Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

INTRODUCTION: Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers. METHODS: We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA. RESULTS: We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for (sf)C-Reactive protein (CRP) (P = 0.039), (sf)lubricin (P = 0.008) and the proteoglycan biomarkers: (sf)Glycosaminoglycan (GAG) (P = 0.019), and (sf)Alanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: (sf)C-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), (sf)C1,2C (P = 0.039), (sf)C-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and (sf)N-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038). CONCLUSIONS: These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis. TRIAL REGISTRATION: The samples used in this study were derived from a clinical trial NCT00332254 registered with ClinicalTrial.gov

Development and application of a comprehensive analytical workflow for the quantification of non-volatile low molecular weight lipids on archaeological stone tools

Source determination of use-related residues on prehistoric stone tools is especially challenging, due to issues related to preservation, contamination and the contribution of residues from multiple sources. To increase confidence in this process, an analytical workflow was developed to include: (1) a sampling strategy that retains spatial information of the recovered residues and enables monitoring of environmental contamination; and (2) a sensitive and selective gas chromatography-tandem mass spectrometry (GC-MS/MS) procedure to quantify non-volatile low molecular weight lipids on stone artefacts. This workflow was applied to 14 stone artefacts excavated from deposits at Liang Bua, a limestone cave on the Indonesian island of Flores. These artefacts range in age between ∼14 000 and 1000 years old, and were preliminarily classified as either potentially showing traces of use (n = 7) or not (n = 7) using low magnification microscopy. Residues were sampled by direct solvent extraction off the surface of the artefacts. The aliquots were spiked with internal standards and derivatised. The trimethylsilyl derivatives of 40 saturated fatty acids, sterols, di- and tri-terpenoids and their analogues were quantified using optimised multiple reaction monitoring (MRM) transitions. Six of the potentially used artefacts contained sterols, phytosterols and terpenoids, either individually or in combination, whereas none of these compounds was commonly found on the seven artefacts preliminarily classified as unused. This suggests that these six artefacts may have been used as implements to process resources, and provides scope for further investigation. This workflow can also be adapted for the analysis of other archaeological objects

Regulating financial conglomerates

We investigate the optimal regulation of financial conglomerates which combine a bank and a non-bank financial institution. The conglomerate’s risk-taking incentives depend upon the level of market discipline it faces, which in turn is determined by the conglomerate’s liability structure. We examine optimal capital requirements for stand-alone institutions, for integrated financial conglomerates, and for financial conglomerates that are structured as holding companies. For a given risk profile, integrated conglomerates have a lower probability of failure than either their stand-alone or decentralized equivalent. However, when risk profiles are endogenously selected, conglomeration may extend the reach of the deposit insurance safety net and hence provide incentives for increased risk-taking. As a result, integrated conglomerates may optimally attract higher capital requirements. In contrast, decentralised conglomerates are able to hold assets in the socially most efficient place. Their optimal capital requirements encourage this. Hence, the practice of “regulatory arbitrage”, or of transferring assets from one balance sheet to another, is welfare-increasing. We discuss the policy implications of our finding in the context not only of the present debate on the regulation of financial conglomerates but also in the light of existing US bank holding company regulation

N-Methylimidazole Promotes The Reaction Of Homophthalic Anhydride With Imines

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described

Evaluation and comparison of native and recombinant LipL21 protein-based ELISAs for diagnosis of bovine leptospirosis

A 21-kDa leptospiral lipoprotein (LipL21) was evaluated for its diagnostic potential to detect bovine leptospirosis by ELISA. Both native LipL21 (nLipL21) and recombinant LipL21 (rLipL21) proteins were tested and compared regarding diagnostic efficiency, and no statistically significant difference was observed. The sensitivity of rLipL21 ELISA for 62 microscopic agglutination test (MAT) positive sera was 100% and the specificity with 378 MAT negative sera was 97.09%. Thus, rLipL21 protein-based ELISA could be used as an alternative to MAT for the diagnosis of bovine leptospirosis

A simulation of the Neolithic transition in Western Eurasia

Farming and herding were introduced to Europe from the Near East and Anatolia; there are, however, considerable arguments about the mechanisms of this transition. Were it people who moved and outplaced the indigenous hunter- gatherer groups or admixed with them? Or was it just material and information that moved-the Neolithic Package-consisting of domesticated plants and animals and the knowledge of its use? The latter process is commonly referred to as cultural diffusion and the former as demic diffusion. Despite continuous and partly combined efforts by archaeologists, anthropologists, linguists, paleontologists and geneticists a final resolution of the debate has not yet been reached. In the present contribution we interpret results from the Global Land Use and technological Evolution Simulator (GLUES), a mathematical model for regional sociocultural development embedded in the western Eurasian geoenvironmental context during the Holocene. We demonstrate that the model is able to realistically hindcast the expansion speed and the inhomogeneous space-time evolution of the transition to agropastoralism in Europe. GLUES, in contrast to models that do not resolve endogenous sociocultural dynamics, also describes and explains how and why the Neolithic advanced in stages. In the model analysis, we uncouple the mechanisms of migration and information exchange. We find that (1) an indigenous form of agropastoralism could well have arisen in certain Mediterranean landscapes, but not in Northern and Central Europe, where it depended on imported technology and material, (2) both demic diffusion by migration or cultural diffusion by trade may explain the western European transition equally well, (3) [...]Comment: Accepted Author Manuscript version accepted for publication in Journal of Archaeological Science. A definitive version will be subsequently published in the Journal of Archaological Scienc