Recent advance in extracellular space changes and mechanisms in peritumor edema regions of brain gliomas / 中华神经医学杂志

As one of the refractory tumors in the world, brain glioma has increased incidence year by year in recent years. Peritumoral brain edema (PTBE), as one of the main clinical features of glioma, has proved to be the main source of recurrent tumor infiltrating area. There are significant changes in the interstitial fluid drainage partition system and the steady state of brain partitions in the extracellular space (ECS) of this area, embodied in ECS space structure (volume fraction and tortuosity), tissue fluid drainage, material diffusion, and space physical polarity. And this process involves a series of changes of molecular biology mechanisms. This paper focuses on the specific changes and related mechanisms of ECS in PTBE region of brain glioma from the perspective of the brain cells microenvironment, so as to further explore the pathophysiological changes in this region and provide theoretical basis for the new model of diagnosis and treatment of glioma based on ECS.

Image smoothing using regularized entropy minimization and self-similarity for the quantitative analysis of drug diffusion

Background: Targetable drug delivery is an important method for the treatment of liver tumors. For the quantitative analysis of drug diffusion, the establishment of a method for information collection and characterization of extracellular space is developed by imaging analysis of magnetic resonance imaging (MRI) sequences. In this paper, we smoothed out interferential part in scanned digital MRI images. Materials and Methods: Making full use of priors of low rank, nonlocal self-similarity, and regularized sparsity-promoting entropy, a block-matching regularized entropy minimization algorithm is proposed. Sparsity-promoting entropy function produces much sparser representation of grouped nonlocal similar blocks of image by solving a nonconvex minimization problem. Moreover, an alternating direction method of multipliers algorithm is proposed to iteratively solve the problem above. Results and Conclusions: Experiments on simulated and real images reveal that the proposed method obtains better image restorations compared with some state-of-the-art methods, where most information is recovered and few artifacts are produced

Tracer-based MRI evaluation on transportation and clearance in extracellular space of rats / 中国医学影像技术

Objective To explore the rule of transportation in extracellular space (ECS) and the changes induced by the external stimulation with tracer-based MRI.Methods Thirty two mature Sprague Dawley rats were randomly divided into four groups,i.e.caudate nucleus-control (Cc) group,thalamus-control (Tc) group,caudate nucleus-moving (Cm) group and thalamus pain stimulation (Tp) group.The rats were anesthetized and a series of MR scanning were performed before and after the injection of Gd-DTPA in ECS of caudate nucleus and thalamus until the intensity of Gd-DTPA was invisible.Half-life of Gd-DTPA in ECS was calculated and analyzed with t-test.Results Gd DTPA in caudate nucleus was transported to the ipsilateral cortices away from the injection points,which only distributed on site in the thalamus.The transportation between the two partitions was not observed.The half-life of Tc group ([49.93±2.11] min) was significantly shorter than that of Cc group ([104.30±54.12];t=2.839,P＜0.05),no difference was observed between the Cm group ([113.42±47.32]min) and Cc group (t=0.359,P＞0.05),while half-life of Tp group ([109.40±10.33]min) was significantly longer than that of Tc group (t=15.954,P＜0.05).Conclusion Tracer-based MRI can be used to investigate the rule of transportation in ECS,and the transportation and clearance of substances into the ECS can be influenced by a selective external stimulation.

Transportation in extracellular space in the caudate nucleus of rat models of Parkinson's disease: a MR imaging study / 中华神经医学杂志

Objective To investigate the transportation alterations in extracellular space (ECS) in the caudate nucleus of rat models of Parkinson's disease (PD).Methods Twenty mature Sprague-Dawley rats were randomly divided into PD model group and control group (n=10).Rats in the model group received daily subcutaneous injection of 1.5 mg/mL rotenone solution at dosage of one mg/kg once daily for a consecutive 7 d,and PD was verified using immunohistochemistry and inclined plane tests;rats in the control group did not receive any treatment.Tracer-based magnetic resonance imaging (MRI) was used to quantitatively investigate the alterations of transportation in ECS.Results The mean tilt angle of rats in the model group was (34.5±3.9)°,and that in the control group was (43.1±3.8)°,with significant difference (t=4.994,P=0.002).Immunohistochemistry indicated that small amount of TH positive cells were noted in the model group,while large numbers of TH positive cells were noted in the control group.The transportation in ECS ofcaudate nucleus in the model group was demonstrated slower as compared with that in the control group,and half-time of tracer was significantly increased as compared with that in the control group ([156.6±10.2] min vs.[114.6±8.7] min,t=9.907,P=0.000).Conclusion Tracer-based MRI can be used to investigate the transportation in ECS in the deep brain regions of PD.

Extracellular diffusion quantified by magnetic resonance imaging during rat C6 glioma cell progression

Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI) method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS) at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM) on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs), collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

The anatomical and physiological changes of rat brain extracellular space during postnatal development / 中国比较医学杂志

Rat brain development is a complicated process.There are significant changes of histology, cytology and molecular biology in the process of fetal and postnatal brain development.The basic structure of brain has formed in the prenatal period.While the formation of connections between different parts and the improvement of the function of the brain occur after birth, during which many of the variations are bases of the nervous system diseases, so the postnatal brain development is still very important.Although the concept of brain microenvironment has been proposed more than 150 years ago, the research about the changing extracellular space ( ECS ) during the postnatal brain development has yet to gain significant progress.The author reviewed the anatomical and physiological characteristics of ECS in the process of postnatal development of the rat, stating the important role of ECS in the individual development, which is expected to provide reliable evidences for the explore of mechanisms and effective treatment approaches of pediatric development related nervous system diseases.

MR Tracer Diffusion in Cerebral Interstitial Fluid of Elderly SD Rats / 中国医学影像学杂志

Purpose With the progression of brain tissue aging, the transport and drainage characteristics of metabolites and secretory products for neurons in extracellular space occurs irreversible change. This paper aims to investigate and quantify MR tracer diffusion characteristics in cerebral interstitial fluid of elderly SD rats. Materials and Methods MR contrast agent Gd-DTPA was injected into the caudate nucleus of two groups of rats including 8 in experimental group (15-17 month old) and 15 in control group (7-10 month old). MR scan was performed at 0.25 h, 0.5 h, 1 h, 2 h, 3 h and 4 h to observe the dynamic distribution in the caudate and measure the diffusion and clearance rate. Results There was no statistically significant difference in diffusion rate and D* between control group with (3.32±0.70)×10-4 mm2/s and experimental group with (3.25±0.46)×10-4 mm2/s (t=1.739, P>0.05). The clearance rate k' was significantly different between control group (0.62±0.12)×10-4/s and experimental group (0.29±0.08)×10-4/s (t=11.602, P<0.05). Conclusion The degeneration of aging brain tissue changes the composition of extracellular space resulting in decreased speed of ISF clearance. This may cause accumulation of metabolites which eventually triggers a variety of age-related diseases.

Clinical study on changes of esophageal impedance and mucosal integrity in acid-induced non-erosive reflux disease / 中华消化杂志

Objective To investigate the correlation between dynamic changes in esophageal impedance and dilated intercellular space (DIS) of patients with acid-induced non erosive reflux disease (NERD).Methods From September 2013 to July 2014,a total of 35 patients with NERD and 20 healthy controls were selected and underwent 24 h multichannel intraluminal impedance and pH monitoring (MII-pH monitoring),acid perfusion test and gastroendoscopy examination.One piece of mucosa tissue was taken under gastroendoscope from the anterior and posterior walls at 2 cm above the dentate line of the esophagus.Intercellular space (ICS) of the esophageal epithelia cells was measured by software after hematoxylin and eosin staining.t test and variance analysis were performed for statistical analysis.Pearson correlation analysis was used for correlation analysis.Results Impedance baseline of distal esophagus and impedance recovery rate of patients with NERD were lower than those of healthy control group,which were (2 998±701) Ω vs (3 880±1 054) Ω and (30.1±14.0) Ω/min vs (53.0±14.5) Ω/min,and the differences were statistically significant (t=3.65,5.41;both P＜0.01).Compared with healthy control group,ICS of the esophageal epithelial cells was obviously wider (1.03 ± 0.20) μm vs (0.66±0.14) μm,and the difference was statistically significant (t=-6.57,P＜0.01).Impedance baseline of esophagus and impedance recovery rate of patients with positive acid perfusion test were lower than those of patients with negative acid perfusion test,which were (2 755±680) Ωvs (3 411±536) Ω and (25.4±13.0) Ω minvs (33.4±9.8) Ω /min,and the differences were statistically significant (t =2.99,2.03;both P＜0.05).The correlation between impedance recovery rate and ICS was negative (r=-0.70,P＜0.01).Conclusions Recurrent reflux induced injury and delayed mucosal headline may be the factors of impaired mucosal integrity in patients with NERD.The changes esophageal of impedance baseline to a certain extent reflected the degree of esophageal mucosal integrity impairment.

A Bama Minipig Model of Laryngopharyngeal Reflux and the Change of Laryngopharyngeal Mucosal Ultrastructure

BACKGROUND/AIMS: To establish an animal model of laryngopharyngeal reflux (LPR) and study the effect of LPR on the laryngopharyngeal mucosal ultrastructure. METHODS: Ten Bama minipigs were randomly divided into control group and stent group. Every pig underwent endoscope, and baseline pH was monitored for 4 hours at laryngopharynx and distal esophagus, then specimens from laryngopharyngeal mucosa were biopsied. For the control group, these procedures were repeated on the 14th day. In the stent group, a custom-designed esophageal stent suit was implanted into esophagus, laryngopharyngeal and distal esophageal pH monitoring lasted for 2 hours, then stent suit was removed 3 days later. At last, the same procedures were done as the control group on the 14th day. Specimens were observed under transmission electron microscope to measure the intercellular space and desmosome number. RESULTS: In the control group, there was no laryngopharyngeal reflux on the first day and 14th day. Before the stent was implanted, there was also no laryngopharyngeal reflux in the stent group. In both 2 hours and 14 days after stent implantation, the num -ber of reflux, reflux time, and percentage time of pH < 4.0 were significantly increased (P < 0.05) in the stent group. There was no difference in intercellular space and desmosomes in the control group between baseline and 14th day. In the stent group, intercellular space of laryngopharyngeal mucosa was significantly increased (0.37 mum vs 0.96 mum, P = 0.008), and the number of desmosomes was significantly decreased (20.25 vs 9.5, P = 0.003). CONCLUSIONS: A Bama minipig model of LPR was established by implanting a custom-designed stent suit. LPR might destroy the laryngophar yngeal mucosal barrier.

Extracellular space diffusion during progression of rat C6 glioma quantificated by magnetic resonance imaging / 中国比较医学杂志

Objective To compare the extracellular space diffusion at different stages of rat C6-gliomas determined by MRI tracer method and analyze the influencing effect of extracellular matrix ( ECM) on the diffusion process.Methods Introducing adolinium-diethylene triaminepentaacetic acid ( Gd-DTPA) into extracellular space ( ECS) as a tracer.The diffusion parameters and half-life time were quantified according to mathematical model of diffusion.The main ECM components ( e.g. chordroitin sulfate proteoglycans ( CSPGs ) , collagen IV tenascin C ) were detected by immunohistochemical and immunoblot analysis.Results Gd-DTPA introduced into 20-day glioma in the rats diffused more slowly [(6.67 ±1.78) ×10 -5 mm2/s vs.(1.26 ±0.27) ×10-4 mm2/s; t =4.265; P<0.01)], deriving a larger tortuosity [(3.99 ±0.57) vs.(2.83 ±0.29);t=4.11;P<0.01)], localized within the tumor with a smaller clearance rate [(7.67 ±2.29) ×10 -5mm2/s)vs.(1.46 ±0.36) ×10 -4mm2/s);t=3.87;P<0.05), and a longer half-life time ((0.86 ±0.23 h)vs.(1.64 ±0.12 h);(t=5.91;p<0.01)] compared with 10-day gliomas in the rats.The increased levels of extracellular matrix of glioma were associated with different diffusion and clearance parameters of 20-day gliomas in the rats in comparision with those in the 10-day rat gliomas, in which the chordroitin sulfate proteoglycans[(0.48 ±0.07) vs.(0.32 ±0.09);t=4.663;P<0.01)], tenascin C [(0.29 ±0.04) vs.(0.58 ±0.11);t =6.50;P<0.01] and collagen IV [(0.24 ±0.07)vs.(0.33 ±0.06);t=3.81;P<0.05] were tested.Conclusions The ECS parameters are changed with the C6 glioma progression due to the increased ECM content.The results of our study may help us to better understanding the glioma micro-environment and provide beneficial references for the brain interstitial drug delivery to treat gliomas.

Informational analysis of brain cell microenvironment / 中华医学科研管理杂志

Brain cell microenvironment,also known as cerebral tissue channel,consists of the brain extracellular space and its contents.For a long time,because of the limit of technology,the research about brain extracellular space hasn't been given enough attention in the field of cognitive sciences and neuroscience.With the development of medical imaging technology,the research about brain extracellular space will open up a new space for brain and cognitive sciences,and provide a new approach for diagnosis and treatment of encephalopathy.Based on the method of medical informatics,this article reveals hot topics on brain science,presents the history of the research about brain cell microenvironment,and analyzes the construction of neurology literature so as to provide reference for the future researchers.

Relevance of Ultrastructural Alterations of Intercellular Junction Morphology in Inflamed Human Esophagus

BACKGROUND/AIMS: Detailed characterization of the ultrastructural morphology of intercellular space in gastroesophageal reflux disease has not been fully studied. We aimed to investigate whether subtle alteration in intercellular space structure and tight junction proteins might differ among patients with gastroesophageal reflux disease. METHODS: Esophageal biopsies at 5 cm above the gastroesophageal junction were obtained from 6 asymptomatic controls, 10 patients with reflux symptoms but without erosions, and 18 patients with erosions. The biopsies were morphologically evaluated by transmission electron microscopy, and by using immunohistochemistry for tight junction proteins (claudin-1 and claudin-2 proteins). RESULTS: The expressions of tight junction proteins did not differ between asymptomatic controls and gastroesophageal reflux disease patients. In patients with gastroesophageal reflux disease, altered desmosomal junction morphology was only found in upper stratified squamous epithelium. Dilated intercellular space occurred only in upper stratified squamous epithelium and in patients with erosive esophagitis. CONCLUSIONS: This study suggests that dilated intercellular space may not be uniformly present inside the esophageal mucosa and predominantly it is located in upper squamous epithelium. Presence of desmosomal junction alterations is associated with increased severity of gastroesophageal reflux disease. Besides dilated intercellular space, subtle changes in ultrastructural morphology of intercellular space allow better identification of inflamed esophageal mucosa relevant to acid reflux.

Dissulfeto isomerase proteica como via integrativa entre estresse oxidativo e resposta a proteínas mal-enoveladas na reparação à lesão vascular / Protein disulfide isomerase as an integrative way between oxidative stress and unfolded protein response during vascular repair to injury

O remodelamento vascular é um determinante fundamental do lúmen em doenças vasculares, porém os mecanismos envolvidos não estão completamente elucidados. Nós investigamos o papel da chaperona redox residente do retículo endoplasmático Dissulfeto Isomerase Proteica (PDI) e sua fração localizada na superfície celular (peri/epicelular=pecPDI) no calibre e arquitetura vascular durante reparação à lesão. Em artérias ilíacas de coelho submetidas à lesão in vivo, houve importante aumento do mRNA e expressão proteica (~25x aumento 14 dias pós-lesão vs. controle) da PDI. O silenciamento da PDI por siRNA (cultura de órgãos) acentuou o estresse do retículo e apoptose, diferentemente da inibição da pecPDI com anticorpo neutralizante (PDI Ab). Bloqueio in vivo da pecPDI por aplicação de gel perivascular contendo PDI Ab no 12° dia após lesão, com análise após 48 h, promoveu ca.25% redução no calibre vascular analisado por arteriografia e diminuição similar na área total do vaso detectada por tomografia de coerência óptica. Neste processo, não ocorreu alteração no tamanho da neoíntima, indicando assim, que PDI Ab acentuou remodelamento constrictivo. Neutralização da pecPDI promoveu importantes alterações na arquitetura da matriz de colágeno e citoesqueleto, resultando em fibras com orientação invertida e desorganizadas. Diminuição na produção de espécies reativas de oxigênio e óxidos de nitrogênio também ocorreu. Análise de propriedades viscoelásticas nas artérias indicou redução na ductilidade vascular, evidenciada pela menor distância para ruptura. As alterações subcelulares no citoesqueleto observadas in vivo após PDI Ab foram recapituladas em um modelo de estiramento cíclico em células musculares lisas vasculares, com importante redução na formação das fibras de estresse. Em modelo de migração randômica de células musculares lisas, a exposição a PDI Ab reduziu a resiliência de regulação da polaridade. Embora a neutralização da pecPDI não tenha afetado a atividade...

Whole-vessel remodeling is a critical lumen caliber determinant in vascular disease, but underlying mechanisms are poorly understood. We investigated the role of endoplasmic reticulum chaperone Protein Disulfide Isomerase(PDI) and cell-surface PDI(peri/epicellular=pecPDI) pool in vascular caliber and architecture during vascular repair after injury(AI). After rabbit iliac artery balloon injury, there was marked increase in PDI mRNA and protein (25-fold vs. basal at day 14AI), with increase in both intracellular and pecPDI. Silencing PDI by siRNA (organ culture) induced ER stress augmentation and apoptosis, contrarily to pecPDI neutralization with PDI-antibody(PDI Ab). PecPDI neutralization in vivo with PDIAb-containing perivascular gel from days 12-14AI promoted ca.25% decrease in vascular caliber at arteriography and similar decreases in total vessel circumference at optical coherence tomography, without changing neointima, indicating increased constrictive remodeling. PecPDI neutralization promoted marked changes in collagen and cytoskeleton architecture, with inverted fiber orientation and disorganization. Decreased ROS and nitrogen oxide production also occurred. Viscoelastic artery properties assessment showed decreased ductility, evidenced by decreased distance to rupture. Subcellular cytoskeletal disruption by PDI Ab was recapitulated in vascular smooth muscle cell stretch model, with marked decrease in stress fiber buildup. Also, PDI Ab incubation promoted decreased regulation resilience of vascular smooth muscle migration properties. While pecPDI neutralization did not affect global RhoA activity, there was altered RhoA redistribution to the cell surface and association with caveolin-containing clusters, which mislocalized after stretch. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling. Thus, strongly-expressed PDI after injury reshapes matrix and cytoskeleton architecture to support an...

Role of Corticotrophin-releasing Factor in the Stress-induced Dilation of Esophageal Intercellular Spaces

Corticotrophin-releasing factor (CRF) plays a major role in coordinating stress responses. We aimed to test whether blocking endogenous CRF activity can prevent the stress-induced dilation of intercellular spaces in esophageal mucosa. Eighteen adult male rats were divided into 3 groups: 1) a non-stressed group (the non-stressed group), 2) a saline-pretreated stressed group (the stressed group), 3) and an astressin-pretreated stressed group (the astressin group). Immediately after completing the experiments according to the protocol, distal esophageal segments were obtained. Intercellular space diameters of esophageal mucosa were measured by transmission electron microscopy. Blood was sampled for the measurement of plasma cortisol levels. Mucosal intercellular spaces were significantly greater in the stressed group than in the non-stressed group. Mucosal intercellular spaces of the astressin group were significantly smaller than those of the stressed group. Plasma cortisol levels in the stressed group were significantly higher than in the non-stressed group. Pretreatment with astressin tended to decrease plasma cortisol levels. Acute stress in rats enlarges esophageal intercellular spaces, and this stress-induced alteration appears to be mediated by CRF. Our results suggest that CRF may play a role in the pathophysiology of reflux-induced symptoms or mucosal damage.

Effects of fluid resuscitation on cerebral extracellular neuroactive amino acids in a rat model of traumatic head injury combined with acute hemorrhagic shock / 中华麻醉学杂志

Objective To compare the effects of 0.9% NaCl (normal saline, NS), 10% hydroxyethyl starch (HES, 200/0.5) and hypertonic-hyperoncotic solution (HHS, 7.5% NaCl-10% HES 1:1) on cerebral extracellular excitatory amino acids (EAA) and inhibitory amino acids (IAA) in a rat model of traumatic head injury (THI) combined with acute hemorrhagic shock (AHS). Methods Nineteen healthy adult male SD rats weighing 300-350 g were randomized into 3 groups: NS group (n = 7); HES group ( n = 6) and HHS group ( n = 6). THI was produced by modified Feeney method (a 20g weight drops from a height of 40 cm on the parietal region) and AHS was induced by modified Wiggers method (Blood was removed from femoral artery and MAP was maintained at 40 mm Hg for 1 hour). Fluid resuscitation was started at 1 hour of AHS with 0.9% NS (3 times the volume of the removed whole blood) or 10% HES (in a one to one ratio) or HHS 4 ml?kg-1 administered over 15 min. The extracellular fluid of injured brain tissue was collected using intracerebral microdialysis before head injury (baseline) during THI + AHS (1h) and resuscitatin (2h) for determination of the levels of EAA (glutamate, aspartate) and IAA (glycine, GABA, taurine) by HPLC.Results The 5 amino acids were significantly increased during THI + AHS as compared with their baseline values. Glutamate level was further increased during resuscitation with NS. GABA and taurine concentrations were maintained at high level during resuscitation with HES or HHS. The increase in glutamate was inhibited by resuscitation with HES and the increase in glutamate, aspartate and glycine were inhibited by HHS. Conclusions In a rat model of THI combined with AHS, resuscitation with NS can increase cerebral extracellular EAA. Both HES and HHS resuscitation can inhibit the increase in cerebral extracellulaar EAA and HHS is more effective.

Effects of alterations in extracellular pH on the respiratory burst in neutrophils / 中国病理生理杂志

The respiratory burst of neutrophils is an important response in inflammation. The alterations in extracellular pH per se is not a sufficient trigger to the respiratory burst in neutrophils. While neutrophils in respose to conventional agonists, the respiratory burst in neutrophils is affected by the alterations in extracellular pH, and there is a direct relationship between intracellular and extracellular pH. O-? 2 production in neutrophils is decreased while H 2O 2 production is increased at acidic pH. O-? 2 release in neutrophils is enhanced at weak alkaline pH. Na+/H+ exchanger plays an important role in the regulation of the respiratory burst of neutrophils.