| 1. |
- Biglarnia, Ali Reza, et al.
(författare)
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The multifaceted role of complement in kidney transplantation
- 2018
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Ingår i: Nature Reviews Nephrology. - : Nature Publishing Group. - 1759-5061 .- 1759-507X. ; 14:12, s. 767-781
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Forskningsöversikt (refereegranskat)abstract
- Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HL A incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.
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| 2. |
- Huber-Lang, Markus, et al.
(författare)
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Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions
- 2018
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Ingår i: Seminars in Immunopathology. - : Springer. - 1863-2297 .- 1863-2300. ; 40:1, s. 87-102
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Forskningsöversikt (refereegranskat)abstract
- Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation.
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| 3. |
- Nystedt, Jessika, et al.
(författare)
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Altered white matter microstructure in lupus patients : A diffusion tensor imaging study
- 2018
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of this study was to investigate whether white matter microstructure is altered in patients suffering from systemic lupus erythematosus (SLE), and if so, whether such alterations differed between patients with and without neuropsychiatric symptoms. Methods: Structural MRI and diffusion tensor imaging (DTI) were performed in 64 female SLE patients (mean age 36.9 years, range 18.2-52.2 years) and 21 healthy controls (mean age 36.7 years, range 23.3-51.2 years) in conjunction with clinical examination, laboratory tests, cognitive evaluation, and self-assessment questionnaires. The patients were subgrouped according to the American College of Rheumatology Neuropsychiatric Systemic Lupus Erythematosus case definitions into non-neuropsychiatric SLE (nonNPSLE) and neuropsychiatric SLE (NPSLE). Results: Comparisons between the SLE group and healthy controls showed that the mean fractional anisotropy (FA) was significantly reduced in the right rostral cingulum (p=0.038), the mid-sagittal corpus callosum (CC) (p=0.050), and the forceps minor of the CC (p=0.015). The mean diffusivity (MD) was significantly increased in the left hippocampal cingulum (p=0.017). No significant differences in MD or FA values were identified between NPSLE and nonNPSLE patients. Disease duration among all SLE patients correlated significantly with reduced FA in the CC (p<0.05). No correlations were found between DTI parameters and white matter hyperintensities, SLE Disease Activity Index-2000, Systemic Lupus International Collaborating Clinical/ACR Organ Damage Index, or Montgomery Asberg Depression Rate Score Self-report. Conclusions: We found alterations of white matter microstructure in SLE patients that were related to disease duration and fatigue. Our results indicate that cerebral involvement in SLE is not isolated to the NPSLE subgroup.
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| 4. |
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| 5. |
- Went, Molly, et al.
(författare)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
- 2018
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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| 6. |
- Ali, Mina, et al.
(författare)
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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 1649-
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined = 2.5 × 10−27; βcombined = −0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause–effect relationship. Our results provide mechanistic insight into MM predisposition.
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| 7. |
- Beaney, Thomas, et al.
(författare)
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May Measurement Month 2017 : an analysis of blood pressure screening results worldwide
- 2018
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Ingår i: The Lancet Global Health. - 2214-109X. ; 6:7, s. 736-743
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods: This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings: Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation: Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding: International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.
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| 8. |
- Brusini, Lorenza, et al.
(författare)
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Assessing tissue heterogeneity by non-Gaussian measures in a permeable environment
- 2018
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Ingår i: 2018 26th European Signal Processing Conference, EUSIPCO 2018. - 9789082797015 ; 2018-September, s. 1147-1151
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Konferensbidrag (refereegranskat)abstract
- In diffusion MRI, the deviation of the Ensemble Average Propagator (EAP) from Gaussianity conveys information about the microstructural heterogeneity within an imaging voxel. Different measures have been proposed for assessing this heterogeneity. This paper assesses the performance of the Diffusional Kurtosis Imaging (DKI) and Simple Harmonics Oscillator Reconstruction and Estimation (SHORE) approaches using Monte Carlo simulations of water diffusion within synthetic axons with a permeable myelin sheath. The aim was also to understand the impact of myelin features such as its number of wrappings and relaxation (T2) rate on MR-observable parameters. To this end, a substrate consisting of parallel cylinders coated by a multi-layer sheet was considered, and simulations were used to generate the synthetic diffusion-weighted signal. Results show that myelin features affects the parameters quantified by both DKI and SHORE. A strong agreement was found between DKI and SHORE parameters, highlighting the consistency of the methods in characterising the diffusion-weighted signal.
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| 9. |
- Bäckström, Erica, et al.
(författare)
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Uncovering the regional localization of inhaled salmeterol retention in the lung
- 2018
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Ingår i: Drug Delivery. - : Taylor & Francis Group. - 1071-7544 .- 1521-0464. ; 25:1, s. 838-845
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d(3)-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.
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| 10. |
- Cheetham, A., et al.
(författare)
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Discovery of a brown dwarf companion to the star HIP 64892
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 615
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of a bright, brown dwarf companion to the star HIP 64892, imaged with VLT/SPHERE during the SHINE exoplanet survey. The host is a B9.5V member of the Lower-Centaurus-Crux subgroup of the Scorpius Centaurus OB association. The measured angular separation of the companion (1.2705 +/- 0.0023) corresponds to a projected distance of 159 +/- 12AU. We observed the target with the dual-band imaging and long-slit spectroscopy modes of the IRDIS imager to obtain its spectral energy distribution (SED) and astrometry. In addition, we reprocessed archival NACO L-band data, from which we also recover the companion. Its SED is consistent with a young (<30 Myr), low surface gravity object with a spectral type of M9 gamma +/- 1. From comparison with the BT-Settl atmospheric models we estimate an effective temperature of T-eff = 2600 +/- 100 K, and comparison of the companion photometry to the COND evolutionary models yields a mass of similar to 29-37 M-J at the estimated age of 16(-7)(+15) Myr for the system. The star HIP 64892 is a rare example of an extreme-mass ratio system (q similar to 0.01) and will be useful for testing models relating to the formation and evolution of such low-mass objects.
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