| 1. |
- Björk, Per, et al.
(författare)
-
Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.
- 2009
-
Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 7:4, s. 800-812
-
Tidskriftsartikel (refereegranskat)abstract
- Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides have been elusive although these compounds are currently in Phase II and III development for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine a direct association between human S100A9 and quinoline-3-carboxamides. This interaction was strictly dependent on both Zn++ and Ca++. We also show that S100A9 in the presence of Zn++ and Ca++ is an efficient ligand of receptor for advanced glycation end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides. A clear structure-activity relationship (SAR) emerged with regard to the binding of quinoline-3-carboxamides to S100A9, as well as these compounds potency to inhibit interactions with RAGE or TLR4/MD2. The same SAR was observed when the compound's ability to inhibit acute experimental autoimmune encephalomyelitis in mice in vivo was analysed. Quinoline-3-carboxamides would also inhibit TNFalpha release in a S100A9-dependent model in vivo, as would antibodies raised against the quinoline-3-carboxamide-binding domain of S100A9. Thus, S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases.
|
|
| 2. |
- Grubb, Anders, et al.
(författare)
-
Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator
- 2014
-
Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 60:7, s. 974-986
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.METHODS:Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR.RESULTS:We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.CONCLUSIONS:A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.
|
|
| 3. |
- Hansson, Lars-Anders, et al.
(författare)
-
Food-chain length alters community responses to global change in aquatic systems
- 2013
-
Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 3, s. 228-233
-
Tidskriftsartikel (refereegranskat)abstract
- Synergies between large-scale environmental changes, such as climate change1 and increased humic content (brownification)2, will have a considerable impact on future aquatic ecosystems. On the basis of modelling, monitoring and experimental data, we demonstrate that community responses to global change are determined by food-chain length and that the top trophic level, and every second level below, will benefit from climate change, whereas the levels in between will suffer. Hence, phytoplankton, and thereby algal blooms, will benefit from climate change in three-, but not in two-trophic-level systems. Moreover, we show that both phytoplankton (resource) and zooplankton (consumer) advance their spring peak abundances similarly in response to a 3 °C temperature increase; that is, there is no support for a consumer/resource mismatch in a future climate scenario. However, in contrast to other taxa, cyanobacteria—known as toxin-producing nuisance phytoplankton3—benefit from a higher temperature and humic content irrespective of the food-chain composition. Our results are mirrored in natural ecosystems. By mechanistically merging present food-chain theory with large-scale environmental and climate changes, we provide a powerful framework for predicting and understanding future aquatic ecosystems and their provision of ecosystem services and water resources.
|
|
| 4. |
- Malmgren, Linnea, et al.
(författare)
-
The complexity of kidney disease and diagnosing it - Cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.
- 2023
-
Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 293:3, s. 293-308
-
Tidskriftsartikel (refereegranskat)abstract
- Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous GFR-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterised by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules < 1kDa dominating the glomerular filtrate e.g., water, urea, creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterised by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.
|
|
| 5. |
- Rydén, Patrik, 1969-, et al.
(författare)
-
Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence
- 2012
-
Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 205:2, s. 297-304
-
Tidskriftsartikel (refereegranskat)abstract
- Background. We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data.Methods. A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden.Results. Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks.Conclusions. This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.
|
|
| 6. |
- Barbu, Mikael, et al.
(författare)
-
Dextran- versus crystalloid-based prime in cardiac surgery: A prospective randomized pilot study.
- 2020
-
Ingår i: The Annals of thoracic surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 110:5, s. 1541-7
-
Tidskriftsartikel (refereegranskat)abstract
- The optimum priming fluid for the cardiopulmonary bypass (CPB) circuit is still debated. We compared a new hyperoncotic priming solution containing dextran 40, which has an electrolyte composition that mimics extracellular fluid, with a standard crystalloid-based prime.Eighty cardiac surgery patients were included in this double-blind randomized single-centre study. The patients were randomized to either a dextran-based prime or a crystalloid prime containing Ringer acetate and mannitol. The primary endpoint was colloid oncotic pressure (COP) in serum during CPB. Secondary endpoints included fluid balance, bleeding and transfusion requirements, pulmonary function, hemolysis, systemic inflammation, and markers of renal, hepatic, myocardial, and brain injury. Blood samples were collected before, during, and after CPB.COP was higher in the dextran group than in the crystalloid prime group on CPB (18.8±2.9 vs. 16.4±2.9 mmHg, p<0.001) and 10 min after CPB (19.2±2.7 vs. 16.8±2.9 mmHg, p<0.001). Patients in the dextran group required less intravenous fluid during CPB (1090±499 vs. 1437±543 ml; p=0.003) and net fluid balance was less positive 12h after surgery (+1,431±741 vs. +1,901±922 ml; p=0.014). Plasma free hemoglobin was significantly lower in the dextran group 2h after CPB (0.18±0.11 vs 0.41±0.33, p=0.001). There were no significant differences in bleeding, transfusion requirements, organ function, systemic inflammation, or brain and myocardial injury markers between the groups at any time point.Our results suggest that a hyperoncotic dextran-based priming solution preserves intraoperative COP compared to crystalloid prime. Larger studies with clinically valid endpoints are necessary to evaluate hyperoncotic prime solutions further.
|
|
| 7. |
- Bjartell, Anders, et al.
(författare)
-
Production of alpha-1-antichymotrypsin by PSA-containing cells of human prostate epithelium
- 1993
-
Ingår i: Urology. - 1527-9995. ; 42:5, s. 502-510
-
Tidskriftsartikel (refereegranskat)abstract
- Prostate-specific antigen (PSA) is a chymotrypsin-like serine protease exclusively produced by the prostate epithelium, and abundant in seminal fluid. In serum, PSA is predominantly complexed to a liver-derived serine protease inhibitor, alpha-1-antichymotrypsin (ACT). A higher proportion of serum PSA is complexed to ACT in prostate cancer than in benign prostate hyperplasia. Since the molecular basis for this is unclear, we have investigated whether or not ACT may be produced in the prostate gland. Immunocytochemistry, using either monoclonal or polyclonal IgGs, demonstrated specific immunostaining for ACT in normal PSA-containing prostate epithelium. Production of ACT in the normal PSA-producing prostate epithelium was demonstrated by means of nonradioactive in situ hybridization using 30-mer anti-sense DNA probes for ACT and for PSA. The ACT and PSA coding transcripts, as detected by in situ hybridization, were distributed perinuclearly, in contrast to the specific immunostaining for ACT and PSA which was most intense in the apical portion of the secretory cells. The results strongly suggest local production and release of ACT by the normal prostate epithelium that may be important for interaction between PSA and ACT in extracellular compartments.
|
|
| 8. |
- Björk, Anders, et al.
(författare)
-
Applied Real-Time Acoustic Chemometrics for Measurements of Canadian Standard Freeness
- 2005
-
Ingår i: Paperi ja puu. - 0031-1243. ; 87:7, s. 452-457
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper we present a method for measuring Canadian Standard Freeness (CSF) on-line in real-time using acoustic measurements. The method can be used to present a new CSF value every second. The higher measurement rate and the reduced time-delay compared to conventional pulp sensors make it a suitable tool for improved refiner control. The method was developed during full-scale trials on two separate Sunds Defibrator double disc refiners at SCA Ortviken, Sweden. Acoustic measurements were performed using an accelerometer affixed to the refiner blow line. Trial conditions have been varied over a wide range of pulp quality and disturbances in the vibration signal. CSF was for example varied in the range 62-453 ml and refiner-housing pressure was varied from 0,35 to 0,39 MPa. The vibration signals collected during I second were treated to yield power spectra that were used for all further work. A median spectrum was calculated for each experimental point and these spectra were combined with reference values for freeness to make up the calibration matrices. The spectra were pre-treated using Orthogonal Signal Correction (OSC) and Subsequently Partial Least Squares Regression (PLSR) was used to build models between spectra and freeness. For model validation leave-one-out cross validation has been used. Over the range 90-250 ml we can predict CSF from median power spectra with a Root Mean Square Error of Prediction (RMSEP) of 23 ml. Over the larger CSF range of 62-453 mt the RMSEP deteriorates to 39 mt. Data from two separate trials on different refiners and from different seasons were included in these models.
|
|
| 9. |
- Björk, Jonas, et al.
(författare)
-
A novel method for creatinine adjustment makes the revised Lund-Malmö GFR estimating equation applicable in children
- 2020
-
Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 80:6, s. 456-463
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2-40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund-Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P30) of mGFR. Remarkable improvements in bias and accuracy were observed; P30 increased from 56% to 74% after creatinine adjustments in children with mGFR <75 mL/min/1.73 m2 (n = 932), while P30 was relatively unchanged (89-90%) at mGFR ≥75 mL/min/1.73 m2 (n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.
|
|
| 10. |
- Björk, Jonas, et al.
(författare)
-
Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays: a cross-sectional study in Sweden
- 2015
-
Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 53:3, s. 403-414
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The recently established international cystatin C calibrator makes it possible to develop non-laboratory specific glomerular filtration rate (GFR) estimating (eGFR) equations. This study compares the performance of the arithmetic mean of the revised Lund-Malmo creatinine and CAPA cystatin C equations (MEAN(LM-REV+CAPA)), the arithmetic mean of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine and cystatin C equations (MEAN(CKD-EPI)), and the composite CKD-EPI equation (CKD-EPICREA+CYSC) with the corresponding single marker equations using internationally standardized calibrators for both cystatin C and creatinine. Methods: The study included 1200 examinations in 1112 adult Swedish patients referred for measurement of GFR (mGFR) 2008-2010 by plasma clearance of iohexol (median 51 mL/min/1.73 m(2)). Bias, precision (interquartile range, IQR) and accuracy (percentage of estimates +/- 30% of mGFR; P-30) were compared. Results: Combined marker equations were unbiased and had higher precision and accuracy than single marker equations. Overall results of MEAN(LM-REV+CAPA)/MEAN(CKD-EPI)/CKD-EPICREA+CYSC were: median bias -2.2%/-0.5%/-1.6%, IQR 9.2/9.2/8.8 mL/min/1.73 m(2), and P-30 91.3%/91.0%/91.1%. The P-30 figures were about 7-14 -percentage points higher than the single marker equations. The combined equations also had a more stable performance across mGFR, age and BMI intervals, generally with P-30 >= 90% and never <80%. Combined equations reached P-30 of 95% when the difference between eGFR(CREA) and eGFR(CYSC) was <10% but decreased to 82% at a difference of >= 40%. Conclusions: Combining cystatin C and creatinine assays improves GFR estimations with P-30 >= 90% in adults. Reporting estimates of both single and combined marker equations in clinical settings makes it possible to assess the validity of the combined equation based on the agreement between the single marker equations.
|
|
