Summary Objective To study the effect of intra-articular injection of meloxicam (Mobic) on the development of osteoarthritis (OA) in rats and examine concomitant changes in nociceptive behavior and ...the expression of mitogen-activated protein kinases (MAPKs) in articular cartilage chondrocytes. Methods OA was induced in Wistar rats by right anterior cruciate ligament transection (ACLT); the left knee was not treated. The OA + meloxicam (1.0 mg) group was injected intra-articularly in the ACLT knee with 1.0 mg of meloxicam once a week for 5 consecutive weeks starting 5 weeks after ACLT. The OA + meloxicam (0.25 mg) group was treated similarly with 0.25 mg meloxicam. The sham group underwent arthrotomy only and received vehicle of 0.1 mL sterile 0.9% saline injections, whereas the naive rats in meloxicam-only groups were treated similarly with 1.0- and 0.25-mg meloxicam. Nociception was measured as secondary mechanical allodynia and hind paw weight-bearing distribution at before (pre-) and 5, 10, 15, and 20 weeks post-ACLT. Histopathology of the cartilage and synovia was examined 20 weeks after ACLT. Immunohistochemical analysis was performed to examine the effect of meloxicam on MAPKs (p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)) expression in the articular cartilage chondrocytes. Results OA rats receiving intra-articular meloxicam treatment showed significantly less cartilage degeneration and synovitis than saline-treated controls. Nociception were improved in the OA + meloxicam groups compared with the OA group. Moreover, meloxicam attenuated p38 and JNK but enhanced ERK expression in OA-affected cartilage. Conclusions Intra-articular injection of meloxicam (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cellular p38 and JNK, but enhances ERK expression.
The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best‐characterized endothelium‐derived relaxing factor (EDRF) is nitric oxide ...(NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium‐dependent hyperpolarizations, EDH‐mediated responses). As regards the latter, hydrogen peroxide (H2O2) now appears to play a dominant role. Endothelium‐dependent relaxations involve both pertussis toxin‐sensitive Gi (e.g. responses to α2‐adrenergic agonists, serotonin, and thrombin) and pertussis toxin‐insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low‐density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin‐sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H2O2), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium‐derived contracting factors. Recent evidence confirms that most endothelium‐dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium‐dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium‐dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin‐1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
In this study, we investigate detailed electron dynamics in strong guide‐field reconnection (the normalized guide field is ∼1.5). This reconnection event is observed by the Magnetospheric Multiscale ...(MMS) spacecraft at the center of a flux rope in the magnetotail. With the presence of a large parallel electric field (E‖) in the electron current sheet, electrons are accelerated when streaming into this E‖ region from one direction, and decelerated from the other direction. Some decelerated electrons can reduce the parallel speed to ∼0 to form relatively isotropic electron distributions at one side of the electron current sheet, as the estimated acceleration potential satisfies the relation eΦ‖ ≥ kTe,‖, where Te,‖ is the electron temperature parallel to the magnetic field. Therefore, a large E‖ is generated to balance the parallel electron pressure gradient across the electron current sheet, since electrons at the other side of the current sheet are still anisotropic. Based on these observations, we further show that the electron beta is an important parameter in guide‐field reconnection, providing a new perspective to solve the large parallel electric field puzzle in guide‐field reconnection.
Plain Language Summary
Magnetic reconnection is a universal process that rapidly converts energy from the magnetic field to plasma. The energy conversion at kinetic scales is of particular interest to researchers, as it is directly related to reconnection process in the central diffusion region. In general, the reconnecting magnetic fields do not have to be antiparallel, and an additional magnetic component known as the guide field (Bg) can appear in the direction perpendicular to the reconnecting plane. Recently, observations from Magnetospheric Multiscale (MMS) mission show a large electric field parallel to the local magnetic field, which is several times larger than the reconnection electric field, can appear in guide‐field reconnection, and impact electrons significantly. However, the generation of this large parallel electric field in strong guide‐field reconnection is still not fully understood. In this study, we suggest that the electron beta (ratio of the electron thermal pressure to the magnetic pressure) is an important parameter in guide‐field reconnection. Only within some proper electron beta range, a parallel pressure gradient across the electron current sheet can form to balance the large parallel electric field.
Key Points
We present detailed electron dynamics in guide‐field reconnection at the center of a flux rope
With eΦ‖ ≥ kTe,‖, the observed electron behaviors can be well explained
We suggest that electron beta is an important parameter for the generation of a large parallel electric field in guide‐field reconnection
Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis is essential for the cancer metastasis. Endothelin-1 (ET-1) has ...been implicated in tumor angiogenesis and metastasis. However, the relationship of ET-1 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here, we found that the expression of ET-1 and VEGF were correlated with tumor stage and were significantly higher than that in the normal cartilage. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. ET-1 increased VEGF expression and angiogenesis through ETAR, integrin-linked kinase (ILK), Akt and hypoxia-inducible factor-1α (HIF-1α) signaling cascades. Knockdown of ET-1 decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. In addition, in the xenograft tumor angiogenesis model, knockdown of ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results indicate that ET-1 occurs through ETAR, ILK and Akt, which in turn activates HIF-1α, resulting in the activation of VEGF expression and contributing to the angiogenesis and tumor growth of human chondrosarcoma cells.
Objectives
Parkinson's disease (PD) is a neurodegenerative disease. A decreased risk of cancer, except for melanoma, has been observed in patients with PD. The aim of this study was to evaluate the ...association between brain tumor and PD in a Taiwanese population.
Materials and methods
We used data from the National Health Insurance program of Taiwan. The PD cohort contained 2998 patients, and each patient was frequency‐matched, based on age and sex, with 4 people without PD, who were randomly selected from the general population. Cox's proportional hazard regression analysis was conducted to estimate the effects of PD on the risk of brain tumor.
Results
The risk of developing brain tumor was significantly higher in patients with PD than in those without PD (adjusted hazard ratio = 2.11; 95% confidence interval (CI) = 1.24–3.59), and benign brain tumor exhibited a particularly elevated risk of 2.16‐fold (95% CI = 1.26–3.68). The hazard ratio (HR) for developing a benign brain tumor was higher in female patients with PD than in female patients without PD, with the risk being 2.65‐fold (95% CI = 1.30–5.43). An analysis of the two age groups, 50–64 years and ≥65 years, showed that the HR of only the 50–64‐year group was significantly higher between the PD and non‐PD groups (HR = 2.77, 95% CI = 1.07–7.14).
Conclusion
The present study showed that Taiwanese patients with PD are at a higher risk of developing brain tumor than the general population. The exact underlying etiologies require further investigation.
We present improved germanium-based constraints on sub-GeV dark matter via dark matter-electron (χ-e) scattering using the 205.4 kg·day dataset from the CDEX-10 experiment. Using a novel calculation ...technique, we attain predicted χ-e scattering spectra observable in high-purity germanium detectors. In the heavy mediator scenario, our results achieve 3 orders of magnitude of improvement for m_{χ} larger than 80 MeV/c^{2} compared to previous germanium-based χ-e results. We also present the most stringent χ-e cross-section limit to date among experiments using solid-state detectors for m_{χ} larger than 90 MeV/c^{2} with heavy mediators and m_{χ} larger than 100 MeV/c^{2} with electric dipole coupling. The result proves the feasibility and demonstrates the vast potential of a new χ-e detection method with high-purity germanium detectors in ultralow radioactive background.
The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is ...nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
Agyrotropic electron distributions are frequently taken as an indicator of electron diffusion regions of magnetic reconnection. However, they have also been found at electron‐scale boundaries of the ...non‐reconnecting magnetopause and are generated by the electron finite gyroradius effect. Here, we present magnetospheric multiscale observations of agyrotropic electron distributions in the foreshock region. These distributions are generated by the electron finite gyroradius effect after magnetic curvature scattering at a thin electron‐scale boundary. Meanwhile, the signatures of magnetic reconnection are absent at this boundary. The test‐particle simulation is adopted to verify the generation of the agyrotropic electron distributions by assuming one‐dimensional magnetic geometry. These observations suggest that agyrotropic electron distributions can be more widely formed at electron‐scale boundaries in space plasma environment.
Plain Language Summary
The agyrotropic electron distributions, which could be unstable to generate high frequency electrostatic waves, reveal valuable information of electron dynamics at electron scales. However, due to electron's small mass, the related observational study becomes only possible with the high‐resolution magnetospheric multiscale data. In this study, we show that the agyrotropic electron distributions can be also formed in the foreshock transients such as inside an hot flow anomaly, suggesting that agyrotropic electron distributions are ubiquitous in space plasma.
Key Points
We present the first magnetospheric multiscale observations of agyrotropic electron distributions in the foreshock transients
Accompanied with the agytropic electron distributions, clear signatures of magnetic reconnection are absent
The agytropic electron distributions are formed by the electron finite gyroradius effect at electron‐scale boundaries
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