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- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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- Granio, Ophélia, et al.
(författare)
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Improved adenovirus type 5 vector-mediated transduction of resistant cells by piggybacking on coxsackie B-adenovirus receptor-pseudotyped baculovirus.
- 2009
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Ingår i: Journal of virology. - 1098-5514. ; 83:12, s. 6048-66
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Tidskriftsartikel (refereegranskat)abstract
- Taking advantage of the wide tropism of baculoviruses (BVs), we constructed a recombinant BV (BV(CAR)) pseudotyped with human coxsackie B-adenovirus receptor (CAR), the high-affinity attachment receptor for adenovirus type 5 (Ad5), and used the strategy of piggybacking Ad5-green fluorescent protein (Ad5GFP) vector on BV(CAR) to transduce various cells refractory to Ad5 infection. We found that transduction of all cells tested, including human primary cells and cancer cell lines, was significantly improved using the BV(CAR)-Ad5GFP biviral complex compared to that obtained with Ad5GFP or BV(CAR)GFP alone. We determined the optimal conditions for the formation of the complex and found that a high level of BV(CAR)-Ad5GFP-mediated transduction occurred at relatively low adenovirus vector doses, compared with transduction by Ad5GFP alone. The increase in transduction was dependent on the direct coupling of BV(CAR) to Ad5GFP via CAR-fiber knob interaction, and the cell attachment of the BV(CAR)-Ad5GFP complex was mediated by the baculoviral envelope glycoprotein gp64. Analysis of the virus-cell binding reaction indicated that the presence of BV(CAR) in the complex provided kinetic benefits to Ad5GFP compared to the effects with Ad5GFP alone. The endocytic pathway of BV(CAR)-Ad5GFP did not require Ad5 penton base RGD-integrin interaction. Biodistribution of BV(CAR)-Ad5Luc complex in vivo was studied by intravenous administration to nude BALB/c mice and compared to Ad5Luc injected alone. No significant difference in viscerotropism was found between the two inocula, and the liver remained the preferred localization. In vitro, coagulation factor X drastically increased the Ad5GFP-mediated transduction of CAR-negative cells but had no effect on the efficiency of transduction by the BV(CAR)-Ad5GFP complex. Various situations in vitro or ex vivo in which our BV(CAR)-Ad5 duo could be advantageously used as gene transfer biviral vector are discussed.
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- Steen, Stig, et al.
(författare)
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First human transplantation of a nonacceptable donor lung after reconditioning ex vivo.
- 2007
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 83:6, s. 2191-2195
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. This article describes an ex vivo method to recondition and transplant rejected donor lungs. Description. A 19-year-old man was brain dead after a traffic accident. A roentgenogram showed bilateral lung contusion. He had ongoing intratracheal bleeding. After optimizing ventilator treatment and suctioning the airways, PaO2 was 9 kPa (67.5 mm Hg) on FiO(2) = 0.7. The lungs were rejected by all transplantation centers in the Nordic countries. We harvested the lungs for research. The right lung was severely injured. The left lung was edematous with bleeding spots in the lower lobe, and the mediobasal segment was atelectatic. The left lung was reconditioned ex vivo and kept in topical extracorporeal membrane oxygenation until it was transplanted into a 70-year-old man with chronic obstructive pulmonary disease 17 hours later. Evaluation. The transplanted lung functioned very well, and the patient recovered uneventfully. At 3 months control, a computed tomographic thoracic scan and transbronchial biopsies showed a normal left lung, and the patient was in very good clinical condition, only to succumb to death from unrelated events 11 months after the transplantation. Conclusions. Rejected donor lungs may be successfully transplanted after being reconditioned ex vivo.
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- Steen, Stig, et al.
(författare)
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Transplantation of lungs from a non-heart-beating donor
- 2001
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Ingår i: The Lancet. - 1474-547X. ; 357:9259, s. 825-829
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In animals, we have previously done successful lung transplantations using organs from non-heart-beating donors. We have also developed an ex-vivo system of assessing the function of such organs before transplantation. The next stage was to try the technique in human beings. Bearing in mind the sensitive ethical issues involved, our first aim was to find out what procedures would be acceptable, and to use the results to guide a clinical lung transplantation from a non-heart-beating donor. METHODS: The ethical acceptability of the study was gauged from the results of a broad information programme directed at the general public in Sweden, and from discussions with professionals including doctors, nurses, hospital chaplains, and judges. The donor was a patient dying of acute myocardial infarction in a cardiac intensive-care unit after failed cardiopulmonary resuscitation. The next of kin gave permission to cool the lungs within the intact body, and intrapleural cooling was started 65 min after death. Blood samples were sent for virological testing and cross matching. The next of kin then had time to be alone with the deceased. After 3 h, the body was transported to the operating theatre and the heart-lung block removed. The lungs were assessed ex vivo, and the body was transported to the pathology department for necropsy. RESULTS: No contraindications to transplantation were found, and the right lung was transplanted successfully into a 54-year-old woman with chronic obstructive pulmonary disease. The donor lung showed excellent function only 5 min after reperfusion and ventilation, and during the first 5 months of follow-up, the function of the transplanted lung has been good. INTERPRETATION: About half the deaths in Sweden are caused by cardiac and cerebrovascular disease. This group could be a potential source of lung donors. When all hospitals and ambulance personnel in Sweden have received training in non-heart-beating lung donation, we hope that there will be enough donor lungs of good quality for all patients needing a lung transplant.
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- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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- Al Rashidi, Faleh, et al.
(författare)
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Comparison of the effectiveness and safety of a new de-airing technique with a standardized carbon dioxide insufflation technique in open left heart surgery: A randomized clinical trial.
- 2011
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Ingår i: The Journal of thoracic and cardiovascular surgery. - : Elsevier BV. - 1097-685X .- 0022-5223. ; okt, s. 1128-1133
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We have compared the effectiveness, time required for de-airing, and safety of a newly developed de-airing technique for open left heart surgery (Lund technique) with a standardized carbon dioxide insufflation technique. METHODS: Twenty patients undergoing elective open aortic valve surgery were randomized prospectively to the Lund technique (Lund group, n = 10) or the carbon dioxide insufflation technique (carbon dioxide group, n = 10). Both groups were monitored intraoperatively during de-airing and for 10 minutes after weaning from cardiopulmonary bypass by transesophageal echocardiography and online transcranial Doppler for the severity and the number of gas emboli, respectively. The systemic arterial partial pressure of carbon dioxide and pH were also monitored in both groups before, during, and after cardiopulmonary bypass. RESULTS: The severity of gas emboli observed on transesophageal echocardiography and the number of microembolic signals recorded by transcranial Doppler were significantly lower in the Lund group during the de-airing procedure (P = .00634) and in the first 10 minutes after weaning from cardiopulmonary bypass (P = .000377). Furthermore, the de-airing time was significantly shorter in the Lund group (9 vs 15 minutes, P = .001). The arterial pH during the cooling phase of cardiopulmonary bypass was significantly lower in the carbon dioxide group (P = .00351), corresponding to significantly higher arterial partial pressure of carbon dioxide (P = .005196) despite significantly higher gas flows (P = .0398) in the oxygenator throughout the entire period of cardiopulmonary bypass. CONCLUSIONS: The Lund de-airing technique is safer, simpler, and more effective compared with the carbon dioxide insufflation technique. The technique is also more cost-effective because the de-airing time is shorter and no extra expenses are incurred.
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