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| 2. |
- Alvarez, Yolanda, et al.
(författare)
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Selective inhibition of retinal angiogenesis by targeting PI3 kinase
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 4:11, s. e7867-
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Tidskriftsartikel (refereegranskat)abstract
- Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.
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| 3. |
- Brennan, Donal J, et al.
(författare)
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Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 14:9, s. 2681-2689
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model. Experimental Design: A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining. Results: Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmicto-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of CIS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016). Conclusion: Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor.
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| 4. |
- Chen, Yuqing, et al.
(författare)
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Naturally occurring human genetic variation in the 3'-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion
- 2008
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:18, s. 1468-81
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We aimed to determine whether the common variation at the chromogranin A (CHGA) locus increases susceptibility to hypertension. BACKGROUND: CHGA regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. METHODS: We carried out dense genotyping across the CHGA locus in >1,000 individuals with the most extreme blood pressures (BPs) in the population, as well as twin pairs with autonomic phenotypes. We also characterized the function of a trait-associated 3'-untranslated region (3'-UTR) variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. RESULTS: CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurring in the 3'-UTR at C+87T, accounting for up to approximately 12/ approximately 9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by approximately 10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the systolic BP response to stress by approximately 12 mm Hg, and the response was smaller in women (by approximately 6 mm Hg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by approximately 30%. In cultured chromaffin cells, reducing endogenous CHGA expression by small interfering ribonucleic acid caused approximately two-thirds depletion of catecholamine storage vesicles. CONCLUSIONS: Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and we propose steps ("intermediate phenotypes") whereby in a sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension.
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| 5. |
- Hernandez, A. F., et al.
(författare)
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Rationale and design of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND-HF)
- 2009
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Ingår i: Am Heart J. - 1097-6744. ; 157:2, s. 271-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acute decompensated heart failure (ADHF) is a major public health burden with significant mortality and morbidity. Nesiritide is a recombinantly produced intravenous formulation of human B-type natriuretic peptide that promotes vasodilation and increases salt and water excretion, which results in reduced cardiac filling pressures. Prior studies have shown that dyspnea is improved in patients with ADHF 3 hours after nesiritide infusion with significant dose-related reductions in cardiac filling pressures and systemic vascular resistance without significant arrhythmias. However, the effect of nesiritide on dyspnea at 6 or 24 hours is unknown, and no clinical outcome trials have been done to provide a reliable estimate of the effect of nesiritide on morbidity and mortality. METHODS: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial (ASCEND-HF) is a phase III study evaluating the efficacy and safety of nesiritide in patients with ADHF. Patients hospitalized for hear failure will be randomly assigned to receive either intravenous nesiritide or matching placebo for 24 hours to 7 days. The 2 coprimary end points are (1) assessment of acute dyspnea at 6 or 24 hours and (2) death or rehospitalization for hear failure within 30 days. A total of 7,000 patients will be enrolled worldwide between 2007 and 2010. CONCLUSIONS: The data from the ASCEND-HF trial will establish whether nesiritide safely improves acute dyspnea as well as morbidity and mortality at 30 days.
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| 6. |
- McGlynn, Sinead, et al.
(författare)
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GRB 070707 : the first short gamma-ray burst observed by INTEGRAL
- 2008
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 486:2, s. 405-410
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Tidskriftsartikel (refereegranskat)abstract
- Context. INTEGRAL has observed 47 long-duration GRBs (T-90 greater than or similar to 2 s) and 1 short-duration GRB (T-90 less than or similar to 2 s) in five years of observation since October 2002. Aims. This work presents the properties of the prompt emission of GRB 070707, which is the first short hard GRB observed by INTEGRAL. Methods. The spectral and temporal properties of GRB 070707 were determined using the two sensitive coded-mask gamma-ray instruments on board INTEGRAL, IBIS and SPI. Results. The T-90 duration was 0.8 s, and the spectrum of the prompt emission was obtained by joint deconvolution of IBIS and SPI data to yield a best fit power-law with photon index alpha = -1.19(-0.13)(+0.14) , which is consistent with the characteristics of short-hard gamma-ray bursts. The peak flux over 1 s was 1.79(-0.21)(+0.06) photons cm(-2) s(-1) and the fluence over the same interval was (2.07(-0.32)(+0.06) ) x 10(-7) erg cm(-2) in the energy range 20-200 keV. The spectral lag measured between 25-50 keV and 100-300 keV is 20 +/- 5 ms, consistent with the small or negligible lags measured for short bursts. Conclusions. The spectral and temporal properties of GRB 070707 are comparable to those of the short hard bursts detected by other gamma-ray satellites, including BATSE and Swift. We estimate a lower limit on the Lorentz factor Gamma greater than or similar to 25 for GRB 070707, assuming the typical redshift for short GRBs of z = 0.35. This limit is consistent with previous estimates for short GRBs and is smaller than the lower limits of Gamma greater than or similar to 100 calculated for long GRBs. If GRB 070707 is a member of the recently postulated class of short GRBs at z similar to 1, the lower limit on Gamma increases to Gamma greater than or similar to 35.
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| 7. |
- McGlynn, Sinéad, et al.
(författare)
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High energy emission and polarisation limits for the INTEGRAL burst GRB061122
- 2009
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 499:2, s. 465-472
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Tidskriftsartikel (refereegranskat)abstract
- Context. GRB061122 is one of the brightest GRBs detected within INTEGRAL's field of view to date, with a peak flux (20-200 keV) of 32 photons cm(-2) s(-1) and fluence of 2 x 10(-5) erg cm(-2). The Spectrometer aboard INTEGRAL, SPI, can measure linear polarisation in bright GRBs through the process of Compton scattering in the Germanium detectors. Polarisation measurements of the prompt emission are relatively rare. The spectral and polarisation results can be combined to provide vital information about the circumburst region. Aims. The two gamma-ray detectors on INTEGRAL were used to investigate the spectral characteristics of GRB061122. A search for linear polarisation in the prompt emission was carried out on GRB061122 using the SPI multiple event data in the energy range 100 keV-1 MeV. The X-ray properties were examined using data from the X-Ray Telescope (XRT) on Swift. Methods. The gamma-ray spectral and temporal properties of GRB061122 were determined using IBIS and SPI. The afterglow properties were obtained using XRT. The multiple event data of GRB061122 from SPI were analysed and compared with the predicted instrument response obtained from Monte-Carlo simulations using the GEANT 4 INTEGRAL mass model. The chi(2) distributions between the real and simulated data as a function of the percentage polarisation and polarisation angle were calculated and limits on the level and angle of polarisation were obtained from the best-fit value of chi(2). Results. The prompt spectrum was best fit by a combination of a blackbody and a power-law model (the quasithermal model), with evidence for high energy emission continuing above 8 MeV. A pseudo-redshift value of pz = 0.95 +/- 0.18 was determined using the spectral fit parameters. The isotropic energy at this pseudo-redshift is 8.5 x 10(52) erg. The jet opening angle was estimated to be smaller than 2.8 degrees or larger than 11.9 degrees from the X-ray lightcurve. An upper limit of 60% polarisation was determined for the prompt emission of GRB061122, using the multiple event data from the spectrometer on INTEGRAL. Conclusions. The high energy emission observed in the spectrum may be due to the reverse shock interacting with the GRB ejecta when it is decelerated by the circumburst medium. This behaviour has been observed in a small fraction of GRBs to date, but is expected to be more commonly observed by the Fermi Gamma-ray Space Telescope. The conditions for polarisation are met if the jet opening angle is less than 2.8 degrees, but further constraints on the level of polarisation are not possible.
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| 8. |
- Nichol, G., et al.
(författare)
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International Resuscitation Network Registry: design, rationale and preliminary results
- 2005
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 65:3, s. 265-77
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Tidskriftsartikel (refereegranskat)abstract
- There is a lack of high-quality information about the effectiveness of resuscitation interventions and international differences in structure, process and outcome after out-of-hospital cardiac arrest and cardiopulmonary resuscitation because data are not collected uniformly. An internet-based international registry could make such evaluations possible, and enable the conduct of large randomized controlled trials of resuscitation therapies. A prospective international cohort study was performed that included 571 infants, children and adults (a) who experienced cardiac arrest requiring chest compressions or external defibrillation, (b) outside the hospital in the study communities and (c) upon whom resuscitation was attempted by EMS personnel. Cardiac arrest was defined as lack of responsiveness, breathing or movement in individuals for whom the EMS system is activated for whom an arrest record is completed. All data were collated via a secure and confidential web-based method by using automated forms processing software with appropriate variable range checks, logic checks and skip rules. Median number of missing responses for each variable was 0 (interquartile range 0, 0). Twenty-seven percent of the patients had a first recorded rhythm of ventricular fibrillation or ventricular tachycardia, 60% had a witnessed arrest, and 34% received bystander CPR. Mean time from call to arrival on scene was 7.1+/-5.1 min. Six percent of the patients survived to hospital discharge. The resuscitation process was highly variable across centers, and survival and neurological outcome were also significantly and independently different across centers. This study shows that it is possible to collect data prospectively describing the structure, process and outcome associated with cardiac arrest in multiple international sites via the internet. Therefore, it is feasible to conduct adequately powered randomized trials of resuscitation therapies in international settings.
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| 9. |
- Polman, CH, et al.
(författare)
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Diagnostic criteria for multiple sclerosis: 2005 Revisions to the "McDonald Criteria"
- 2005
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 58:6, s. 840-846
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Tidskriftsartikel (refereegranskat)abstract
- New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.
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