Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis

Introduction  

The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.     

Animal regeneration: ancestral character or evolutionary novelty?

An old question about regeneration is whether it is an ancestral character which is a general property of living matter, or whether it represents a set of specific adaptations to the different circumstances faced by different types of animal. In this review, some recent results on regeneration are assessed to see if they can throw any new light on this question. Evidence in favour of an ancestral character comes from the role of Wnt and bone morphogenetic protein signalling in controlling the pattern of whole‐body regeneration in acoels, which are a basal group of bilaterian animals. On the other hand, there is some evidence for adaptive acquisition or maintenance of the regeneration of appendages based on the occurrence of severe non‐lethal predation, the existence of some novel genes in regenerating organisms, and differences at the molecular level between apparently similar forms of regeneration. It is tentatively concluded that whole‐body regeneration is an ancestral character although has been lost from most animal lineages. Appendage regeneration is more likely to represent a derived character resulting from many specific adaptations.     

Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α–Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

Synovial fibroblast proliferation is a hallmark of the invasive pannus in the rheumatoid joint. Activated protein C (APC) is a natural anticoagulant that exerts antiinflammatory and cyto-protective effects in various diseases via endothelial protein C receptor (EPCR) and proteinase-activated receptor (PAR)-mediated pathways. In this study, we investigated the effect and the underlying cellular signaling mechanisms of APC on proliferation of human rheumatoid synovial fibroblasts (RSFs). We found that APC stimulated proliferation of mouse dermal fibroblasts (MDFs) and normal human dermal fibroblasts (HDFs) by up to 60%, but robustly downregulated proliferation of RSFs. APC induced the phosphorylation of extracellular signal–regulated protein kinase (ERK) and enhanced expression of p21 and p27 in a dose-dependent manner in RSFs. The latter effect was inhibited by pre-treatment with the ERK inhibitors PD98059 and U0126 but not by p38 inhibitor SB203580. In addition, APC significantly downregulated tumor necrosis factor (TNF)α-stimulated cell proliferation and activation of p38, c-Jun NH₂-terminal kinase (JNK) and Akt in RSFs. These results provide the first evidence that APC selectively inhibits proliferation and the inflammatory signaling pathways of RSFs. Thus, APC may reduce synovial hyperplasia and pannus invasion in rheumatoid arthritis.     

Variability of albumin adducts of 1,4-benzoquinone, a toxic metabolite of benzene, in human volunteers

A putative haematotoxic and leukaemogenic metabolite of benzene, 1,4-benzoquinone (1,4-BQ), reacts rapidly with macromolecules. The authors previously characterized levels of the albumin (Alb) adduct (1,4-BQ-Alb) of this reactive species in populations of workers exposed to benzene. Since high levels of 1,4-BQ-Alb were also measured in unexposed workers from those investigations, the current study was initiated to determine potential sources of 1,4-BQ in the general population. A single blood sample was collected from 191 healthy subjects from the Research Triangle area, NC, USA, to determine the baseline 1,4-BQ-Alb levels and contributing sources. The median 1,4-BQ-Alb at baseline was 550 pmol g^-1 Alb (interquartile range 435-814 pmol g^-1). A second blood sample was collected approximately 3 months later from a subgroup of 33 subjects to estimate the within- and between-person variation in 1,4-BQ-Alb. Standardized questionnaires were administered to collect information about demographic, dietary and lifestyle factors. Multiple linear regression models identified several significant contributors to 1,4-BQ-Alb levels, including gender, body mass index (BMI), the gender-BMI interaction, automobile refuelling, smoking status, and consumption of fruit and the artificial sweetener, aspartame. The authors predicted that these background levels of 1,4-BQ-Alb were equivalent to occupational exposures between 1 and 3 parts per million of benzene. Mixed effects linear models indicated that the random variation in adduct levels was about equally divided between and within subjects. The observations indicate that levels of 1,4-BQ-Alb cover a wide range in the general population, and they support the hypotheses that demographic, diet and lifestyle factors are contributing sources.     

Deposition of Atlantic salmon Salmo salar carcasses in a Scottish upland catchment

Radio telemetry was utilized to track 38 Atlantic salmon Salmo salar across space and time during and following their spawning run on the Conon system, Scotland. The data collected were used to assess the proportion of S. salar able to migrate successfully from an upland oligotrophic area of the catchment and the distribution of the carcasses of those fish that remained. Of these fish, 35% successfully migrated from the study area after the spawning period. The fish that remained were distributed approximately equally between riverine and lacustrine areas, but with a strong tendency to accumulate in regions of relatively slow water flows.     

Regeneration of neural crest derivatives in the <Emphasis Type="Italic">Xenopus</Emphasis>tadpole tail

Background  

After amputation of the Xenopus tadpole tail, a functionally competent new tail is regenerated. It contains spinal cord, notochord and muscle, each of which has previously been shown to derive from the corresponding tissue in the stump. The regeneration of the neural crest derivatives has not previously been examined and is described in this paper.