| 1. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 2. |
- Berntorp, Erik, et al.
(författare)
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Third Åland islands conference on von Willebrand disease, 26-28 September 2012: meeting report.
- 2013
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 19 Suppl 3, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- The first meeting of international specialists in the field of von Willebrand disease (VWD) was held in the Åland islands in 1998 where Erik von Willebrand had first observed a bleeding disorder in some members of a family from Föglö and a summary of the meeting was published in 1999. The second meeting was held in 2010 and a report of the meeting was published in 2012. Topics covered included progress in understanding of VWD over the last 50 years; multimers; classification of VWD; pharmacokinetics and laboratory assays; genetics; treating the paediatric patient; prophylaxis; geriatrics; gene therapy and treatment guidelines. This third meeting held over 3 days covered the structure and function of von Willebrand factor (VWF); type 1 VWD, the most common form of the disease; a lifespan of pharmacokinetics in VWD; detecting inhibitors in VWD patients; and special challenges in understanding and treating the female VWD patient.
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| 3. |
- Berntorp, Erik, et al.
(författare)
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von Willebrand's disease: a report from a meeting in the Åland islands.
- 2012
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 18 Suppl 6, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- von Willebrand's disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject.
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| 4. |
- Friman, S., et al.
(författare)
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Sotrastaurin, a Novel Small Molecule Inhibiting Protein-Kinase C : Randomized Phase II Study in Renal Transplant Recipients
- 2011
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 11:7, s. 1444-1455
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Tidskriftsartikel (refereegranskat)abstract
- Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1: 2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (+/- standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 +/- 22.3 vs. 49.5 +/- 17.7 mL/min/1.73 m(2), p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.
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| 5. |
- Baumgartner, D., et al.
(författare)
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INFLUENCE OF HEAD ROTATIONAL ACCELERATION PULSE SHAPE ON BRAIN TISSUE STRAINS
- 2014
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Ingår i: Journal of Neurotrauma. - 0897-7151. ; 31:12
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Brain tolerance to rotational acceleration is relevant for understanding injury thresholds and development of injury mitigation techniques for automobiles and sporting events. This computational-modeling study outlined effects of head rotational acceleration pulse shape on strains within brain tissues. A detailed finite element model of the human skull and brain was developed and validated previously. The model was exercised using realistic rotational accelerations with different magnitude and duration characteristics, and the principal strain re- sponse was extracted for parietal cortex, hippocampus, thalamus, and hypothalamus. Rotational acceleration magnitude was varied to three levels: 3.6krad/s 2 (M1), 5.3krad/s 2 (M2), and 6.6krad/s 2 (M3). Duration was varied to 9msec (D1), 18msec (D2), and 27msec (D3). Hippocampus and hypothalamus sustained more strain than cortex and thalamus. With increasing acceleration magnitude from M1 to M2 and M2 to M3, strain in all brain regions was uniformly increased by 42% and 80%. However, strains demonstrated regionally dependent chan- ges with increasing duration (D1 to D3): 68%, 37%, 33% and 14% in parietal cortex, hippocampus, thalamus and hypothalamus, respec- tively. The trend was consistent for all acceleration magnitudes. This study demonstrated differing and independent effects of rotational acceleration magnitude and duration on strains within brain tissues during rotational acceleration. Magnitude has long been a correlate of injury severity and this study supports that finding in that increased acceleration magnitudes led to uniformly higher brain tissue strains (higher injury risk). However, rotational acceleration duration chan- ged the strain distribution within the brain, resulting in different injury risks in different brain regions. This finding is significant as changing strain distribution with different durations can manifest as different injury distributions within the brain and different neuropsychological outcomes following exposure to head rotational acceleration.
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| 6. |
- Russ, G R, et al.
(författare)
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Efficacy of Sotrastaurin Plus Tacrolimus After De Novo Kidney Transplantation : Randomized, Phase II Trial Results
- 2013
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 13:7, s. 1746-1756
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Tidskriftsartikel (refereegranskat)abstract
- Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.
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