Summary Introduction Matrix metalloproteinases and ‘aggrecanase’ ADAMTSs are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix type II collagen and ...aggrecan, and are thus potential targets for development of OA therapies. Objective This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamalysins (or ADAMs) in cartilage, with a view to identifying potentially protective or homeostatic metalloproteinases in the joint and informing consequent selective inhibitor design. Design A comprehensive literature search was performed using PubMed terms ‘osteoarthritis’ and ‘ADAMTS’ or ‘ADAM’. Results Several ADAMTSs and ADAMs were identified as having reportedly increased expression in OA. These include enzymes likely to play roles in cartilage matrix anabolism (e. g. the procollagen N-proteinases ADAMTS-2, ADAMTS-3 and ADAMTS-14), chondrocyte differentiation and proliferation (e. g. ADAM9, ADAM10, ADAM12), as well as enzymes contributing to cartilage catabolism (e. g. COMP-degrading ADAMTS-7 and ADAMTS-12). Conclusions In addition to the well-characterised MMPs, ADAMTS-4 and ADAMTS-5, many other ADAMTSs and ADAMs are expressed in cartilage and several show significantly altered expression in OA. Studies aimed at elucidating the pathophysiological roles of these enzymes in cartilage will contribute to our understanding of OA pathogenesis and enable design of targeted inhibitors that effectively target metalloproteinase-mediated cartilage degradation while sparing cartilage repair pathways.
Summary
Evidence of the incidence and risk of osteonecrosis of the jaw (ONJ) in Asian osteoporosis populations receiving different osteoporosis medications is lacking. We found that there is no ...excess incidence of or risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin under real-world conditions in Taiwan.
Introduction
To provide information on ONJ in Asian populations, this study compares the incidence and risk of ONJ between patients receiving alendronate and those receiving non-bisphosphonate osteoporosis medications in Taiwan.
Methods
Enrollees in the National Health Insurance Research Database (NHIRD) from 2003 to 2007, aged above 50 years, with vertebral/hip fracture, and new to osteoporosis therapy were recruited. Patients with Paget’s disease or cancer during the baseline period were excluded. Patients were classified into either the alendronate or the calcitonin/raloxifene (control) group according to their exposure during follow-up. Previously proposed possible ONJ diagnosis codes were adopted as potential ONJ cases, but qualifying cases also had a repeated ONJ diagnosis within 8 weeks of the first diagnosis and received one or more broad-spectrum oral antibiotics. Cox modeling compared the risk of ONJ between the alendronate and the control groups, which were matched using propensity scores. Results were examined in series sensitivity analyses, including different cumulative dose groups.
Results
We found 25 potential ONJ cases in the alendronate (
N
= 18,030) and 21 in the control groups (
N
= 25,615). Over the 6-year follow-up period, no increased risk of ONJ in the alendronate group in the original (hazard ratio (HR), 0.87; 95 % confidence interval (CI), 0.47–1.58) or propensity score-matched cohorts (HR, 0.86; 95 % CI, 0.44–1.69) was found. All comparison groups exhibited a similar incidence of ONJ, ranging from 6.9 to 8.2/10,000 person-years.
Conclusion
Under real-world conditions, there is no excess risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin.
The self‐organization of the polymer in solar cells based on regioregular poly(3‐hexylthiophene) (RR‐P3HT):6,6‐phenyl C61‐butyric acid methyl ester (PCBM) is studied systematically as a function of ...the spin‐coating time ts (varied from 20–80 s), which controls the solvent annealing time ta, the time taken by the solvent to dry after the spin‐coating process. These blend films are characterized by photoluminescence spectroscopy, UV‐vis absorption spectroscopy, atomic force microscopy, and grazing incidence X‐ray diffraction (GIXRD) measurements. The results indicate that the π‐conjugated structure of RR‐P3HT in the films is optimally developed when ta is greater than 1 min (ts ∼ 50 s). For ts < 50 s, both the short‐circuit current (JSC) and the power conversion efficiency (PCE) of the corresponding polymer solar cells show a plateau region, whereas for 50 < ts < 55 s, the JSC and PCE values are significantly decreased, suggesting that there is a major change in the ordering of the polymer in this time window. The PCE decreases from 3.6 % for a film with a highly ordered π‐conjugated structure of RR‐P3HT to 1.2 % for a less‐ordered film. GIXRD results confirm the change in the ordering of the polymer. In particular, the incident photon‐to‐electron conversion efficiency spectrum of the less‐ordered solar cell shows a clear loss in both the overall magnitude and the long‐wavelength response. The solvent annealing effect is also studied for devices with different concentrations of PCBM (PCBM concentrations ranging from 25 to 67 wt %). Under “solvent annealing” conditions, the polymer is seen to be ordered even at 67 wt % PCBM loading. The open‐circuit voltage (VOC) is also affected by the ordering of the polymer and the PCBM loading in the active layer.
Polymer solar cells based on poly(3‐hexylthiophene) and methanofullerenes are investigated by systematically varying the spin‐coating time used during fabrication (see figure). The rate of solvent evaporation profoundly effects the self‐organization of the polymer. Very high crystallinity of the polymer and consequently optimal solar‐cell performance is achieved for longer “solvent annealing” times.
Summary
Background: Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues ...to increase, information regarding the relative efficacy and safety of statins is required for decision‐making.
Objective: This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low‐density lipoprotein cholesterol (LDL‐C) lowering effect.
Methods: Publications of head‐to‐head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966–2004), MEDLINE (2005‐April of 2006), EMBASE (2005‐April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta‐analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins.
Results: Seventy‐five studies reporting RCTs of head‐to‐head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40–80 mg, and simvastatin 20 mg could decrease LDL‐C by 30–40%, and fluvastatin 40 mg, lovastatin 10–20 mg, pravastatin 20–40 mg, and simvastatin 10 mg could decrease LDL‐C by 20–30%. The only two statins that could reduce LDL‐C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta‐analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data.
Conclusions: At comparable doses, statins are therapeutically equivalent in reducing LDL‐C.
Light, MeV-scale dark matter (DM) is an exciting DM candidate that is undetectable by current experiments. A germanium (Ge) detector utilizing internal charge amplification for the charge carriers ...created by the ionization of impurities is a promising new technology with experimental sensitivity for detecting MeV-scale DM. We analyze the physics mechanisms of the signal formation, charge creation, charge internal amplification, and the projected sensitivity for directly detecting MeV-scale DM particles. We present a design for a novel Ge detector at helium temperature (
∼
4 K) enabling ionization of impurities from DM impacts. With large localized E-fields, the ionized excitations can be accelerated to kinetic energies larger than the Ge bandgap at which point they can create additional electron–hole pairs, producing intrinsic amplification to achieve an ultra-low energy threshold of
∼
0.1 eV for detecting low-mass DM particles in the MeV scale. Correspondingly, such a Ge detector with 1 kg-year exposure will have high sensitivity to a DM-nucleon cross section of
∼
5
×
10
-
45
cm
2
at a DM mass of
∼
10 MeV/c
2
and a DM-electron cross section of
∼
5
×
10
-
46
cm
2
at a DM mass of
∼
1 MeV/c
2
.
The development of targeted medicine has greatly expanded treatment options and spurred new research avenues in cancer therapeutics, with monoclonal antibodies (mAbs) emerging as a prevalent ...treatment in recent years. With mixed clinical success, mAbs still hold significant shortcomings, as they possess limited tumor penetration, high manufacturing costs, and the potential to develop therapeutic resistance. However, the recent discovery of “nanobodies,” the smallest-known functional antibody fragment, has demonstrated significant translational potential in preclinical and clinical studies. This review highlights their various applications in cancer and analyzes their trajectory toward their translation into the clinic.
ABSTRACT Galactic outflows play an important role in galactic evolution. Despite their importance, a detailed understanding of the physical mechanisms responsible for the driving of these winds is ...lacking. In an effort to gain more insight into the nature of these flows, we perform global three-dimensional magnetohydrodynamical simulations of an isolated Milky Way-size starburst galaxy. We focus on the dynamical role of cosmic rays (CRs) injected by supernovae, and specifically on the impact of the streaming and anisotropic diffusion of CRs along the magnetic fields. We find that these microphysical effects can have a significant effect on the wind launching and mass loading factors, depending on the details of the plasma physics. Due to the CR streaming instability, CRs propagating in the interstellar medium scatter on self-excited Alfvén waves and couple to the gas. When the wave growth due to the streaming instability is inhibited by some damping process, such as turbulent damping, the coupling of CRs to the gas is weaker and their effective propagation speed faster than the Alfvén speed. Alternatively, CRs could scatter from "extrinsic turbulence" that is driven by another mechanism. We demonstrate that the presence of moderately super-Alfvénic CR streaming enhances the efficiency of galactic wind driving. Cosmic rays stream away from denser regions near the galactic disk along partially ordered magnetic fields and in the process accelerate more tenuous gas away from the galaxy. For CR acceleration efficiencies broadly consistent with the observational constraints, CRs reduce the galactic star formation rates and significantly aid in launching galactic winds.
We investigate the statistical, dual‐spacecraft correlations of field‐aligned current (FAC) signatures between two Swarm spacecraft. For the first time, we infer the orientations of the current ...sheets of FACs by directly using the maximum correlations obtained from sliding data segments. The current sheet orientations are shown to broadly follow the mean shape of the auroral boundary for the lower latitudes and that these are most well ordered on the dusk side. Orientations at higher latitudes are less well ordered. In addition, the maximum correlation coefficients are explored as a function of magnetic local time and in terms of either the time shift (δt) or the shift in longitude (δlon) between Swarms A and C for various filtering levels and choice of auroral region. We find that the low‐latitude FACs show the strongest correlations for a broad range of magnetic local time centered on dawn and dusk, with a higher correlation coefficient on the dusk side and lower correlations near noon and midnight. The positions of maximum correlation are sensitive to the level of low‐pass filter applied to the data, implying temporal influence in the data. This study clearly reflects the two different domains of FACs: small‐scale (some tens of kilometers), which are time variable, and large‐scale (>50 km), which are rather stationary. The methodology is deliberately chosen to highlight the locations of small‐scale influences that are generally variable in both time and space. We may fortuitously find a potential new way to recognize bursts of irregular pulsations (Pi1B) using low‐Earth orbit satellites.
Key Points
For the first time, we infer the orientations of the current sheets of FACs using a maximum correlation method
This study clearly reflects two different domains of FACs: small‐scale, which are time variable, and large‐scale, which are rather stationary
We find a potential new way to recognize bursts of irregular pulsations (Pi1B) using low‐earth orbit satellites
In the US, biodiesel producers usually follow the 19.8:1 methanol-to-FFA molar ratio for free fatty add (FFA) esterification, as suggested by the National Renewable Energy Laboratory (NREL) without ...optimization studies. In this paper, both laboratory studies and industrial practices of the esterification process were compared, and an optimization study of a used vegetable oil with 5% FFA was conducted. The optimal conditions of this oil, i.e., methanol-to-FFA molar ratio of 40:1, and sulfuric acid usage of 10%, fell out of the suggested range of 19.8:1. The activation energy of the esterification reaction is 20.7 kJ/mol at the optimized condition and 45.9 kJ/mol at the 19.8:1 methanol to FFA ratio. It was found that the 19.8:1 methanol-to-FFA molar ratio worked well only within the FFA range of 15-25% while the suggested 5% sulfuric acid worked well only within the FFA range of 15-35%. Outside these ranges, especially at FFA levels less than 15%, optimization study is necessary. Regression models of methanol and arid dosing have been utilized in two industrial scale biodiesel producing facilities and have successfully reduced the FFA level to less than 0.5%.
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