Autophagy in osteoarthritis

Osteoarthritis is characterized by continuous degeneration of articular cartilage resulting in disability. The death of chondrocytes and the loss of the extracellular matrix are the central peculiarities in cartilage degeneration during osteoarthritis pathogenesis. Autophagy is an essential cellular homeostasis mechanism whereby cellular organelles and macromolecules are recycled to maintain cellular metabolism. Autophagy is reported to be cytoprotective effects for articular cartilage, and osteoarthritis is associated with decreased autophagy. While autophagy is known to be cytoprotective to chondrocytes, its role may vary with differing stages and models of osteoarthritis. Therefore, more in-depth studies on autophagy are needed to determine its impact on cell survival and death in articular cartilage under various in vitro and in vivo conditions. Application of autophagy on osteoarthritis therapeutics will be possible after a profound understanding is established on the role of autophagy in osteoarthritis pathogenesis.     

Quantitative assessment of global cerebral metabolic rate of oxygen (CMRO2) in neonates using MRI

The cerebral metabolic rate of oxygen (CMRO₂) is the rate of oxygen consumption by the brain, and is thought to be a direct index of energy homeostasis and brain health. However, in vivo measurement of CMRO₂ is challenging, in particular for the neonatal population, in whom conventional radiotracer methods are not applicable because of safety concerns. In this study, we propose a method to quantify global CMRO₂ in neonates based on arteriovenous differences in oxygen content, and employ separate measurements of oxygenation and cerebral blood flow (CBF) parameters. Specifically, arterial and venous oxygenation levels were determined with pulse oximetry and the novel T₂ relaxation under spin tagging (TRUST) MRI, respectively. Global CBF was measured with phase contrast (PC) flow velocity MRI. The proposed method was implemented on a standard 3‐T MRI scanner without the need for any exogenous tracers, and the total scan duration was less than 5 min. We demonstrated the feasibility of this method in 12 healthy neonates within an age range of 35–42 gestational weeks. CMRO₂ values were successfully obtained from 10 neonates. It was found that the average CMRO₂ in this age range was 38.3 ± 17.7 µmol/100 g/min and was positively correlated with age (p = 0.007; slope, 5.2 µmol/100 g/min per week), although the highest CMRO₂ value in this age range was still less than half of the adult level. Test–retest studies showed a coefficient of variation of 5.8 ± 2.2% between repeated CMRO₂ measurements. In addition, given the highly variable blood flow velocity within this age range, it is recommended that the TRUST labeling thickness and position should be determined on a subject‐by‐subject basis, and an automatic algorithm was developed for this purpose. Although this method provides a global CMRO₂ measure only, the clinical significance of an energy consumption marker and the convenience of this technique may make it a useful tool in the functional assessment of the neonatal population. Copyright © 2014 John Wiley & Sons, Ltd.     

Silymarin Inhibits Morphological Changes in LPS-Stimulated Macrophages by Blocking NF-κB Pathway

The present study showed that silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), inhibited lipopolysaccharide (LPS)-induced morphological changes in the mouse RAW264.7 macrophage cell line. We also showed that silymarin inhibited the nuclear translocation and transactivation activities of nuclear factor-kappa B (NF-κB), which is important for macrophage activation-associated changes in cell morphology and gene expression of inflammatory cytokines. BAY-11-7085, an NF-κB inhibitor, abrogated LPS-induced morphological changes and NO production, similar to silymarin. Treatment of RAW264.7 cells with silymarin also inhibited LPS-stimulated activation of mitogen-activated protein kinases (MAPKs). Collectively, these experiments demonstrated that silymarin inhibited LPS-induced morphological changes in the RAW264.7 mouse macrophage cell line. Our findings indicated that the most likely mechanism underlying this biological effect involved inhibition of the MAPK pathway and NF-κB activity. Inhibition of these activities by silymarin is a potentially useful strategy for the treatment of inflammation because of the critical roles played by MAPK and NF-κB in mediating inflammatory responses in macrophages.     

Clinical Feasibility of Quantitative Ultrasound Imaging for Suspected Hepatic Steatosis: Intra- and Inter-examiner Reliability and Correlation with Controlled Attenuation Parameter

This study was aimed at investigating the clinical feasibility of quantitative ultrasound (QUS) imaging in the evaluation of suspected hepatic steatosis through assessment of the reliability of measurements and its correlation with the controlled attenuation parameter (CAP). This retrospective study included 117 patients who underwent liver B-mode ultrasound (US) with QUS imaging with a clinical US machine (RS85, Samsung Medison, Seoul, Korea) and CAP measurements between December 2019 and March 2020. For QUS examination, tissue attenuation imaging (TAI) and tissue scatter-distribution imaging (TSI) parameters were obtained. Intra- and inter-examiner reliability were assessed using intra-class correlation coefficients (ICCs), and QUS imaging parameters were correlated with CAP measurements using Spearman's correlation analysis. TAI and TSI revealed excellent intra- and inter-examiner reliability with ICCs of 0.994 and 0.975 and 0.991 and 0.947, respectively. Both TAI and TSI were significantly positively correlated with CAP values. QUS imaging provided good intra-and inter-observer reliability and correlated well with CAP in assessing suspected hepatic steatosis.     

急性有机磷杀虫药中毒中间综合征的临床分析

目的探讨急性有机磷杀虫药中毒中间综合征（intermediate syndrome,IMS）的诊断治疗。方法回顾性分析10例IMS患者临床表现和治疗方法。结果有机磷中毒中间综合征的10例患者均出现不同程度呼吸肌麻痹症,及时建立人工气道及机械通气和乙酰胆碱酯酶（AchE）复能剂应用,治愈8例,死亡2例。结论 IMS应早期识别,建立人工气道与机械通气是抢救成功的重要方法。     

An essential role of PI(4,5)P2 for maintaining the activity of the transient receptor potential canonical (TRPC)4β

The transient receptor potential canonical 4 (TRPC4) channel is a Ca²⁺-permeable nonselective cation channel in mammalian cells and mediates a number of cellular functions. Many studies show that TRPC channels are activated by stimulation of Gα_q-phospholipase C (PLC)-coupled receptors. However, our previous study showed that the TRPC4 current was inhibited by co-expression of a constitutively active form of Gα_q (Gα_q ^Q209L). A shortage of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] in Gα_q ^Q209L may be responsible for reduced TRPC4 activity. Here, we tested this hypothesis by using a rapamycin-inducible system that regulates PI(4,5)P₂ acutely and specifically. Our results showed that the TRPC4β current was reduced by inducible Gα_q ^Q209L, but not by the mutants with impaired binding ability to PLCβ. Depletion of PI(4,5)P₂ by inducing the inositol polyphosphate 5-phosphatase to HEK293 cells that express TRPC4β led to an irreversible inhibition of TRPC4β currents. In contrast, inducing phosphatidylinositol 4-phosphate 5-kinase or intracellular PI(4,5)P₂ application did not activate the TRPC4β current. Finally, we revealed that PI(4,5)P₂ is important in delaying the desensitization of TRPC4β. Taken together, we suggest that PI(4,5)P₂ is not the activator of TRPC4β activation, but it is still necessary for regulating TRPC4β activation.