| 1. |
- Francardo, Veronica, et al.
(författare)
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Chapter 22 - Rodent Models of Treatment-Related Complications in Parkinson Disease
- 2014. - 2nd
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Ingår i: Movement Disorders : Genetics and Models - Genetics and Models. - 9780124051959 ; , s. 373-386
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Bokkapitel (refereegranskat)abstract
- Dopamine replacement therapy effectively relieves the typical motor features of Parkinson disease (PD), but it can cause complications that limit its utility. Dyskinesia (abnormal involuntary movements) and motor fluctuations (abrupt changes in the patients' motor status) occur in most PD patients after a few years of 3,4-dihydroxyphenyl-. l-alanine (l-DOPA) pharmacotherapy. Animal models reproducing these motor complications can be obtained in mice and rats if the nigrostriatal dopamine pathway is severely damaged. Within the large arsenal of neurotoxic and genetic models of PD, rodents with unilateral 6-hydroxydopamine lesions have the best characteristics for the sake of modeling l-DOPA-induced dyskinesia. When treated chronically with high doses of l-DOPA, these rodent models may also display motor response alterations reminiscent of the wearing-off fluctuations that occur in PD patients. Because of research performed on these animal models, our understanding of the molecular and biochemical mechanisms of l-DOPA-induced dyskinesia has made great advances, and several pharmacological approaches to treatment have been recently identified and successfully tested in proof-of-concept trials in PD patients. It is now well recognized that dopaminergic therapies for PD also cause nonmotor fluctuations (e.g., abrupt changes in mood and cognitive performance) and impulse control disorders. Valid rodent models of these nonmotor complications need to be developed as an important tool for basic and translational research on the cognitive and psychiatric features of PD.
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| 2. |
- Lindgren, Hanna, et al.
(författare)
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Putaminal Upregulation of FosB/Delta FosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 1:4, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor Delta FosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and Delta FosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/Delta FosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/Delta FosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/Delta FosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/Delta FosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of Delta FosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
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| 3. |
- Vierth, Inge, 1959-, et al.
(författare)
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Impact of higher road vehicle dimensions on modal split : An ex-post analysis for Sweden
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Road freight transport is responsible for a considerable amount of congestion, noise and various forms of air pollution and policy instruments that reduce these negative external effects are therefore on top of many policy-makers’ lists. One of the discussed initiatives to reduce these externalities is to increase the maximum permissible weight and length of vehicle combinations. There are however concerns that higher vehicle dimensions will reduce road transport cost per tonne-kilometre and therefore lead both to a modal shift and to induced demand for road transportation.The extent to which the introduction of longer and heavier road vehicles attracts freight from competing modes is therefore a crucial question. The purpose of this study is to provide empirical evidence on this matter, by analyzing how the modal split in Sweden has developed following the adoption of increases in the maximum permissible vehicle dimensions.In this study, we utilize official statistics on freight transport by road, rail and water covering the period 1985 to 2013. We first investigate the extent to which LHVs were adopted following the increases in vehicle dimensions in 1990 and 1993. We then construct time-series for the modal split both on the aggregate level and the commodity group-level and analyze the short- and long-run development. We show that the share of tonne-kilometres and vehicle-kilometres performed by trucks with a load capacity above 40 tonnes increased substantially in the 1990s, which mainly came at the expense of the vehicles with the lowest capacity. This shows the high degree of incorporation of LHVs in the Swedish vehicle fleet. Our analysis of the aggregate modal split shows that both the rail and water shares were decreasing from 1985 up until 1995, when the trend reversed for rail transportation. In 2000, rail had regained the market share it had in 1990 and continued to increase in the 2000. Water transportation kept on losing market shares throughout the period of study. The modal share for road transportation developed much in the opposite way. The road share increased steadily between 1985–1990 and continued this way during most of the 1990s, until it stabilized around 60–65 percent. We also show that road and rail have experienced increases in the level of tonne-kilometres since 1990, which implies that the falling rail share between 1990 and 1995 was driven by higher tonne-kilometer growth rates for road transportation than for rail transportation.Our aggregated freight statistics do not allow us to attribute the development of the modal split during this period of study to a particular event such as the increase in maximum weights in 1990 and 1993. In particular, it is not possible to trace out substitution patterns between the transport modes. The weight reforms are likely to have mattered for the modal development, but so are the economic recession in the early 1990s, the railway sector reforms of 1996 and other structural changes in the transport market. What we do document is the lack of breaks in modal split trends at the weight reforms in 1990 and 1993. On the contrary, the share of each mode is continuing its long-term development.
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| 4. |
- Vierth, Inge, 1959-, et al.
(författare)
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Vehicle weight, modal split, and emissions : an ex-post analysis for Sweden
- 2018
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Ingår i: Sustainability. - : MDPI. - 2071-1050. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- This study combines official statistics on freight transportation and emissions to present the long-run development of the use of longer and heavier road vehicles (LHVs), modal split, road freight efficiency, and GHG emissions and air pollution following the increase in the maximum permissible vehicle weight in Sweden in 1990 and 1993. We find that LHVs were quickly incorporated in the vehicle fleet and that road freight efficiency of the largest vehicles increased after the reforms. There was no discernable break in modal split trends as the modal share for road continued its long-run development. We show that road transportation contributes by far the most to emission costs. The composition of the emissions from road freight changed after the weight reforms, with an increasing share of GHG-emissions.
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| 5. |
- Vierth, Inge, 1959-, et al.
(författare)
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Vehicle weight, modal split, and emissions : an ex-post analysis for Sweden
- 2018
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Ingår i: Sustainable Freight Transport. - : MDPI. - 9783038974352 - 9783038974369 ; , s. 57-71
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Bokkapitel (refereegranskat)abstract
- This study combines official statistics on freight transportation and emissions to present the long-run development of the use of longer and heavier road vehicles (LHVs), modal split, road freight efficiency, and GHG emissions and air pollution following the increase in the maximum permissible vehicle weight in Sweden in 1990 and 1993. We find that LHVs were quickly incorporated in the vehicle fleet and that road freight efficiency of the largest vehicles increased after the reforms. There was no discernable break in modal split trends as the modal share for road continued its long-run development. We show that road transportation contributes by far the most to emission costs. The composition of the emissions from road freight changed after the weight reforms, with an increasing share of GHG-emissions.
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| 6. |
- Aleman, Soo, et al.
(författare)
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Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population
- 2011
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:9, s. 1118-1126
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. Patients and methods. 373 patients with hemochromatosis detected through routine health checkups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 +/- 5.8 years. The degree of liver fibrosis and survival were analyzed. Results. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Conclusion. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.
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| 7. |
- Andersson, Lisa, et al.
(författare)
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Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 642-646
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Tidskriftsartikel (refereegranskat)abstract
- Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.
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| 8. |
- Arja, Katriann, et al.
(författare)
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Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents
- 2018
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Ingår i: ChemistryOpen. - : Wiley-VCH Verlagsgesellschaft. - 2191-1363. ; 7:7, s. 495-503
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Tidskriftsartikel (refereegranskat)abstract
- Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro-2-deoxy glucose (FDG) moiety at the fourth site are presented. The fluoro-glycoconjugated porphyrins exhibit properties for multimodal imaging and photodynamic therapy, as well as specificity towards cancer cells. We foresee that our findings might aid in the chemical design of heterobifunctional glycoconjugated porphyrins that could be utilized as theranostic agents.
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| 9. |
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| 10. |
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| 11. |
- Bengtsson, Christoffer, et al.
(författare)
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Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents
- 2012
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 54, s. 637-646
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Tidskriftsartikel (refereegranskat)abstract
- Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC50’s between 9-50 μM.
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| 12. |
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| 13. |
- Bergquist, Annika, et al.
(författare)
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Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis
- 2008
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Ingår i: Clinical Gastroenterology and Hepatology. - New York : Elsevier. - 1542-3565 .- 1542-7714. ; 6:8, s. 939-943
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. Methods: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. Results: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6–84.4), 11.1 (3.3–37.8), and 2.3 (0.9–6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3–4.9) and for Crohn's disease 1.4 (0.8–2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9–18.9). Conclusions: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.
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| 14. |
- Bjornsson, Einar, et al.
(författare)
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Akut leversvikt - viktigt med snabb multidisciplinär handläggning
- 2007
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Ingår i: Läkartidningen. - 0023-7205. ; 104:4, s. 210-213
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Tidskriftsartikel (refereegranskat)abstract
- A recent study in Sweden on patients with acute liver failure (ALF) 1994-2003 demonstrated that the most common causes were paracetamol toxicity (42%) and idiosyncratic drug reactions (15%). In 11% of cases of ALF no definite etiology could be established. Among patients with paracetamol toxicity, the spontaneous survival without liver transplantation was 82% compared to 49% in patients with reactions to other drugs and 29% among the patients with indeterminate cause. Patients with ALF need a rapid and effective diagnostic work-up to detect the etiology as this often determines the outcome. In ALF it is of major importance to make an early contact with a transplant centre as the search for a suitable donor organ may take time in patients who are candidates for a liver transplantation. Patients with acute liver failure need a multidisciplinary care with co-operation between hepatologists, intensive care unit specialists and transplant surgeons.
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| 15. |
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| 16. |
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| 17. |
- Björnsson, Einar, et al.
(författare)
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Akut leversvikt - viktigt med snabb multidisciplinär handläggning : [Acute liver failure--rapid multidisciplinary management]
- 2007
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 104:4, s. 210-213
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A recent study in Sweden on patients with acute liver failure (ALF) 1994-2003 demonstrated that the most common causes were paracetamol toxicity (42%) and idiosyncratic drug reactions (15%). In 11% of cases of ALF no definite etiology could be established. Among patients with paracetamol toxicity, the spontaneous survival without liver transplantation was 82% compared to 49% in patients with reactions to other drugs and 29% among the patients with indeterminate cause. Patients with ALF need a rapid and effective diagnostic work-up to detect the etiology as this often determines the outcome. In ALF it is of major importance to make an early contact with a transplant centre as the search for a suitable donor organ may take time in patients who are candidates for a liver transplantation. Patients with acute liver failure need a multidisciplinary care with co-operation between hepatologists, intensive care unit specialists and transplant surgeons.
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| 18. |
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| 19. |
- Bybrant, Mara Cerqueiro, et al.
(författare)
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The prevalence of having coeliac disease in children with type 1 diabetes was not significantly higher during the Swedish coeliac epidemic
- 2023
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 112:10, s. 2175-2181
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Tidskriftsartikel (refereegranskat)abstract
- Aim: From 1986 to 1996, there was a four-fold increase in coeliac disease among young Swedish children, known as the Swedish coeliac epidemic. Children with type 1 diabetes have an increased risk of developing coeliac disease. We studied whether the prevalence of coeliac disease differed in children with type 1 diabetes born during and after this epidemic.Methods: We compared national birth cohorts of 240 844 children born in 1992–1993 during the coeliac disease epidemic and 179 530 children born in 1997–1998 after the epidemic. Children diagnosed with both type 1 diabetes and coeliac disease were identified by merging information from five national registers.Results: There was no statistically significant difference in the prevalence of coeliac disease among children with type 1 diabetes between the two cohorts: 176/1642 (10.7%, 95% confidence interval 9.2%–12.2%) in the cohort born during the coeliac disease epidemic versus 161/1380 (11.7%, 95% confidence interval 10.0%–13.5%) in the post-epidemic cohort.Conclusion: The prevalence of having both coeliac disease and type 1 diabetes was not significantly higher in children born during, than after, the Swedish coeliac epidemic. This may support a stronger genetic disposition in children who develop both conditions.
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| 20. |
- Carta, Manolo, et al.
(författare)
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Role of striatal l-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats.
- 2006
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 96:6, s. 1718-1727
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Tidskriftsartikel (refereegranskat)abstract
- We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.
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| 21. |
- Cenci Nilsson, Angela, et al.
(författare)
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Advances in understanding l-DOPA-induced dyskinesia.
- 2007
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Ingår i: Current Opinion in Neurobiology. - : Elsevier BV. - 1873-6882 .- 0959-4388. ; 17:6, s. 665-671
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Tidskriftsartikel (refereegranskat)abstract
- The crucial role of dopamine (DA) in movement control is illustrated by the spectrum of motor disorders caused by either a deficiency or a hyperactivity of dopaminergic transmission in the basal ganglia. The degeneration of nigrostriatal DA neurons in Parkinson's disease causes poverty and slowness of movement. These symptoms are greatly improved by pharmacological DA replacement with l-3,4-dihydroxy-phenylalanine (l-DOPA), which however causes excessive involuntary movements in a majority of patients. l-DOPA-induced dyskinesia (abnormal involuntary movements) provides a topic of investigation at the interface between clinical and basic neuroscience. In this article, we review recent studies in rodent models, which have uncovered two principal alterations at the basis of the movement disorder, namely, an abnormal pre-synaptic handling of exogenous l-DOPA, and a hyper-reactive post-synaptic response to DA. Dysregulated nigrostriatal DA transmission causes secondary alterations in a variety of non-dopaminergic transmitter systems, the manipulation of which modulates dyskinesia through mechanisms that are presently unclear. Further research on l-DOPA-induced dyskinesia will contribute to a deeper understanding of the functional interplay between neurotransmitters and neuromodulators in the motor circuits of the basal ganglia.
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| 22. |
- Cenci Nilsson, Angela, et al.
(författare)
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Rodent models of impulsive compulsive behaviors in Parkinson's disease: how far have we reached?
- 2015
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 82:aug 29, s. 561-573
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Forskningsöversikt (refereegranskat)abstract
- There is increasing awareness that the medications used to treat the motor symptoms of Parkinson's disease (PD) contribute to the development of behavioral addictions, which have been clinically defined as impulsive compulsive behaviors (ICBs). These features include pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, excessive hobbyism or punding, and the excessive use of dopaminergic medication. ICBs frequently have devastating effects on the social and occupational function of the affected individuals as well as their families. Although ICBs are an important clinical problem in PD, the number of studies in which these symptoms have been modeled in rodents is still limited. This may depend on uncertainties regarding, on one hand, the pathophysiology of these behaviors and, on the other hand, the experimental paradigms with which similar features can be induced in rodents. To help compose these uncertainties, we will here review the characteristics of ICBs in PD patients and then describe behavioral methods to approximate them in rodents. We will discuss both the challenges and the possibilities of applying these methods to animals with PD-like lesions, and review the recent progress made to this end. We will finally highlight important questions deserving further investigation. Rodent models having both face validity and construct validity to parkinsonian ICBs will be essential to further pathophysiological and therapeutic investigations into this important area.
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| 23. |
- Divakar, Pradeep K., et al.
(författare)
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Evolution of complex symbiotic relationships in a morphologically derived family of lichen-forming fungi
- 2015
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 208:4, s. 1217-1226
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Tidskriftsartikel (refereegranskat)abstract
- We studied the evolutionary history of the Parmeliaceae (Lecanoromycetes, Ascomycota), one of the largest families of lichen-forming fungi with complex and variable morphologies, also including several lichenicolous fungi. We assembled a six-locus data set including nuclear, mitochondrial and low-copy protein-coding genes from 293 operational taxonomic units (OTUs). The lichenicolous lifestyle originated independently three times in lichenized ancestors within Parmeliaceae, and a new generic name is introduced for one of these fungi. In all cases, the independent origins occurred c. 24 million yr ago. Further, we show that the Paleocene, Eocene and Oligocene were key periods when diversification of major lineages within Parmeliaceae occurred, with subsequent radiations occurring primarily during the Oligocene and Miocene. Our phylogenetic hypothesis supports the independent origin of lichenicolous fungi associated with climatic shifts at the Oligocene-Miocene boundary. Moreover, diversification bursts at different times may be crucial factors driving the diversification of Parmeliaceae. Additionally, our study provides novel insight into evolutionary relationships in this large and diverse family of lichen-forming ascomycetes.
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| 24. |
- Dumanski, Jan P., et al.
(författare)
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Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 98:6, s. 1208-1219
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Tidskriftsartikel (refereegranskat)abstract
- Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
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| 25. |
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| 26. |
- Dumanski, Jan P., et al.
(författare)
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Smoking is associated with mosaic loss of chromosome Y
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6217, s. 81-83
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Tidskriftsartikel (refereegranskat)abstract
- Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
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| 27. |
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| 28. |
- Elmberg, Maria, et al.
(författare)
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Increased Mortality Risk in Patients With Phenotypic Hereditary Hemochromatosis But Not in Their First-Degree Relatives
- 2009
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 137:4, s. 1301-1309
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. METHODS: We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. RESULTS: Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27-2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00-1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01-1.10); this RR was similar to that of patients' spouses (RR, 1.09; 95% CI, 0.86-1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI 0.67-1.62; 21 deaths). CONCLUSIONS: Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives.
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| 29. |
- Fegraeus, Kim, et al.
(författare)
-
An endothelial regulatory module links blood pressure regulation with elite athletic performance
- 2024
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 20:6
-
Tidskriftsartikel (refereegranskat)abstract
- The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.
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| 30. |
- FitzGerald, Edward A., et al.
(författare)
-
Multiplexed experimental strategies for fragment library screening using SPR biosensors
- 2020
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Surface plasmon resonance biosensor technology (SPR) is ideally suited for fragment-based lead discovery. However, generally suitable experimental procedures or detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are lacking. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. By adopting a multiplexed strategy, the range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded. We here illustrate innovative strategies using five challenging targets and variants thereof. Two libraries of 90 and 1056 fragments were screened using two different flow-based SPR biosensor systems, allowing different experimental approaches. Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted.Competing Interest StatementAnna Moberg, Maria T. Lindgren and Claes Holmgren work for Cytiva, which produce Biacore systems.
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| 31. |
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| 32. |
- FitzGerald, Edward, et al.
(författare)
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Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors
- 2024
-
Ingår i: SLAS Discovery. - : Elsevier. - 2472-5560 .- 2472-5552. ; :1, s. 40-51
-
Tidskriftsartikel (refereegranskat)abstract
- Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery. However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau (tau K18M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads.
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| 33. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 34. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
-
Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 35. |
- Forsberg, Lars A., et al.
(författare)
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Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
-
Tidskriftsartikel (refereegranskat)abstract
- Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
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| 36. |
- Forward, Sonja, 1956-, et al.
(författare)
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Effekterna av begränsat antal handledarskap : en utvärdering
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Tidigare kunde en handledare ha ett obegränsat antal godkännanden men i och med de nya föreskrifterna begränsades dessa till 15 stycken. Det övergripande syftet med denna studie är att undersöka huruvida denna begränsning har haft en effekt på den olagliga körskoleverksamheten. Ett annat viktigt syfte är att ge förslag på alternativa åtgärder för att stävja denna verksamhet. För att svara på dessa frågor har vi använt oss av tre olika angreppssätt; en registerstudie, en intervjustudie och en enkätstudie. Resultaten från intervjustudien visar att det finns en rad olika tjänster som den olagliga verksamheten erbjuder mot betalning; förfalskning av handledarintyg, handledd körträning, kunskapsprov som man filmat på plats och som andra kan få tillgång till, hjälp att svara på kunskapsfrågorna i samband med prov via en öronsnäcka och bokning av förarprov. Det vanligaste enligt de intervjuade är att man erbjuder handledning vid körträning. Hur omfattande den olagliga verksamheten är gav intervjustudien inte något entydigt svar på. Svaren varierade allt från att den är väldigt stor till liten.Resultat från enkätstudien ger dock indikationer på att det finns en olaglig verksamhet som är relativt utbredd. På frågan om regelverket haft en positiv eller negativ inverkan på den olagliga verksamheten var de intervjuade tämligen överens om att den inte haft någon effekt alls. Argumentet var att de som idag sysslar med denna verksamhet, i varje fall den grövre, är så pass raffinerade att de säkert kommer på olika sätta att kringgå även dessa regler. Trots det fanns det några som skulle vilja se en ytterligare sänkning, även om detta inte skulle räcka för att stävja den olagliga verksamheten. Man pratade då istället om att en sänkning tydligt visar att det handlar om en privat verksamhet och inte en yrkesverksamhet. Det övergripande resultatet från studierna är att en illegal verksamhet kan rubba förtroendet för det svenska körkortet. Rapporten avslutas med 16 olika åtgärdsförslag som tillsammans kan hjälpa till att stävja den olaglig verksamhet. Detta innebär att en åtgärd inte löser problemet.
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| 37. |
- Fuchsberger, Christian, et al.
(författare)
-
The genetic architecture of type 2 diabetes
- 2016
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 38. |
-
Global hälsa : en praktisk guide
- 2023. - 2
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Introduktion: Behovet av ett globalt perspektiv på hälsa.Det har gått fem år sedan Global Hälsa – En praktisk guide släpptes. Sedan dess har världen förändrats. Covid-19-pandemin har i grunden påverkat förutsättningarna för den global hälsan och visar på hur svårt det är att isolera sig från globala hälsohot. Hälsokonsekvenserna av klimatförändringarna, liksom hälso- och sjukvårdens klimatpåverkan har tydliggjorts. Fler väpnade konflikter, inklusive kriget i Ukraina, riskerar många år av folkhälsoarbete. I kriser drabbas de fattigaste hårdast. Detta gäller globalt såväl som i Sverige.I årets halvtidsgenomgång av världens utvecklingsagenda, Agenda 2030 och de globala målen, konstateras att många viktiga framsteg har gjorts, men att dessa hotas av det förändrade världsläget. Ett förnyat fokus på globala hälsofrågor krävs och här är svensk kunskap viktig. Många av de utmaningar som Sverige står inför delar vi dessutom med andra länder, såsom till exempel personalbrist, som leder till stängda vårdplatser och för låg täckning i primärvården. Här kan vi lära av varandra.Svenska Läkaresällskapet har sedan 2013 aktivt arbetat med globala hälsofrågor, med övertygelsen om att större medvetenhet om global hälsa kan minska konsekvenserna från världens gemensamma utmaningar. Sedan den förra guiden kom ut har läkaresällskapet bidragit till mobilisering och kunskapsspridning om Covid-19 under pandemin, en hybridkonferens om planetär hälsa har hållits med världsledande forskare, och svensk hälso- och sjukvårds möjligheter att stötta den ukrainska befolkningen under pågående krig har lyfts i en webinarie-serie.Liksom förra gången är guiden framtagen av läkarstudenter och läkare tidigt i karriären under handledning av kommittén för global hälsa. Den är tänkt som ett handfast stöd för de som vill engagera sig för global hälsa – genom klinik, forskning eller folkhälsoarbete och berör bland annat hälso- och sjukvårdens utmaningar i omställningen till ett klimatneutralt samhälle.Fältets ambition om att skapa alltmer jämlika samarbeten, genom att ifrågasätta äldre beslutsstrukturer, berörs också som en röd tråd genom guiden.Därför vill vi rikta ett stort tack till de studenter och yngre läkare som med vägledning av projektledarna har möjliggjort denna nya och förbättrade upplaga av guiden!Tillsammans kan vi verka för förbättrad hälsa, här hemma och utomlands!
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| 39. |
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| 40. |
- Hassellöv, Ida-Maja, 1974, et al.
(författare)
-
Miljörisker sjunkna vrak
- 2014
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Arbetet med en nationell strategi för hantering av miljöfarliga vrak påbörjades 2007 med Statskontorets utredning Vrak och ägarlösa båtar, men ingen enskild myndighet har tilldelats övergripande ansvar för vrakfrågan. Utöver ansvarsfrågan har också förväntade höga kostnader för inspektion och sanering av vrak fördröjt det fortsatta arbetet. Ett steg närmare en nationell strategi redovisas här genom regeringsuppdraget Miljörisker sjunkna vrak. Genom samordning och ökat informationsutbyte mellan berörda myndigheter finns stor potential att minska de förväntade kostnaderna för inspektion av vrak och omgivande miljö. Om den föreslagna strategin antas, beräknas informationsläget avseende vraken att snabbt förbättras så att det år 2030 inte längre finns några potentiellt miljöfarliga vrak i svenska vatten.Havs- och vattenmyndigheten (HaV) och Naturvårdsverket har idag delat ansvar för övervakning och åtgärdande av miljögifter i marin miljö. Mot denna bakgrund hade det varit naturligt att låta HaV få ett övergripande ansvar för hantering av miljöfarliga vrak. Genom flexibelt upplägg avseende tidsramar bedöms övervakning och inspektion av potentiellt miljöfarliga vrak kunna utföras genom att HaV ger de berörda myndigheterna uppdrag; kartering och sjömätning (Sjöfartsverket), ROV och dykinspektion (Kustbevakningen och/eller Försvarsmakten), sediment- och bottenförhållanden (Statens geologiska undersökning). En förutsättning är dock väl fungerande samverkan och kommunikation mellan berörda myndigheter. Existerande plattformar för detta finns redan på såväl operativ nivå i form av Projekt ”Sjöstjärnan” - samordning och samverkan mellan myndigheter avseende information och inhämtning av djup- och bottendata; respektive högsta ledningsnivå i form av Samordningsgruppen för havs- och vattenmiljöfrågor (SamHav).Enligt Sjöfartsverkets tidigare inventering (Miljörisker från fartygsvrak, 2011) finns det utmed Sveriges kust knappt tre tusen vrak som inte kan avskrivas utan vidare informationsinhämtning. Drygt trehundra av dessa klassades som potentiellt miljöfarliga. Av dessa har 31 listats som de sannolikt mest miljöfarliga vraken. Listan över de 31 vraken har därför varit utgångspunkt för projektet Miljörisker sjunkna vrak, vars syfte var att ta fram en metod för prioritering och inspektion av potentiellt miljöfarliga vrak.Undervattensinspektion av vrak är kostsamt och kostnaden ökar kraftigt om vrakets läge är otillgängligt. Av de 31 vraken valdes därför nio relativt lättillgängliga vrak ut för noggrannare arkivstudier, samt sjömätning. Utifrån informationen från arkivstudierna och sjömätningen gjordes ett ytterligare urval om fyra vrak (Altnes, Skytteren, Thetis och Villon), vilka även inspekterades med ROV och/eller dykare. Huvudsyftet var att, inför och under arbetet med inspektionerna, utarbeta Standard Operating Procedures (SOPs) som framgent kan användas som stöd inför kommande operationer rörande potentiellt miljöfarliga vrak.Under arbetet med inspektionerna observerades inte några pågående läckage av olja från vraken. Trots denna positiva information är det viktigt att komma ihåg att endast bevis på tomma tankar kan fullt ut avskriva vraken från listan över potentiellt miljöfarliga vrak. Även om det under projektets fältarbete inte observerades läckage av olja, finns dokumenterade läckage sedan tidigare (senast 2008-04-26) för Skytteren. Noterbart är också att Kustbevakningen 2014-06-29, fick rycka ut för att omhänderta olja som börjat läcka efter vraket Immen, norr om Gotska Sandön. Immen var inte med bland fallstudieobjekten i projektet.I tillägg till undervattensinspektion placerades strömmätningsutrustning ut vid vraken Skytteren och Villon. Strömdata kan sedan användas för att modellera ett hypotetiskt spill av olja från ett vrak och ge en indikation på var läckage av olja kan tänkas påverka den marina miljön negativt. Exempel på sådana negativa effekter kan vara försämrad förmåga hos sedimentlevande organismer att omsätta näringsämnen, vilket i sin tur kan påverka hela det marina ekosystemet. Strömdata är också ett viktigt underlag för utformning av övervakningsprogram, exempelvis med passiva provtagare för att detektera läckage av miljöfarlig substans från vrak.Samtlig insamlad data kommer att användas för att validera riskbedömningsverktyget VRAKA, som möjliggör resurseffektiv prioritering av vilka vrak som bör undersökas och/eller saneras. VRAKA, SOPs för inspektion, samt tillgång till specifik kompetens för utvärdering av samtliga resultat är nyckelelement för att kunna presentera en tillförlitlig riskbedömning av potentiellt miljöfarliga vrak. Havs- och vattenmyndigheten skulle kunna vara lämplig myndighet med huvudansvar för miljöfarliga vrak, i operativ samverkan med övriga berörda myndigheter.
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| 41. |
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| 42. |
- Hassellöv, Ida-Maja, 1974, et al.
(författare)
-
Miljörisker sjunkna vrak II. Undersökningsmetoder och miljöaspekter
- 2015
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- During 2015 the Swedish Maritime Administration continued the second phase of thegovernmental task Environmental risks from sunken wrecks which first report was finalized2014-10-31 (Dnr: 1399-14-01942-6).The main conclusions from the 2014 report remain; for future handling of potentially pollutingshipwrecks it is recommended that the Swedish Agency for Water and Marine Management isgiven a coordinating responsibility in close cooperation with other competent nationalauthorities, such as Swedish Maritime Administration, Swedish Coastguard, Swedish NationalMaritime Museums, the Geological Survey of Sweden, SMHI, Swedish EPA, and SwedishCivil Contingencies Agency. Through coordination of wreck related operations and activitieswithin the concerned competent authorities’ ordinary areas of responsibility, resourceefficiency is improved. The estimated extra cost for implementation of a national strategy forhandling of the wrecks are estimated to be 10-15 MSEK which should be allocated to thecompetent authorities by the Swedish Agency for Water and Marine Management.The conclusions from 2014 was reinforced during 2015, e.g. through the validation of the riskassessment model VRAKA, which is now available in a first operative version. Additionalecotoxicological experiments on the development of tolerance against PAHs in meiofauna andmicroorganism communities were conducted in a field study in Brofjorden. The mainconclusions from this work is that comprehensive analyzes of PAHs should include alkylatedPAHs, and that exposure to PAHs over time can lead to tolerance development in ammoniumoxidizing bacteria, at the expense of their ability to perform the essential ecosystem servicenitrification.Continued measurements of the bottom currents were made at the wrecks Villon and Skytteren,and at the dumping area west of Måseskär. Measurement series yielded important informationon how measuring equipment at the wreck can be deployed in an optimized way in futuremonitoring program; to calculate the possible spreading of pollution from a wreck, currentmeasurements should be performed upstream from the wreck site, while sensors for thedetection of, for example, oil should be put into the turbulence downstream of the wreck.The current measurement instruments (RDCP) deployed at the Måseskär dump site was trawledup after only three weeks of measurements, but still gave valuable information on the extensivebottom trawling that resuspend (stir up) sediments. Earlier geochemical surveys have shownsignificantly elevated arsenic concentrations in the area and sediment resuspension greatlyincreased the risk for spread of any contaminants in the area. Trawling is not prohibited in thearea, and the current lack of knowledge regarding potential effects on human health whenconsuming seafood from dump areas calls for reflection upon the suitability of trawling in thearea.In addition to the current measurements Swedish Maritime Administration and the SwedishNavy conducted hydrographic survey with multibeam and side scan sonar and ROVinvestigation of the wrecks in the dumping area at Måseskär. 28 wrecks were found, and ROVinvestigation showed cargo holds with dumped torpedoes or mines and other containers in some SjöfartsverketDnr: 1399-14-01942-156of the wrecks. There is some discrepancy between the previously measured elevated arsenicconcentrations in the Måseskär area and recently presented data from historical archives thatdoes not support the theory that chemical weapons were dumped in the area. However, there isa very good correlation between the dominant current direction in the area, and the highestmeasured arsenic concentrations in the area downstream of the wrecks, suggesting some formof arsenic source in the area.
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| 43. |
- Holmquist Mengelbier, Linda, et al.
(författare)
-
Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
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| 44. |
- Ikram, M. Arfan, et al.
(författare)
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Common variants at 6q22 and 17q21 are associated with intracranial volume
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 539-544
-
Tidskriftsartikel (refereegranskat)abstract
- During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Johnsen, Annika, et al.
(författare)
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Literature review on the acceptance and road safety, ethical, legal, social and economic implications of automated vehicles
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This deliverable summarizes the findings of an extensive literature review on the acceptance, behavioural intentions, road safety, as well as ethical, legal, social (ELSI) and economic considerations in the scope of vehicle automation.The theoretical fundaments and relevant findings of recent public opinion research regarding user acceptance of automation are presented. Also the view of organised stakeholders is taken into account.Regarding road safety there is a potential for increased road safety but drivers tend to pick up non-related driving tasks instead. These problems are due to several traditional HMI concerns. In the future autonomous cars must make decisions that touch on ethical issues that have not yet been sufficiently and transparently discussed. Although in many countries legislation is now reacting to the new technology, many aspects – like liability and privacy / data protection – are not yet regulated by law. Automated vehicles promise to have several clear benefits that might change the entire transport system. The positive externalities that come from the technological advantages of automated vehicles might be outweighed by the negative externalities coming from the potential increases in travelling by private vehicles.
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| 49. |
- Landquist, Hanna, 1984, et al.
(författare)
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A fault tree model to assess probability of contaminant discharge from shipwrecks
- 2014
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Ingår i: Marine Pollution Bulletin. - : Elsevier BV. - 0025-326X .- 1879-3363. ; 88:1-2, s. 239-248
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Tidskriftsartikel (refereegranskat)abstract
- Shipwrecks on the sea floor around the world may contain hazardous substances that can cause harm to the marine environment. Today there are no comprehensive methods for environmental risk assessment of shipwrecks, and thus there is poor support for decision-making on prioritization of mitigation measures. The purpose of this study was to develop a tool for quantitative risk estimation of potentially polluting shipwrecks, and in particular an estimation of the annual probability of hazardous substance discharge. The assessment of the probability of discharge is performed using fault tree analysis, facilitating quantification of the probability with respect to a set of identified hazardous events. This approach enables a structured assessment providing transparent uncertainty and sensitivity analyses. The model facilitates quantification of risk, quantification of the uncertainties in the risk calculation and identification of parameters to be investigated further in order to obtain a more reliable risk calculation.
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| 50. |
- Landquist, Hanna, 1984, et al.
(författare)
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Environmental Risk Assessment of Shipwrecks: a fault-tree model to assess probability of contaminant release
- 2012
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Ingår i: SETAC North America 33rd Annual Meeting.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- RP247 Environmental risk assessment for shipwrecks: a fault-tree model to assess probability of contaminant release H. Landquist, I. Hassellov, Chalmers University of Technology / Shipping and Marine Technology; L. Rosen, Chalmers University of Technology / Civil and Environmental Engineering; F. Lindgren, Chalmers University of Technology / Shipping and Marine Technology; I. Dahllof, The University of Gothenburg; T. Norberg, Chalmers University of Technology / Mathematical Sciences; A. Lindhe, Chalmers University of Technology / Civil and Environmental Engineering. Shipwrecks lying on the sea floor around the world may contain hazardous substances which can cause harm to the maritime environment. Today there are no comprehensive methods for environmental risk assessment of shipwrecks and thus there is poor support for decision-making on prioritisation of mitigation measures. The purpose of this study has been to develop a framework for risk assessment of potentially polluting shipwrecks, focusing on a detailed probabilistic assessment of the release of hazardous substances. The framework is based on international standards for risk management and the assessment of the probability for release was done using fault-tree analysis. This approach enables a structure assessment and provides an excellent possibility of uncertainty and sensitivity analysis. The fault tree model was tested by groups of experts in the field of maritime administration, maritime archaeology and in other areas to validate the method. The developed framework facilitates risk assessment of potentially polluting shipwrecks and can support risk management as well as provide well founded input for decision-making. In particular the fault-tree analysis provides a quantitative method for assessing the probability of leakage and can facilitate uncertainty and sensitivity analyses.
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