| 1. |
- Mohebnasab, Maedeh, et al.
(författare)
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Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 10, s. 1-13
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Forskningsöversikt (refereegranskat)abstract
- Aberrations in complement system functions have been identified as either direct or indirect pathophysiological mechanisms in many diseases and pathological conditions, such as infections, autoimmune diseases, inflammation, malignancies, and allogeneic transplantation. Currently available techniques to study complement include quantification of (a) individual complement components, (b) complement activation products, and (c) molecular mechanisms/function. An emerging area of major interest in translational studies aims to study and monitor patients on complement regulatory drugs for efficacy as well as adverse events. This area is progressing rapidly with several anti-complement therapeutics under development, in clinical trials, or already in clinical use. In this review, we summarized the appropriate indications, techniques, and interpretations of basic complement analyses, exemplified by a number of clinical disorders.
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| 2. |
- Nilsson Ekdahl, Kristina, et al.
(författare)
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Is generation of C-3(H2O) necessary for activation of the alternative pathway in real life?
- 2019
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Ingår i: Molecular Immunology. - : Elsevier. - 0161-5890 .- 1872-9142. ; 114, s. 353-361
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Tidskriftsartikel (refereegranskat)abstract
- In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the "C3b-like" C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces. During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by the classical/lectin pathway (CP/LP) convertases. After the discovery of LP's recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules. Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases. Therefore, C3(H2O) generation in vivo may be less important for AP activation during specific attack or dysregulated homeostasis, but may be an important ligand for C3 receptors in cell-cell interactions and a source of C3 for the intracellular complement reservoir.
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| 3. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 4. |
- van Griensven, Martijn, et al.
(författare)
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PROTECTIVE EFFECTS OF THE COMPLEMENT INHIBITOR COMPSTATIN CP40 IN HEMORRHAGIC SHOCK
- 2019
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Ingår i: Shock. - Alphen aan den Rijn : LIPPINCOTT WILLIAMS & WILKINS. - 1073-2322 .- 1540-0514. ; 51:1, s. 78-87
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Tidskriftsartikel (refereegranskat)abstract
- Trauma-induced hemorrhagic shock (HS) plays a decisive role in the development of immune, coagulation, and organ dysfunction often resulting in a poor clinical outcome. Imbalanced complement activation is intricately associated with the molecular danger response and organ damage after HS. Thus, inhibition of the central complement component C3 as turnstile of both inflammation and coagulation is hypothesized as a rational strategy to improve the clinical course afterHS. Applying intensive care conditions, anaesthetized, monitored, and protectively ventilated nonhuman primates (NHP; cynomolgusmonkeys) received a pressure-controlled severe HS (60min at mean arterial pressure 30 mmHg) with subsequent volume resuscitation. Thirty minutes after HS, animals were randomly treated with either an analog of the C3 inhibitor compstatin (i.e., Cp40) in saline (n =4) or with saline alone (n =4). The observation period lasted 300 min after induction of HS. We observed improved kidney function in compstatin Cp40-treated animals after HS as determined by improved urine output, reduced damage markers and a tendency of less histopathological signs of acute kidney injury. Sham-treated animals revealed classical signs ofmucosal edema, especially in the ileum and colon reflected by worsened microscopic intestinal injury scores. In contrast, Cp40-treated HS animals exhibited only minor signs of organ edema and significantly less intestinal damage. Furthermore, early systemic inflammation and coagulation dysfunction were both ameliorated by Cp40. The data suggest that therapeutic inhibition of C3 is capable to significantly improve immune, coagulation, and organ function and to preserve organ-barrier integrity early after traumatic HS. C3-targeted complement inhibition may therefore reflect a promising therapeutic strategy in fighting fatal consequences of HS.
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| 5. |
- Went, Molly, et al.
(författare)
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Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes
- 2019
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Ingår i: Human Genomics. - : Springer Science and Business Media LLC. - 1479-7364. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWhile genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).ResultsGWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80–491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.ConclusionsOur findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.
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| 6. |
- Alexander, Daniel C., et al.
(författare)
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Imaging brain microstructure with diffusion MRI : Practicality and applications
- 2019
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Ingår i: NMR in Biomedicine. - : Wiley. - 0952-3480 .- 1099-1492. ; 32:4, s. 3841-3841
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Forskningsöversikt (refereegranskat)abstract
- This article gives an overview of microstructure imaging of the brain with diffusion MRI and reviews the state of the art. The microstructure-imaging paradigm aims to estimate and map microscopic properties of tissue using a model that links these properties to the voxel scale MR signal. Imaging techniques of this type are just starting to make the transition from the technical research domain to wide application in biomedical studies. We focus here on the practicalities of both implementing such techniques and using them in applications. Specifically, the article summarizes the relevant aspects of brain microanatomy and the range of diffusion-weighted MR measurements that provide sensitivity to them. It then reviews the evolution of mathematical and computational models that relate the diffusion MR signal to brain tissue microstructure, as well as the expanding areas of application. Next we focus on practicalities of designing a working microstructure imaging technique: model selection, experiment design, parameter estimation, validation, and the pipeline of development of this class of technique. The article concludes with some future perspectives on opportunities in this topic and expectations on how the field will evolve in the short-to-medium term.
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| 7. |
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| 8. |
- Beaney, Thomas, et al.
(författare)
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May Measurement Month 2018 : a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 40:25, s. 2006-2017
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. METHODS AND RESULTS: Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. CONCLUSION: May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.
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| 9. |
- Brusini, Lorenza, et al.
(författare)
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Monte Carlo simulations of water exchange through myelin wraps : Implications for diffusion MRI
- 2019
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Ingår i: IEEE Transactions on Medical Imaging. - 1558-254X. ; 38:6, s. 1438-1445
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Tidskriftsartikel (refereegranskat)abstract
- Diffusion MRI yields parameters sensitive to brain tissue microstructure. A structurally important aspect of this microstructure is the myelin wrapping around the axons. This study investigated the forward problem concerning whether water exchange via the spiraling structure of the myelin can meaningfully contribute to the signal in dMRI. Monte Carlo simulations were performed of a system with intra-axonal, myelin and extra-axonal compartments. Diffusion in the myelin was simulated as a spiral wrapping the axon, with a custom number of wraps. Exchange (or intra-axonal residence) times, were analyzed for various number of wraps and axon diameters. Pulsed gradient sequences were employed to simulate the dMRI signal, which was analyzed using different methods. Diffusional kurtosis imaging analysis yielded the radial diffusivity (RD) and radial kurtosis (RK), while the two-compartment Kärger model yielded estimates of the intra-axonal volume fraction (νic) and exchange time (τ). Results showed that τ was on the sub-second level for geometries with axon diameters below 1.0 μm and less than eight wraps. Otherwise, exchange was negligible compared to typical experimental durations, with τ of seconds or longer. In situations where exchange influenced the signal, estimates of RK and νic increased with the number of wraps, while RD decreased. τ estimates from simulated signals were in agreement with predicted ones. In conclusion, exchange through spiraling myelin permits sub-second τ for small diameters and low number of wraps. Such conditions may arise in the developing brain or in neurodegenerative disease, and thus the results could aid the interpretation of dMRI studies.
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| 10. |
- D'Orazi, V., et al.
(författare)
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Mapping of shadows cast on a protoplanetary disk by a close binary system
- 2019
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 3:2, s. 167-172
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Tidskriftsartikel (refereegranskat)abstract
- For a comprehensive understanding of planetary formation and evolution, we need to investigate the environment in which planets form: circumstellar disks. Here we present high-contrast imaging observations of V4046 Sagittarii, a 20-Myr-old close binary known to host a circumbinary disk. We have discovered the presence of rotating shadows in the disk, caused by mutual occultations of the central binary. Shadow-like features are often observed in disks(1,2), but those found thus far have not been due to eclipsing phenomena. We have used the phase difference due to light travel time to measure the flaring of the disk and the geometrical distance of the system. We calculate a distance that is in very good agreement with the value obtained from the Gaia mission's Data Release 2 (DR2), and flaring angles of alpha = (6.2 +/- 0.6)degrees and alpha = (8.5 +/- 1.0)degrees for the inner and outer disk rings, respectively. Our technique opens up a path to explore other binary systems, providing an independent estimate of distance and the flaring angle, a crucial parameter for disk modelling.
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