Assessment of the efficacy of different statins in murine collagen‐induced arthritis

Objective

Hydroxymethylglutaryl‐coenzyme A reductase inhibitors (statins) are widely used lipid‐lowering agents. In addition to their well‐known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen‐induced arthritis, a well‐described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model.

Methods

Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols.

Results

Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti–type II collagen IgG production), and biochemical (interleukin‐6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels.

Conclusion

This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune‐mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.

     

Does socio-demographic status influence the effect of pollens and molds on hospitalization for asthma? Results from a time-series study in 10 Canadian cities

PURPOSE: Social status influences asthma morbidity but the mechanisms are not well understood. To determine if sociodemographics influence the susceptibility to ambient aeroallergens, we determined the association between daily hospitalizations for asthma and daily concentrations of ambient pollens and molds in 10 large Canadian cities. METHODS: Daily time-series analyses were performed and results were adjusted for day of the week, temperature, barometric pressure, relative humidity, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide. Results were then stratified by age, gender, and neighborhood family education and income. RESULTS: There appeared to be age and gender interactions in the relation between aeroallergens and asthma. An increase in basidiomycetes equivalent to its mean value, about 300/m3, increased asthma admissions for younger males (under 13 years of age) by 9.3% (95% CI, 4.8%, 13.8%) vs. 4.2% (95% CI, - 0.1%, 8.5%) for older males. The reverse was true among females with increased effect in the older age group: 2.3% (95% CI, 1.2%, 5.8%) in those under 13 years vs. 7.1% (95% CI, 4.1%, 10.1%) for older females. Associations were seen between aeroallergens and asthma hospitalization in the lowest but not the highest education group. CONCLUSIONS: Our results suggest that younger males and those within less educated families may be more vulnerable to aeroallergens as reflected by hospitalization for asthma.     

Two point analysis 15-minute 14C-urea breath test for diagnosing Helicobacter pylori infection.

The value of a two point analysis (double sample) 14C-urea breath test in diagnosing Helicobacter pylori (HP) infection in patients with suspected acid peptic disease has been studied and compared to histology and to a rapid agar plate urease test in 76 patients. Using the histological finding of HP as the gold standard, the 14C-breath test was positive in 59 of the 61 histologically confirmed infected patients and in 3 of the 15 noninfected ones, giving a sensitivity of 97% and specificity of 80%. In 12 patients, a smaller dose of 3 mu Ci 14C-urea was used. The results correlated well with those in whom the higher dose of 10 mu Ci was used. We conclude that a two point 14C-urea breath test with analysis at 5 and 15 min is effective in diagnosing HP infection thus obviating the need for endoscopy and biopsy.     

Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils

Closely similar but nonidentical NH2-terminal amino acid sequences have been reported for a protein or proteins in human neutrophils whose bioactivities is/are diverse (as a serine protease, antibiotic, and Wegener's granulomatosis autoantigen) but that share(s) several features: localization in the azurophil granules, a molecular mass of approximately 29 kD, reactivity with diisopropylfluorophosphate, and the ability to degrade elastin. We previously purified one such entity, termed p29b. Using a monospecific antibody, we have cloned from human bone marrow a cDNA encoding the complete p29b protein in its mature form, along with pre- and pro-sequences. The predicted amino acid sequence agrees closely with the NH2-terminal sequence obtained previously from purified p29b, as well as with sequences newly obtained from CNBr fragments. The primary structure is highly homologous to elastase, cathepsin G, T cell granzymes, and other serine proteases, and shares both the catalytic triad and substrate binding pocket of elastase. Hybridization of the full-length cDNA with restriction enzyme digests of human genomic DNA revealed only one fragment. This suggests that the closely related species described previously are the same, and can be subsumed by the term used for the first-described activity, proteinase 3. Proteinase 3 is more abundant in neutrophils than elastase and has a similar proteolytic profile and specific activity. Thus, proteinase 3 may share the role previously attributed to neutrophil elastase in tissue damage, and has the potential to function as an antimicrobial agent.     

Effect of hypothermia in patients undergoing simultaneous carotid endarterectomy and coronary artery bypass graft surgery

The co-existence of coronary, carotid, peripheral and renal atherosclerotic diseases is not infrequent and it was reported that 24% of patients with coronary artery disease have at least one additional atherosclerotic lesion.1 In previous studies, 4.6 to 8.0% of patients with coronary artery disease (CAD) had severe coronary artery stenosis (CAS), the extent of the atherosclerotic involvement being significantly correlated with the carotid and coronary arteries.2,3 Simultaneous surgical management of concomitant coronary and carotid artery disease has been the focus of interest in the past two decades since success rates of coronary artery bypass grafting (CABG) has substantially increased while a preventive approach for adverse neurological outcomes has gained popularity.4 Carotid stenosis and previous history of cerebrovascular disease were reported to be among the most prominent risk factors for peri-operative stroke and neurocognitive decline in patients undergoing CABG.5The optimal decision for the timing of carotid endarterectomy (CEA) is controversial in patients submitted for CABG since data focusing on establishing the best strategy of practice are limited.6 There have been numerous cross-sectional studies reporting favourable outcomes for both simultaneous and staged CEA and CABG procedures,7-9 and some authors have suggested that the decision to perform the two procedures simultaneously should be made based on strict patient selection criteria.10 Nevertheless, delaying the CEA was found to be an independent predictor of early stroke and death in one recent randomised trial.11 This uncertainty led to an increasing trend towards individualisation of the treatment in patients with concomitant disease.Some earlier studies implied the potential role of hypothermia as a preventative measure against adverse postoperative outcomes in patients undergoing single-stage on-pump CABG and CEA.12,13 However, these studies fell short of their goal of determining whether hypothermia provides protection, because none of them involved a control group of patients undergoing CEA under normothermic conditions. In this study we sought to determine whether hypothermia provided any benefit in patients undergoing simultaneous CABG and CEA using one of two different surgical strategies.     

Antibiotic proteins of human polymorphonuclear leukocytes.

Nine polypeptide peaks with antibiotic activity were resolved from human polymorphonuclear leukocyte azurophil granule membranes. All but 1 of the 12 constituent polypeptides were identified by N-terminal sequence analysis. Near quantitative recovery of protein and activity permitted an assessment of the contribution of each species to the overall respiratory-burst-independent antimicrobial capacity of the cell. Three uncharacterized polypeptides were discovered, including two broad-spectrum antibiotics. One of these, a defensin that we have designated human neutrophil antimicrobial peptide 4, was more potent than previously described defensins but represented less than 1% of the total protein. The other, named azurocidin, was abundant and comparable to bactericidal permeability-increasing factor in its contribution to the killing of Escherichia coli.     

Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis

ObjectivesRecent evidence suggests a role for interleukin (IL)-33 and its receptor ST2 in arthritis. In this study, we quantified IL-33 and soluble (s)ST2 levels in serum and synovial fluid (SF), and assessed synovial IL-33 expression levels and pattern in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or osteoarthritis (OA).MethodsSerum and SF IL-33 and sST2 levels were assessed by ELISA. IL-33 mRNA was quantified by RT-qPCR. Synovial IL-33 protein expression pattern was examined by immunohistochemistry.ResultsSerum and SF IL-33 levels tended to be higher in RA than in OA patients. In contrast to RA, IL-33 was not detectable in PsA serum and SF. Serum sST2 levels were higher in RA than in OA. There was a wide variation of synovial tissue IL-33 mRNA expression within each disease group and IL-33 mRNA levels were not significantly different between the groups. A similar IL-33 protein expression pattern was observed in RA, PsA and OA synovium, with strong nuclear expression of IL-33 in endothelial cells and, in a subset of RA, PsA and OA patients, in cells morphologically consistent with synovial fibroblasts.Discussion/ConclusionsThis study confirms increased circulating IL-33 levels in RA. In addition, we report that IL-33 is undetectable in the serum or SF of PsA patients. Local expression of IL-33 in the synovium was observed at similar variable levels in RA, PsA and OA, suggesting that inflamed joints do not represent the primary source of elevated serum and SF levels of IL-33 in RA.