Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis

Introduction

We tested the hypothesis that there exist relationships between the onset of early stage radiographically defined knee osteoarthritis (OA), pain and changes in biomarkers of joint metabolism.

Methods

Using Kellgren-Lawrence (K/L) grading early radiographic knee OA (K/L 2) was detected in 16 of 46 patients. These grades (K/L 1 is no OA and K/L 2 is early OA) were divided into two groups according to the presence or absence of persistent knee pain. Sera (s) and urines (u) were analysed with biomarkers for cartilage collagen cleavage (sC2C and uCTX-II) and synthesis (sCPII), bone resorption (uNTx) and synovitis (hyaluronic acid: sHA).

Results

sCPII decreased and sC2C/sCPII, uCTX-II/sCPII and sHA increased with onset of OA (K/L 2 versus K/L 1) irrespective of joint pain. In contrast, sC2C and uCTX-II remained unchanged in early OA patients. Of the patients with K/L grades 1 and 2 sC2C, sCPII, sHA, uNTX and uCTX-II were all significantly increased in patients with knee pain independent of grade. Among the K/L grade 2 subjects, only uCTX-II and uCTX-II/sCPII were increased in those with knee pain. In grade 1 patients both sC2C and sCPII were increased in those with knee pain. No such grade specific changes were seen for the other biomarkers including sHA.

Conclusions

These results suggest that changes in cartilage matrix turnover detected by molecular biomarkers may reflect early changes in cartilage structure that account directly or indirectly for knee pain. Also K/L grade 1 patients with knee pain exhibit biomarker features of early OA.     

Senescence marker protein 30 protects intestinal epithelial cells against inflammation-induced cell death by enhancing Nrf2 activity

Senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases during senescence. SMP30 deficiency increases susceptibility to cytokine-induced apoptosis in the liver and to radiation-induced apoptosis in the small intestine. Furthermore, colonic epithelial cell death is associated with the severity of colitis. Therefore, in the present study, we investigated the function of SMP30 during intestinal inflammation. In SMP30 deficient mice, colitis was significantly exacerbated as demonstrated by increased mortality (p?=?0.001), body weight loss (p?=?0.0105 at day 8), rectal bleeding (p?=?0.0047 at day 8) and diarrhea (p?=?0.0030 at day 8), histological scores (ulcers, p?=?0.0002; edema, p?=?0.0125; leukocyte infiltration, p?=?0.0016) and productions of pro-inflammatory cytokines (IL-1α, p?=?0.0452; IL-6, p?=?0.0074; G-CSF, p?=?0.0036). In addition, greater proportions of apoptotic cells and lower levels of anti-apoptotic marker proteins (total PARP-1 and Bcl-2) were observed in the inflamed intestines of SMP30 deficient mice than in wild type controls. In vitro experiments on colonic epithelial cells showed that stable SMP30 expression inhibited but that SMP30 siRNA expression increased TNF-α-induced apoptosis. SMP30 inhibition decreased Nrf2 mRNA expression levels (p?<?0.0001), but SMP30 overexpression increased Nrf2 mRNA expression levels (p?=?0.0495). The underlying mechanism by which SMP30 protected cells appeared to be by inhibiting Nrf2 ubiquitination and Keap1 expression, and thus enhancing Nrf2 activity. Moreover, SMP30 deficiency increased the incidence of colitis-associated colon cancer as determined by increased mortality (p?=?0.0572) and average polyp number (p?=?0.0277). Collectively, these findings suggest that SMP30 protects intestinal epithelial cells from apoptosis and this can contribute to amelioration of colitis and colitis-associated colon cancer.     

Work Engagement as a Predictor of Onset of Major Depressive Episode (MDE) among Workers,Independent of Psychological Distress: A 3-Year Prospective Cohort Study

Objective

This study investigated work engagement as a baseline predictor of onset of major depressive episode (MDE).

Methods

The study used a prospective cohort design, conforming to the STROBE checklist. Participants were recruited from the employee population of a private think tank company (N = 4,270), and 1,058 (24.8%) of them completed a baseline survey, of whom 929 were included in this study. Work engagement and psychological distress at baseline were assessed as predictor variables. MDE was measured at baseline and at each of the follow-ups as the outcome, using the web-based, self-administered version of the Japanese WHO-CIDI 3.0 depression section based upon DSM-IV-TR/DSM-5 criteria. Cox discrete-time hazards analyses were conducted to estimate hazard ratios (95% confidence intervals CIs).

Results

Follow-up rates of participants (N = 929) were 78.4%, 67.2%, and 51.6% at 1-, 2-, and 3-year follow-ups, respectively. The association between work engagement at baseline and the onset of MDE was U-shaped. Compared with a group with low work engagement scores, groups with the middle and high scores showed significantly (HR = 0.19, 95% CI = 0.05 to 0.64; p = 0.007) and marginally significantly (HR = 0.48, 95% CI = 0.20 to 1.15, p = 0.099) lower risks of MDE, respectively, over the follow-ups, after adjusting for covariates. The pattern remained the same after additionally adjusting for psychological distress.

Conclusions

The present study first demonstrated work engagement as an important predictor of the onset of MDE diagnosed according to an internationally standard diagnostic criteria of mental disorders.     

Experimental animal model for analyzing immunobiological responses following vaccination with formalin‐inactivated respiratory syncytial virus

Formalin‐inactivated respiratory syncytial virus (FI‐RSV) vaccine was developed in the 1960s. However, this vaccine does not prevent infection in RSV‐naïve recipients and has the paradoxical effect of increasing the severity of RSV illness following natural infection, which has been a major obstacle to developing RSV vaccines. Several experimental animal models for determining the cause of the severe symptoms in FI‐RSV recipients have been developed. In the present study, cotton rats immunized with FI‐RSV were challenged with RSV and histopathological findings and recovery of infectious virus were studied. Copy numbers of mRNA of Th1 and Th2 cytokines were measured in lung tissues to gain better understanding of their immune responses. Infiltration of inflammatory cells and prominent interstitial pneumonitis were observed in the FI‐RSV group, as was induction of mRNA of Th2 cytokines such as IL‐4, IL‐10, IL‐13 and RANTES. Rats immunized with recombinant measles virus expressing the RSV F protein (MVAIK/RSV/F) and those treated with anti‐RSV mAb (palivizumab) showed very mild interstitial pneumonitis. Amounts of mRNA of IL‐1β, IFN‐γ and IL‐4 were higher in the MVAIK/RSV/F group. Administration of palivizumab before RSV challenge decreased the severity of interstitial pneumonitis in the FI‐RSV group. FI‐RSV induced skewed Th2 responses, resulting in severe inflammatory responses.     

Early stalked stages in ontogeny of the living isocrinid sea lily Metacrinus rotundus

The early stalked stages of an isocrinid sea lily, Metacrinus rotundus, were examined up to the early pentacrinoid stage. Larvae induced to settle on bivalve shells and cultured in the laboratory developed into late cystideans. Three‐dimensional (3D) images reconstructed from very early to middle cystideans indicated that 15 radial podia composed of five triplets form synchronously from the crescent‐shaped hydrocoel. The orientation of the hydrocoel indicated that the settled postlarvae lean posteriorly. In very early cystideans, the orals, radials, basals and infrabasals, with five plates each in the crown, about five columnals in the stalk, and five terminal stem plates in the attachment disc, had already formed. In mid‐cystideans, an anal plate appeared in the crown. Late cystideans cultured in the field developed into pentacrinoids about 5 months after settlement. These pentacrinoids shared many crown structures with adult sea lilies. On the other hand, many features of the stalk differed from those in adult isocrinids, while sharing many characteristics with the stalk of feather star pentacrinoids, including disc‐like proximal columnals, high and slender median columnals, synarthrial articulations developmentally derived from the symplexial articulations, limited formation of cirri only in the proximal columnal(s), and an attachment disc. On the basis of these findings, phylogenetic relationships among extant crinoid orders are discussed.     

Detection and Genomic Characterization of Motility in Lactobacillus curvatus: Confirmation of Motility in a Species outside the Lactobacillus salivarius Clade

Lactobacillus is the largest genus within the lactic acid bacteria (LAB), with almost 180 species currently identified. Motility has been reported for at least 13 Lactobacillus species, all belonging to the Lactobacillus salivarius clade. Motility in lactobacilli is poorly characterized. It probably confers competitive advantages, such as superior nutrient acquisition and niche colonization, but it could also play an important role in innate immune system activation through flagellin–Toll-like receptor 5 (TLR5) interaction. We now report strong evidence of motility in a species outside the L. salivarius clade, Lactobacillus curvatus (strain NRIC 0822). The motility of L. curvatus NRIC 0822 was revealed by phase-contrast microscopy and soft-agar motility assays. Strain NRIC 0822 was motile at temperatures between 15°C and 37°C, with a range of different carbohydrates, and under varying atmospheric conditions. We sequenced the L. curvatus NRIC 0822 genome, which revealed that the motility genes are organized in a single operon and that the products are very similar (>98.5% amino acid similarity over >11,000 amino acids) to those encoded by the motility operon of Lactobacillus acidipiscis KCTC 13900 (shown for the first time to be motile also). Moreover, the presence of a large number of mobile genetic elements within and flanking the motility operon of L. curvatus suggests recent horizontal transfer between members of two distinct Lactobacillus clades: L. acidipiscis in the L. salivarius clade and L. curvatus in the L. sakei clade. This study provides novel phenotypic, genetic, and phylogenetic insights into flagellum-mediated motility in lactobacilli.