[Epidural photobiomodulation accelerates the drainage of brain interstitial fluid and its mechanism].

OBJECTIVE: To evaluate the effect of photobiomodulation (PBM) on the drainage of brain interstitial fluid (ISF) and to investigate the possible mechanism of the positive effect of PBM on Alzheimer's disease (AD). METHODS: Twenty-four SD male rats were randomly divided into PBM group (n=12), sham PBM group (n=6), and negative control group (n=6). According to the injection site of tracer, the PBM group was further divided into PBM-ipsilateral traced group (n=6) and PBM-contralateral traced group (n=6). Rats in the PBM group and the sham PBM group were exposed to the dura minimally invasively on the skull corresponding to the frontal cortical area reached by ISF drainage from caudate nucleus region. The PBM group was irradiated by using 630 nm red light (5-6 mW/cm2), following an irradiation of 5 min with a 2 min pause, and a total of 5 times; the sham PBM group was kept in the same position for the same time using the light without power. The negative control group was kept without any measure. After PBM, tracer was injected into caudate nucleus of each group. The changes of ISF drainage in caudate nucleus were observed according to the diffusion and distribution of tracer molecule by tracer-based magnetic resonance imaging, and the structural changes of brain extracellular space (ECS) were analyzed by diffusion rate in ECS-mapping (DECS-mapping) technique. Finally, parameters reflecting the structure of brain ECS and the drainage of ISF were obtained: volume fraction (α), tortuo-sity (λ), half-life (T1/2), and DECS. The differences of parameters among different groups were compared to analyze the effect of PBM on brain ECS and ISF. One-Way ANOVA post hoc tests and independent sample t test were used for statistical analysis. RESULTS: The parameters including T1/2, DECS, and λ were significantly different among the PBM-ipsilateral traced group, the PBM-contralateral traced group, and the sham PBM group (F=79.286, P < 0.001; F=13.458, P < 0.001; F=10.948, P=0.001), while there was no difference in the parameter α of brain ECS among the three groups (F=1.217, P=0.324). Compared with the sham PBM group and the PBM-contralateral traced group, the PBM-ipsilateral traced group had a significant decrease in the parameter T1/2 [(45.45±6.76) min vs. (76.01±3.44) min, P < 0.001; (45.45±6.76) min vs. (78.07±4.27) min, P < 0.001], representing a significant acceleration of ISF drainage; the PBM-ipsilateral traced group had a significant increase in the parameter DECS [(4.51±0.77)×10-4 mm2/s vs. (3.15±0.44)×10-4 mm2/s, P < 0.001; (4.51±0.77)×10-4 mm2/s vs. (3.01±0.38)×10-4 mm2/s, P < 0.001], representing a significantly increased molecular diffusion rate of in the brain ECS; the PBM-ipsilateral traced group had a significant decrease in the parameter λ (1.51±0.21 vs. 1.85±0.12, P=0.001; 1.51±0.21 vs. 1.89±0.11, P=0.001), representing a significant decrease in the degree of tortuosity in the brain ECS. CONCLUSION: PBM can regulate the brain ISF drainage actively, which may be one of the potential mechanisms of the effect of PBM therapy on AD. This study provides a new method for enhancing the brain function via ECS pathway.

[Improved synthesis process of optical-magnetic bimodal probe of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes].

OBJECTIVE: To improve the methods to synthesize and purify of optical-magnetic bimodal molecular probe of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluorescein thioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes. METHODS: Target compound (7), optical-magnetic bimodal molecular molecular probe, was synthesized by the use of 1, 4, 7, 10-tetraazacyclododecane (1) as starting material via substitution reaction, hydrolysis reaction, coupling reaction and complexation reaction with metal. RESULTS: The synthetic route of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes was improved. The optical-magnetic bimodal molecular probes were synthesized by substitution reaction, hydrolysis reaction, coupling reaction and complex reaction with metal respectively. For the improved route, the total yield could reach 34.6% which was higher than the original route (18.0%). The structures of those compounds were identified by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and mass spectrometry. The improved route could avoid the uncontrollable disadvantage of the substitution reaction, this process could reduce the formation of impurities and made the purification process easier, and in the aspect of purification and separation, the preparative high-performance liquid chromatography with less sample loading and high cost was improved to a column chromatography with many sample loads and being easy to operate. Therefore, the use of column chromatography could be more conducive to mass production of the optical-magnetic bimodal molecular molecular probe. CONCLUSION: The improved synthetic route improves the controllability of the reaction conditions and makes it easier to purify and separate the compounds. At the same time, the improved synthetic route can increase the total yield significantly. The optical-magnetic bimodal molecular probe can combine the living magnetic resonance imaging with the in vitro optical imaging to realize the dual synchronous detection of magneto-optics, so that the detection results of the living magnetic resonance imaging and the in vitro optical imaging are mutually verified. In other words, this synthetic optical-magnetic bimodal molecular probe will make the experimental results more accurate and reliable. In subsequent biological experimental studies, the optical-magnetic bimodal molecular probe can be applied to related research of brain structure and function, and the probe can be used for the brain-related diseases researches, such as brain tumors. after intravenous administration, and thus the optical-magnetic bimodal molecular probe can play an important role in medical treatment of brain tumors and cerebrovascular diseases.

[Effect of convection enhanced delivery on the microstructure of brain extracellular space in aged rats].

OBJECTIVE: To compare the changes of extracellular space (ECS) structure and local drug distribution in adult brain and aged brain at different drug delivery rates in minimally invasive treatment of encephalopathy by convection enhanced delivery (CED) via ECS pathway. METHODS: Thirty-six SD male rats were divided into adult rats group (2-8 months, n=18) and aged rats group (18-24 months, n=18) according to the age of the month. According to the drug rates (0.1 µL/min, 0.2 µL/min, and 0.3 µL/min), they were randomly divided into 3 subgroups, 6 in each subgroup. Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) with a concentration of 10 mmol/L were introduced into the caudate nucleus of each group of rats by stereotactic injection. Tracer-based magnetic resonance imaging (MRI) was used to dynamically monitor the diffusion and distribution images of the Gd-DTPA in the brain interstitial system (ISS). Using the self-developed MRI image measurement and analysis system software to process and analyze the obtained images, the diffusion coefficient, clearance rate, volume fraction, and half-life of each group of rats in the caudate nucleus ECS could be acquired. The effects and differences of drug clearance and ECS structural function in the brain of aged rats and adult rats were compared and analyzed at different drug delivery rates. Magnetic tracer DECS-mapping technique was used to observe the distribution and drainage of tracer in caudate nucleus. RESULTS: At the injection rate of 0.1 µL/min, the volume fraction in the aged rats was increased compared with that in the adult rats (18.20%±0.04% vs. 17.20%±0.03%, t=3.752, P=0.004), and the degree of tortuosity was decreased (1.63±0.04 vs. 1.78±0.09, t=-3.680, P=0.004), the drug clearance rate was decreased [(1.94±0.68) mm2/s vs. (3.25±0.43) mm2/s, t=-3.971, P=0.003], and the molecular diffusion in ECS was increased [(3.99±0.21)×10-4 mm2/s vs. (3.36±0.37)×10-4 mm2/s, t=3.663, P=0.004]. When the rate of injection increased to 0.2 µL/min, the drug clearance in ECS of the aged rats was slowed down [(2.53±0.45) mmol/L vs. (3.37±0.72) mmol/L, t=-1.828, P=0.021]. However, there were no significant differences in volume fraction, molecular diffusion in ECS and macroscopic drug metabolism parameters. When the rate of injection increased to 0.3 µL/min, the volume fraction in the aged rats was decreased (17.20%±0.03% vs. 18.20%±0.05%, t=-0.869, P=0.045), and the drug clearance rate in ECS was significantly accelerated [(4.04±0.76) mmol/L vs. (3.26±0.55) mmol/L, t=1.786, P=0.014], and there was no significant difference in tortuosity and the rate of molecular diffusion in the ECS. CONCLUSION: The drug clearance and ECS structural parameters of brain ECS in aged brain with CED administration were changed at different rates, and it has the least effect on ECS in the aged brain at the injection rate of 0.2 µL/min. For the application of CED for the treatment of encephalopathy, we should consider the influence of factors such as age and injection rate, and provide reference for the development of individualized clinical treatment plan for minimally invasive treatment of encephalopathy via ECS pathway.

[Discovery of a new division system in brain and the regionalized drainage route of brain interstitial fluid].

Brain extracellular space (ECS) is a narrow, irregular space, which provides immediate living environment for neural cells and accounts for approximately 15%-20% of the total volume of living brain. Twenty-five years ago, as an interventional radiologist, the author was engaged in investigating early diagnosis and treatment of cerebral ischemic stroke, and the parameters of brain ECS was firstly derived and demonstrated during the study of the permeability of blood-brain barrier (BBB) and its diffusion changes in the cerebral ischemic tissue. Since then, the author and his team had been working on developing a novel measuring method of ECS: tracer-based magnetic resonance imaging (MRI), which could measure brain ECS parameters in the whole brain scale and make the dynamic drainage process of the labelled brain interstitial fluid (ISF) visualized. By using the new method, the team made a series of new findings about the brain ECS and ISF, including the discovery of a new division system in the brain, named regionalized ISF drainage system. We found that the ISF drainage in the deep brain was regionalized and the structural and functional parameters in different interstitial system (ISS) divisions were disparate. The ISF in the caudate nucleus could be drained to ipsilateral cortex and finally into the subarachnoid space, which maintained the pathway of ISF-cerebrospinal fluid (CSF) exchange. However, the ISF in the thalamus was eliminated locally in its anatomical division. After verifying the nature of the barrier structure between different drainage divisions, the author proposed the hypothesis of "regionalized brain homeostasis". Thus, we demonstrated that the brain was protected not only by the BBB, which avoided potential exogenous damage through the vascular system, but was also protected by an internal ISF drainage barrier to avoid potentially harmful interference from other ECS divisions in the deep brain. With the new findings and the proposed hypothesis, an innovative therapeutic method for the treatment of encephalopathy with local drug delivery via the brain ECS pathway was established. By using this new administration method, the drug was achieved directly to the space around neurons or target regions, overwhelming the impendence from the blood-brain barrier, thus solved the obstacles of low efficiency in traditional drug investigation. At present, new methods and discoveries developed by the author and his team have been widely applied in several frontier fields including neuroscience, new drug research and development, neurodevelopment aerospace medicine, clinical encephalopathy treatment,new neural network modeling and so on.

[Clinicopathological and molecular characteristics of Epstein-Barr virus associated gastric cancer: a single center large sample case investigation].

OBJECTIVE: Epstein-Barr virus associated gastric cancer (EBVaGC) is different from the traditional gastric cancer (Epstein-Barr virus non-associated gastric cancer, EBVnGC), and has unique clinicopathological features. This study investigated the largest single center cancer series so as to establish the clinicopathological and molecular characteristics of EBVaGC in China. METHODS: A retrospective analysis was conducted on EBVaGC and EBVnGC patients diagnosed at Peking University Cancer Hospital from 2003 to 2018 by comparing their clinicopathological features and prognosis. The gastric cancer (GC) dataset of public database was analyzed to obtain differentially expressed genes. The expression of important genes and their association with prognosis of GC were verified in GC tissues from our hospital. RESULTS: In this study, 3 241 GC patients were included, and a total of 163 EBVaGC (5.0%) patients were identified. Compared with EBVnGC, EBVaGC was higher in male and younger patients, and positively associated with remnant GC, poorly differentiated adenocarcinoma, and mixed type GC. EBVaGC was inversely related to lymph node metastasis. The 5-year survival rate of EBVnGC and EBVaGC was 59.6% and 63.2% respectively (P<0.05). In order to explore molecular features of EBVaGC, the Cancer Genome Atlas (TCGA) dataset was analyzed (n=240), and 7 404 significant differentially expressed genes were obtained, involving cell proliferation, apoptosis, invasion and metastasis. The down-regulated invasion/metastasis gene SALL4 and the up-regulated immune checkpoint gene PD-L1 were important molecular features of EBVaGC. Validation of these two genes in large GC series showed that the majority of the EBVaGC was SALL4 negative (1/92, 1.1%, lower than EBVnGC, 303/1 727, 17.5%), and that PD-L1 was mostly positive in EBVaGC (81/110, 73.6%, higher than EBVnGC, 649/2 350, 27.6%). GC patients with SALL4 negative and PD-L1 positive were often associated with better prognosis. CONCLUSION: EBVaGC is a unique subtype of GC with less metastasis and a good prognosis. It also has a distinct molecular background. The down-regulation of invasion/metastasis gene SALL4 and up-regulation of immune checkpoint gene PD-L1 are important molecular features.

[Application of diffusion tensor imaging combined with virtual reality three-dimensional reconstruction in the operation of gliomas involved eloquent regions].

OBJECTIVE: To investigate the values of diffusion tensor imaging (DTI) and virtual reality (VR) techniques in design surgery program of gliomas near eloquent regions. METHODS: In this study, 35 cases were retrospectively analyzed with gliomas involved language areas or rolandic regions operated in Department of Neurosurgery, Peking University Third Hospital from January 2015 to January 2019. Surgery programs were performed by Dextroscope virtual reality system. The pre-operative data, such as the magnetic resonance imaging (MRI), magnetic resonance arteriography (MRA) and DTI was transferred into the VR computer for restitution,Tumors, neural fiber tracts and blood vessels were reconstructed to simulate operation and design individual surgical plan. Neurological function was evaluated 1 week, 1 month and 3 months after operation. RESULTS: Virtual reality three-dimensional images of the 35 cases were successfully achieved, including neural fiber tracts,blood vessels and the lesions. The displacement and destruction of fiber tracts, the anatomic relationship between tumor and important fiber bundle, artery and vein could be shown clearly. Surgical simulation and surgery program of VR of the 35 patients were successfully performed. The 3D images obtained from virtual reality near to the real surgery. Ten of the 35 cases were defined as rolandic regions tumors, 14 of the 35 cases were defined as language areas tumors and 11 of the 35 cases involved both language areas and rolandic regions. Complete resection of enhancing tumor (CRET) was achieved in 30 cases (85.7%), subtotal resection in 5 cases (14.3%), neurological function improved in 34 cases (97.1%) after operation,and 1 case had no improvement compared with that before(2.9%). Thirteen cases without neurological deficit pre-operation, showed transient neurological deficit ,which were recovered about 10 days post-operation, 12 of 22 cases with pre-operative neurologic deficit, improved one week postoperation, 9 of 22 cases with pre-operative neurologic deficit improved one month after operation, the rest 1 case was recurrent with glioblastoma with aggravated hemiplegia symptom after operation, who died of cerebral hernia 2 months later. CONCLUSION: Dextroscope virtual reality system can clearly expose and quantify the 3D anatomic relationship of tumors, neural fiber tracts and blood vessels surrounding gliomas near eloquent regions, which is helpful to design the best individualized surgery program, to improve surgical effect.

[Role of aquaporin-4 in the change of interstitial fluid drainage in Alzheimer's disease].

OBJECTIVE: To observe the characteristics of the interstitial fluid (ISF) drainage in the Alzheimer's disease (AD) rats through magnetic resonance imaging (MRI) tracer gadolinium-diethylene triamine pentacetic acid (Gd-DTPA)spread in the brain extracellular space (ECS) and to discuss the role of aquaporin-4 (Aqp4) in the AD. METHODS: Wild type SD rats (300-350 g) and Aqp4 gene knock out (Aqp4-/-) SD rats (300-350g) were divided into Sham group, AD group, Aqp4-/--Sham group and Aqp4-/--AD group. Sham group and Aqp4-/--Sham group were injected with saline by intraperitoneal each day for 6 weeks, and the AD group and Aqp4-/--AD group were injected with D-galactose by intraperitoneal each day for 6 weeks. MRI tracer Gd-DTPA (10 mmol/L, 2 µL) was injected into the hippocampus of the rats. MRI scan was performed at the end of 0.5 h, 1.5 h, 1 h, 2 h, and 3 h to observe the dynamic distribution of the Gd-DTPA in the hippocampus and the diffusion rate D*, clearance rate k' and half-life t1/2 measured. RESULTS: The diffusion rate D* in Sham group was (2.66±0.36)×10-6 mm2/s, the diffusion rate D* in AD group was (2.72±0.62)×10-6 mm2/s, the diffusion rate D* in Aqp4-/--Sham group was (2.75±0.47)×10-6 mm2/s, the diffusion rate D* in Aqp4-/--AD group was (2.802±0.55)×10-6 mm2/s, and there was no statistically significant difference in the four groups (One-Way ANOVA, P>0.05).The clearance rate k' in Sham group was (4.57±0.14)×10-4/s, the clearance rate k' in AD group was (3.68±0.22)×10-4/s, the clearance rate k' in Aqp4-/--Sham group was (3.17±0.16)×10-4/s, the clearance rate k' in Aqp4-/--AD group was (2.59±0.19)×10-4/s, and there was significant difference in the four groups (One-Way ANOVA, P<0.05). The half-life t1/2 in Sham group was (0.67±0.12) h, the half-life t1/2 in AD group was (0.88±0.08) h, the half-life t1/2 in Aqp4-/--Sham group was (1.12±0.15) h, the half-life t1/2 in Aqp4-/--AD group was (1.58±0.11) h, and there was significance difference in the four groups(one-way ANOVA,P<0.05). CONCLUSION: The ISF drainage is slow after AD and the loss of Aqp4 in the AD makes the ISF drainage obviously slow down, Aqp4 plays an important role in AD to remove the metabolism of waste out of the brain.

[Application of anoptomagnetic probe Gd-DO3A-EA-FITC in imaging and analyzing the brain interstitial space].

OBJECTIVE: To investigate the application of the optical magnetic bimodal molecular probe Gd-DO3A-ethylthiouret-fluorescein isothiocyanate (Gd -DO3A-EA-FITC) in brain tissue imaging and brain interstitial space (ISS). METHODS: In the study, 24 male SD rats were randomly divided into 3 groups, including magnetic probe group (n=6), optical probe group (n=6) and optical magnetic bimodal probe group (n=12), then the optical magnetic bimodal probe group was divided equally into magnetic probe subgroup (n=6) and optical probe subgroup (n=6). Referencing the brain stereotaxic atlas, the coronal globus pallidus as center level, the probes including gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), fluorescein isothiocyanate (FITC) and Gd-DO3A-EA-FITC of 2 µL (10 mmol/L) were injected into the caudate nucleus respectively, magnetic resonance imaging (MRI) was performed in the magnetic probe group and magnetic probe subgroup to image the dynamic diffusion and distribution of the probes in the brain ISS, a self-developed brain ISS image processing system was used to measure the diffusion coefficient, clearance, volume fraction and half-time in these two groups. Laser scanning confocal microscope (LSCM) was performed in vitro in the optical probe group and optical probe subgroup for fluorescence imaging at the time points 2 hours after the injection of the probe, and the distribution in the oblique sagittal slice was compared with the result of the first two groups. RESULTS: For the magnetic probe group and magnetic probe subgroup, there were the same imaging results between the probes of Gd-DTPA and Gd-DO3A-EA-FITC. The diffusion parameters of Gd-DTPA and Gd-DO3A-EA-FITC were as follows: the average diffusion coefficients [(3.31±0.11)×10-4 mm2/s vs. (3.37±0.15)×10-4 mm2/s, t=0.942, P=0.360], the clearance [(3.04±0.37) mmol/L vs. (2.90±0.51) mmol/L, t=0.640, P=0.531], the volume fractions (17.18%±0.14% vs. 17.31%±0.15%, t=1.961, P=0.068), the half-time [(86.58±3.31) min vs. (84.61±2.38) min, t=1.412, P=0.177], the diffusion areas [(23.25±0.68) mm2 vs. (22.71±1.00) mm2, t=1.100, P=0.297]. The statistical analysis of each brain was made by t test, and the diffusion parameters were not statistically significant. Moreover, for the optical probe group and optical probe subgroup, the diffusion area of Gd-DO3A-EA-FITC [(22.61±1.16) mm2] was slightly larger than that of FITC [(22.10±1.29) mm2], the statistical analysis of each brain was made by t test, and the diffusion parameters were not statistically significant (t=0.713, P=0.492). CONCLUSION: Gd-DO3A-EA-FITC shows the same imaging results as the traditional GD-DTPA, and it can be used in measuring brain ISS.

RAPID COMMUNICATION: Generation of FGF5 knockout sheep via the CRISPR/Cas9 system.

Sheep are an important source of fiber production. Fibroblast growth factor 5 (FGF5) is a dominant inhibitor of length of the anagen phase of the hair cycle. Knockout or silencing of the gene results in a wooly coat in mice, donkeys, dogs, and rabbits. In sheep breeding, wool length is one of the most important wool quality traits. However, traditional breeding cannot accurately and efficiently mediate an advanced genotype into the sheep genome. In this study, we generated 3 knockout sheep via the 1-step clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Sequencing analysis confirmed that mutations in the gene existed in all germ lines of 3 founders: besides the intact sequence, 3 kinds of deletions in the gene (including 5, 13, and 33 bp) were detected. The changes in the primary and senior structure of the FGF5 protein due to the 3 deletions in founders suggested that the FGF5 protein was dysfunctional. In addition, the expression level of intact mRNA in heterozygous individuals decreased compared with the wild types ( < 0.01). Functionally, we discovered that wool length in founders was significantly longer than in wild types ( < 0.05). Collectively, the knockout sheep with the longer wool length phenotype will provide an efficient way for fast genetic improvement of sheep breeding and promote the development of wool industry.

[Drainage characteristic of the brain interstitial fluid detected by using fluorescence and magnetic tracer method].

OBJECTIVE: Compare the results of molecular diffusion and mass flow in the interstitial space(ISS) displayed by using optical and magnetic probes and study partitioned drainage of the brain interstitial fluid (ISF). METHODS: In the study, 36 male SD rats were randomly divided into fluorescent inspection group (18), magnetic tracer group (18). Then they were divided equally into caudate nucleus (Cn), thalamus (T) and substantia nigra (Sn) subgroup, 6 rats in each subgroup. Referencing the brain stereotaxic atlas, the coronal globus pallidus as center level, Cn, T or Sn were acted as puncture positioning target. A 10 µL microsyringe was stereotaxically positioned and the lucifer yellow (LY) solution of 2 µL 10 mmol/L was infused into centric position. The coronary slices undergo cardiac perfusion and fix respectively in time point Cn 3 h, T 2 h and Sn 1 h. The rat brain was placed in rat stainless steel brain matrices and cut backward along visual intersection. The injection point of coronal slice as the center level, take 3 slices in front of the center level and 2 slices behind of it. 1 mm for each slice and 6 slices in total. Then slices were detected by laser scanning confocal microscope (LSCM). Simultaneous, in the same coordinate brain regions of another three groups, a gadolinium-diethylene triamine pentaacetic acidm (Gd-DTPA) solution of 2 µL 10 mmol/L was infused into different injection and detected by MRI tracer-based method. Then the Radiant can be used to measure distribution area of Gd-DTPA. RESULTS: LY and Gd-DTPA have different distribution regions in Cn, T and Sn. After LY and Gd-DTPA were introduced into the Cn subgroup 3 h, compare the 1 to 6 levels distribution area of LY and Gd-DTPA as follows: (10.95±4.27) mm2 vs. (8.33±2.25) mm2, (18.16±4.74) mm2 vs. (16.42±2.88) mm2, (24.57±3.65) mm2 vs. (20.75±2.29) mm2, (34.81±3.32) mm2 vs. (28.88±1.51) mm2, (30.53±3.12) mm2 vs. (20.92±2.75) mm2, (12.15±4.92) mm2 vs. (10.00±1.89) mm2. The statistical analysis of every level was made by T test, and the difference of the distribution area between the two tracers were not statistically significant (t=0.940, P=0.400; t=0.546, P=0.614; t=1.534, P=0.200; t=2.809, P=0.480; t=2.693, P=0.055; t=0.707, P=0.518); After LY and Gd-DTPA were introduced into the T subgroup 2 h, compare the 1-6 levels distribution area of LY and Gd-DTPA as follows: (5.56±4.61) mm2 vs. (3.33±2.25) mm2, (16.21±3.36) mm2 vs. (11.42±2.88) mm2, (19.00±5.21) mm2 vs. (15.75±2.29) mm2, (25.32±5.49) mm2 vs. (22.33±3.25) mm2, (17.34±5.31) mm2 vs. (15.92±2.75) mm2, (7.67±6.19) mm2 vs. (5.00±1.89) mm2. The statistical analysis of every level was made by T test, and the difference of the distribution area between the two tracers were not statistically significant (t=0.753, P=0.493; t=1.875, P=0.134; t=0.990, P=0.378; t=0.810, P=0.464; t=0.413, P=0.701; t=0.716, P=0.514); After LY and Gd-DTPA were introduced into the Sn subgroup 1 h, compare the 1-6 levels distribution area of LY and Gd-DTPA as follows: (6.78±4.56) mm2 vs. (4.75±2.00) mm2, (12.65±5.04) mm2 vs. (10.44±1.13) mm2, (19.51±6.54) mm2 vs. (17.55±0.30) mm2, (28.72±5.45) mm2 vs. (24.48±1.32) mm2, (21.34±4.42) mm2 vs. (17.72±0.25) mm2, (13.00±5.46) mm2 vs. (12.00±2.88) mm2. The statistical analysis of every level was made by T test and the difference of the distribution area between the two tracers were not statistically significant (t=0.705, P=0.519; t=0.743, P=0.499; t=0.517, P=0.656; t=1.310, P=0.260; t=1.416, P=0.292; t=0.281, P=0.793), but the distribution area of LY is slightly more than Gd-DTPA. CONCLUSION: LSCM imaging technology confirmed partitioned drainage of the brain ISF found by MRI tracer-based method and provided technology and method validation for MRI tracer-based method. LSCM imaging technology with higher contrast and resolution, therefore more sophisticated partitioned drainage of the brain interstitial fluid were got.

A comprehensive review of microRNA-related polymorphisms in gastric cancer.

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules of about 22 nucleotides in length. miRNAs are highly conserved in both plants and animals, and function as gene regulators by binding to the 3'-untranslated region of target mRNAs for cleavage and/or translational repression. miRNA biogenesis, stability, and regulation of expression are strongly sequence dependent. Sequence variants, such as single nucleotide polymorphisms (SNPs) in pri-miRNA, pre-miRNA, promoter regions, or miRNA-target sites, can influence miRNA function, thereby contributing to the pathological features of human disease. In this review, we focus on miRNA-related SNPs in gastric cancer and comprehensively analyze some commonly studied SNPs.

Protective effects of thrombomodulin on microvascular permeability after subarachnoid hemorrhage in mouse model.

The enhanced vascular permeability is a major early brain injury following subarachnoid hemorrhage (SAH). However, its mechanism is not clear yet. In this work, we explored its potential mechanism and investigated the roles of thrombomodulin (TM) in maintaining microvascular integrity after SAH. SAH models were established in adult male ICR mice (28-32 g) by endovascular perforation. TM was immediately administered by femoral vein injection following SAH. The brain water content, Evans Blue content and neurological functions were evaluated. Brain edema was also detected by magnetic resonance imaging (MRI) (T2 map). The siRNA technique, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and western blotting were performed to explore the potential mechanism of TM treatment. The number of microthrombi in the hippocampus microvessels was also recorded. TM significantly decreased brain water content and Evans Blue content, alleviated brain edema and neurological deficits after SAH. The plasma concentration of activated protein C was increased after TM treatment. In addition, the levels of phospho-p38MAPK, phospho-p53, cleaved caspase-3, phospho-NF-κB (p65) were markedly decreased. Additionally, the loss of VE-cadherin and Occludin (markers of vascular integrity) and the number of microthrombi in the hippocampus were also reduced. Our results indicated that TM has protective effects on preserving microvascular integrity following SAH partly through preserving endothelial junction proteins and quenching apoptosis/inflammation in endothelial cells via blocking p38MAPK-p53/NF-κB (p65) pathway.

Investigation of a fenofibrate-hydroxypropyl-beta-cyclodextrin system prepared by a co-grinding method.

Considering the poor water solubility and the low oral bioavailability in humans, the complex formation of fenofibrate (FNB) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solution was studied. The effect of temperature on the complexation was examined and thermodynamic parameters of the complexation process such as Gibbs free energy change (deltaG), enthalpy change (deltaH) and entropy (deltaS) change were also determined. Meanwhile, the solid dispersion of FNB with HP-beta-CD was prepared and characterized by X-ray diffractometry and Fourier IR spectroscopy. The experimental results indicated that a 1:1 molar ratio complex of FNB with HP-beta-CD could form in aqueous solution and the complexation was exothermic and enthalpy-driven process. The FNB-HP-beta-CD solid dispersion presented a remarkable improvement in the solubility and dissolution rate of the drug. This might be attributed to the amorphous state, the enhanced wettability and as well as the complex formation of the drug with HP-beta-CD in aqueous solution.

Monocytes-macrophages phagocytosis as a potential marker for disease resistance in generation 1 of dwarf chickens.

Monocytes-macrophages play an indispensable role in the immune system. The current study investigated the effect of selection for monocytes-macrophages phagocytosis on disease resistance in generation 1 (G1) of dwarf chickens. Five hundred dwarf chickens of generation 0 (G0) were divided into high and low phagocytic index (PI) groups (HPIG and LPIG, respectively) based on their PI of monocytes-macrophages at 290 d of age. Then, 2 x 2 mating combinations were conducted. Sixty G0 chickens from another dwarf chicken group were used to measure the levels of monocytes-macrophages phagocytosis at different developmental stages. Among a total of 2,500 randomly selected G1 chickens, 2,100 individuals were used for a surviving and growing test under adverse feeding circumstances, and the other 400 individuals were tested for Salmonella Pullorum challenge. The results showed that progenies of HPIG hens (female symbol) were more resistant to Salmonella Pullorum. After challenge, the death rate of progeny from HPIG female symbol (28.9%) was only 58% that of progeny from LPIG female symbol (49.4%, P < 0.001). In addition, the natural infection rate of Salmonella Pullorum before 207 d for offspring from HPIG female symbol (35.0%) was significantly lower than that for offspring from LPIG female symbol (48.3%, P < 0.001). The natural mortality before 56 d in progeny of HPIG female symbol (22.6%) was significantly lower than that in progeny of LPIG female symbol (29.1%) with a P-value of 0.001. The G1 chickens of HPIG G0 female symbol weighed more than those born to LPIG G0 female symbol at 28 and 42 d of age, whereas the difference was not statistically significant at 56 d of age. The heritability of monocytes-macrophages phagocytosis was 0.40, which was moderate. The PI values were at a low level before 126 d and increased dramatically until they declined significantly after 294 d. It could be concluded that phagocytosis of monocytes-macrophages is a marker for breeding excellent progeny with strong disease resistance.

Interviews for the assessment of long-term incapacity for work: a study on adherence to protocols and principles.

BACKGROUND: Assessments for long-term incapacity for work are performed by Social Insurance Physicians (SIPs) who rely on interviews with claimants as an important part of the process. These interviews are susceptible to bias. In the Netherlands three protocols have been developed to conduct these interviews. These protocols are expert- and practice-based. We studied to what extent these protocols are adhered to by practitioners. METHODS: We compared the protocols with one another and with the ICF and the biopsychosocial approach. The protocols describe semi-structured interviews with comparable but not identical topics. All protocols prescribe that the client's opinion on his capacity for work, and his arguments, need to be determined and assessed. We developed a questionnaire to elicit the adherence SIPs have to the protocols, their underlying principles and topics. We conducted a survey among one hundred fifty-five experienced SIPs in the Netherlands. RESULTS: Ninety-eight SIPs responded (64%). All respondents used some form of protocol, either one of the published protocols or their own mix. We found no significant relation between training and the use of a particular protocol. Ninety percent use a semi-structured interview. Ninety-five percent recognise having to verify what the claimant says and eighty-three percent feel the need to establish a good relation (p = 0.019). Twelve topics are basically always addressed by over eighty percent of the respondents. The claimant's opinion of being fit for his own work or other work, and his claim of incapacity and his health arguments for that claim, reach a hundred percent. Description of claimants' previous work reaches ninety-nine percent. CONCLUSION: Our study shows professional consensus among experienced Dutch SIPs about the principle of assessment on arguments, the principle of conducting a semi-structured interview and the most crucial interview topics. This consensus can be used to further develop a protocol for interviewing in the assessment of incapacity for work in social insurance. Such a protocol can improve the quality of the assessments in terms of transparency and reproducibility, as well as by enabling clients to better prepare themselves for the assessments.

Work ability in sick-listed patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is often a chronic relapsing disease resulting in work disability. For evaluation purposes a practical set of aspects of work ability would be helpful. AIM: To identify the most important disease-specific aspects of work ability for sick-listed employees with MDD. METHODS: An expert brainstorming session identified the specific abilities that were thought to be associated with work ability in sick-listed employees with MDD and that could also be associated with the items of the Hamilton Rating scale for Depression. Sixty-four insurance physicians (IPs) were then selected to participate in a two-round Delphi study. The aim of the first Delphi round was to identify the abilities that were thought to be important by at least 80% of the IPs. In the second Delphi round, the abilities ranked in the top 10 by at least 55% of the IPs were identified as being the most important items. RESULTS: Sixty-one IPs participated in the two Delphi rounds. The most important abilities to be evaluated in work ability evaluation for sick-listed employees with MDD were to take notice, to sustain attention, to focus attention, to complete operations, to think in a goal-directed manner, to remember, to perform routine operations, to undertake structured work activities, to recall and to perform autonomously. CONCLUSION: According to 55% of the IPs, there were 10 important aspects of work ability that have to be considered in a work ability evaluation of sick-listed employees with MDD.

Work-ability evaluation: a piece of cake or a hard nut to crack?

PURPOSE: To describe what aspects, categorized according to the ICF model, insurance physicians (IPs) take into account in assessing short- and long-term work-ability. METHOD: An interview study on a random sample of 60 IPs of the Dutch National Institute for Employee Benefit Schemes, stratified by region and years of experience. RESULTS: In determining work-ability, a wide range of aspects were used. In the case of musculoskeletal disease, 75% of the IPs considered the 'function and structures' component important. With psychiatric and other diseases, however, the 'participation factor' component was considered important by 85 and 80%, respectively. Aspects relating to the 'environmental factor' and 'personal factor' components were mentioned as important by fewer than 25%. In assessing the short- and long-term prognosis of work-ability, the 'disease or disorder' component was primarily used with a rate of over 75%. CONCLUSIONS: In determining work-ability, insurance physicians predominantly consider aspects relating to the 'functions and structures' and 'participation' components of the ICF model important. The 'environmental factor' and 'personal factor' components were not often mentioned. In assessing the short- and long-term prognosis of work-ability, the 'disease or disorder' component was predominantly used. It can be argued that 'environmental factors' and 'personal factors' should also more often be used in assessing work-ability.

Prognostic factors for work ability in sicklisted employees with chronic diseases.

OBJECTIVE: Identifying prognostic factors for work ability in sicklisted employees with myocardial infarction (MI), chronic low back pain (cLBP) and major depressive disorder (MDD) in order to establish an objective basis for work ability evaluation. DESIGN: Systematic literature search in PubMed database (1 January 1990 to 1 July 2006) with the Yale prognostic research filter. Inclusion criteria were as follows: (1) work-disabled employees; (2) MI, cLBP or MDD patients; (3) longitudinal designs; and (4) return to work or compensation status as outcome measure. RESULTS: four studies on mi met the inclusion criteria and described the following prognostic factors for work ability in the acute phase of the disease and disablement: lower age; male gender; no financial basis on which to retire; lower physical job demands; fewer somatic complaints; no anxiety attacks; no diabetes; no heart failure; no atrial fibrillation; no Q waves; and a short time interval between MI and presentation at the occupational medicine clinic. Two studies on cLBP met the inclusion criteria and described the following prognostic factors for work ability after 3 months' work disablement: lower age; male gender; no treatment before sick listing; surgery in the first year of sick listing; being a breadwinner; less pain; better general health; higher job satisfaction; lower physical and/or psychological demands at work; and a higher decision latitude at work. No relevant MDD studies were found. CONCLUSION: In the earlier phases of work disablement in MI and cLBP patients, only a few studies describe disease-specific, environmental and personal prognostic factors for return to work. No studies describe prognostic factors for MDD. More evidence is needed on the topic of prognostic factors for return to work in employees with chronic diseases.