Summary
Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease‐modifying therapy is available. For a long time, OA was ...considered a non‐inflammatory disease that was the result of ‘wear‐and‐tear’ and abnormal mechanics, and therefore many considered the term ‘osteoarthritis’ a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low‐grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted.
Whereas osteoarthritis was historically considered a disease solely of the articular cartilage, it is nowadays broadly accepted that inflammation plays a crucial role in the disease development. Of particular interest in the inflammatory cascade during osteoarthritis are the alarmins, which are released upon cell stress and lie at the basis of the immune reaction. This review gives an overview of the inflammatory processes that are involved in osteoarthritis, with a particular focus on alarmins, and provides possibilities to inhibit these alarmins.
Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host ...cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1A through S1D. Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1B. We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1A. When multivalently displayed on nanoparticles, S1 or S1A bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5-N-glycolylation and (7,)9-O-acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus–Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen.
Human papillomavirus (HPV)-related screening technologies and HPV vaccination offer enormous potential for cancer prevention, notably prevention of cervical cancer. The effectiveness of these ...approaches is, however, suboptimal owing to limited implementation of screening programmes and restricted indications for HPV vaccination. Trials of HPV vaccination in women aged up to 55 years have shown almost 90% protection from cervical precancer caused by HPV16/18 among HPV16/18-DNA-negative women. We propose extending routine vaccination programmes to women of up to 30 years of age (and to the 45-50-year age groups in some settings), paired with at least one HPV-screening test at age 30 years or older. Expanding the indications for HPV vaccination and much greater use of HPV testing in screening programmes has the potential to accelerate the decline in cervical cancer incidence. Such a combined protocol would represent an attractive approach for many health-care systems, in particular, countries in Central and Eastern Europe, Latin America, Asia, and some more-developed parts of Africa. The role of vaccination in women aged >30 years and the optimal number of HPV-screening tests required in vaccinated women remain important research issues. Cost-effectiveness models will help determine the optimal combination of HPV vaccination and screening in public health programmes, and to estimate the effects of such approaches in different populations.
Osteoarthritis year in review 2020: biology van den Bosch, M.H.J.
Osteoarthritis and cartilage,
February 2021, 2021-02-00, 20210201, Letnik:
29, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This year in review about osteoarthritis biology highlights a selection of articles published between the 2019 and 2020 Osteoarthritis Research Society International (OARSI) World Congress meetings, ...within the field of osteoarthritis biology. Highlights were selected from PubMed searches covering osteoarthritis (OA) cartilage, subchondral bone, synovium and aging. Subsequently, a personal selection was based on new and emerging themes together with common research topics that were studied by multiple groups. Themes discussed include novel insights into the inflammatory changes during OA, with a number of noteworthy publications concerning the role of macrophages in healthy and osteoarthritic joints. Next, the application of mesenchymal stem cells as OA-dampening therapy is discussed, including possible ways to improve their efficacy by pre-treatment. Other significant themes including treatment of OA with metformin, enhancing autophagy to alleviate OA and the involvement of the gastro-intestinal microbiome in development of OA symptoms and structural damage are discussed. An effort was made to connect the seemingly distant topics from which the overarching conclusion can be drawn that over the last year promising breakthroughs have been achieved in further understanding the biology of OA development and that new therapeutic possibilities have been explored.
Context.
Until recently, the 3D shape, and therefore density (when combining the volume estimate with available mass estimates), and surface topography of the vast majority of the largest (
D
≥ 100 ...km) main-belt asteroids have remained poorly constrained. The improved capabilities of the SPHERE/ZIMPOL instrument have opened new doors into ground-based asteroid exploration.
Aims.
To constrain the formation and evolution of a representative sample of large asteroids, we conducted a high-angular-resolution imaging survey of 42 large main-belt asteroids with VLT/SPHERE/ZIMPOL. Our asteroid sample comprises 39 bodies with
D
≥ 100 km and in particular most
D
≥ 200 km main-belt asteroids (20/23). Furthermore, it nicely reflects the compositional diversity present in the main belt as the sampled bodies belong to the following taxonomic classes: A, B, C, Ch/Cgh, E/M/X, K, P/T, S, and V.
Methods.
The SPHERE/ZIMPOL images were first used to reconstruct the 3D shape of all targets with both the ADAM and MPCD reconstruction methods. We subsequently performed a detailed shape analysis and constrained the density of each target using available mass estimates including our own mass estimates in the case of multiple systems.
Results.
The analysis of the reconstructed shapes allowed us to identify two families of objects as a function of their diameters, namely “spherical” and “elongated” bodies. A difference in rotation period appears to be the main origin of this bimodality. In addition, all but one object (216 Kleopatra) are located along the Maclaurin sequence with large volatile-rich bodies being the closest to the latter. Our results further reveal that the primaries of most multiple systems possess a rotation period of shorter than 6 h and an elongated shape (
c
∕
a
≤ 0.65). Densities in our sample range from ~1.3 g cm
−3
(87 Sylvia) to ~4.3 g cm
−3
(22 Kalliope). Furthermore, the density distribution appears to be strongly bimodal with volatile-poor (
ρ
≥ 2.7 g cm
−3
) and volatile-rich (
ρ
≤ 2.2 g cm
−3
) bodies. Finally, our survey along with previous observations provides evidence in support of the possibility that some C-complex bodies could be intrinsically related to IDP-like P- and D-type asteroids, representing different layers of a same body (C: core; P/D: outer shell). We therefore propose that P/ D-types and some C-types may have the same origin in the primordial trans-Neptunian disk.
We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were ...evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics.
Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma AA and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing.
The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different.
In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.
OBJECTIVES:Early identification of potential recovery of postanoxic coma is a major challenge. We studied the additional predictive value of EEG.
METHODS:Two hundred seventy-seven consecutive ...comatose patients after cardiac arrest were included in a prospective cohort study on 2 intensive care units. Continuous EEG was measured during the first 3 days. EEGs were classified as unfavorable (isoelectric, low-voltage, burst-suppression with identical bursts), intermediate, or favorable (continuous patterns), at 12, 24, 48, and 72 hours. Outcome was dichotomized as good or poor. Resuscitation, demographic, clinical, somatosensory evoked potential, and EEG measures were related to outcome at 6 months using logistic regression analysis. Analyses of diagnostic accuracy included receiver operating characteristics and calculation of predictive values.
RESULTS:Poor outcome occurred in 149 patients (54%). Single measures unequivocally predicting poor outcome were an unfavorable EEG pattern at 24 hours, absent pupillary light responses at 48 hours, and absent somatosensory evoked potentials at 72 hours. Together, these had a specificity of 100% and a sensitivity of 50%. For the remaining 203 patients, who were still in the “gray zone” at 72 hours, a predictive model including unfavorable EEG patterns at 12 hours, absent or extensor motor response to pain at 72 hours, and higher age had an area under the curve of 0.90 (95% confidence interval 0.84–0.96). Favorable EEG patterns at 12 hours were strongly associated with good outcome. EEG beyond 24 hours had no additional predictive value.
CONCLUSIONS:EEG within 24 hours is a robust contributor to prediction of poor or good outcome of comatose patients after cardiac arrest.
Planet Hunters IX. KIC 8462852 – where's the flux? Boyajian, T. S; LaCourse, D. M; Rappaport, S. A ...
Monthly notices of the Royal Astronomical Society,
04/2016, Letnik:
457, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Over the duration of the Kepler mission, KIC 8462852 was observed to undergo irregularly shaped, aperiodic dips in flux of up to ∼20 per cent. The dipping activity can last for between 5 and 80 d. We ...characterize the object with high-resolution spectroscopy, spectral energy distribution fitting, radial velocity measurements, high-resolution imaging, and Fourier analyses of the Kepler light curve. We determine that KIC 8462852 is a typical main-sequence F3 V star that exhibits no significant IR excess, and has no very close interacting companions. In this paper, we describe various scenarios to explain the dipping events observed in the Kepler light curve. We confirm that the dipping signals in the data are not caused by any instrumental or data processing artefact, and thus are astrophysical in origin. We construct scenario-independent constraints on the size and location of a body in the system that are needed to reproduce the observations. We deliberate over several assorted stellar and circumstellar astrophysical scenarios, most of which have problems explaining the data in hand. By considering the observational constraints on dust clumps in orbit around a normal main-sequence star, we conclude that the scenario most consistent with the data in hand is the passage of a family of exocomet or planetesimal fragments, all of which are associated with a single previous break-up event, possibly caused by tidal disruption or thermal processing. The minimum total mass associated with these fragments likely exceeds 10−6 M⊕, corresponding to an original rocky body of >100 km in diameter. We discuss the necessity of future observations to help interpret the system.
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