| 1. |
- Eklund, Birgitta I., et al.
(författare)
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Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs
- 2007
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 73:11, s. 1829-1841
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Tidskriftsartikel (refereegranskat)abstract
- cis-6-(2-Acetylvinylthio)purine (cAVTP) and trans-6-(2-acetylvinylthio)guanine (tAVTG) are thiopurine prodrugs provisionally inactivated by an α,β-unsaturated substituent on the sulfur of the parental thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). The active thiopurines are liberated intracellularly by glutathione (GSH) in reactions catalyzed by glutathione transferases (GSTs) (EC 2.5.1.18). Catalytic activities of 13 human GSTs representing seven distinct classes of soluble GSTs have been determined. The bioactivation of cAVTP and tAVTG occurs via a transient addition of GSH to the activated double bond of the S-substituent of the prodrug, followed by elimination of the thiopurine. The first of these consecutive reactions is rate-limiting for thiopurine release, but GST-activation of this first addition is shifting the rate limitation to the subsequent elimination. Highly active GSTs reveal the transient intermediate, which is detectable by UV spectroscopy and HPLC analysis. LC/MS analysis of the reaction products demonstrates that the primary GSH conjugate, 4-glutathionylbuten-2-one, can react with a second GSH molecule to form the 4-(bis-glutathionyl)butan-2-one. GST M1-1 and GST A4-4 were the most efficient enzymes with tAVTG, and GST M1-1 and GST M2-2 had highest activity with cAVTP. The highly efficient GST M1-1 is polymorphic and is absent in approximately half of the human population. GST P1-1, which is overexpressed in many cancer cells, had no detectable activity with cAVTP and only minor activity with tAVTG. Other GST-activated prodrugs have targeted GST P1-1-expressing cancer cells. Tumors expressing high levels of GST M1-1 or GST A4-4 can be predicted to be particularly vulnerable to chemotherapy with cAVTP or tAVTG.
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| 2. |
- Arnadottir, Solveig A, 1968-, et al.
(författare)
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Are rural older Icelanders less physically active than those living in urban areas? : a population-based study
- 2009
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 37:4, s. 409-417
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Older people in rural areas have been labelled as physically inactive on the basis of leisure-time physical activity research. However, more research is needed to understand the total physical activity pattern in older adults, considering all domains of physical activity, including leisure, work, and domestic life. AIMS: We hypothesised that: (a) total physical activity would be the same for older people in urban and rural areas; and (b) urban and rural residency, along with gender and age, would be associated with differences in domain-specific physical activities. METHODS: Cross-sectional data were collected in Icelandic rural and urban communities from June through to September 2004. Participants were randomly selected, community-dwelling, 65-88 years old, and comprised 68 rural (40% females) and 118 urban (53% females) adults. The Physical Activity Scale for the Elderly (PASE) was used to obtain a total physical activity score and subscores in leisure, during domestic life, and at work. RESULTS: The total PASE score was not associated with rural vs. urban residency, but males were, in total, more physically active than females, and the 65-74-year-olds were more active than the 75-88-year-olds. In the leisure domain, rural people had lower physical activity scores than urban people. Rural males were, however, most likely of all to be physically active in the work domain. In both urban and rural areas, the majority of the physical activity behaviour occurred in relation to housework, with the rural females receiving the highest scores. CONCLUSIONS: Older Icelanders in rural areas should not be labelled as less physically active than those who live in urban areas. Urban vs. rural living may, however, influence the physical activity patterns among older people, even within a fairly socioeconomically and culturally homogeneous country such as Iceland. This reinforces the need to pay closer attention to the living environment when studying and developing strategies to promote physical activity.
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| 3. |
- Gamborg, Michael, et al.
(författare)
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Birth weight and systolic blood pressure in adolescence and adulthood : meta-regression analysis of sex- and age-specific results from 20 Nordic studies
- 2007
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 166:6, s. 634-645
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Tidskriftsartikel (refereegranskat)abstract
- The authors investigated the shape, sex- and age-dependency, and possible confounding of the association between birth weight and systolic blood pressure (SBP) in 197,954 adults from 20 Nordic cohorts (birth years 1910-1987), one of which included 166,249 Swedish male conscripts. Random-effects meta-regression analyses were performed on estimates obtained from age- and sex-stratified analyses within each of the cohorts. There was an inverse association between birth weight and SBP, irrespective of adjustment for concurrent body mass index. The association was linear for males, but for females with a birth weight greater than 4 kg, SBP increased with birth weight (p < 0.01). The association was stronger in the older age groups (p < 0.05), although this could have been a birth cohort effect. The association was stronger among females than among males (p = 0.005) when birth weight was less than or equal to 4 kg. The estimated effect of birth weight on SBP at age 50 years was -1.52 mmHg/kg (95% confidence interval: -2.27, -0.77) in men and -2.80 mmHg/kg (95% confidence interval: -3.85, -1.76) in women. Exclusion of the Swedish conscripts produced nearly identical results. This meta-analysis supports the evidence of an inverse birth weight-SBP association, regardless of adjustment for concurrent body size. It also reveals important heterogeneity in the shape and strength of the association by sex and age.
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| 4. |
- Gudbjartsson, T, et al.
(författare)
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Congenital diaphragmatic hernia: Improved surgical results should influence abortion decision making
- 2008
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Ingår i: Scandinavian Journal of Surgery. - 1799-7267. ; 97:1, s. 71-76
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To compare surgical results for congenital diaphragmatic hernia (CDH) in two Scandinavian university hospitals and to evaluate the effects of abortions on the clinical profile of CDH in Iceland. Methods: A retrospective study including all CDH-cases in Iceland 1983-2002 and children referred to Lund University Hospital 1993-2002. Aborted fetuses with CDH from a nation-wide Icelandic abort-registry were also included. Results: In Iceland, 19 out of 23 children with CDH were diagnosed < 24 hours from delivery, one with associated anomalies. Eight fetuses were diagnosed prenatally and seven of them aborted, three having isolated CDH at autopsy. In Iceland, 15 of 18 children operated on survived surgery (83% operative survival). In Lund 28 children were treated with surgery, 23 of them diagnosed early after birth or prenatally. Four children did not survive surgery (86% operative survival) and 9 (31%) had associated anomalies. All the discharged children treated in Iceland and Lund are alive, 3-22 years postoperatively. Conclusion: CDH is a serious anomaly where morbidity and mortality is directly related to other associated anomalies and pulmonary hypoplasia. However, majority of CDH patients do not have other associated anomalies. In spite of improved surgical results (operative mortality < 20%), a large proportion of pregnancies complicated with CDH are terminated. We conclude that the improved survival rate after corrective surgery must be emphasized when giving information to parents regarding abortion of fetuses with a prenatally diagnosed CDH.
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| 5. |
- Lyon, Helen N., et al.
(författare)
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The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts
- 2007
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 3:4
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Tidskriftsartikel (refereegranskat)abstract
- A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.
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