO mice. Graft sizes and number of infiltrating CD4- and CD8-positive lymphocytes were determined by stereological methods at 4 days and 2, 4, and 6 weeks after the transplants. Microglial accumulation was determined using the optical densitometrical method. Intraparenchymal deposition of IgG was investigated at 4 days and 2 weeks.RESULTS: The majority of IgKO mice had surviving grafts for up to 4 weeks, whereas survival was minimal in control mice beyond 4 days. Graft sizes differed significantly between IgKO and control mice at 2 weeks (P<0.01, Kruskal Wallis ANOVA, followed by Mann Whitney test). The majority of infiltrating lymphocytes were CD4-positive in control mice but CD8-positive in IgKO mice. Microglial accumulation was strong around surviving grafts in IgKO mice at 4 weeks. Prominent staining of IgG, diffuse in the transplanted hemisphere and specific on grafted neurons, was found in control mice.CONCLUSIONS: Our results suggest that immunoglobulins play an initiating role in rejection of discordant neural xenografts. After a prolonged graft survival of approximately 4 weeks, a cellular response with a large proportion CD8-positive cells leads to rejection in IgKO mice.
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32.
  • Larsson, Lena C., 1965- (författare)
  • Disentangling small genetic differences in large Atlantic herring populations: comparing genetic markers and statistical power
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Genes are the foundation of evolution and biodiversity. The genetic structure of natural populations needs to be understood to maintain exploited resources rationally. This thesis focuses on genetic variability and methods to determine spatial and temporal genetic heterogeneities. Intense human exploitation generates particular challenges to conserve genetic diversity of fishes since it has genetic effects. My research concerns one of our most valuable fish species: the Atlantic herring (Clupea harengus).I analyzed Atlantic herring samples from the North and Baltic Seas. The objectives were to determine: 1) spatial genetic structure, 2) whether allozymes and microsatellites provide similar descriptions of the differentiation pattern, or 3) if they are influenced by selection, 4) factors affecting statistical power when testing for genetic differentiation, and 5) the temporal stability of the genetic structure.The results show: 1) very low levels of spatial genetic differentiation in Atlantic herring; a major component is a difference between the Baltic and North Seas, 2) a concordant pattern with allozymes and microsatellites, 3) that selection influences a microsatellite locus, which can be a low salinity adaptation, 4) that statistical power is substantial for frequently used sample sizes and markers; the difference in power between organelle and nuclear loci is partly dependent on the populations’ stage of divergence, and 5) no changes in amount of genetic variation or spatial genetic structure over a 24-year period; the selection pattern in one microsatellite locus remained.The notion that the large population sizes make herring unlikely to lose genetic diversity may be disputed. I found small local effective population sizes, and the evidence of selection hints of a distinct evolutionary lineage in the Baltic. When Atlantic herring is managed as very large units, there can be detrimental genetic effects if certain population segments are excessively harvested.
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33.
  • Larsson, Lena Cecilia, et al. (författare)
  • Simultaneous inhibition of B7 and LFA-1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L.
  • 2002
  • Ingår i: Xenotransplantation. - : Wiley. - 0908-665X. ; 9:1, s. 68-76
  • Tidskriftsartikel (refereegranskat)abstract
    • Transplantation of embryonic human neural tissue can restore dopamine neurotransmission and improve neurological function in patients with Parkinson's disease. Logistical and ethical factors limit the availability of human embryonic allogeneic tissue. Embryonic xenogeneic neural tissue from porcine donors is an alternative form of donor tissue, but effective immunomodulatory techniques are warranted for neural xenotransplantation to become clinically feasible. We transplanted embryonic porcine ventral mesencephalic tissue into the brains of adult untreated C57BL/6 mice, untreated CD40L-/-mice and CD40L-/-mice that received injections of anti-LFA-1, CTLA41g or both compounds. Double-treated CD40L-/-mice had large grafts with high numbers of dopaminergic neurons 4 wk after transplantation. The grafts were completely devoid of lymphocytes, macrophages and activated microglia. Untreated C57BL/6 mice had rejected their grafts. Untreated CD40L-/-mice and CD40L-/-mice treated with monotherapy of anti-LFA-1 or CTLA41g had smaller grafts and more microglial and lymphocytic infiltration than double-treated CD40L-/-mice. We conclude that immunomodulation with concomitant inhibition of LFA-1 and B7 signaling in the perioperative period in CD40L-/-mice prevented the rejection of discordant neural xenografts. The treatment most likely reduced antigen presenting capacity and interfered with the costimulatory signaling needed for T cell activation to occur.
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34.
  • Larsson, Lena C., et al. (författare)
  • Statistical power for detecting genetic divergence–organelle versus nuclear markers
  • 2009
  • Ingår i: Conservation Genetics. - : Springer Science and Business Media LLC. - 1566-0621 .- 1572-9737. ; 10:5, s. 1255-1264
  • Tidskriftsartikel (refereegranskat)abstract
    • Statistical power is critical in conservation for detecting genetic differences in space or time from allele frequency data. Organelle and nuclear genetic markers have fundamentally different transmission dynamics; the potential effect of these differences on power to detect divergence have been speculated on but not investigated. We examine, analytically and with computer simulations, the relative performance of organelle and nuclear markers under basic, ideal situations. We conclude that claims of a generally higher resolving power of either marker type are not correct. The ratio R = FST,organelle/FST,nuclear varies between 1 and 4 during differentiation and this greatly affects the power relationship. When nuclear FST is associated with organelle differentiation four times higher, the power of the organelle marker is similar to two nuclear loci with the same allele frequency distribution. With large sample sizes (n C 50) and several populations or many alleles per locus (C5), the power difference may typically be disregarded when nuclear FST[0.05. To correctly interpret observed patterns of genetic differentiation in practical situations, the expected FSTs and the statistical properties (i.e., power analysis) of the genetic markers used should be evaluated, taking the observed allele frequency distributions into consideration.
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35.
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36.
  • Larsson, Lena C., et al. (författare)
  • Temporally stable genetic structure of heavily exploited Atlantic herring (Clupea harengus) in Swedish waters
  • 2010
  • Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 104:1, s. 40-51
  • Tidskriftsartikel (refereegranskat)abstract
    • Information on the temporal stability of genetic structures is important to permit detection of changes that can constitute threats to biological resources. Large scale harvesting operations are known to potentially alter the composition and reduce the variability of populations, and Atlantic herring (Clupea harengus) has a long history of heavy exploitation. In the Baltic Sea and Skagerrak waters the census population sizes have declined by 35-50% over the last three decades. We compared the genetic structure of Atlantic herring in these waters sampled at least two different times between 1979 and 2003 by assaying eleven allozyme and nine microsatellite loci. We cannot detect any changes in the amount of genetic variation or spatial structure, and differentiation is weak with overall FST=0.003 among localities for the older samples and FST=0.002 for the newer ones. There are indications of temporal allele frequency changes, particularly in one of five sampling localities that is reflected in a relatively small local Ne estimate of c. 400. The previously identified influence of selection at the microsatellite locus Cpa112 remains stable over the 24-year period studied here. In spite of little genetic differentiation, migration among localities appears small enough to permit demographic independence between populations.
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37.
  • Larsson, Lena, et al. (författare)
  • Geographical variation and predictors of physical activity level in adults with congenital heart disease
  • 2019
  • Ingår i: International Journal of Cardiology : Heart & Vasculature. - : Elsevier. - 2352-9067. ; 22, s. 20-25
  • Tidskriftsartikel (refereegranskat)abstract
    • Physical activity is important to maintain and promote health. This is of particular interest in patients with congenital heart disease(CHD) where acquired heart disease should be prevented. The World Health Organization (WHO) recommends a minimum of 2.5 h/week of physical activity exceeding 3 metabolic equivalents (METS) to achieve positive health effects. It is unknown whether physical activity levels (PAL) in adult CHD patients differ by country of origin.Methods3896 adults with CHD recruited from 15 countries over 5 continents completed self-reported instruments, including the Health Behaviour Scale (HBS-CHD), within the APPROACH-IS project. For each patient, we calculated whether WHO recommendations were achieved or not. Associated factors were investigated using Generalized Linear Mixed Models.ResultsOn average, 31% reached the WHO recommendations but with a great variation between geographical areas (India: 10%–Norway: 53%). Predictors for physical activity level in line with the WHO recommendations, with country of residence as random effect, were male sex (OR 1.78, 95%CI 1.52–2.08), NYHA-class I (OR 3.10, 95%CI 1.71–5.62) and less complex disease (OR 1.46, 95%CI 1.16–1.83). In contrast, older age (OR 0.97, 95%CI 0.96–0.98), lower educational level (OR 0.41, 95%CI 0.26–0.64) and being unemployed (OR 0.57, 95%CI 0.42–0.77) were negatively associated with reaching WHO recommendations.ConclusionsA significant proportion of patients with CHD did not reach the WHO physical activity recommendations. There was a large variation in physical activity level by country of origin. Based on identified predictors, vulnerable patients may be identified and offered specific behavioral interventions.
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38.
  • Larsson, Marie C., et al. (författare)
  • Rapid identification of pneumococci, enterococci, beta-haemolytic streptococci and S. aureus from positive blood cultures enabling early reports
  • 2014
  • Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 14:146
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:The aim of this study was to evaluate diagnostic tests in order to introduce a diagnostic strategy to identify the most common gram-positive bacteria (pneumococci, enterococci, β-haemolytic streptococci and S. aureus) found in blood cultures within 6 hours after signalling growth.METHODS:The tube coagulase test was optimized and several latex agglutination tests were compared and evaluated before a validation period of 11 months was performed on consecutive positive blood culture patient samples from Kalmar County Hospital, Sweden.RESULTS:During the validation period 150 (91%) of a total of 166 gram-positive cocci (119 in clusters, 45 in chains or pairs and 2 undefined morphology) were correctly identified as S. aureus, CoNS, Pneumococci, Enterococci or group A streptococci (GAS), group B streptococci (GBS), group G streptococci (GGS) within 6 hours with a minimal increase in work-load and costs. The remaining samples (9%) were correctly identified during the next day. No samples were incorrectly grouped with this diagnostic strategy and no patient came to risk by early reporting.CONCLUSION:A simple strategy gives reliable and cost-effective reporting of >90% of the most common gram-positive cocci within 6 hours after a blood cultures become positive. The high specificity of the tests used makes preliminary reports reliable. The reports can be used to indicate the focus of infection and not the least, support faster administration of proper antimicrobial treatment for patients with serious bacterial infections.
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39.
  • Larsson, R., et al. (författare)
  • To tape or not to tape: annular ligament (pulley) injuries in rock climbers-a systematic review
  • 2022
  • Ingår i: Bmc Sports Science Medicine and Rehabilitation. - : Springer Science and Business Media LLC. - 2052-1847. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Popularity of rock climbing is steadily increasing. With its inclusion in the Olympic Games this will likely continue. Injuries from rock climbing are also increasing. The most common injury is to the flexor pulley system, consisting of the finger flexors and five annular ligaments (pulleys). Treatment of this injury includes taping of affected fingers, but evaluation of this treatment was previously lacking. The aim of this review was therefore to assess whether taping is associated with better outcomes than non-taping. A secondary aim was to present treatment recommendations or areas for future research. Methods Systematic searches of PubMed, Scopus, SPORTDiscus, Cochrane Library, PEDro and CINAHL. Free text searches of Google Scholar. Citation searching. No restrictions to language, date of publication or study design. Included studies were assessed using Cochrane scale for clinical relevance, by two independent authors. Results were presented in narrative synthesis. Certainty of evidence (GRADE) was assessed by three authors. Review was done according to PICO-protocol and reported according to PRISMA-guidelines. Results After removing duplicates, 595 records were identified. Eight studies and one case report (in nine articles, one poster) were included, consisting of 206 rock climbers, four non-climbers, 23 pairs of cadaver hands. Clinical relevance ranged from 0 to 5 (median 2). Evidence of low to moderate certainty suggests that taping might reduce bowstringing of the finger flexor tendons by 15-22%. Evidence regarding pain, time for return to sports, shearing forces against pulleys, pulley ruptures and maximum voluntary contraction (MVC) were all regarded as "very low", "very low to low" or "low", and were not considered reliable. Evidence of moderate certainty suggests that taping has no effect on MVC or muscle activation in uninjured rock climbers. No adverse effects of taping were reported. Conclusion Low to moderate evidence suggests that taping might reduce bowstringing of the finger flexor tendons. Moderate evidence suggests that taping has no effect on MVC or muscle activation in uninjured climbers. For other outcomes more studies evaluating the effects of taping are needed. Trial registration: PROSPERO CRD42021241271, date of registration: 18-04-2021.
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40.
  • Maekawa, S., et al. (författare)
  • BMP Gene-Immobilization to Dental Implants Enhances Bone Regeneration
  • 2022
  • Ingår i: Advanced Materials Interfaces. - : Wiley. - 2196-7350. ; 9:22
  • Tidskriftsartikel (refereegranskat)abstract
    • For individuals who have experienced tooth loss, dental implants are an important treatment option for oral reconstruction. For these patients, alveolar bone augmentation and acceleration of osseointegration optimize implant stability. Traditional oral surgery often requires invasive procedures, which can result in prolonged treatment time and associated morbidity. It has been previously shown that chemical vapor deposition (CVD) polymerization of functionalized [2.2]paracyclophanes can be used to anchor gene encoding vectors onto biomaterial surfaces and local delivery of a bone morphogenetic protein (BMP)-encoding vector can increase alveolar bone volume and density in vivo. This study is the first to combine the use of CVD technology and BMP gene delivery on titanium for the promotion of bone regeneration and bone to implant contact in vivo. BMP-7 tethered to titanium surface enhances osteoblast cell differentiation and alkaline phosphatase activity in vitro and increases alveolar bone regeneration and % bone to implant contact similar to using high doses of exogenously applied BMP-7 in vivo. The use of this innovative gene delivery strategy on implant surfaces offers an alternative treatment option for targeted alveolar bone reconstruction.
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41.
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42.
  • Nookaew, Intawat, 1977, et al. (författare)
  • Adipose Tissue Resting Energy Expenditure and Expression of Genes Involved in Mitochondrial Function Are Higher in Women than in Men.
  • 2013
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 98:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Context:Men and women differ in body fat distribution and adipose tissue metabolism as well as in obesity comorbidities and their response to obesity treatment.Objective:The objective of the study was a search for sex differences in adipose tissue function.Design and Setting:This was an exploratory study performed at a university hospital.Participants and Main Outcome Measures:Resting metabolic rate (RMR), body composition, and sc adipose tissue genome-wide expression were measured in the SOS Sib Pair study (n = 732).Results:The relative contribution of fat mass to RMR and the metabolic rate per kilogram adipose tissue was higher in women than in men (P value for sex by fat mass interaction = .0019). Women had increased expression of genes involved in mitochondrial function, here referred to as a mitochondrial gene signature. Analysis of liver, muscle, and blood showed that the pronounced mitochondrial gene signature in women was specific for adipose tissue. Brown adipocytes are dense in mitochondria, and the expression of the brown adipocyte marker uncoupling protein 1 was 5-fold higher in women compared with men in the SOS Sib Pair Study (P = 7.43 × 10(-7)), and this was confirmed in a cross-sectional, population-based study (n = 83, 6-fold higher in women, P = .00256).Conclusions:The increased expression of the brown adipocyte marker uncoupling protein 1 in women indicates that the higher relative contribution of the fat mass to RMR in women is in part explained by an increased number of brown adipocytes.
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43.
  • Olsson, Erika, 1970- (författare)
  • Diet and common neurological disorders: cohort studies on dementia, Parkinson’s disease, and stroke
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Risk factors for dementia, Parkinson’s disease, and stroke have been widely studied but there are still research gaps concerning the role of diet for the development of these diseases. The overall aim of this thesis was to investigate whether various aspects of diet are associated with common disorders and diseases in the brain. Paper I and II are based on the Uppsala Longitudinal Study of Adult Men (ULSAM). Paper III and IV are based on the Swedish Mammography Cohort (SMC) and the Cohort of Swedish Men (COSM). In paper I, we investigated the associations between three different dietary patterns and incidence of Alzheimer’s disease (AD), dementia, and cognitive impairment. We observed no associations between adherence to the Healthy Diet Indicator and any of the outcomes studied, or between adherence to a Mediterranean-like diet (mMDS) and AD or dementia. There was a tendency towards a lower risk of cognitive impairment with higher adherence to the mMDS, and a weak association between adherence to a Low Carbohydrate High Protein score and higher risk of all-type dementia. Overall, there were no strong associations with the studied dietary patterns and development of dementia or cognitive impairment. In paper II, we found no associations of vitamin D measured as vitamin D intake, plasma 25-hydroxyvitamin D concentrations, or a vitamin D synthesis genetic risk score with incident AD, vascular dementia, dementia, or performance in the Mini-Mental State Examination.In paper III, we observed a weak higher risk of PD associated with milk consumption but there was no dose-response relationship. Thus, this association needs to be interpreted with caution. Fermented milk intake was not associated with PD.In paper IV, we found that a higher long-term milk consumption based on repeated measures of intake was not associated with total stroke, weakly and non-linearly associated with lower risk of cerebral infarction and higher risk of hemorrhagic stroke. Fermented milk consumption was not associated with any stroke type. Our results highlight the importance of repeated measurements of food intake, separate analyses of milk and fermented milk consumption, and to study stroke types separately.Despite the lack of strong associations, the findings of this thesis have increased our knowledge about the potential role of overall diet, vitamin D, and milk and fermented consumption in the prevention or development of common neurodegenerative diseases and stroke.
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44.
  • Olsson, Erika, 1970-, et al. (författare)
  • Milk and Fermented Milk Consumption and Risk of Stroke : Longitudinal Study
  • 2022
  • Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:5
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of milk and fermented milk consumption in stroke risk is unclear. We investigated associations of time-updated information on milk and fermented milk consumption (1997 and 2009) with total stroke, cerebral infarction, and hemorrhagic stroke risk among 79,618 Swedish women and men (mean age 61.3 years). During a mean follow-up of 17.7 years, we identified 9735 incident cases of total stroke, of which 7573 were cerebral infarctions, 1470 hemorrhagic strokes, and 692 unspecified strokes. Compared with an intake of 100 g/day of milk, the multivariable-adjusted hazard ratios (95% confidence interval) of cerebral infarction were 1.05 (1.02-1.08) for 0 g/day, 0.97 (0.95-0.99) for 200 g/day, 0.96 (0.92-1.00) for 400 g/day, 0.98 (0.94-1.03) for 600 g/day, and 1.01 (0.94-1.07) for 800 g/day. Corresponding estimates for hemorrhagic stroke were 0.98 (0.91-1.05) for 0 g/day, 1.02 (0.97-1.07) for 200 g/day, 1.07 (0.98-1.17) for 400 g/day, 1.13 (1.02-1.25) for 600 g/day, and 1.19 (1.03-1.36) for 800 g/day. No associations were observed between milk consumption and total stroke or for fermented milk consumption and any of the stroke outcomes. Higher long-term milk consumption based on repeated measures of intake was weakly and non-linearly associated with cerebral infarction, and was directly associated with hemorrhagic stroke.
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45.
  • Olsson, Erika, et al. (författare)
  • Milk and Fermented Milk Intake and Parkinson's Disease : Cohort Study
  • 2020
  • Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 12:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Milk and fermented milk consumption has been linked to health and mortality but the association with Parkinson's disease (PD) is uncertain. We conducted a study to investigate whether milk and fermented milk intakes are associated with incident PD. This cohort study included 81,915 Swedish adults (with a mean age of 62 years) who completed a questionnaire, including questions about milk and fermented milk (soured milk and yogurt) intake, in 1997. PD cases were identified through linkage with the Swedish National Patient and Cause of Death Registers. Multivariable-adjusted hazard ratios were obtained from Cox proportional hazards regression models. During a mean follow-up of 14.9 years, 1251 PD cases were identified in the cohort. Compared with no or low milk consumption (<40 mL/day), the hazard ratios of PD across quintiles of milk intake were 1.29 (95% CI 1.07, 1.56) for 40-159 mL/day, 1.19 (95% CI 0.99, 1.42) for 160-200 mL/day, 1.29 (95% CI 1.08, 1.53) for 201-400 mL/day, and 1.14 (95% CI 0.93, 1.40) for >400 mL/day. Fermented milk intake was not associated with PD. We found a weak association between milk intake and increased risk of PD but no dose-response relationship. Fermented milk intake was not associated with increased risk of PD.
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46.
  • Pilipchuk, Sophia P, et al. (författare)
  • Micropatterned Scaffolds with Immobilized Growth Factor Genes Regenerate Bone and Periodontal Ligament-Like Tissues.
  • 2018
  • Ingår i: Advanced healthcare materials. - : Wiley. - 2192-2659 .- 2192-2640. ; 7:22
  • Tidskriftsartikel (refereegranskat)abstract
    • Periodontal disease destroys supporting structures of teeth. However, tissue engineering strategies offer potential to enhance regeneration. Here, the strategies of patterned topography, spatiotemporally controlled growth factor gene delivery, and cell-based therapy to repair bone-periodontal ligament (PDL) interfaces are combined. Micropatterned scaffolds are fabricated for the ligament regions using polycaprolactone (PCL)/polylactic-co-glycolic acid and combined with amorphous PCL scaffolds for the bone region. Scaffolds are modified using chemical vapor deposition, followed by spatially controlled immobilization of vectors encoding either platelet-derived growth factor-BB or bone morphogenetic protein-7, respectively. The scaffolds are seeded with human cells and delivered to large alveolar bone defects in athymic rats. The effects of dual and single gene delivery with and without micropatterning are assessed after 3, 6, and 9 weeks. Gene delivery results in greater bone formation at three weeks. Micropatterning results in regenerated ligamentous tissues similar to native PDL. The combination results in more mature expression of collagen III and periostin, and with elastic moduli of regenerated tissues that are statistically indistinguishable from those of native tissue, while controls are less stiff than native tissues. Thus, controlled scaffold microtopography combined with localized growth factor gene delivery improves the regeneration of periodontal bone-PDL interfaces.
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47.
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48.
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49.
  • Shebanits, Kateryna, et al. (författare)
  • Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference
  • 2018
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple genetic studies have linked copy number variation (CNV) in different genes to body mass index (BMI) and obesity. A CNV on chromosome 10q11.22 has been associated with body weight. This CNV region spans NPY4R, the gene encoding the pancreatic polypeptide receptor Y4, which has been described as a satiety-stimulating receptor. We have investigated CNV of the NPY4R gene and analysed its relationship to BMI, waist circumference and self-reported dietary intake from 558 individuals (216 men and 342 women) representing a wide BMI range. The copy number for NPY4R ranged from 2 to 8 copies (average 4.6 +/- 0.8). Rather than the expected negative correlation, we observed a positive correlation between NPY4R copy number and BMI as well as waist circumference (r = 0.267, p = 2.65x 10(-7) and r = 0.256, p = 8x10(-7), respectively). Each additional copy of NPY4R correlated with 2.6 kg/m(2) increase in BMI and 5.67 cm increase in waist circumference (p = 3.3x10(-7) and p = 1x10(-6), respectively) for women. For men, there was no statistically significant correlation between CNV and BMI. Our results suggest that NPY4R genetic variation influences body weight in women, but the exact role of this receptor appears to be more complex than previously proposed.
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50.
  • Sjöström, Lars, et al. (författare)
  • Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial.
  • 2009
  • Ingår i: The lancet oncology. - 1474-5488. ; 10:7, s. 653-62
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. METHODS: The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] >or=34 kg/m(2) in men, and >or=38 kg/m(2) in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99.9% and the median follow-up time was 10.9 years (range 0-18.1 years). FINDINGS: Bariatric surgery resulted in a sustained mean weight reduction of 19.9 kg (SD 15.6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1.3 kg (SD 13.7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0.67, 95% CI 0.53-0.85, p=0.0009). The sex-treatment interaction p value was 0.054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0.58, 0.44-0.77; p=0.0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0.97, 0.62-1.52; p=0.90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. INTERPRETATION: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. FUNDING: Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.
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