Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application

We aimed to assess the effect of ovariectomy on cartilage turnover and degradation, to evaluate whether ovariectomized (OVX) rats could form an experimental model of postmenopausal osteoarthritis. The effect of ovariectomy on cartilage was studied using two cohorts of female Sprague–Dawley rats, aged 5 and 7 months. In a third cohort, the effect of exogenous estrogen and a selective estrogen receptor modulator was analyzed. Knee joints were assessed by histological analysis of the articular cartilage after 9 weeks. Cartilage turnover was measured in urine by an immunoassay specific for collagen type II degradation products (CTX-II), and bone resorption was quantified in serum using an assay for bone collagen type I fragments (CTX-I). Surface erosion in the cartilage of the knee was more severe in OVX rats than in sham-operated animals, particularly in the 7-month-old cohort (P = 0.008). Ovariectomy also significant increased CTX-I and CTX-II. Both the absolute levels of CTX-II and the relative changes from baseline seen at week 4 correlated strongly with the severity of cartilage surface erosion at termination (r = 0.74, P < 0.01). Both estrogen and the selective estrogen receptor modulator inhibited the ovariectomy-induced acceleration of cartilage and bone turnover and significantly suppressed cartilage degradation and erosion seen in vehicle-treated OVX rats. The study indicates that estrogen deficiency accelerates cartilage turnover and increases cartilage surface erosion. OVX rats provide a useful experimental model for the evaluation of the chondroprotective effects of estrogens and estrogen-like substances and the model may be an in vivo representation of osteoarthritis in postmenopausal women

Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se?

INTRODUCTION AND HYPOTHESIS: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage. METHODS: This was an observational study including 1176 elderly women 60–85 years old. Women were genotyped for epsilon (ɛ) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected. RESULTS: Presence of the ApoE ɛ4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (≥6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures. CONCLUSION: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures

Depot-Dependent Effects of Adipose Tissue Explants on Co-Cultured Hepatocytes

We have developed an in vitro hepatocyte-adipose tissue explant (ATE) co-culture model enabling examination of the effect of visceral and subcutaneous adipose tissues on primary rat hepatocytes. Initial analyses of inflammatory marker genes were performed in fractionated epididymal or inguinal adipose tissues. Expressions of inflammation related genes (IL-6, TNF-α, COX-2) were higher in the inguinal than the epididymal ATE. Similarly, expressions of marker genes of macrophage and monocyte (MPEG-1, CD68, F4/80, CD64) were higher in the stromal vascular fraction (SVF) isolated from inguinal ATE than that from epididymal ATE. However, expressions of lipolysis related genes (ATGL, HSL, perilipin-1) were higher in the epididymal adipocytes than inguinal adipocytes. Moreover, secretion of IL-6 and PGE2 was higher from inguinal ATEs than from epididymal ATEs. There was a trend that the total levels of IL-6, TNF-α and PGE2 in the media from inguinal ATEs co-cultured with primary rat hepatocytes were higher than that in the media from epididymal ATEs co-cultured with hepatocytes, although the significant difference was only seen in PGE2. Lipolysis, measured as glycerol release, was similar in the ATEs isolated from inguinal and epididymal adipose tissues when cultured alone, but the glycerol release was higher in the ATEs isolated from epididymal than from inguinal adipose tissue when co-cultured with hepatocytes. Compared to epididymal ATEs, the ATEs from inguinal adipose tissue elicited a stronger cytotoxic response and higher level of insulin resistance in the co-cultured hepatocytes. In conclusion, our results reveal depot-dependent effects of ATEs on co-cultured primary hepatocytes, which in part may be related to a more pronounced infiltration of stromal vascular cells (SVCs), particularly macrophages, in inguinal adipose tissue resulting in stronger responses in terms of hepatotoxicity and insulin-resistance

Hot flushes in prostatic cancer patients during androgen-deprivation therapy with monthly dose of degarelix or leuprolide

International audienceThe aim of the study was to compare the onset, incidence rate, frequency and intensity of hot flushes during androgen deprivation therapy with a GnRH blocker versus an agonist using data from a pivotal Phase 3 trial. Six hundred ten prostate cancer patients received either monthly degarelix (sc, 240 mg/80 mg, n=207, or 240/160 mg, n=202) or leuprolide (im, 7.5 mg, n=201) for 12 months. Data on hot flushes was collected as self-reported adverse events and in a subgroup of 254 patients with daily electronic diaries. The onset of hot flushes was faster on degarelix versus leuprolide. Median daily hot flush scores were larger in degarelix-treated patients during the first 3 month, but showed no differences over the 12 months. Incidence rates during the first 3 months were 17% (degarelix 240/80 mg and leuprolide) and 22% (degarelix 240/160 mg). Subsequently, rates dropped below 6%, whilst prevalence rates remained constant. Body weight and heart rate at baseline were independent predictors of hot flushes (p<0.05). Except for a more rapid onset with the GnRH antagonist, there were no major differences in the pattern of hot flushes between treatments. Weight control may help to minimise the incidence of hot flushes

Designing and scaling level-specific writing tasks in alignment with the CEFR: a test-centered approach

The Common European Framework of Reference (CEFR; Council of Europe, 2001) provides a competency model that is increasingly used as a point of reference to compare language examinations. Nevertheless, aligning examinations to the CEFR proficiency levels remains a challenge. In this article, we propose a new, level-centered approach to designing and aligning writing tasks in line with the CEFR levels. Much work has been done on assessing writing via tasks spanning over several levels of proficiency but little research on a level-specific approach, where one task targets one specific proficiency level. In our study, situated in a large-scale assessment project where such a level-specific approach was employed, we investigate the influence of the design factors tasks, assessment criteria, raters, and student proficiency on the variability of ratings, using descriptive statistics, generalizability theory, and multifaceted Rasch modeling. Results show that the level-specific approach yields plausible inferences about task difficulty, rater harshness, rating criteria difficulty, and student distribution. Moreover, Rasch analyses show a high level of consistency between a priori task classifications in terms of CEFR levels and empirical task difficulty estimates. This allows for a test-centered approach to standard setting by suggesting empirically grounded cut-scores in line with the CEFR proficiency levels targeted by the tasks