| 1. |
- Ostergaard, Henrik, et al.
(författare)
-
Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide
- 2011
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:8, s. 2333-2341
-
Tidskriftsartikel (refereegranskat)abstract
- Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341)
|
|
| 2. |
- Sondergaard, Mads T., et al.
(författare)
-
Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes
- 2015
-
Ingår i: The FEBS Journal. - : Wiley. - 1742-464X. ; 282:4, s. 803-816
-
Tidskriftsartikel (refereegranskat)abstract
- Calmodulin (CaM) is the central mediator of intracellular Ca2+ signalling in cardiomyocytes, where it conveys the intricate Ca2+ transients to the proteins controlling cardiac contraction. We recently linked two separate mutations in CaM (N53I and N97S) to dominantly inherited catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmic disorder in which exercise or acute emotion can lead to syncope and sudden cardiac death. Given the ubiquitous presence of CaM in all eukaryote cells, it is particular intriguing that carriers of either mutation show no additional symptoms. Here, we investigated the effects of the CaM CPVT mutations in a zebrafish animal model. Three-day-old embryos injected with either CaM mRNA showed no detectable pathologies or developmental abnormalities. However, embryos injected with CPVT CaM mRNA displayed increased heart rate compared to wild-type CaM mRNA under -adrenergic stimulation, demonstrating a conserved dominant cardiac specific effect between zebrafish and human carriers of these mutations. Motivated by the highly similar physiological phenotypes, we compared the effects of the N53I and N97S mutations on the biophysical and functional properties of CaM. Surprisingly, the mutations have opposing effects on CaM C-lobe Ca2+ binding affinity and kinetics, and changes to the CaM N-lobe Ca2+ binding are minor and specific to the N53I mutation. Furthermore, both mutations induce differential perturbations to structure and stability towards unfolding. Our results suggest different molecular disease mechanisms for the CPVT (N53I and N97S mutations) and strongly support that cardiac contraction is the physiological process most sensitive to CaM integrity.
|
|
| 3. |
- Beelen, Rob, et al.
(författare)
-
Natural-Cause Mortality and Long-Term Exposure to Particle Components : An Analysis of 19 European Cohorts within the Multi-Center ESCAPE Project
- 2015
-
Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 525-533
-
Forskningsöversikt (refereegranskat)abstract
- Background: Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality. Objectives: Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter. Methods: Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori-selected components of particulate matter ( PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions <= 2.5 mu m (PM2.5) and <= 10 mu m (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis. Results: The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200ng/m(3)). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced. Conclusions: Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5.
|
|
| 4. |
- Bekoe, Samuel Oppong, et al.
(författare)
-
Detection and quantification of antibiotic residues in urine samples of healthy individuals from rural and urban communities in Ghana using a validated SPE-LC-MS/MS method
- 2020
-
Ingår i: SN APPLIED SCIENCES. - 2523-3963. ; 2:11
-
Tidskriftsartikel (refereegranskat)abstract
- The role of unregulated and inappropriate dispensing, and use of antibiotics remains significant in the development of antimicrobial resistance in infectious disease endemic regions of developing countries. The exposure to antibiotics from unfamiliar and unsuspecting sources such as drinking water and food, and adulterated herbal medicines remains a cause for concern. A sensitive SPE-LC-MS/MS method was developed and validated for the quantification and qualification of 12 antibiotics, including amoxicillin, clavulanic acid, metronidazole, ampicillin, cefuroxime, tetracycline, ceftriaxone, sulphamethoxazole, trimethoprim, ciprofloxacin, benzylpenicillin, and erythromycin, in the urine of healthy volunteers. The method was linear (r(2) > 0.98) within the concentration range 50-5000 ngmL(-1) for all the analytes. Instrument precision of 8-27% and 4-21% at 100 and 1000 ngmL(-1) levels were demonstrated. High mean recoveries between 71 and 125% with minimal variations were obtained for all compounds in the accuracy study. Limits of detection and quantification ranged between 70.3-271.0 ngmL(-1) and 213-821 ngmL(-1) respectively. The validated method successfully detected and quantified 9 of the 12 analytes, with the exception of clavulanic acid, cefuroxime, and benzylpenicillin. Most of the samples contained one analyte (52, 86.7%), with a handful containing two (7, 11.7%) and three analytes (1, 1.7%). Ciprofloxacin was the modal analyte detected (17, 24.6%), with amoxicillin and trimethoprim recording the average lowest (22.76 x 10(3) ngmL(-1)) and highest concentrations (255.47 x 10(3) ngmL(-1)) respectively. The developed method is a useful tool for non-invasive monitoring of consumption and the irrational use of antibiotics in microbial resistant-prone regions of the world.
|
|
| 5. |
- Bekoe, Samuel Oppong, et al.
(författare)
-
Detection and quantification of antibiotic residues in urine samples of healthy individuals from rural and urban communities in Ghana using a validated SPE-LC-MS/MS method
- 2020
-
Ingår i: SN APPLIED SCIENCES. - : Springer Science and Business Media LLC. - 2523-3963 .- 2523-3971. ; 2:11
-
Tidskriftsartikel (refereegranskat)abstract
- The role of unregulated and inappropriate dispensing, and use of antibiotics remains significant in the development of antimicrobial resistance in infectious disease endemic regions of developing countries. The exposure to antibiotics from unfamiliar and unsuspecting sources such as drinking water and food, and adulterated herbal medicines remains a cause for concern. A sensitive SPE-LC-MS/MS method was developed and validated for the quantification and qualification of 12 antibiotics, including amoxicillin, clavulanic acid, metronidazole, ampicillin, cefuroxime, tetracycline, ceftriaxone, sulphamethoxazole, trimethoprim, ciprofloxacin, benzylpenicillin, and erythromycin, in the urine of healthy volunteers. The method was linear (r(2) > 0.98) within the concentration range 50-5000 ngmL(-1) for all the analytes. Instrument precision of 8-27% and 4-21% at 100 and 1000 ngmL(-1) levels were demonstrated. High mean recoveries between 71 and 125% with minimal variations were obtained for all compounds in the accuracy study. Limits of detection and quantification ranged between 70.3-271.0 ngmL(-1) and 213-821 ngmL(-1) respectively. The validated method successfully detected and quantified 9 of the 12 analytes, with the exception of clavulanic acid, cefuroxime, and benzylpenicillin. Most of the samples contained one analyte (52, 86.7%), with a handful containing two (7, 11.7%) and three analytes (1, 1.7%). Ciprofloxacin was the modal analyte detected (17, 24.6%), with amoxicillin and trimethoprim recording the average lowest (22.76 x 10(3) ngmL(-1)) and highest concentrations (255.47 x 10(3) ngmL(-1)) respectively. The developed method is a useful tool for non-invasive monitoring of consumption and the irrational use of antibiotics in microbial resistant-prone regions of the world.
|
|
| 6. |
- Bjerregaard, Bine Kjoller, et al.
(författare)
-
Tobacco smoke and bladder cancer-in the European prospective investigation into cancer and nutrition
- 2006
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 119:10, s. 2412-2416
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to investigate the association between smoking and the development of bladder cancer. The study population consisted of 429,906 persons participating in the European Prospective Investigation into Cancer and Nutrition (EPIC), 633 of whom developed bladder cancer during the follow-up period. An increased risk of bladder cancer was found for both current- (incidence rate ratio 3.96, 95% confidence interval: 3.07-5.09) and ex- (2.25, 1.74-2.91) smokers, compared to never-smokers. A positive association with intensity (per 5 cigarettes) was found among current-smokers (1.18, 1.09-1.28). Associations (per 5 years) were observed for duration (1.14, 1.08-1.21), later age at start (0.75, 0.66-0.85) and longer time since quitting (0.92, 0.86-0.98). Exposure to environmental tobacco smoke (ETS) during childhood increased the risk of bladder cancer (1.38, 1.00-1.90), whereas for ETS exposure as adult no effect was detected. The present study confirms the strong association between smoking and bladder cancer. The indication of a higher risk of bladder cancer for those who start smoking at a young age and for those exposed to ETS during childhood adds to the body of evidence suggesting that children are more sensitive to carcinogens than adults. (c) 2006 Wiley-Liss, Inc.
|
|
| 7. |
- Fuks, Kateryna B., et al.
(författare)
-
Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE)
- 2017
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:13, s. 983-990
-
Tidskriftsartikel (refereegranskat)abstract
- Aims We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter <= 2.5 mu m (PM2.5), <= 10 mu m (PM10), >2.5, and <= 10 mu m (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP >= 140mmHg or diastolic BP >= 90mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI): 1.08; 1.37] per 5 mu g/m(3)) and PM2.5 absorbance (RR 1.13 [95% CI: 1.02; 1.24] per 10(-5) m(-1)). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.
|
|
| 8. |
- Holmstrup, Martin, et al.
(författare)
-
Cold acclimation and lipid composition in the earthworm Dendrobaena octaedra
- 2007
-
Ingår i: Comparative Biochemistry and Physiology A. - : Elsevier BV. - 1531-4332. ; 147:4, s. 911-919
-
Tidskriftsartikel (refereegranskat)abstract
- We have investigated the lipid chemistry during cold acclimation in the freeze tolerant earthworm Dendrobaena octaedra. The dominant phospholipid fatty acids (PLFA) of D. octaedra were 20:4, 20:5 and 20:1 (50% of total PLFA) followed by 18:0, 18:1 and 18:2 omega 6,9 (25% of total PLFA). The ability to tolerate freezing in this species was acquired after acclimation at low temperature for 2-4 weeks. During this period one particular membrane PLFA, 18:2 omega 6,9, increased significantly and there was a good correlation between the proportion of this PLFA and the survival of freezing. The composition of neutral lipid fatty acids (NLFA), most likely representing storage lipids (triacylglycerides), also changed during cold acclimation so that the overall degree of unsaturation increased. Using a common-garden experiment approach, we compared lipid composition of three genetically different populations (Denmark, Finland and Greenland) that differed in their freeze tolerance. Inter-populational differences and differences due to cold acclimation in overall fatty acid composition were evident in both PLFAs and NLFAs. Specifically, the PLFAs, 20:4 and 20:5, were considerably more represented in worms from Greenland, and this contributed to a higher U1 of PLFAs in this population. (c) 2007 Elsevier Inc. All rights reserved.
|
|
| 9. |
- Li, Kefei, et al.
(författare)
-
Long-term field exposure of structural concretes in marine environment: state-of-the-art review by RILEM TC 289-DCM
- 2022
-
Ingår i: Materials and Structures/Materiaux et Constructions. - : Springer Science and Business Media LLC. - 1359-5997. ; 55:7
-
Tidskriftsartikel (refereegranskat)abstract
- This paper reviews the technical aspects related to the long-term field exposure practice in marine environments, based on the return of experiences of major marine exposure sites in world-wide scope. The long-term exposure practice helps both the research on durability mechanisms of structural concretes under real environments and the calibration of durability models to support the life-cycle management of concrete structures. The presentation of the field exposure data can be categorized into the information relevant to exposure sites, the data related to the exposed materials and specimens, the information of environmental actions, and the data related to the performance of materials. A standardized presentation of these data can help the efficiency of data sharing and exploitation. The exploitation of exposure data employs various models to represent the chloride ingress and the induced corrosion risk of the embedded steel bars. There are needs for models addressing the strong environment-material interactions, and simple yet reliable durability indicators for engineering use. The design and operation of exposure stations need the careful choice of exposure sites and specimens, the appropriate scheme for monitoring and inspection of exposed specimens, the systematic recording and management of exposure data, and the regular maintenance of exposure facilities. The support of exposure data for life-cycle management is demonstrated through the durability planning of a real project case. The good practice of long-term field exposure is summarized in the end.
|
|
| 10. |
- Matthiessen, Jeppe, et al.
(författare)
-
Reduction in pedometer-determined physical activity in the adult Danish population from 2007 to 2012
- 2015
-
Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 43:5, s. 525-533
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: To examine the development in pedometer-determined physical activity from 2007-2008 to 2011-2012 in the adult Danish population. Methods: The study population comprised two random samples of 18-75-year-old individuals who took part in cross-sectional studies in 2007-2008 (n=224) and 2011-2012 (n=1515). Pedometer data (sealed Yamax SW 200) were obtained for seven consecutive days. Data for 1624 participants (48.2% men) were included in the analysis. An overall step-defined activity level was examined based on a graduated step index (sedentary, low active, somewhat active, active, highly active). The pedometer-determined outcomes were analysed using regression models. Results: A borderline significant decline (p=0.077) from 8788 to 8341 steps/day (-446 (95% confidence intervals -50, 943)) was found between 2007-2008 and 2011-2012. Furthermore, a 23.7% (95% confidence intervals -41.7%, -0.1%) lower overall step-defined activity level was observed in 2011-2012 compared to 2007-2008. These changes were primarily due to a reduced level of activity among women. The proportion of individuals taking 10,000 steps/day decreased non-significantly from 34.8% to 29.3%, whereas the proportion taking <5000 steps/day did not differ between survey periods. Conclusions: This nationally representative survey suggests an overall reduction in the physical activity level among Danish adults. The reduction was due to a shift in the population distribution from higher to lower levels of activity. If this shift is true, it is worrying from a public health perspective. Our study result needs, however, to be confirmed by other population studies.
|
|
| 11. |
- Pedersen, Marie, et al.
(författare)
-
Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts
- 2018
-
Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 4:1, s. 113-120
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Ambient air pollution contains low concentrations of carcinogens implicated in the etiology of urinary bladder cancer (BC). Little is known about whether exposure to air pollution influences BC in the general population. Objective: To evaluate the association between long-term exposure to ambient air pollution and BC incidence. Design, setting and participants: We obtained data from 15 population-based cohorts enrolled between 1985 and 2005 in eight European countries (N = 303 431; mean follow-up 14.1 yr). We estimated exposure to nitrogen oxides (NO2 and NOx), particulate matter (PM) with diameter <10 mu m (PM10), <2.5 mu m (PM2.5). between 2.5 and 10 mu m (PM2.5-10). PM2.5 absorbance (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project. Outcome measurements and statistical analysis: We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and meta-analyses to estimate summary hazard ratios (HRS) for BC incidence. Results and limitations: During follow-up, 943 incident BC cases were diagnosed. In the meta-analysis, none of the exposures were associated with BC risk. The summary HRs associated with a 10-mu g/m(3) increase in NO2 and 51-mu g/m(3) increase in PM2.5 were 0.98 (95% confidence interval [CI] 0.89-1.08) and 0.86 (95% CI 0.63-1.18), respectively. Limitations include the lack of information about lifetime exposure. Conclusions: There was no evidence of an association between exposure to outdoor air pollution levels at place of residence and risk of BC. Patient summary: We assessed the link between outdoor air pollution at place of residence and bladder cancer using the largest study population to date and extensive assessment of exposure and comprehensive data on personal risk factors such as smoking. We found no association between the levels of outdoor air pollution at place of residence and bladder cancer risk.
|
|
| 12. |
- Sorensen, Annette, et al.
(författare)
-
Identifying and characterizing the most significant beta-glucosidase of the novel species Aspergillus saccharolyticus
- 2012
-
Ingår i: Canadian Journal of Microbiology. - 0008-4166. ; 58:9, s. 1035-1046
-
Tidskriftsartikel (refereegranskat)abstract
- The newly discovered fungal species Aspergillus saccharolyticus was found to produce a culture broth rich in beta-glucosidase activity. In this present work, the main beta-glucosidase of A. saccharolyticus responsible for the efficient hydrolytic activity was identified, isolated, and characterized. Ion exchange chromatography was used to fractionate the culture broth, yielding fractions with high beta-glucosidase activity and only 1 visible band on an SDS-PAGE gel. Mass spectrometry analysis of this band gave peptide matches to beta-glucosidases from aspergilli. Through a polymerase chain reaction approach using degenerate primers and genome walking, a 2919 bp sequence encoding the 860 amino acid BGL1 polypeptide was determined. BGL1 of A. saccharolyticus has 91% and 82% identity with BGL1 from Aspergillus aculeatus and BGL1 from Aspergillus niger, respectively, both belonging to Glycoside Hydrolase family 3. Homology modeling studies suggested beta-glucosidase activity with preserved retaining mechanism and a wider catalytic pocket compared with other beta-glucosidases. The bgl1 gene was heterologously expressed in Trichoderma reesei QM6a, purified, and characterized by enzyme kinetics studies. The enzyme can hydrolyze cellobiose, p-nitrophenyl-beta-D-glucoside, and cellodextrins. The enzyme showed good thermostability, was stable at 50 degrees C, and at 60 degrees C it had a half-life of approximately 6 h.
|
|
| 13. |
- Weinmayr, Gudrun, et al.
(författare)
-
Particulate matter air pollution components and incidence of cancers of the stomach and the upper aerodigestive tract in the European Study of Cohorts of Air Pollution Effects (ESCAPE)
- 2018
-
Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 120, s. 163-171
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Previous analysis from the large European multicentre ESCAPE study showed an association of ambient particulate matter < 2.5 mu m (PM2.5) air pollution exposure at residence with the incidence of gastric cancer. It is unclear which components of PM are most relevant for gastric and also upper aerodigestive tract (UADT) cancer and some of them may not be strongly correlated with PM mass. We evaluated the association between long-term exposure to elemental components of PM2.5 and PM10 and gastric and UADT cancer incidence in European adults.Methods: Baseline addresses of individuals were geocoded and exposure was assessed by land-use regression models for copper (Cu), iron (Fe) and zinc (Zn) representing non-tailpipe traffic emissions; sulphur (S) indicating long-range transport; nickel (Ni) and vanadium (V) for mixed oil-burning and industry; silicon (Si) for crustal material and potassium (K) for biomass burning. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses.Results: Ten cohorts in six countries contributed data on 227,044 individuals with an average follow-up of 14.9 years with 633 incident cases of gastric cancer and 763 of UADT cancer. The combined hazard ratio (HR) for an increase of 200 ng/m(3) of PM2.5_S was 1.92 (95%-confidence interval (95%-CI) 1.13; 3.27) for gastric cancer, with no indication of heterogeneity between cohorts (I-2= 0%), and 1.63 (95%-CI 0.88; 3.01) for PM2.5_Zn (I-2= 70%). For the other elements in PM2.5 and all elements in PM10 including PM10_S, non-significant HRs between 0.78 and 1.21 with mostly wide CIs were seen. No association was found between any of the elements and UADT cancer. The HR for PM2.5_S and gastric cancer was robust to adjustment for additional factors, including diet, and restriction to study participants with stable addresses over follow-up resulted in slightly higher effect estimates with a decrease in precision. In a two-pollutant model, the effect estimate for total PM2.5 decreased whereas that for PM2.5_S was robust.Conclusion: This large multicentre cohort study shows a robust association between gastric cancer and long-term exposure to PM2.5 S but not PM10 S, suggesting that S in PM2.5 or correlated air pollutants may contribute to the risk of gastric cancer.
|
|
