Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify ...joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.
BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION ...AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD.
Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score).
CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts.
The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.
Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to ...have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera
Aspergillus
,
Penicillium
,
Talaromyces
,
Fusarium
, and
Arthrinium
, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy.
Key points
•
Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium.
•
Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries.
•
Quinones are grouped into families and compared between genera according to the revised taxonomy.
Summary Animal models of osteoarthritis (OA) are essential tools for investigating the development of the disease on a more rapid timeline than human OA. Mice are particularly useful due to the ...plethora of genetically modified or inbred mouse strains available. The majority of available mouse models of OA use a joint injury or other acute insult to initiate joint degeneration, representing post-traumatic osteoarthritis (PTOA). However, no consensus exists on which injury methods are most translatable to human OA. Currently, surgical injury methods are most commonly used for studies of OA in mice; however, these methods may have confounding effects due to the surgical/invasive injury procedure itself, rather than the targeted joint injury. Non-invasive injury methods avoid this complication by mechanically inducing a joint injury externally, without breaking the skin or disrupting the joint. In this regard, non-invasive injury models may be crucial for investigating early adaptive processes initiated at the time of injury, and may be more representative of human OA in which injury is induced mechanically. A small number of non-invasive mouse models of PTOA have been described within the last few years, including intra-articular fracture of tibial subchondral bone, cyclic tibial compression loading of articular cartilage, and anterior cruciate ligament (ACL) rupture via tibial compression overload. This review describes the methods used to induce joint injury in each of these non-invasive models, and presents the findings of studies utilizing these models. Altogether, these non-invasive mouse models represent a unique and important spectrum of animal models for studying different aspects of PTOA.
Little is known about the effects of subzero temperatures on the formation
of secondary organic aerosol (SOA) from α-pinene. In the current
work, ozone-initiated oxidation of α-pinene at initial
...concentrations of 10 and 50 ppb, respectively, is performed at
temperatures of 20, 0, and −15 ∘C in
the Aarhus University Research on Aerosol (AURA) smog chamber during the Aarhus Chamber Campaign on Highly Oxygenated
Organic Molecules and Aerosols (ACCHA). Herein, we show how temperature influences the
formation and chemical composition of α-pinene-derived SOA with a
specific focus on the formation of organic acids and dimer esters. With
respect to particle formation, the results show significant increase in
particle-formation rates, particle number concentrations, and particle mass
concentrations at low temperatures. In particular, the number concentrations
of sub-10 nm particles were significantly increased at the lower 0 and −15 ∘C temperatures. Temperature also affects
the chemical composition of formed SOA. Here, detailed offline chemical
analyses show that organic acids contribute from 15 % to 30 % by mass,
with highest contributions observed at the lowest temperatures, indicative
of enhanced condensation of these semivolatile species. In comparison, a
total of 30 identified dimer esters were seen to contribute between 4 % and 11 % to the total SOA mass. No significant differences in the chemical
composition (i.e. organic acids and dimer esters) of the α-pinene-derived SOA particles are observed between experiments performed at
10 and 50 ppb initial α-pinene concentrations, thus suggesting a
higher influence of reaction temperature compared to that of α-pinene loading on the SOA chemical composition. Interestingly, the effect
of temperature on the formation of dimer esters differs between the
individual species. The formation of less oxidized dimer esters – with
oxygen-to-carbon ratio (O:C)<0.4 – is shown to increase at low
temperatures, while the formation of the more oxidized species (O:C>0.4) is suppressed, consequently resulting in
temperature-modulated composition of the α-pinene-derived SOA.
Temperature ramping experiments exposing α-pinene-derived SOA to
changing temperatures (heating and cooling) reveal that the chemical
composition of the SOA with respect to dimer esters is governed almost
solely by the temperature at which oxidization started and is insusceptible to
subsequent changes in temperature. Similarly, the resulting SOA mass
concentrations were found to be more influenced by the initial α-pinene oxidation temperatures, thus suggesting that the formation
conditions to a large extent govern the type of SOA formed, rather than the
conditions to which the SOA is later exposed. For the first time, we discuss the relation between the identified dimer
ester and the highly oxygenated organic molecules (HOMs) measured by
chemical ionization–atmospheric pressure interface–time-of-flight mass spectrometer (CI-APi-ToF) during the ACCHA experiments. We propose
that, although very different in chemical structures and O:C ratios, many
dimer esters and HOMs may be linked through similar RO2 reaction
pathways and that dimer esters and HOMs merely represent two different
fates of the RO2 radicals.
Summary
Background TZP‐101 is a synthetic, selective ghrelin agonist in development for gastroparesis.
Aim To assess safety and effects of TZP‐101 in diabetes patients with symptomatic ...gastroparesis.
Methods Adults with type 1 or type 2 diabetes mellitus received placebo and TZP‐101 (80, 160, 320 or 600 μg/kg) infusions in a cross‐over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic‐euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses.
Results Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate‐to‐severe gastroparesis symptoms and ≥29% retention 4 h after a radiolabelled solid meal were enrolled. TZP‐101 produced significant reductions in solid meal half‐emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP‐101 infusion were not statistically significant. Most adverse events were mild and self‐limiting and there were no identifiable differences in numbers or types of adverse events between TZP‐101 and placebo.
Conclusions This proof‐of‐concept study demonstrates that the ghrelin agonist TZP‐101 is well‐tolerated in diabetes patients with moderate‐to‐severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.
The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic ...shock remains unclear.
In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation.
A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval CI, 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09).
The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).
We present constraints on the annihilation cross section of weakly interacting massive particles dark matter based on the joint statistical analysis of four dwarf galaxies with VERITAS. These results ...are derived from an optimized photon weighting statistical technique that improves on standard imaging atmospheric Cherenkov telescope (IACT) analyses by utilizing the spectral and spatial properties of individual photon events. We report on the results of ∼230 hours of observations of five dwarf galaxies and the joint statistical analysis of four of the dwarf galaxies. We find no evidence of gamma-ray emission from any individual dwarf nor in the joint analysis. The derived upper limit on the dark matter annihilation cross section from the joint analysis is 1.35×10−23 cm3 s−1 at 1 TeV for the bottom quark (bb¯) final state, 2.85×10−24 cm3 s−1 at 1 TeV for the tau lepton (τ+τ−) final state and 1.32×10−25 cm3 s−1 at 1 TeV for the gauge boson (γγ) final state.
ABSTRACT
We report on the discovery and validation of TOI 813 b (TIC 55525572 b), a transiting exoplanet identified by citizen scientists in data from NASA’s Transiting Exoplanet Survey Satellite ...(TESS) and the first planet discovered by the Planet Hunters TESS project. The host star is a bright (V = 10.3 mag) subgiant ($R_\star =1.94\, R_\odot$, $M_\star =1.32\, M_\odot$). It was observed almost continuously by TESS during its first year of operations, during which time four individual transit events were detected. The candidate passed all the standard light curve-based vetting checks, and ground-based follow-up spectroscopy and speckle imaging enabled us to place an upper limit of $2\, M_{\rm Jup}$ (99 per cent confidence) on the mass of the companion, and to statistically validate its planetary nature. Detailed modelling of the transits yields a period of $83.8911 _{ - 0.0031 } ^ { + 0.0027 }$ d, a planet radius of 6.71 ± 0.38 R⊕ and a semimajor axis of $0.423 _{ - 0.037 } ^ { + 0.031 }$ AU. The planet’s orbital period combined with the evolved nature of the host star places this object in a relatively underexplored region of parameter space. We estimate that TOI 813 b induces a reflex motion in its host star with a semi-amplitude of ∼6 m s−1, making this a promising system to measure the mass of a relatively long-period transiting planet.
Abstract
We present 2241 exoplanet candidates identified with data from the Transiting Exoplanet Survey Satellite (TESS) during its 2 yr Prime Mission. We list these candidates in the TESS Objects of ...Interest (TOI) Catalog, which includes both new planet candidates found by TESS and previously known planets recovered by TESS observations. We describe the process used to identify TOIs, investigate the characteristics of the new planet candidates, and discuss some notable TESS planet discoveries. The TOI catalog includes an unprecedented number of small planet candidates around nearby bright stars, which are well suited for detailed follow-up observations. The TESS data products for the Prime Mission (sectors 1–26), including the TOI catalog, light curves, full-frame images, and target pixel files, are publicly available at the Mikulski Archive for Space Telescopes.
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