| 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. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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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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| 7. |
- 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
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
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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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| 8. |
- Hassellöv, Ida-Maja, 1974, et al.
(författare)
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Miljörisker sjunkna vrak
- 2014
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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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| 9. |
- Ikram, M. Arfan, et al.
(författare)
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Common variants at 6q22 and 17q21 are associated with intracranial volume
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 539-544
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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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| 10. |
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