Adenosine 5′-triphosphate,uridine 5′-triphosphate,bradykinin, and lysophosphatidic acid induce different patterns of calcium responses by human articular chondrocytes

Small calcium-mobilizing inflammatory mediators have been implicated in joint pathology. Here we demonstrate that bradykinin, adenosine 5′-triphosphate, uridine 5′-triphosphate, and lysophosphatidic acid raise the intracellular calcium concentration ([Ca²⁺]_i) in human articular chondrocytes. Heterologous cross-desensitization experiments showed that the uridine 5′-triphosphate response was abolished by prior treatment with adenosine 5′-triphosphate and conversely, that the adenosine 5′-triphosphate response was abolished by prior treatment with uridine 5′-triphosphate: this indicated competition for the same receptor site, whereas bradykinin and lysophosphatidic acid did not compete with other ligands. Pretreatment with thapsigargin abolished ligand-mediated Ca²⁺ responses but not vice versa: this confirmed that Ca²⁺ release occurred from intracellular stores. Single-cell analysis of Fura-2 acetoxymethyl ester loaded chondrocytes showed mediator-dependent patterns of oscillatory Ca²⁺ changes in a subset of cells when challenged with submaximal concentrations of bradykinin, adenosine 5′-triphosphate, or uridine 5′-triphosphate in the presence of extracellular Ca²⁺. However, no oscillatory responses were seen after a challenge with lysophosphatidic acid. Therefore, although a number of different Ca²⁺-mobilizing ligands activate chondrocytes, the differences that occur in the temporal patterning of Ca²⁺ responses may result in unique mediator-dependent changes in cellular activity.     

11β⁃羟化类固醇脱氢酶敲除对高脂饮食喂养小鼠认知功能的影响

目的：探究11β-羟化类固醇脱氢酶1（11β-hydroxysteroid dehydrogenase,11β-HSD1）基因敲除对小鼠整体代谢和认知功能的影响。方法：将C57BL/6J为遗传背景的野生对照组及11β-HSD1基因敲除组各15只小鼠高脂喂养20周,代谢笼评估能量代谢,行为学评估观察小鼠认知功能,电镜评估海马体的线粒体结构,免疫荧光及PCR确定其认知功能、线粒体功能相关基因及炎症基因的变化。结果：11β-HSD1基因敲除能够提高高脂喂养小鼠学习和记忆能力,改善握力,改善海马体的微结构、线粒体含量变多,认知相关基因、线粒体呼吸功能相关基因上调,炎症相关基因改变。结论：11β-HSD1敲除后高脂饮食喂养小鼠认知功能显著改善,握力显著提高,可能是治疗认知功能障碍的有效靶点。     

Quality assurance in IMRT: importance of the transmission through the jaws for an accurate calculation of absolute doses and relative distributions

The goal of IMRT is to achieve an isodose distribution conformed to the tumor while avoiding the organs at risk. For these tasks several gantry angles are selected, each one containing a series of different leaf configurations for the multileaf collimator (MLC) (segments). Verifying the relative distributions as well as the absolute doses is an important step for quality assurance issues. We have observed that an accurate modeling of the transmission of the primary x-ray fluence through the jaws and MLC as well as the head scatter is crucial for a precise calculation of relative doses and monitor units. Also, an inaccurate calculation of the output factor for small size segments can lead to important differences in the absolute dose for points under these segments. Incorrect models could lead to systematic errors of around 5% to 10% in the calculated monitor units and a shift in the isodose curves.     

Body composition estimates using different measurement techniques in a sample of highland subsistence farmers in Guatemala

This study aims at assessing the accuracy of estimates of body composition provided by bioimpedance (BIA) equations developed for U.S. populations when applied to a sample of Guatemalan farmers. If these equations were shown to have low validity, the second objective was to develop more accurate estimates of fat-free mass (FFM). One hundred males and females 19 to 45 years of age were randomly selected from four rural communities in the Western Highlands of Guatemala. Bioimpedance equations explained 59 and 33% of the variation in FFM, with a RMSE of 2.7 and 2.8 kg in males and females, respectively. Body fat (BF) predictions had a lower R². Using the “all possible regressions” procedure, the best subset for prediction of FFM used anthropometric and BIA variables as predictors. The best model for men and women included only anthropometric variables: 75% of the variance in FFM for men and 70% of the variance in women was explained by this model. The RMSE was 2.1 and 1.9 kg for both groups, respectively. It is concluded that FFM can be estimated from anthropometric dimensions with a high degree of accuracy and use of BIA does not provide more valid estimates.     

Molecular characterization of a coxsackievirus A24 variant that caused an outbreak of acute haemorrhagic conjunctivitis in Spain, 2004

BACKGROUND: Coxsackievirus A24 variant is one of the major etiological agents involved in acute haemorrhagic conjunctivitis. STUDY DESIGN: An outbreak of acute hemorrhagic conjunctivitis occurred in the Southeast of Spain between September and November 2004. Cellular and molecular methods were used to identify and characterize the viral agent associated with the epidemic. RESULTS: Enterovirus was detected in the conjunctival swabs of 35 patients. None of the viruses isolated could be typed by conventional neutralization assays; however, amplification and sequencing of the 3'-end VP1 region of 19 of the samples identified coxsackievirus A24 variant as the serotype causing the outbreak. Phylogenetic analysis of the 5'-half VP1 region of the genome revealed that Spanish sequences, like other strains isolated during outbreaks of hemorrhagic conjunctivitis in American and African countries in 2003 and 2004, were closely related to the isolates detected in Korea (2002), thus proving their worldwide spread. CONCLUSIONS: This is the first report of an epidemic of acute hemorrhagic conjunctivitis due to a coxsackievirus A24 variant in Spain. Molecular typing in combination with phylogenetic analysis is useful to study the enterovirus epidemiology associated with epidemics.     

Evolution of foot-and-mouth disease virus

Foot-and-mouth disease virus evolution is strongly influenced by high mutation rates and a quasispecies dynamics. Mutant swarms are subjected to positive selection, negative selection and random drift of genomes. Adaptation is the result of selective amplification of subpopulations of genomes. The extent of adaptation to a given environment is quantified by a relative fitness value. Fitness values depend on the virus and its physical and biological environment. Generally, infections involving large population passages result in fitness gain and population bottlenecks lead to fitness loss. Very different types of mutations tend to accumulate in the foot-and-mouth disease virus (FMDV) genome depending on the virus population size during replication. Quasispecies dynamics predict higher probability of success of antiviral strategies based on multivalent vaccines and combination therapy, and this has been supported by clinical and veterinary practice. Quasispecies suggest also new antiviral strategies based on virus entry into error catastrophe, and such procedures are under investigation. Studies with FMDV have contributed to the understanding of quasispecies dynamics and some of its biological implications.     

Does the beneficial effect of HRT on endothelial function depend on lipid changes

OBJECTIVES: To determine whether improvement in endothelial function of the brachial artery observed in women treated with hormone replacement therapy (HRT) may be explained by changes in lipid profile or blood pressure, information was used obtained in a single-centre, randomised, double blind, placebo-controlled trial. METHODS: Hundred-and-five healthy postmenopausal women, aged 50-65 years, were treated with 0.625 mg conjugated equine estrogens (CEE) combined with 2.5 mg medroxyprogesterone acetate (MPA) (CEE+MPA), 2.5 mg tibolone or placebo for 3 months. At baseline and after 3 months, endothelial function was assessed using flow-mediated dilatation (FMD) and nitro glycerine-mediated dilatation (NMD). Furthermore, lipids were measured. Multivariate linear regression analysis was applied to address the research question. RESULTS: Treatment with CEE+MPA resulted in an improvement in FMD of 2.0% (95% CI: -0.1; 4.1). CEE/MPA reduced total cholesterol with 13% (95% CI: -18%; -7%), LDL-cholesterol with 23% (95% CI: -30%; -15%) and lipoprotein(a) (Lp(a)) with 14% (95% CI: -26%; -2%). The magnitude of the relation of CEE/MPA with endothelial function was attenuated to from 2.0 to 1.6% when change in Lp(a) was taken into account. Adjustments for other lipids or blood pressure did not attenuate the association. CONCLUSIONS: The improvement in endothelial function in postmenopausal women treated with CEE+MPA appears to be partially mediated by change in Lp(a), and apparently not by changes in other lipids.     

Pemphigus Vulgaris Autoantibody Response is Linked to HLA-DQB10503 in Pakistani Patients

ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. We found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 ( p = 0.01), DQA1*0101 ( p = 0.02), and DQB1*0503 ( p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 ( p < 10⁻⁶), DQA1*0101 ( p < 10⁻⁵) and DQB1*0503 ( p < 10⁻⁶), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives’ families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.