Urinary metabolic fingerprinting for thioacetamide-induced rat acute hepatic injury using fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS), with reference to detection of potential biomarkers for hepatotoxicity

In this study, we performed urinary metabolic fingerprinting using Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) in the thioacetamide (TAA)-induced rat model of acute hepatic injury to search for useful biomarkers involved in the acute hepatic toxicity. TAA was intraperitonealy administered a single dose of 300 mg/kg, and urine sample and livers were collected on predose, and days 1, 3, 5, and 7 postdose (Days 1, 3, 5, and 7). Histopathologically, infiltration of macrophages occurred in the TAA-induced centrilobular injured area on Days 1 and 3, and the injured liver recovered on Days 5 and 7. On the scores plot of principal component analysis (PCA), the ion profiles of Days 1 and 3 were different from those of the predose, Days 5 and 7. The loading plot revealed that the metabolites causing PCA results were m/z 266.05390, 401.20737, and 429.23882. The ion at m/z 266.05390 was identified as a potassium ion adduct of deoxycytidine (dCyt). Because the appearance of urinary dCyt was corresponding to macrophage infiltration in the rat-injured liver, it was considered that the urinary dCyt might be released from infiltrated macrophages. dCty might be a biomarker for the acute hepatotoxicity in rats.     

Human articular cartilage proteoglycans are not undersulfated in osteoarthritis

Chondroitin sulfate is the major constituent of cartilage. Inadequate sulfate availability results in the production of undersulfated proteoglycans. In osteoarthritis, there is a net loss of articular cartilage proteoglycans. Theoretically, it is possible that during the progress of disease undersulfated glycosaminoglycans are synthesized producing proteoglycans with poorer biological properties. In this study, we tested whether in early human osteoarthritic articular cartilage (Mankin's score of 2 and 3) or more advanced disease (Mankin's score over 3), there are proteoglycans that contain a higher relative amount of nonsulfated chondroitin disaccharide isomer in their chondroitin sulfate chains by analyzing the molar ratios of chondroitin sulfate disaccharide isoforms with fluorophore-assisted carbohydrate electrophoresis. Our results indicated that the nonsulfated disaccharide of chondroitin sulfate formed in average only 1-2% of the total chondroitin sulfate. More important, the molar ratio of nonsulfated disaccharide did not appear to be increased in the osteoarthritic articular cartilage. We conclude that undersulfation of articular cartilage proteoglycans is not present in the human osteoarthritic joint.     

Characterization of CYP2C Induction in Cryopreserved Human Hepatocytes and Its Application in the Prediction of the Clinical Consequences of the Induction

CYP2C enzymes play key roles in drug metabolism, and clinical drug-drug interactions caused by CYP2C induction have been reported. The aim of this study was to establish a method to predict the potency of CYP2C inductions considering the mechanism. We first investigated the relations of CYP2C induction with CYP3A4 or CYP2B6 induction in human hepatocytes after 48-h exposure with 19 inducers. The fold-induction values of CYP2C8 and CYP2C9 were well correlated with those of CYP3A4, whereas the inducers were separated into 2 groups showing different correlations with CYP2B6 induction for CYP2C8 and CYP2C9 induction. In the regression models established, the fold-induction values of CYP2C8 and CYP2C9 were well expressed as the functions of those of CYP3A4 and CYP2B6, while no such obvious correlation was observed for CYP2C19 induction. These results suggest that CYP2Cs are not simply coinduced with CYP3A4 and that CYP2C8 and CYP2C9 inductions are regulated by both pregnane X receptor and constitutive androstane receptor with different contributions. Finally, simple correlations were proposed using the experimental E_max values obtained and plasma concentrations of CYP2C9 substrates from the literature, and positive correlations were observed. These data provide methods to estimate the clinical impact of CYP2C9 induction from in vitro data.     

Will biomarker-based diagnosis of Alzheimer’s disease maximize scientific progress? Evaluating proposed diagnostic criteria

A recently published framework for the diagnosis of Alzheimer’s disease (AD) in research studies would allow diagnosis on the sole basis of two biomarkers (β-amyloid and pathologic tau), even in people with no objective or subjective memory or cognitive changes. This revision will have substantial implications for future Alzheimer’s research, and the changes should be rigorously evaluated before widespread adoption. We propose three principles for evaluating any revision to diagnostic frameworks for AD: (1) does the revision improve the validity of the diagnosis; (2) does the revision improve the reliability or reduce the expense of the diagnosis; and (3) will the revision foster innovative and rigorous research across populations. The new diagnostic framework is unlikely to achieve any of these goals. Instead, it has the potential to handicap future researchers, and slow progress towards identifying effective strategies to prevent or treat AD.     

Total Knee Arthroplasty with an Uncemented Trabecular Metal Tibial Component : A Registry-Based Analysis

Previous poor results have kept the appeal of uncemented total knee arthroplasties (TKAs) minimal. We analyzed the mid-term survivorship and reasons for failures of a contemporary uncemented porous tantalum monoblock tibial component nation-wide. During the study period (2003–2010), such tibial components were used in 1143 primary TKAs recorded in the Finnish Arthroplasty Registry. Seven-year survivorship of these TKAs was 100% (95% CI 99–100) with revision for aseptic loosening of the tibial component, and 97% (95% CI 96–98) with revision for any reason as the respective end points. The most common reasons for revisions were instability and prosthetic joint infections. In conclusion, TKAs using an uncemented porous tantalum monoblock tibial component showed excellent mid-term survivorship in a population-based setting.     

Long‐term outcome of intraventricular conduction delays in the general population

BackgroundPrevious population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD).MethodsWe studied long‐term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12‐lead ECG. For left bundle branch block (LBBB) and non‐specific IVCD (NSIVCD), two different definitions were used.ResultsDuring 16.5 years’ follow‐up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04–2.31, p = .032) and 1.27 (95% confidence interval 0.80–2.02, p = .308) for the Strauss’ definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R‐R’ pattern was not associated with any adverse outcome.ConclusionsIn a population study with long‐term follow‐up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.