支气管哮喘不同时期证候演变规律的临床调查研究?

目的探讨支气管哮喘急性发作期、慢性持续期、临床缓解期的证候演变规律。方法收集17家三级甲等中医院支气管哮喘患者资料,运用SPSS 18.0统计软件包建立以中医辨证为特征的临床调查研究数据库,并进行频率的统计描述及卡方检验。结果发放表格2 500份,收回表格2 481份,有效2 428份。急性发作期以实证为主,临床表现为外寒内饮证、痰热壅肺证、痰浊阻肺证、风痰阻肺证、血瘀证;慢性持续期以虚实兼杂为主;缓解期以虚证为主,表现为肺气虚证、肺肾气虚证、肺脾气虚证、肺肾气阴两虚证、肺肾阳虚证。结论支气管哮喘中医证候演变有一定的规律性,可为本病的防治提供依据。     

Toll样受体8基因rs3764880多态性与汉族男性缺血性中风的关联性研究

目的探讨Toll样受体8(TLR8)基因rs3764880遗传多态性与缺血性中风风痰瘀阻证、气虚血瘀证的易感性及相关数量性状的关联。方法纳入缺血性中风风痰瘀阻证患者311例、气虚血瘀证284例,对照组605例。用real-time PCR技术检测外周血TLR8基因表达水平,Sequenom Mass ARRAY platform进行基因分型,ELISA法测定炎性细胞因子血清水平。以PLINK、SPSS 16.0软件进行统计分析。结果 TLR8基因rs3764880多态性与中国汉族男性中风风痰瘀阻证易感性的关联有统计学意义(等位基因模型P0.05)。在气虚血瘀证患者中,携带GG基因型者的血清白细胞介素8(IL-8)水平较携带AA+GG基因型者高(P0.05);携带GG+AG基因型者的肿瘤坏死因子α(TNF-α)、IL-8血清水平高于携带AA基因型者(P0.05)。rs3764880多态性与男性气虚血瘀证患者的胆固醇(TC)(加性模型:β=-0.03,Padj=0.001)、低密度脂蛋白(LDL)水平(加性模型:βb=-0.25,Padj=0.018)显著关联。结论TLR8基因rs3764880多态性可能影响中国汉族男性缺血性中风风痰瘀阻证发生,并影响气虚血瘀证的炎性反应和脂质代谢。     

Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production

Toll-like receptors (TLRs) signal through two main pathways: a myeloid differentiation factor (MyD)88-dependent pathway that acts via nuclear factor kappaB (NF-kappaB) to induce proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and a MyD88-independent pathway that acts via type I interferons to increase the expression of interferon-inducible genes. Repeated signalling through TLR4 and a number of other TLRs has been reported to result in a reduction in the subsequent proinflammatory cytokine response, a phenomenon known as TLR tolerance. In this study we have shown that, whilst NF-kappaB activation and production of TNF-alpha and interleukin-12 by murine RAW264.7 and J774.2 cells in response to stimulation by TLR4, -5, -7 or -9, was reduced by prior stimulation with TLR4, -5, -7 or -9 ligands, the primary stimulation of TLR3, which does not use the MyD88 pathway, did not reduce the TNF-alpha or interleukin-12 responses to subsequent TLR stimulation. The response to TLR3 stimulation was not diminished by prior TLR ligand exposure. Furthermore, the production of interferon-beta (IFN-beta) following stimulation of TLR3 or -4, which is MyD88-independent, was increased by prior activation of TLR4, -5, -7 or -9. In contrast, TLR9 ligand-induced IFN-beta production, which is MyD88-dependent, was tolerized by prior TLR stimulation. These results are consistent with differential regulation of MyD88-dependent and MyD88-independent cytokine production following serial activation of TLRs.     

Phenotypes of invasion in sporadic colorectal carcinomas related to aberrations of the adenomatous polyposis coli (APC ) gene

AIMS: To determine whether the dissociation of tumour cells from neoplastic glands in colorectal carcinomas is caused by disruption of the wnt-signalling pathway and whether the adenomatous polyposis coli (APC) protein is implicated in this. METHODS AND RESULTS: In a series of 99 clinically sporadic colorectal carcinomas, APC exon 15 mutations, loss of heterozygosity (LOH) and promoter methylation were found in 49, 20 and 23 cases, respectively. Singly, these APC aberrations were not associated with the degree of tumour cell dissociation, but dissociation was higher for the cases with combined APC mutation and LOH. Immunohistochemical beta-catenin translocation to the nucleus correlated with APC aberrations. Tumour growth pattern (expansive/infiltrative/diffuse) and tumour stroma (desmoplastic common-type versus keloid-like) showed a statistically significant association with tumour cell dissociation and with beta-catenin translocation. Of other molecular alterations tested (p53 mutation; LOH at 17p13, 18q, 9p21; CpG island methylator phenotype), only the highly microsatellite unstable status (n = 11) was negatively associated. CONCLUSIONS: In colorectal carcinomas, wnt dysregulation relates to APC aberrations, but wnt dysregulation and APC aberrations are not strictly required for tumour cell dissociation, and additional and/or alternative factors must play a role. Of these, outside-in signalling by cancer cell-matrix interactions, as partially mirrored in histomorphological features, could be important.     

Sleep architecture and NREM alterations in children and adolescents with Asperger syndrome

STUDY OBJECTIVES: To analyze sleep in children with Asperger syndrome (AS) by means of standard sleep questionnaires, to evaluate sleep architecture and NREM sleep alterations by means of cyclic alternating pattern (CAP) and to correlate objective sleep parameters with cognitive behavioral measures. DESIGN: Cross-sectional study involving validated sleep questionnaires, neuropsychological scales, and PSG recording. SETTING: Sleep medicine center. PARTICIPANTS: Eight children with AS, 10 children with autism, and 12 healthy control children. INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Children with AS had a higher prevalence of problems of initiating sleep and daytime sleepiness. Sleep architecture parameters showed minor differences between the 3 groups. CAP parameters showed an increased percentage of A1 and a decreased percentage of A2 subtypes in subjects with AS vs. controls. All A subtype indexes (number per hour of NREM sleep) were decreased, mostly in sleep stage 2 but not in SWS. With respect to children with autism, subjects with AS showed increased CAP rate in SWS and A1 percentage. In subjects with AS, verbal IQ had a significant positive correlation with total CAP rate and CAP rate in SWS and with global and SWS A1 index. The percentage of A2 negatively correlated with full scale IQ, verbal and performance IQ. CBCL total score correlated positively with CAP rate and A1 index while externalizing score correlated negatively with A3%. CONCLUSIONS: This study shows peculiar CAP modifications in children with AS and represents an attempt to correlate the quantification of sleep EEG oscillations with the degree of mental ability/disability.     

Genomic variants of TLR1--it takes (TLR-)two to tango

Toll-like receptors (TLR) are innate immune sensors of microbial cell wall products that initiate early host responses. The TLR2 receptor complex has been shown to contain heterodimers of TLR2 with either TLR1 or TLR6 enabling the host to detect different microbial molecules, such as lipopeptides of different chemical composition. In this issue of the European Journal of Immunology, an important role in the sensing of microbial products for I602S, a single nucleotide polymorphism (SNP) in human TLR1 has been identified. This result, in combination with another recently published report on this polymorphism elucidating a functional role in cell trafficking (surface expression of the receptor complex in individuals carrying the SNP was altered), provide genetic evidence affirming the important function of TLR1 as an essential co-receptor for TLR2.     

Visuomotor learning in immersive 3D virtual reality in Parkinson’s disease and in aging

Successful adaptation to novel sensorimotor contexts critically depends on efficient sensory processing and integration mechanisms, particularly those required to combine visual and proprioceptive inputs. If the basal ganglia are a critical part of specialized circuits that adapt motor behavior to new sensorimotor contexts, then patients who are suffering from basal ganglia dysfunction, as in Parkinson's disease should show sensorimotor learning impairments. However, this issue has been under-explored. We tested the ability of 8 patients with Parkinson's disease (PD), off medication, ten healthy elderly subjects and ten healthy young adults to reach to a remembered 3D location presented in an immersive virtual environment. A multi-phase learning paradigm was used having four conditions: baseline, initial learning, reversal learning and aftereffect. In initial learning, the computer altered the position of a simulated arm endpoint used for movement feedback by shifting its apparent location diagonally, requiring thereby both horizontal and vertical compensations. This visual distortion forced subjects to learn new coordinations between what they saw in the virtual environment and the actual position of their limbs, which they had to derive from proprioceptive information (or efference copy). In reversal learning, the sign of the distortion was reversed. Both elderly subjects and PD patients showed learning phase-dependent difficulties. First, elderly controls were slower than young subjects when learning both dimensions of the initial biaxial discordance. However, their performance improved during reversal learning and as a result elderly and young controls showed similar adaptation rates during reversal learning. Second, in striking contrast to healthy elderly subjects, PD patients were more profoundly impaired during the reversal phase of learning. PD patients were able to learn the initial biaxial discordance but were on average slower than age-matched controls in adapting to the horizontal component of the biaxial discordance. More importantly, when the biaxial discordance was reversed, PD patients were unable to make appropriate movement corrections. Therefore, they showed significantly degraded learning indices relative to age-matched controls for both dimensions of the biaxial discordance. Together, these results suggest that the ability to adapt to a sudden biaxial visuomotor discordance applied in three-dimensional space declines in normal aging and Parkinson disease. Furthermore, the presence of learning rate differences in the PD patients relative to age-matched controls supports an important contribution of basal ganglia-related circuits in learning novel visuomotor coordinations, particularly those in which subjects must learn to adapt to sensorimotor contingencies that were reversed from those just learned.     

A Mathematical Model and Experimental Verification of Optimal Nozzle Diameter in Needle-Free Injection

Needle-free injection (NFI), as an alternative drug delivery strategy, owns great potential. It is able to reduce complaints about needle phobia and avoid the occurring of accidental needle stick injuries. The nozzle diameter is inherently important in determining the injection dose, injection depth, and pain associated with NFIs. In this work, needle-free injectors with nozzle diameters of 0.17, 0.20, 0.30, 0.40, and 0.50 mm were studied in the simulation and experiment. This article optimizes the mathematical model for spring-powered NFI by considering the hydraulic loss due to the abrupt change in the nozzle exit area and the friction force between the piston and ampoule. We explore the dispersion pattern in gels with different nozzle diameters. Mice insulin injection was conducted to investigate the pharmacological effect of different injection methods. The experimental results show that there is the best dispersion effect and available injection depth while the nozzle diameter is 0.30 mm, which is in agreement with the result predicted by the mathematical model. Also, there is a satisfactory pharmacological effect on the mice insulin injection under the same injection condition. Undoubtedly, the mathematical model is capable of predicting the suitable nozzle diameter under the given conditions.     

Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.