| 1. |
- Tran, Phong, et al.
(författare)
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De novo dNTP production is essential for normal postnatal murine heart development
- 2019
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 394:44, s. 15889-15897
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Tidskriftsartikel (refereegranskat)abstract
- The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.
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| 2. |
- Andrén, Eva, et al.
(författare)
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Öppna prioriteringar inom nya områden : logopedi, nutritionsbedömning, habilitering och arbetsterapi
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Det finns fortfarande ett behov av att öka kunskapen om och stödja den praktiska tillämpningen av riksdagens riktlinjer för öppna prioriteringar inom svensk hälso- och sjukvård. Flera förslag på hur ett sådant stöd kan se ut har tagits fram de senaste åren. Spridning av goda exempel är ett sådant förslag, metodstöd ett annat (PrioriteringsCentrum 2007). En mer påtaglig form av metodstöd är den nationella modell som vuxit fram för att konkretisera innebörden i riktlinjerna (Carlsson m fl 2007). Den får idag anses som välbeprövad inom ett flertal områden och har bidragit till att samsynen och kommunicerbarheten kring prioriteringar har ökat i landet. Erfarenheter visar dock att det behövs pedagogisk vägledning i hur modellen kan tillämpas. För att möta upp efterfrågan på sådant metodstöd erbjuder Prioriteringscentrum handledning i grupp. Den första handledningsgruppen är nu avslutad och det är deltagarnas prioriteringsarbeten som presenteras i denna rapport i syfte att sprida konkreta exempel på försök att tillämpa prioriteringsriktlinjerna.I rapporten presenteras fyra prioriteringsarbeten med fokus på: Regionsamverkan inom arbetsterapi Logopedi Yrkesspecifika prioriteringar på väg till teamet Från projekt till integrerat redskapExemplet med prioriteringar i regionsamverkan utgörs av det prioriteringsarbete som genomförts i det s k femklövernätverket bestående av en samverkansgrupp för arbetsterapeuter i ledningsposition på sjukhusen i Uppland, Västmanland, Södermanland, Gävleborg och Dalarna. Arbetet var ett försök att skapa gemensamma prioriteringar i regionen för ett sjukdomsområde som kändes relevant. Valet kom att falla på arbetsterapi inom reumatologi. Arbetet har sedan huvudsakligen bedrivits i en projektgrupp, bestående av en representant från varje sjukhus där arbetet växlat mellan arbete på hemmaplan och avstämningsträffar i projektgruppen.Försöket har visat att det finns en samsyn inom regionen kring prioriteringar inom arbetsterapi och reumatologi. Säkerheten i prioriteringarna har ökat i och med att fem arbetsterapiorganisationer tillsammans bidragit med ett stort underlagsmaterial bl a genom att delge varandra sina kliniska erfarenheter. Förutsättningarna för en mer likartad vård i regionen har ökat. Arbetet har också gett upphov till frågor om i vilka situationer det är att föredra att prioriteringsarbete bedrivs lokalt, regionvis och/eller nationellt.
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| 3. |
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| 4. |
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| 5. |
- Nilsson-Ardnor, Sofie, et al.
(författare)
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Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
- 2005
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 36:8, s. 1666-1671
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.
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| 6. |
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| 7. |
- Rentoft, Matilda, et al.
(författare)
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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:17, s. 4723-4728
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Tidskriftsartikel (refereegranskat)abstract
- Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that severalSAMHD1mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of oneSAMHD1allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associatedSAMHD1mutations increase mutation rates in cancer cells.
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| 8. |
- Sundell, Anna Lena, et al.
(författare)
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Body Mass Index and Association With Caries in School-Aged Children With Orofacial Cleft : A Case-Control Study.
- 2020
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Ingår i: The Cleft Palate-Craniofacial Journal. - : Sage Publications. - 1055-6656 .- 1545-1569. ; 57:2, s. 169-176
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Data on the association between body mass index (BMI) and dental caries in children with orofacial clefts are sparse. Therefore, studies on the impact of BMI on caries frequency in children with cleft lip and/or palate (CL/P) are of importance. The aim of the current study was to investigate the association between BMI and frequency of dental caries in children with and without CL/P. Height, weight, and BMI in children with CL/P were also compared to controls.DESIGN: This study used a cross-sectional case-control design.PARTICIPANTS: One hundred and thirty-nine 5- and 10-year-old children with CL/P and 299 age-matched controls.MAIN OUTCOME MEASURES: Caries was recorded according to the International Caries Detection and Assessment System. Height and weight were recorded, and BMI was calculated as weight/height2.RESULTS: There was no correlation between BMI and caries frequency. Weight, height, and BMI were significantly lower in all children with CL/P compared to controls. After adjustment for international adoption, only BMI was significantly lower in CL/P children compared to controls. Non-adopted children with CL/P were significantly heavier and longer than adopted children with CL/P.CONCLUSIONS: Five- and 10-year-old children with corrected CL/P seemed to have a lower BMI than controls, but there was no association between BMI and caries frequency. Internationally adopted children with CL/P were lighter and shorter than non-adopted CL/P children and controls.
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| 9. |
- Sundell, Anna Lena, et al.
(författare)
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Caries prevalence and enamel defects in 5-and 10-year-old children with cleft lip and/or palate: A case-control study
- 2016
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Ingår i: Acta Odontologica Scandinavica. - : TAYLOR & FRANCIS LTD. - 0001-6357 .- 1502-3850. ; 74:2, s. 90-95
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the prevalence of dental caries and enamel defects in 5- and 10-year-old Swedish children with cleft lip and/or palate (CL(P)) in comparison to non-cleft controls. Materials and methods. The study group consisted of 139 children with CL(P) (80 subjects aged 5 years and 59 aged 10 years) and 313 age-matched non-cleft controls. All children were examined by one of two calibrated examiners. Caries was scored according to the International Caries Detection and Assessment System (ICDAS-II) and enamel defects as presence and frequency of hypoplasia and hypomineralization. Results. The caries prevalence among the 5-year-old CL(P) children and the non-cleft controls was 36% and 18%, respectively (p < 0.05). The CL(P) children had higher caries frequency (initial and cavitated lesions) in the primary dentition than their controls (1.2 vs 0.9; p < 0.05). A significantly higher prevalence of enamel defects was found in CL(P) children of both age groups and anterior permanent teeth were most commonly affected. Conclusions. Preschool children with cleft lip and/or palate seem to have more caries in the primary dentition than age-matched non-cleft controls. Enamel defects were more common in CL(P) children in both age groups.
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| 10. |
- Wanrooij, Paulina H., et al.
(författare)
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Elimination of rNMPs from mitochondrial DNA has no effect on its stability
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:25, s. 14306-14313
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Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1(-/-) mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.
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