| 1. |
- Drake, Isabel, et al.
(författare)
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The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65, s. 128-139
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. Methods Participants (n = 4022; 58.6% women) in the Malmo Diet and Cancer Study-Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 +/- 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 +/- 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 x 10(-11)). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. Results Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 x 10(-89)) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 x 10(-3)). Conclusions/interpretation Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.
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| 2. |
- Gummesson, Anders, 1973, et al.
(författare)
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Longitudinal plasma protein profiling of newly diagnosed type 2 diabetes
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- Background: Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status. Methods: To elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes. Findings: Early stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM. Interpretation: The results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments. Funding: This work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
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| 3. |
- Holmqvist, Fredrik, et al.
(författare)
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A decade of catheter ablation of cardiac arrhythmias in Sweden : ablation practices and outcomes
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:10, s. 820-830
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Catheter ablation is considered the treatment of choice for many tachyarrhythmias, but convincing 'real-world' data on efficacy and safety are lacking. Using Swedish national registry data, the ablation spectrum, procedural characteristics, as well as ablation efficacy and reported adverse events are reported.Methods and Results: Consecutive patients (≥18 years of age) undergoing catheter ablation in Sweden between 01 January 2006 and 31 December 2015 were included in the study. Follow-up (repeat ablation and vital status) was collected through 31 December 2016. A total of 26 642 patients (57 ± 15 years, 62% men), undergoing a total of 34 428 ablation procedures were included in the study. In total, 4034 accessory pathway/Wolff-Parkinson-White syndrome (12%), 7358 AV-nodal re-entrant tachycardia (21%), 1813 atrial tachycardia (5.2%), 5481 typical atrial flutter (16%), 11 916 atrial fibrillation (AF, 35%), 2415 AV-nodal (7.0%), 581 premature ventricular contraction (PVC, 1.7%), and 964 ventricular tachycardia (VT) ablations (2.8%) were performed. Median follow-up time was 4.7 years (interquartile range 2.7-7.0). The spectrum of treated arrhythmias changed over time, with a gradual increase in AF, VT, and PVC ablation (P < 0.001). Decreasing procedural times and utilization of fluoroscopy with time, were seen for all arrhythmia types. The rates of repeat ablation differed between ablation types, with the highest repeat ablation seen in AF (41% within 3 years). The rate of reported adverse events was low (n = 595, 1.7%). Death in the immediate period following ablation was rare (n = 116, 0.34%).Conclusion: Catheter ablations have shifted towards more complex procedures over the past decade. Fluoroscopy time has markedly decreased and the efficacy of catheter ablation seems to improve for AF.
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| 4. |
- Holmqvist, Fredrik, et al.
(författare)
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Increasing Ablation Volumes And A Shift Towards More Complex Arrhythmias : Data From The Swedish National Catheter Ablation Registry
- 2018
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Konferensbidrag (refereegranskat)abstract
- Background: Catheter ablation has become the treatment of choice for many tachyarrhythmias. The ablation techniques are continuously refined and the indications expanded, enabling treatment of more complex substrates. Hence, the spectrum of treated arrhythmias is likely to have changed over time, but compelling data on this are lacking.Objective: The present study set out to explore the changing pattern of ablations performed in the setting of a universal, single-payer healthcare system, using data from the Swedish national catheter ablation registry.Methods: The Swedish National Catheter Ablation Registry covers virtually all (>97%) catheter ablations performed in Sweden since 2005 and comprises 42,192 ablations on 32,237 individual patients. In the present analysis, all ablations performed between 2005 and 2016 were included.Results: In 2005, there were 7 ablation centers in Sweden performing a total of 1,584 ablations (226/center; 175/million). In 2016, 11 ablation centers performed 5,022 ablations (457/center; 502/million). Ablation of atrial fibrillation increased from 326 ablations (21% of all) in 2005 to 2,063 (41%) in 2016. Although, the number of ablation procedures for ventricular tachycardia and premature ventricular contractions is increasing, it is still on a relatively modest level (Figure). In contrast to other reports, there is no apparent decline in the number of accessory pathway ablations.Conclusion: In the setting of a universal, single-payer healthcare system, the number of ablations more than tripled over a 10-year period. Ablation of atrial fibrillation is the main driver behind this increase and accounted for 41% of all ablations in Sweden in 2016.
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| 5. |
- Khamisi, Selwan, et al.
(författare)
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Comparison between thyroid stimulating immunoglobulin and TSH-receptor antibodies in management of Graves' orbitopathy
- 2023
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Ingår i: Experimental and clinical endocrinology & diabetes. - : Georg Thieme Verlag KG. - 0947-7349 .- 1439-3646. ; 131:04, s. 236-241
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Tidskriftsartikel (refereegranskat)abstract
- Objectives TSH-receptor antibodies (TRAb) targeting the TSH receptor (TSH-R) induce hyperthyroidism in Graves´ disease (GD). Graves´ orbitopathy (GO) is influenced by stimulation of the TSH-R in the orbita. GO has been, among other factors, linked to high TRAb levels. Thyroid stimulating immunoglobulins (TSI) is a relatively new method for assessing TSH-receptor antibodies. The aim of this study was to investigate the role of TSI in the management of GO.Methods Patients with newly diagnosed GD (n=30, median age 55 years (range 35–72), 29 women) received pharmacological therapy (methimazole+++thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. Eleven patients had GO at diagnosis, and another six developed GO during treatment. Blood samples for TSI and other thyroidal biomarkers were obtained at baseline and on five occasions during the 24-month follow-up. Twenty-two subjects completed the drug regimen without surgery or radioiodine treatment.Results At baseline, TSI was highly correlated with TRAb (r s =0.64, p<0.001), and both assays similarly correlated to fT3 values. TSI and TRAb did not differ significantly between GO and non-GO patients for visit v1 (n=30, 17 GO during the whole study) or at follow-up (n=22, 12 GO during the whole study). During follow-up, levels of TSI and TRAb decreased and normalized in both groups.Conclusion The present study does not support any added benefit of TSI compared to TRAb for the prediction and management of GO.
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| 6. |
- Lindholm, Lena, et al.
(författare)
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Regional oxygenation and systemic inflammatory response during cardiopulmonary bypass: influence of temperature and blood flow variations.
- 2003
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Ingår i: Journal of cardiothoracic and vascular anesthesia. - : Elsevier BV. - 1053-0770. ; 17:2, s. 182-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the role of target temperature (28 degrees or 34 degrees C) in cardiac surgery on regional oxygenation during hypothermia and rewarming and systemic inflammatory response. DESIGN: Prospective, controlled, and randomized clinical study. SETTING: University hospital. PARTICIPANTS: Elderly patients (mean age 70 +/- 2 years) with acquired heart disease with an anticipated bypass time exceeding 120 minutes (n = 30). INTERVENTIONS: The patients were cooled to either 28 degrees C (n = 15) or 34 degrees C (n = 15). At hypothermia, bypass blood flow was reduced twice from full flow (2.4 L/min/m(2) body surface area [BSA]) to 2.0 L/min/m(2). MEASUREMENTS AND MAIN RESULTS: Hepatic and jugular venous oxygen tension and saturation were higher at 28 degrees C than at 34 degrees C. In comparison with the preoperative values, at 28 degrees C hepatic venous values were higher; whereas at 34 degrees C, they were lower. The reduction of pump blood flow during hypothermia, from 2.4 to 2.0 L/min/m(2)was accompanied by reductions of central, jugular, and hepatic oxygenation at both target temperatures. During rewarming, central and regional venous oxygenation decreased irrespective of the preceding temperature. The decrease was most pronounced in hepatic venous blood, with the lowest individual values <10%. Serum concentrations of C3a and IL-6 increased during hypothermia and increased further during rewarming irrespective of the preceding temperature. CONCLUSION: During cardiopulmonary bypass, hypothermia at 28 degrees C increases regional and central venous oxygenation better than at 34 degrees C. In contrast, venous oxygenation decreases during rewarming irrespective of the preceding temperature. No significant difference in the systemic inflammatory response associated with target temperature was detected.
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| 7. |
- Lundqvist, Peter, et al.
(författare)
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No trace of a single-degenerate companion in late spectra of supernovae 2011fe and 2014J
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 577
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Tidskriftsartikel (refereegranskat)abstract
- Aims. This study aims at constraining the origin of the nearby Type Ia supernovae (SNe), 2011fe and 2014J. The two most favoured scenarios for triggering the explosion of the white dwarf supernova progenitor is either mass loss from a non-degenerate companion or merger with another white dwarf. In the former, there could be a significant amount of leftover material from the companion at the centre of the supernova. Detecting such material would therefore favour the single-degenerate scenario. Methods. The left-over material from a possible non-degenerate companion can reveal itself after about one year, and in this study such material was searched for in the spectra of SN 2011fe (at 294 days after the explosion) using the Large Binocular Telescope and for SN 2014J using the Nordic Optical Telescope (315 days past explosion). The observations were interpreted using numerical models simulating the expected line emission from ablated material from the companion star. The spectral lines sought for are H alpha, [O I] lambda 6300, and [Ca II] lambda lambda 7291,7324, and the expected width of these lines is similar to 1000 km s(-1), which in the case of the [Ca II] lines blend to a broader feature. Results. No signs of H alpha, [O I] lambda 6300, or [Ca II] lambda lambda 7291, 7324 could be traced for in any of the two supernovae. When systematic uncertainties are included, the limits on hydrogen-rich ablated gas are 0 : 003 M-circle dot in SN 2011fe and 0 : 0085 M-circle dot in SN 2014J, where the limit for SN 2014J is the second lowest ever, and the limit for SN 2011fe is a revision of a previous limit. Limits are also put on helium-rich ablated gas, and here limits from [O I] lambda 6300 provide the upper mass limits 0 : 002 M-circle dot and 0 : 005 M-circle dot for SNe 2011fe and 2014J, respectively. These numbers are used in conjunction with other data to argue that these supernovae can stem from double-degenerate systems or from single-degenerate systems with a spun-up/spun-down super-Chandrasekhar white dwarf. For SN 2011fe, other types of hydrogen-rich donors can very likely be ruled out, whereas a main-sequence donor system with large intrinsic separation is still possible for SN 2014J. Helium-rich donor systems cannot be ruled out for any of the two supernovae, but the expected short delay time for such progenitors makes this possibility less likely, especially for SN 2011fe. Published data for SNe 1998bu, 2000cx, 2001el, 2005am, and 2005cf are used to constrain their origin. We emphasise that the results of this study depend on the sought-after lines emerging unattenuated from the central regions of the nebula. Detailed radiative transfer calculations with longer line lists than are presently used are needed to confirm that this is, in fact, true. Finally, the broad lines of SNe 2011fe and 2014J are discussed, and it is found that the [Ni II] lambda 7378 emission is redshifted by similar to+ 1300 km s(-1), as opposed to the known blueshift of similar to-1100 km s(-1) for SN 2011fe. [Fe II] lambda 7155 is also redshifted in SN 2014J. SN 2014J belongs to a minority of SNe Ia that both have a nebular redshift of [Fe II] lambda 7155 and [Ni II] lambda 7378, and a slow decline of the Si II lambda 6355 absorption trough just after B-band maximum.
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| 8. |
- Nilsson, Lino, 1988-
(författare)
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Nitrogen Cycling at Cold Climate Mine Sites in Northen Sweden
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- High nitrogen discharge from mining sites has been an environmental issue that has been closely studied in the recent years. The environmental effects of high nitrogen discharge are mainly eutrophication, but can also lead to changed species composition and algae blooms. Nitrogen is a highly abundant element and is the most abundant element in the atmosphere, where 78% by volume is present as dinitrogen (N2 ). Nitrogen is present in reduced form in all organic life as ammonium (NH4 + ). Nitrogen is also present in reduced form as nitrate (NO3 - ) or nitrite (NO2 - ) in most aquatic systems. Both nitrate and ammonium is contributing to eutrophication problems worldwide and ammonia (NH3 ) is direct toxic in high concentration to certain sensitive aquatic species. Nitrate in high concentration is also direct toxic, both to humans but also to aquatic biota. To trace and quantify different nitrogen transforming processes, their sources and their sinks is called tracing nitrogen cycling and is important due to the environmental effect of nitrogen. Nitrogen is available in many different species and oxidation states which all have their respective geochemistry. This thesis focuses on tracing the complex nitrogen cycle in two different cold climate mining systems in northern Sweden using two different methods. The two studied systems are:The LKAB underground iron ore mine in KirunaBoliden Minerals AB open pit copper ore mine Aitik outside Gällivare Two different approaches were used to trace the nitrogen cycling. The LKAB Kiruna mine was investigated using stable nitrogen isotopes. The isotope analysis showed high capability to trace nitrogen cycling, both quantative and qualitative. We also showed the origin of the isotope signals which gives indication to the different sources of nitrogen in the mine. The presented study shows presence of nitrification, ammonium volatilization and ammonium adsorption to waste rock to occur in the water transport system. The nitrogen cycling in the Boliden Aitik mine was investigated using a nitrogen model which we developed as part of this thesis. The model is based on Yakushevs Redox Layer model (ROLM). The model contains the state variables ammonium, nitrate, nitrite, plankton, phosphate, dead organic material (both particulate and dissolved) as well as oxygen. The nitrogen concentrations in the Boliden Aitik mine was modeled for the clarification pond and showed, in general, low biological activity. The biological mediated reactions such as nitrification, denitrification, phytoplankton growth and grazing were low in relation to natural lake systems
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| 9. |
- Nilsson, Magnus, et al.
(författare)
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Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
- 2022
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Ingår i: Drug Design, Development and Therapy. - : Informa Healthcare. - 1177-8881. ; 16, s. 2901-2917
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 mu g/kg and AZD4604 at 30 mu g/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
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| 10. |
- Plymoth, Martin, et al.
(författare)
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Targeting tularemia : clinical, laboratory, and treatment outcomes from an 11-year retrospective observational cohort in northern sweden
- 2024
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 78:5, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tularemia is an important re-emerging disease with a multimodal transmission-pattern. Treatment outcomes of current recommended antibiotic regimens (including ciprofloxacin and doxycycline) remain unclear. In this retrospective cohort study, we report clinical, laboratory, geographical, and treatment outcomes of laboratory-confirmed tularemia cases over an 11-year period in Northern Sweden.Methods: Data from reported tularemia cases (aged >10 years at time of study) in Norrbotten county between 2011-2021 were collected through review of electronic medical records and participant questionnaires; with 415 out of 784 accepting participation (52.9%). Of these, 327 were laboratory-confirmed cases (serology and/or PCR). A multivariable logistic regression model was used to investigate variables associated with re-treatment.Results: Median age of participants was 54 years (IQR 41.5-65) and 49.2% were female. While ulceroglandular tularemia was the predominant form (n=215, 65.7%), there were several cases of pulmonary tularemia (n=40; 12.2%). Inflammatory markers were largely non-specific, with monocytosis frequently observed (n=36/75; 48%). Tularemia was often misdiagnosed upon presentation (n=158, 48.3%), with 65 (19.9%) receiving initial inappropriate antibiotics, and 102 (31.2%) re-treated. Persistent lymphadenopathy was infrequent (n=22, 6.7%), with 10 undergoing surgical interventions. In multivariable analysis of variables associated with re-treatment, we highlight differences in time until receiving appropriate antibiotics (8 [IQR 3.25-20.75] vs. 7 [IQR 4-11.25] days; adjusted p=0.076), and doxycycline-based treatment regimen (vs. ciprofloxacin; adjusted p=0.084), although not significant after correction for multiple comparisons.Conclusion: We comprehensively summarize clinical, laboratory, and treatment outcomes of type B tularemia. Targeting tularemia requires clinical awareness, early diagnosis and timely commencement of treatment for an appropriate duration.
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