| 1. |
- Axelsson, Bengt, et al.
(författare)
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Båtbottenfärgers effektivitet och miljörisker
- 1989
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Tennbaserade båtbottenfärger har nyligen förbjudits. För att få en uppfattning om effektivitet och miljörisker med på marknaden förekommande alternativa färger har IVL genomfört en undersökning av dessa färger. Försöksmaterialet innefattade följande färgkategorier: konventionella kopparfärger, kopparpolymerfärger, färger med andra aktiva komponenter, färger utan aktiva komponenter samt tennbaserade färger (numera förbjudna). Färgerna testades med avseende på effektivitet och giftighet. Effektiviteten undersöktes genom att polystyrenplattor målades med respektive färg och placerades på fyra lokaler: insjö, Bottenhavet, Östersjön och västkusten. Påväxten kvantifierades, vilket låg till grund för bedömningen av färgernas effektivitet. Giftigheten undersöktes i laboratorium genom korttidsförsök på bakterier, Nitocra (kräftdjur) och andmat (flytbladsväxt).
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| 2. |
- Barth, Claudia, et al.
(författare)
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In vivo white matter microstructure in adolescents with early-onset psychosis : a multi-site mega-analysis
- 2023
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 28, s. 1159-1169
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age=16.6 years, interquartile range (IQR)=2.14, 46.4% females) and 265 adolescent healthy controls (median age=16.2 years, IQR=2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d=0.37), posterior corona radiata (d=0.32), and superior fronto-occipital fasciculus (d=0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.
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| 3. |
- Gisselsson Nord, David, et al.
(författare)
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Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas
- 2007
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Ingår i: Journal of Carcinogenesis. - : Medknow. - 0974-6773 .- 1477-3163. ; 6, s. 15-15
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. METHODS: We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. RESULTS: Tumours clustered in four sub-groups, dominated respectively by (1) gene amplification in double minute chromosomes and few other aberrations, (2) gene amplification and loss of 1p sequences, (3) loss of 1p and other structural aberrations including gain of 17q, and (4) whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1-3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. CONCLUSION: The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.
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| 4. |
- Ivanov Öfverholm, Ingegerd, et al.
(författare)
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Detailed gene dose analysis reveals recurrent focal gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia
- 2016
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Ingår i: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 57:9, s. 2161-2170
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Tidskriftsartikel (refereegranskat)abstract
- To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p
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| 5. |
- Lundberg, Gisela, et al.
(författare)
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Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas.
- 2011
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 50:4, s. 250-62
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Tidskriftsartikel (refereegranskat)abstract
- Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.
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| 6. |
- Lundberg, Gisela, et al.
(författare)
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Binomial mitotic segregation of MYCN-carrying double minutes in neuroblastoma illustrates the role of randomness in oncogene amplification.
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection.
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| 7. |
- Lundberg, Gisela
(författare)
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Chromosome dynamics and genomic instablity in neuroblastoma. Three genomic pillars: MYCN amplification, numerical and structural changes.
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, the main focus has been on the childhood cancer neuroblastoma, one of the most common and lethal childhood tumours. Neuroblastoma has througout the years continued to be a clinical and biological enigma. Our first focus was on one of the most important biological risk factors in neuroblastoma -- amplification of the oncogene MYCN in the tumour cells. Because amplified MYCN typically reside in ring-formed chromatin structures lacking centromeres (so-called double minutes, DMs) it remained unknown for a long time how the amplified sequences were maintained in the growing tumour. We could show that MYCN-carrying DMs in neuroblastoma cells translocate from the nuclear interior to the periphery at the interphase-prophase transition and that they are preferentially anchored to human chromosomes at sites adjacent to the telomeres, resulting in a random segregation pattern of DMs to post-mitotic neuroblastoma cells. Furthermore, by making human/murine hybrids we showed that DMs do not bind to specific positional elements in human chromosomes. Our data explain the vast intercellular variety of MYCN copy number in neuroblastoma. Moving on from here, in our next study we found that telomeres without detectable TTAGGG-repeats were associated with MYCN amplification and the generation of chromosomal breakage-fusion bridge cycles and could confirm that MYCN amplification was associated with reduced tumour telomere length in vivo. We also found a possible association between poor survival and elongated telomeres, which needs to be studied further. Our third pillar was that of whole chromosome changes, with a focus on intratumoural diversity. We demonstrated a previously unreported high degree of intercellular variation in chromosome copy number and found indications that loss of chromosomes from a tetraploid state is a major route towards this prominent intra-tumour genomic diversity in aneuploid neuroblastomas. Taken together, these studies suggest that neuroblastoma genomes are highly plastic, which may to some extent explain the poor response to oncological treatment for some of these tumours.
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| 8. |
- Lundberg, G, et al.
(författare)
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Inmatning av sebrafisk, Brachydanio rerio, med halogenerade substanser extraherade från lax och ål. Studier av bioackumulering och reproduktionskapacitet.
- 1992
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Fiskoljor extraherades från ål (Anguilla anguilla) och lax (Salmo salar). Fiskarna var fångade i både förorenade och relativt opåverkade områden. Toxiciteten av oljorna samt en fraktion (triacylglyceroler och fria fettsyror) av oljorna testades med avseende på effekter orsakade av Extraherbar Organiskt bunden Klor (EOCl). Sebrafiskhonor (Brachydanio rerio) utfodrades med frystorkade mygglarver som kontaminerats med de olika fiskoljorna och fraktionerna varefter bioackumulering av EOCl och reproduktionskapacitet (antal lagda ägg och kläckningsprocent) studerades. Den fraktionerade oljan från ål fångad i ett förorenat område var mer toxisk än motsvarande fraktion från ett relativt opåverkat område. Utfodring med de ursprungliga fiskoljorna gav inga skillnader i reproduktionskapacitet trots skillnader i halten EOCl. Analyserad halt EOCl i oljorna visade god korrelation med koncentrationerna i oljorna även om upptagseffektiviteten varierade för de olika oljorna. De funna effekterna kunde inte enbart förklaras av EOCl-intaget men utfodringsförsöket visade ändå att exponering för kontaminerat foder är en relevant metod för att studera biologiska effekter orsakade av lipofila ämnen.
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| 9. |
- Lundberg, Gisela, et al.
(författare)
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Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastomas (NBs) are tumours of the sympathetic nervous system accounting for 8-10% of paediatric cancers. NBs exhibit extensive intertumour genetic heterogeneity, but their extent of intratumour genetic diversity has remained unexplored. We aimed to assess intratumour genetic variation in NBs with a focus on whole chromosome changes and their underlying mechanism. Allelic ratios obtained by SNP-array data from 30 aneuploid primary NBs and NB cell lines were used to quantify the size of clones harbouring specific genomic imbalances. In 13 cases, this was supplemented by fluorescence in situ hybridisation to assess copy number diversity in detail. Computer simulations of different mitotic segregation errors, single cell cloning, analysis of mitotic figures, and time lapse imaging of dividing NB cells were used to infer the most likely mechanism behind intratumour variation in chromosome number. Combined SNP array and FISH analyses showed that all cases exhibited higher inter-cellular copy number variation than non-neoplastic control tissue, with up to 75% of tumour cells showing non-modal chromosome copy numbers. Comparisons of copy number profiles, resulting from simulations of different segregation errors to genomic profiles of 120 NBs indicated that loss of chromosomes from a tetraploid state was more likely than other mechanisms to explain numerical aberrations in NB. This was supported by a high frequency of lagging chromosomes at anaphase and polyploidisation events in growing NB cells. The dynamic nature of numerical aberrations was corroborated further by detecting substantial copy number diversity in cell populations grown from single NB cells. We conclude that aneuploid NBs typically show extensive intratumour chromosome copy number diversity, and that this phenomenon is most likely explained by continuous loss of chromosomes from a polyploid state.
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| 10. |
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| 11. |
- Nilsson, Tsvetelina, et al.
(författare)
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Emergency Department Chest Pain Patients With or Without Ongoing Pain : Characteristics, Outcome, and Diagnostic Value of the Electrocardiogram
- 2020
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Ingår i: Journal of Emergency Medicine. - : Elsevier BV. - 0736-4679. ; 58:6, s. 874-881
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Tidskriftsartikel (refereegranskat)abstract
- Background: In emergency department (ED) chest pain patients, it is believed that the diagnostic accuracy of the electrocardiogram (ECG) for acute coronary syndrome (ACS) is higher during ongoing than abated chest pain. Objectives: We compared patient characteristics and the diagnostic performance of the ECG in ED patients presenting with ongoing, vs. abated, chest pain. Methods: In total, 1132 unselected ED chest pain patients were analyzed. The patient characteristics and diagnostic accuracy for index visit ACS of the emergency physicians’ interpretation of the ECG was compared in patients with and without ongoing chest pain. Logistic regression analysis was performed to control for possible confounders. Results: Patients with abated chest pain (n = 508) were older, had more comorbidities, and had double the risk of index visit ACS (15%) and major adverse cardiac events (MACE) at 30 days (15.6%) compared with patients with ongoing pain (n = 631; ACS 7.3%, 30-day MACE 7.4%). Sensitivity of the ECG for ACS was 24% in patients with ongoing pain and 35% in those without, specificity was 97% in both groups, negative predictive value was 94% and 89%, respectively, and positive likelihood ratio 10.6 and 7.8, respectively. When the diagnostic performance was controlled for confounders, there was no significant difference between the groups. Conclusion: Our results indicate that ED chest pain patients with ongoing pain at arrival are younger, healthier, and have less ACS and 30-day MACE than patients with abated pain, but that there is no difference in the diagnostic accuracy of the ECG for ACS between the two groups.
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| 12. |
- Robba, Chiara, et al.
(författare)
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Oxygen targets and 6-month outcome after out of hospital cardiac arrest : a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial
- 2022
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535 .- 1466-609X. ; 26, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients’ outcome. Methods: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. Results: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003). Conclusions: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration: clinicaltrials.gov NCT02908308, Registered September 20, 2016.
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| 13. |
- Robba, Chiara, et al.
(författare)
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Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients : a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial
- 2022
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 48:8, s. 1024-1038
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The optimal ventilatory settings in patients after cardiac arrest and their association with outcome remain unclear. The aim of this study was to describe the ventilatory settings applied in the first 72 h of mechanical ventilation in patients after out-of-hospital cardiac arrest and their association with 6-month outcomes. Methods: Preplanned sub-analysis of the Target Temperature Management-2 trial. Clinical outcomes were mortality and functional status (assessed by the Modified Rankin Scale) 6 months after randomization. Results: A total of 1848 patients were included (mean age 64 [Standard Deviation, SD = 14] years). At 6 months, 950 (51%) patients were alive and 898 (49%) were dead. Median tidal volume (VT) was 7 (Interquartile range, IQR = 6.2–8.5) mL per Predicted Body Weight (PBW), positive end expiratory pressure (PEEP) was 7 (IQR = 5–9) cmH20, plateau pressure was 20 cmH20 (IQR = 17–23), driving pressure was 12 cmH20 (IQR = 10–15), mechanical power 16.2 J/min (IQR = 12.1–21.8), ventilatory ratio was 1.27 (IQR = 1.04–1.6), and respiratory rate was 17 breaths/minute (IQR = 14–20). Median partial pressure of oxygen was 87 mmHg (IQR = 75–105), and partial pressure of carbon dioxide was 40.5 mmHg (IQR = 36–45.7). Respiratory rate, driving pressure, and mechanical power were independently associated with 6-month mortality (omnibus p-values for their non-linear trajectories: p < 0.0001, p = 0.026, and p = 0.029, respectively). Respiratory rate and driving pressure were also independently associated with poor neurological outcome (odds ratio, OR = 1.035, 95% confidence interval, CI = 1.003–1.068, p = 0.030, and OR = 1.005, 95% CI = 1.001–1.036, p = 0.048). A composite formula calculated as [(4*driving pressure) + respiratory rate] was independently associated with mortality and poor neurological outcome. Conclusions: Protective ventilation strategies are commonly applied in patients after cardiac arrest. Ventilator settings in the first 72 h after hospital admission, in particular driving pressure and respiratory rate, may influence 6-month outcomes.
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