Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis

Introduction

To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.

Methods

In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.

Results

68% of the patients had accelerated hand BMD loss (>-0.003 g/cm²) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.

Conclusions

In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.     

Transcriptional profiling of bovine intervertebral disc cells: implications for identification of normal and degenerate human intervertebral disc cell phenotypes

Introduction  

Nucleus pulposus (NP) cells have a phenotype similar to articular cartilage (AC) cells. However, the matrix of the NP is clearly different to that of AC suggesting that specific cell phenotypes exist. The aim of this study was to identify novel genes that could be used to distinguish bovine NP cells from AC and annulus fibrosus (AF) cells, and to further determine their expression in normal and degenerate human intervertebral disc (IVD) cells.     

Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-β-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C _max and shorter mean T _max (about 2 h earlier) and about 1.32-fold higher mean AUC_0–24 values for the F3 chewable tablets compared to ET-filled capsules.     

纳米颗粒Gd@C_(82)(OH)_(22)抑制哺乳动物细胞外排转运的研究

目的 探讨纳米颗粒Gd@C_(82)(OH)_(22)体外对哺乳动物细胞外排转运的影响,研究该外排转运抑制作用与MRP1蛋白和ATP酶活性间的关系,为Gd@C_(82)(OH)_(22)应用于耐药肿瘤治疗提供初步实验依据.方法 通过Calcein-AM(C-AM)摄入法,以仓鼠肾细胞BHK-21、转染表达多药耐药相关蛋白MRP1的BHK-21/MRP1细胞以及肿瘤细胞PC-3为模型测定Gd@C_(82)(OH)_(22)对细胞外排转运的整体影响;用比色法测定Gd@C_(82)(OH)_(22)对MRP1蛋白截短体及BHK-21/MRP1质膜微囊的ATP酶活性的影响.结果 经Gd@C_(82)(OH)_(22)处理后,3种细胞的C-AM摄入量均上调,BHK-21与BHK-21/MRP1摄入量增加相似;用MRP1抑制剂MK571处理BHK-21/MRP1后,细胞C-AM摄入增长趋势不变;Gd@C_(82)(OH)_(22)对MRP1蛋白截短体及质膜微囊的ATP酶活性没有抑制作用.结论 表明Gd@C_(82)(OH)_(22)可抑制哺乳动物细胞的外排转运,其抑制作用并不是通过抑制MRP1蛋白或ATP酶活性来实现的.     

Coding "what" and "when" in the Archer fish retina

Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, “what”, can be estimated from the responses of best single cells with an accuracy comparable to that of the animal''s psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “when”, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.

Authors Summary

In our interaction with the environment we are flooded with a stream of numerous objects and events. Our brain needs to understand the nature of these complex and rich stimuli in order to react. Research has shown ways in which a ‘what’ stimulus was presented can be encoded by the neural responses. However, to understand ‘what was the nature of the stimulus’ the brain needs to know ‘when’ the stimulus was presented. Here, we investigated how the onset of visual stimulus can be signalled by the retina to higher brain regions. We used archer fish as a framework to test the notion that the answer to the question of ‘when’ something has been presented lies within the larger cell population, whereas the answer to the question of ‘what’ has been presented may be found at the single-neuron level. The utility of the archer fish as model animal stems from its remarkable ability to shoot down insects settling on the foliage above the water level, and its ability to distinguish between artificial targets. Thus, the archer fish can provide the fish equivalent of a monkey or a human that can report psychophysical decisions.     

Potentiation of epithelial innate host responses by intercellular communication

The epithelium efficiently attracts immune cells upon infection despite the low number of pathogenic microbes and moderate levels of secreted chemokines per cell. Here we examined whether horizontal intercellular communication between cells may contribute to a coordinated response of the epithelium. Listeria monocytogenes infection, transfection, and microinjection of individual cells within a polarized intestinal epithelial cell layer were performed and activation was determined at the single cell level by fluorescence microscopy and flow cytometry. Surprisingly, chemokine production after L. monocytogenes infection was primarily observed in non-infected epithelial cells despite invasion-dependent cell activation. Whereas horizontal communication was independent of gap junction formation, cytokine secretion, ion fluxes, or nitric oxide synthesis, NADPH oxidase (Nox) 4-dependent oxygen radical formation was required and sufficient to induce indirect epithelial cell activation. This is the first report to describe epithelial cell-cell communication in response to innate immune activation. Epithelial communication facilitates a coordinated infectious host defence at the very early stage of microbial infection.     

Three Members of the 6-cys Protein Family of Plasmodium Play a Role in Gamete Fertility

The process of fertilization is critically dependent on the mutual recognition of gametes and in Plasmodium, the male gamete surface protein P48/45 is vital to this process. This protein belongs to a family of 10 structurally related proteins, the so called 6-cys family. To identify the role of additional members of this family in Plasmodium fertilisation, we performed genetic and functional analysis on the five members of the 6-cys family that are transcribed during the gametocyte stage of P. berghei. This analysis revealed that in addition to P48/45, two members (P230 and P47) also play an essential role in the process of parasite fertilization. Mating studies between parasites lacking P230, P48/45 or P47 demonstrate that P230, like P48/45, is a male fertility factor, consistent with the previous demonstration of a protein complex containing both P48/45 and P230. In contrast, disruption of P47 results in a strong reduction of female fertility, while males remain unaffected. Further analysis revealed that gametes of mutants lacking expression of p48/45 or p230 or p47 are unable to either recognise or attach to each other. Disruption of the paralog of p230, p230p, also specifically expressed in gametocytes, had no observable effect on fertilization. These results indicate that the P. berghei 6-cys family contains a number of proteins that are either male or female specific ligands that play an important role in gamete recognition and/or attachment. The implications of low levels of fertilisation that exist even in the absence of these proteins, indicating alternative pathways of fertilisation, as well as positive selection acting on these proteins, are discussed in the context of targeting these proteins as transmission blocking vaccine candidates.     

Indicators of environmentally sound land use in the humid tropics: The potential roles of expert opinion,knowledge engineering and knowledge discovery

Despite abundant literature on indicators for sustainable resource management, practical tools to help local users to apply its general concepts at a local to regional level are scarce. This means that decisions over land evaluation and land use at a local level are often not based on the formal application of indicators or decision support systems for environmentally sound management but instead on the opinion of local expertise, for instance forest managers, cattle breeders, farmers and/or academics. This is particularly seen to be the case in the tropics where access to modern communication and information technologies is restricted.As the opinions of experts are often based on and influenced by personal experience, intuition, heuristics and bias, their evaluations and decision are often unclear to the non-expert working at a local level. In order to make their reasoning more comprehensible to the non-expert, the ecological condition of 176 plots in the tropical Southeast of Mexico were evaluated by experts on soil fertility, forest management, cattle breeding and agriculture. With the assistance of a knowledge engineer (one who converts expert knowledge and reasoning into a model), these expert opinions and reasoning were then translated into a formal computer model.As an alternative approach we applied a knowledge discovery technique, namely the induction of regression trees and automatically developed models using the expert evaluations as training data. Where knowledge engineering was tedious and time consuming, regression models could be rapidly generated. Moreover, the correspondence between regression trees and expert opinions was considerably higher than the correspondence between expert opinion and their own models. The regression trees used less explicative variables than the models generated by the experts. The minimisation of sampling effort due to variable space reduction means that the application of regression tree induction has a high potential for a rapid development of indicators for narrowly defined ecological assessments, needed for decision making on a local or regional scale.