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- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Dormandy, J. A., et al.
(författare)
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Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
- 2005
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Ingår i: Lancet. - 1474-547X. ; 366:9493, s. 1279-89
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
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| 3. |
- Palm, Fredrik, et al.
(författare)
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Angiotensin II Type 2 Receptors and Nitric Oxide Sustain Oxygenation in the Clipped Kidney of Early Goldblatt Hypertensive Rats
- 2008
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 51:2, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O2) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (PO2) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (NG-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical PO2 of clipped kidneys was significantly lower than contralateral kidneys (35±1 versus 51±1 mm Hg; n=40 each). ACEI lowered renal venous PO2, cortical PO2, renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and NG-nitro-L-arginine methyl ester, but not candesartan, reduced the PO2 of clipped kidneys and blocked the fall in PO2 with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.
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| 4. |
- Tangelder, Marco J. D., et al.
(författare)
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Effect of ximelagatran on ischemic events and death in patients with atrial fibrillation after acute myocardial infarction in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial
- 2008
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 155:2, s. 382-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: New-onset trial fibrillation (AF) occurs commonly after acute myocardial infarction (MI) and is associated with a poor prognosis due to stroke or death. The optimal antithrombotic therapy is unknown. The aim of this study was to investigate whether an oral direct thrombin inhibitor, ximelagatran, added to aspirin, reduced the risk of death, myocardial infarction (MI), and stroke in patients who developed AF after their qualifying MI in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial. METHODS: The ESTEEM trial evaluated 6 months treatment with ximelagatran together with aspirin, compared to aspirin alone, for prevention of ischemic events in 1883 patients randomized within 14 days after an MI. After their qualifying MI, 174 (9%) patients developed AF in hospital. Multivariate hazard ratios for ximelagatran compared with placebo were calculated by presence AF. RESULTS: Of 101 patients with AF treated with ximelagatran 7 (6.9%) had either death, MI, or stroke, compared with 15 (20.6%) in 73 patients allocated to placebo. Ximelagatran reduced the risk of death, MI, or stroke by 70% (hazard ratio 0.30, 95% CI 0.12-0.74). For the separate outcome events, we found similar, nonsignificant trends. One major bleeding event occurred in each treatment group. CONCLUSIONS: For patients with MI complicated by AF, the combination of aspirin and an oral direct thrombin inhibitor seems beneficial. The high risk for death, MI, and stroke in this population and the increasing use of percutaneous interventions in MI patients may suggest a combination of long-term antiplatelet and anticoagulant therapy. Randomized clinical trials are warranted.
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