| 11. |
- Fridriksson, Jon Örn, et al.
(författare)
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Long-term adverse effects after retropubic and robot-assisted radical prostatectomy : Nationwide, population-based study
- 2017
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Ingår i: Journal of Surgical Oncology. - : Wiley. - 0022-4790 .- 1096-9098. ; 116:4, s. 500-506
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: Surgery for prostate cancer is associated with adverse effects. We studied long-term risk of adverse effects after retropubic (RRP) and robot-assisted radical prostatectomy (RARP).Methods: In the National Prostate Cancer Register of Sweden, men who had undergone radical prostatectomy (RP) between 2004 and 2014 were identified. Diagnoses and procedures indicating adverse postoperative effects were retrieved from the National Patient Register. Relative risk (RR) of adverse effects after RARP versus RRP was calculated in multivariable analyses adjusting for year of surgery, hospital surgical volume, T stage, Gleason grade, PSA level at diagnosis, patient age, comorbidity, and educational level.Results: A total of 11 212 men underwent RRP and 8500 RARP. Risk of anastomotic stricture was lower after RARP than RRP, RR for diagnoses 0.51 (95%CI = 0.42-0.63) and RR for procedures 0.46 (95%CI = 0.38-0.55). Risk of inguinal hernia was similar after RARP and RRP but risk of incisional hernia was higher after RARP, RR for diagnoses 1.48 (95%CI = 1.01-2.16), and RR for procedures 1.52 (95%CI = 1.02-2.26).Conclusions: The postoperative risk profile for RARP and RRP was quite similar. However, risk of anastomotic stricture was lower and risk of incisional hernia higher after RARP.
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| 12. |
- Friðriksson, Jón Örn, et al.
(författare)
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Rehospitalization after radical prostatectomy in a nationwide, population-based study
- 2014
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 192:1, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate readmission frequencies during the 90 days following radical prostatectomy and to assess readmission risk associated with potentially related variables.MATERIALS AND METHODS: Using the population-based, nationwide database Prostate Cancer data Base Sweden (PCBaSe), we identified men diagnosed with incident prostate cancer between 2000 and 2011 who underwent radical prostatectomy (RP) as their primary treatment, and we used logistic regression analysis to examine the association of the risk of 90-day postoperative readmission with surgical method, calendar period, tumor risk category, hospital case load, and patient characteristics.RESULTS: During the 90 postoperative days, 2,317 (10%) of the 24,122 men identified were non-electively readmitted, specifically 10% after retropubic radical prostatectomy (RRP), 9% after robot-assisted RP (RALP) and 11% after laparoscopic RP (LRP). The range in the readmission frequency between hospitals was 0-35%. A higher risk of readmission was associated with early calendar period (2009-2011 vs. 2000-2002: odds ratio (OR), 0.71; 95% confidence interval (CI), 0.61-0.83), greater age (≥70 years vs. <60 years: OR, 1.17; 95% CI, 1.00-1.36), higher risk category (high vs. low-risk category: OR, 1.78; 95% CI, 1.57-2.03), high comorbidity (Charlson comorbidity index ≥3 vs. 0: OR, 1.77; 95% CI, 1.29-2.44), and low hospital surgical volume (≥150 vs. <30 RPs per year: OR, 0.70; 95% CI, 0.60-0.81).CONCLUSIONS: Readmission rates after different RP methods were similar, ranging from 9% to 11%, with a wide variation between hospitals. Readmission rates can be used as an indicator of perioperative care quality, but potential confounders need to be adjusted to avoid bias.
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| 13. |
- Frisk, Junmei Hu, et al.
(författare)
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Differential expression of enzymes in thymidylate biosynthesis in zebrafish at different developmental stages : implications for dtymk mutation-caused neurodegenerative disorders
- 2022
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Ingår i: BMC Neuroscience. - : Springer Nature. - 1471-2202. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDeoxythymidine triphosphate (dTTP) is an essential building block of DNA, and defects in enzymes involved in dTTP synthesis cause neurodegenerative disorders. For instance, mutations in DTYMK, the gene coding for thymidylate kinase (TMPK), cause severe microcephaly in human. However, the mechanism behind this is not well-understood. Here we used the zebrafish model and studied (i) TMPK, an enzyme required for both the de novo and the salvage pathways of dTTP synthesis, and (ii) thymidine kinases (TK) of the salvage pathway in order to understand their role in neuropathology.ResultsOur findings reveal that maternal-stored dNTPs are only sufficient for 6 cell division cycles, and the levels of dNTPs are inversely correlated to cell cycle length during early embryogenesis. TMPK and TK activities are prominent in the cytosol of embryos, larvae and adult fish and brain contains the highest TMPK activity. During early development, TMPK activity increased gradually from 6 hpf and a profound increase was observed at 72 hpf, and TMPK activity reached its maximal level at 96 hpf, and remained at high level until 144 hpf. The expression of dtymk encoded Dtymk protein correlated to its mRNA expression and neuronal development but not to the TMPK activity detected. However, despite the high TMPK activity detected at later stages of development, the Dtymk protein was undetectable. Furthermore, the TMPK enzyme detected at later stages showed similar biochemical properties as the Dtymk enzyme but was not recognized by the Dtymk specific antibody.ConclusionsOur results suggest that active dNTP synthesis in early embryogenesis is vital and that Dtymk is essential for neurodevelopment, which is supported by a recent study of dtymk knockout zebrafish with neurological disorder and lethal outcomes. Furthermore, there is a novel TMPK-like enzyme expressed at later stages of development.
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| 14. |
- Fu, Le, et al.
(författare)
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Biodegradable Si3N4 bioceramic sintered with Sr, Mg and Si for spinal fusion : Surface characterization and biological evaluation
- 2018
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Ingår i: Applied Materials Today. - : Elsevier BV. - 2352-9407. ; 12, s. 260-275
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Tidskriftsartikel (refereegranskat)abstract
- Silicon nitride (Si3N4) is an industrial ceramic used in spinal fusion and maxillofacial reconstructionbecause of its excellent mechanical properties and good biocompatibility. This study compares the sur-face properties, apatite formation ability, bacterial infection, cell-biomaterial interactions, and in vivotoxicity (zebrafish) of newly developed Si3N4 bioceramics (sintered with bioactive sintering additivesSrO, MgO and SiO2) with two standard biomaterials; titanium (Ti) and traditional Si3N4 bioceramics (sin-tered with standard sintering additives Al2O3 and Y2O3). In general, Si3N4 bioceramics (both the newlydeveloped and the traditional) displayed less in vitro bacterial affinity than Ti, which may arise fromdifferences in the surface properties between these two types of material. The newly developed Si3N4bioceramics developed lower biofilm coverage and thinner biofilm, compared to traditional Si3N4 bioce-ramics. The effects of ionic dissolution products (leach) on proliferation and differentiation of MC3T3-E1cell were also investigated. Ionic dissolution products containing moderate amount of Sr, Mg and Siions (approximately 4.72 mg/L, 3.26 mg/L and 3.67 mg/L, respectively) stimulated osteoblast prolifera-tion during the first 2 days in culture. Interestingly, ionic dissolution products from the traditional Si3N4bioceramics that contained small amount of Si and Y ions achieved the greatest stimulatory effect foralkaline phosphatase activity after 7 days culture. The toxicity of ionic dissolution products was investi-gated in a putative developmental biology model: zebrafish (Danio rerio). No toxicity, or developmentalabnormalities, was observed in zebrafish embryos exposed to ionic dissolution products, for up to 144 hpost fertilization. These newly developed Si3N4 bioceramics with bioactive sintering additives show greatpotential as orthopedic implants, for applications such as spinal fusion cages. Future work will focus onevaluation of the newly developed Si3N4 bioceramics using a large animal model.
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| 15. |
- Golosovskaia, Elena, 1993-
(författare)
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Development of in silico methods to aid chemical risk assessment : focusing on kinetic interactions in mixtures
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The environment and biota are constantly exposed to numerous chemicals through contaminated food, soil, water, and air. These chemicals can be taken up and distributed to reach sensitive tissues where they may cause various effects. Many of these chemicals lack data on their environmental and human health effects. Traditional toxicological tests relying on animal experiments are today being phased out in favor of cell-based and computational methods for early hazard detection and exposure assessment. This thesis focuses on developing computational tools for various stages of chemical risk assessment with a particular focus on bisphenols and per- and polyfluoroalkyl substances (PFAS). In Paper I, quantitative structure-activity relationship (QSAR) models covering molecular targets of the thyroid hormone (TH) system were developed and applied to two data sets to prioritize chemicals of concern for detailed toxicological studies. In Papers II and III, experimental and computational approaches were combined to study toxicokinetics and maternal transfer in zebrafish. Our main focus was to study potential mixture effects on administration, distribution, metabolism, and elimination (ADME) processes, i.e., to reveal if co-exposed chemicals impact each other’s ADME. Physiologically based kinetic (PBK) mixture models were developed to allow translation of external exposure concentrations into tissue concentrations and modelling plausible mechanisms of chemical interactions in a mixture.Main findings of this thesis are summarized as follows:• Application of QSAR models (Paper I) to two chemical inventories revealed that chemicals found in human blood could induce a large iirange of pathways in the TH system whereas chemicals used in Sweden with predicted high exposure index to consumers showed a lower likelihood to induce TH pathways.• Two zebrafish experiments (Paper II and Paper III) did not reveal statistically significant mixture effects on ADME of chemicals.• In Paper II, a PBK mixture model for PFAS accounting for competitive plasma protein binding was developed. The model demonstrated good predictive performance. Competitive plasma protein binding did not affect the predicted internal concentrations.• In Paper III we developed a binary PBK model parametrized for two bisphenols and PFOS showing that competitive plasma protein binding has an effect on ADME of bisphenols at PFOS concentrations at μg/L levels. At these levels internal concentrations of bisphenols were shown to decrease, implying that PFOS outcompeted bisphenols from studied plasma proteins resulting in higher excretion rates.Developed QSAR models showed good predictive power and the ability to identify and prioritize chemicals of concern with confidence. Additionally, PBK models aid in hypotheses testing and predicting exposure concentrations at which co-exposed chemicals could potentially influence each other’s ADME properties. These tools will provide overall early tier data on exposure and effects using non-testing methods in assessment of risks of chemicals.
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| 16. |
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| 17. |
- Golosovskaia, Elena, 1993-, et al.
(författare)
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Studying mixture effects on uptake and tissue distribution of PFAS in zebrafish (Danio rerio) using physiologically based kinetic (PBK) modelling
- 2024
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 912
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Tidskriftsartikel (refereegranskat)abstract
- Per- and polyfluoroalkyl substances (PFAS) are ubiquitously distributed in the aquatic environment. They include persistent, mobile, bioaccumulative, and toxic chemicals and it is therefore critical to increase our understanding on their adsorption, distribution, metabolism, excretion (ADME). The current study focused on uptake of seven emerging PFAS in zebrafish (Danio rerio) and their potential maternal transfer. In addition, we aimed at increasing our understanding on mixture effects on ADME by developing a physiologically based kinetic (PBK) model capable of handling co-exposure scenarios of any number of chemicals. All studied chemicals were taken up in the fish to varying degrees, whereas only perfluorononanoate (PFNA) and perfluorooctanoate (PFOA) were quantified in all analysed tissues. Perfluorooctane sulfonamide (FOSA) was measured at concerningly high concentrations in the brain (Cmax over 15 μg/g) but also in the liver and ovaries. All studied PFAS were maternally transferred to the eggs, with FOSA and 6:2 perfluorooctane sulfonate (6,2 FTSA) showing significant (p < 0.02) signs of elimination from the embryos during the first 6 days of development, while perfluorobutane sulfonate (PFBS), PFNA, and perfluorohexane sulfonate (PFHxS) were not eliminated in embryos during this time-frame. The mixture PBK model resulted in >85 % of predictions within a 10-fold error and 60 % of predictions within a 3-fold error. At studied levels of PFAS exposure, competitive binding was not a critical factor for PFAS kinetics. Gill surface pH influenced uptake for some carboxylates but not the sulfonates. The developed PBK model provides an important tool in understanding kinetics under complex mixture scenarios and this use of New Approach Methodologies (NAMs) is critical in future risk assessment of chemicals and early warning systems.
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| 18. |
- Golovko, Oksana, et al.
(författare)
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Assessing the cumulative pressure of micropollutants in Swedish wastewater effluents and recipient water systems using integrated toxicological and chemical methods
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- In recent decades, a substantial amount of work has been conducted to determine the occurrence, fate, and effects of organic micropollutants (OMPs) in aquatic environments. Incomplete removal of OMPs by conventional wastewater treatment plants (WWTPs) has been observed, and OMPs have been detected in surface water worldwide. In this study, WWTP influent, effluent, and sludge, and upstream and downstream waters in WWTP recipients, were analyzed for a total of 225 OMPs, including pharmaceuticals, hormones, personal care products, industrial chemicals, PFASs, and pesticides. The OMPs were selected based on annual usage in a wide range of household products and concerns about possible effects on humans and aquatic organisms. In addition, 11 different types of toxicity bioassays and fish embryo toxicity tests were applied to WWTP influent and effluent, and upstream and downstream waters in WWTP recipients.A total of 158 contaminants were detected in at least one sample, in mean concentrations ranging from ng/L to mg/L in wastewater samples and from ng/L to μg/L in surface water samples. Two industrial chemicals (tetraethyleneglycol, laureth-5 and di-(2-ethylhexyl)phosphoric acid), 15 pharmaceuticals (salicylic acid, diclofenac, losartan, valsartan, venlafaxine, oxazepam, lamotrigine, carbamazepine, tramadol, hydrochlorothiazide, theophyline, furosemide, ranitidine, bicalutamide, and metformin), and the stimulants caffeine and nicotine were responsible for 70% of the combined concentration of pollutants in WWTP influent and effluent, and in surface water. Of the 225 target OMPs, 104 were detected in sludge samples. Analysis of sludge revealed large variations in concentrations between individual WWTPs, which can be explained by differences in OMP composition in influent water and in operating conditions at WWTPs.In vitro toxicity testing showed relatively high activities for the studied endpoints in influent waters. The removal efficiency in WWTPs varied between endpoint and plant. For estrogenic and androgenic activities, the removal efficiency was consistently high (97-99%). For AhR activity and oxidative stress, the removal efficiency ranged from 60 to 99% in different WWTPs.The results revealed that the high concentrations of OMPs in WWTPs and sludge are introduced to aquatic environments. However, there is limited information about the removal mechanisms of OMPs in WWTPs. Advanced technologies, namely membrane filtration, carbon adsorption, and AOPs (advanced oxidative processes), are now being widely adopted for OMPs removal, but the performance and cost of different unit processes vary by case. Therefore, the influence of treatment performance and process stability in WWTPs on reducing the effects and concentrations of OMPs should be evaluated. The results could provide a theoretical basis for optimization of existing treatment systems of different designs, and could contribute significantly to protecting recipient waters.
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| 19. |
- Golovko, Oksana, et al.
(författare)
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Occurrence and removal of chemicals of emerging concern in wastewater treatment plants and their impact on receiving water systems
- 2021
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 754
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Tidskriftsartikel (refereegranskat)abstract
- Wastewater treatment plants (WWTPs) are considered the main sources of chemicals of emerging concern (CECs) in aquatic environments, and can negatively impact aquatic ecosystems. In this study, WWTP influent, effluent, and sludge, and upstream and downstream waters from the WWTP recipient were investigated at 15 locations for a total of 164 CECs, including pharmaceuticals, personal care products, industrial chemicals, per- and polyfluoroalkyl substances (PFASs), and pesticides. In addition, zebrafish (Dania rerio) embryo toxicity tests (ZFET) were applied to WWTP influent and effluent, and upstream and downstream waters from WWTP recipients. A total of 119 CECs were detected in at least one sample, mean concentrations ranging from 0.11 ng/L (propylparaben) to 64,000 ng/L (caffeine), in wastewater samples and from 0.44 ng/L (ciprofloxacin) to 19,000 ng/L (metformin) in surface water samples. Large variations of CEC concentrations were found between the selected WWTPs, which can be explained by differences in CEC composition in influent water and WWTP treatment process. The sludge-water partitioning coefficient (K-d) of CECs showed a significant linear con-elation to octanol/warer partition coefficient (K-ow) (p < 0.001), and thus could be used for predicting their fare in the aqueous and solid phase. The Sigma CEC concentrations in WWTPs declined by on average 60%, based on comparisons of WWTP influent and effluent concentrations. The high concentrations of CECs in WWTP effluent resulted in, on average, 50% higher concentrations of CECs in water downstream of WWTPs compared with upstream. Some WWTP samples showed toxicity in ZFET compared with the respective control group, but no individual CECs or groups of CECs could explain this toxicity. These results could provide a theoretical basis for optimization of existing treatment systems of different designs, and could significantly contribute to protecting recipient waters. (C) 2020 The Authors. Published by Elsevier B.V.
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| 20. |
- Hallberg, Ida, et al.
(författare)
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Perfluorononanoic acid (PFNA) alters lipid accumulation in bovine blastocysts after oocyte exposure during in vitro maturation
- 2019
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 84, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids present in human tissues. In this study, effects on early embryo development after PFNA exposure were investigated using the bovine in vitro production system. Oocytes were exposed to PFNA during maturation in vitro (10 μg mL-1 and 0.1 μg mL-1), and then fertilized and cultured in parallel with control groups. Developmental parameters (cleavage, blastocyst formation) were followed and embryo quality evaluated (stage, grade). Embryos developed after exposure to 0.1 μg mL-1 were stained to distinguish nuclei, active mitochondria and neutral lipids. 10 μg mL-1 of PFNA had a severe negative effect on blastocyst formation (OR: 0.27 p < 0.05), an effect not observed at 0.1 μg mL-1. However, lipid droplet distribution was significantly altered in embryos exposed to 0.1 μg mL-1, suggesting a disturbance of lipid metabolism after exposure to sublethal levels of PFNA during oocyte maturation in vitro.
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