Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

Convergence analysis of Chinese urban green land-use efficiency.

Convergence analysis of China's urban green land-use efficiency (GLUE) will help to explore whether regional differences in GLUE determined by regional economic development and imbalance of resource endowments gradually decrease over time. We construct a DEA model considering variable returns to scale to measure Chinese urban GLUE, and discuss the convergence of Chinese urban GLUE. We find that Chinese urban GLUE is generally low. GLUE of eastern cities is the best. GLUE of non-resource-based (NRB) cities is higher than that of resource-based (RB) cities. GLUE of Pearl River Delta Economic Zone is the highest, while that of Comprehensive Economic Zone of Central 6 Provinces is the lowest. Chinese urban GLUE is mainly affected by technological change. Chinese urban GLUE shows absolute and conditional ß convergence, and the gap of GLUE between cities is constantly narrowing. Cities in different locations, resource dependence degrees, and economic zones have different convergence rates. The conclusions help the Chinese government to formulate policies for intensive land use, improve national GLUE, and promote urban intensive and high-quality development.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

The Mechanism of Downregulated Interstitial Fluid Drainage Following Neuronal Excitation.

The drainage of brain interstitial fluid (ISF) has been observed to slow down following neuronal excitation, although the mechanism underlying this phenomenon is yet to be elucidated. In searching for the changes in the brain extracellular space (ECS) induced by electrical pain stimuli in the rat thalamus, significantly decreased effective diffusion coefficient (DECS) and volume fraction (α) of the brain ECS were shown, accompanied by the slowdown of ISF drainage. The morphological basis for structural changes in the brain ECS was local spatial deformation of astrocyte foot processes following neuronal excitation. We further studied aquaporin-4 gene (APQ4) knockout rats in which the changes of the brain ECS structure were reversed and found that the slowed DECS and ISF drainage persisted, confirming that the down-regulation of ISF drainage following neuronal excitation was mainly attributable to the release of neurotransmitters rather than to structural changes of the brain ECS. Meanwhile, the dynamic changes in the DECS were synchronized with the release and elimination processes of neurotransmitters following neuronal excitation. In conclusion, the downregulation of ISF drainage following neuronal excitation was found to be caused by the restricted diffusion in the brain ECS, and DECS mapping may be used to track the neuronal activity in the deep brain.

A trade-related CO2 emissions and its composition: Evidence from China.

Trade-related CO2 emissions has been widely studied in existing research and them have mainly calculated the CO2 emissions embodied in overall trade; however, China's domestic value chain (DVC) has developed rapidly, and different regions have different emissions effects due to different trade patterns. This study divides Chinese interregional trade into four trade patterns from the perspective of domestic production fragmentation. Then we develop a decomposition model of the interregional trade-related CO2 emissions and pollution heaven hypothesis (PHH) of different trade patterns based on China's interregional input-output table for 2002 to 2010. Finally, we explore the influencing factors of the changes of environmental effects using structural decomposition analysis method. The results show that from 2002 to 2010, the volume of CO2 emissions embodied in interregional trade increased significantly with the share of CO2 emissions induced by traditional trade in intermediate products always representing a major proportion but which still underwent a downward trend. Interregional trade activities increase China's CO2 emissions, and the PHH holds at the national level. Among them, trade in final products is conducive to reducing national CO2 emissions while the other three patterns of interregional trade are opposite. In particular, the balance of avoided CO2 emissions (BAC) in trade related to the DVC is positive, meaning that the DVC is polluting. In addition, domestic trade activities of the central region, northwestern region, and northern coast are not conducive to reducing regional and national CO2 emissions while the southern coast and northeastern region are opposite.

Carbon emission intensity embodied in trade and its driving factors from the perspective of global value chain.

As a global problem, climate warming has received widespread attention recently. With trade development and labor division deepening, there exist large differences in carbon emission intensity (CEI) embodied in different trade patterns. Assessing environmental costs of different trade patterns is the core issue for policy makers. We decompose the overall CEI embodied in trade into CEI embodied in final goods trade, domestic trade, traditional intermediate trade, and global value chain trade. Using global multi-region input-output table provided by the WIOD database, we calculate the CEI embodied in different trade patterns during 1995-2014. Further, we analyze the influencing factors of CEI embodied in different trade patterns. We find that CEI embodied in domestic trade is lower than that of international trade. All kinds of embodied CEI in developing countries are higher than that in developed countries. Furthermore, the driving factors of the overall embodied CEI, including domestic trade and international trade, are population, PGDP, energy intensity, and trade. The expansion of industrialization can effectively reduce the CEI embodied in trade of developing countries. The increase of PGDP and industrialization can effectively reduce the CEI embodied in trade related to global value chain and traditional intermediate trade, while only the increase of PGDP can effectively reduce the CEI embodied in domestic trade and final goods trade. Population can reduce the embodied CEI in trade related to global value chain and traditional intermediate trade of developed countries. Economic development can almost promote the reduction of the CEI embodied in all trade patterns. Although industrialization has insignificant impact on the CEI embodied in final goods trade of the developed countries, it can reduce such CEI of developing countries.

Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium.

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein, effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol, atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

The Drainage of Interstitial Fluid in the Deep Brain is Controlled by the Integrity of Myelination.

In searching for the drainage route of the interstitial fluid (ISF) in the deep brain, we discovered a regionalized ISF drainage system as well as a new function of myelin in regulating the drainage. The traced ISF from the caudate nucleus drained to the ipsilateral cortex along myelin fiber tracts, while in the opposite direction, its movement to the adjacent thalamus was completely impeded by a barrier structure, which was identified as the converged, compact myelin fascicle. The regulating and the barrier effects of myelin were unchanged in AQP4-knockout rats but were impaired as the integrity of boundary structure of drainage system was destroyed in a demyelinated rat model. We thus proposed that the brain homeostasis was maintained within each ISF drainage division locally, rather than across the brain as a whole. A new brain division system and a new pathogenic mechanism of demyelination are therefore proposed.

[Association of TLR4 gene polymorphisms with large artery atherosclerotic stroke and vascular bed selectivity of atherosclerotic lesions].

OBJECTIVE: To assess the association of TLR4 gene polymorphisms with large artery atherosclerosis (LAA) stroke and liability to atherosclerosis in an ethnic Han population from northern China. METHODS: The study has involved 286 LAA stroke patients and 300 healthy controls. The LAA group has been divided 4 subsets according to angiostenosis conditions. Polymerase chain reaction-restriction fragment length polymorphism and pyrosequencing were employed to analyze three single nucleotide polymorphism (SNPs) (rs1927914, rs1927911 and rs2149356) of the TLR4 gene. A Haploview software package was used to analyze the haplotypes. RESULTS: SNPs rs1927911 and rs2149356 were associated with LAA stroke. Genotypic and allelic frequencies of rs1927914 did not differ significantly between the two groups. Genetic variants of the three SNPs did not vary significantly between all subsets. Haplotype analysis was revealed a significant difference between the LAA group and the control group. Compared with the controls, the frequencies of haplotypes H2 and H8 were lower, and that of H3 was greater in the LAA group. CONCLUSION: An association between the TLR4 gene polymorphisms and LAA stroke subtype in ethnic Han population in northern China has been found. However, no association of liability to atherosclerosis in different vascular bed has been found with these polymorphisms.