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- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 4. |
- Engelfriet, P, et al.
(författare)
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Adherence to guidelines in the clinical care for adults with congenital heart disease: The Euro Heart Survey on adult congenital heart disease
- 2006
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 27:6, s. 737-745
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Tidskriftsartikel (refereegranskat)abstract
- Aims To investigate the role of guidelines in structuring the clinical care for adult patients with congenital heart disease (CHD), and to assess adherence to the guidelines in Europe. Methods and results A selected number of current guidelines were chosen pertaining to operative procedures, investigations, and the use of medication ('interventions'). The source for this analysis was the database of the Euro Heart Survey on adult CHD, which contains retrospectively collected data on 4110 patients followed-up for a median of 5.1 years. For each guideline investigated, patients were selected from the database for whom the particular guideline was relevant. The selected cases were classified according to two criteria: was there an indication for the particular intervention and did the intervention take place? In this manner, cases of 'undue treatment' and 'insufficient treatment' were identified. Adherence to guidelines was found to be good in the case of operative procedures and prophylactic drug treatment. However, regarding diagnostic procedures there had been adherence to guidelines in only slightly more than half of the cases. Conclusion Guidelines have an important role in the actual clinical care of adults with CHD. However, large outcome studies are needed to develop more precise guidelines.
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| 5. |
- Engelfriet, P, et al.
(författare)
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The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period - The Euro Heart Survey on adult congenital heart disease
- 2005
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 26:21, s. 2325-2333
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Tidskriftsartikel (refereegranskat)abstract
- Aims To describe clinical and demographic characteristics at baseline of a European cohort of adults with congenital heart disease (CHD) and to assess mortality and morbidity in a 5 year follow-up period. Methods and results Data collected as part of the Euro Heart Survey on adult CHD was analysed. This entailed information transcribed from the files of 4110 patients diagnosed with one of eight congenital heart conditions ('defects'), who consecutively visited the outpatient clinics of one of the participating centres in 1998. The patients were included retrospectively and followed until the end of 2003 for a median follow-up of 5.1 years. Notwithstanding their overall relatively good functional class and low mortality over the follow-up period, a considerable proportion of the patients had a history of endocarditis, arrhythmias, or vascular events. There were major differences between the eight defects, both in morbidity and regarding specific characteristics. Outcomes were worst in cyanotic defects and in the Fontan circulation, but a considerable proportion of the other patients also suffer from cardiac symptoms. In particular, arrhythmias are common. Conclusion The spectrum of adult CHD in Europe emerging from this survey is one of a predominantly young population with substantial morbidity but relatively low mortality in a 5 year period.
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| 6. |
- Fex, Malin, et al.
(författare)
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A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 271-280
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. METHODS: To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. RESULTS: We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. CONCLUSIONS/INTERPRETATION: Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipid-derived signal essential for normal insulin secretion.
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| 7. |
- Lyssenko, Valeriya, et al.
(författare)
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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 82-88
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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