Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures: results of the VERO clinical trial.

FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. INTRODUCTION: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. METHODS: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 µg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. RESULTS: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. CONCLUSION: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Fasting and postprandial regulation of the intracellular localization of adiponectin and of adipokines secretion by dietary fat in rats.

BACKGROUND/OBJECTIVE: Dietary fat sources modulate fasting serum concentration of adipokines, particularly adiponectin. However, previous studies utilized obese animals in which adipose tissue function is severely altered. Thus, the present study aimed to assess the postprandial regulation of adipokine secretion in nonobese rats that consumed high-fat diet (HFD) composed of different types of fat for a short time. METHODS: The rats were fed a control diet or a HFD containing coconut, safflower or soybean oil (rich in saturated fatty acid, monounsaturated fatty acid or polyunsaturated fatty acid, respectively) for 21 days. The serum concentrations of adiponectin, leptin, retinol, retinol-binding protein-4 (RBP-4), visfatin and resistin were determined at fasting and after refeeding. Adiponectin multimerization and intracellular localization, as well as the expression of endoplasmic reticulum (ER) chaperones and transcriptional regulators, were evaluated in epididymal white adipose tissue. RESULTS: In HFD-fed rats, serum adiponectin was significantly decreased 30 min after refeeding. With coconut oil, all three multimeric forms were reduced; with safflower oil, only the high-molecular-weight (HMW) and medium-molecular-weight (MMW) forms were decreased; and with soybean oil, only the HMW form was diminished. These reductions were due not to modifications in mRNA abundance or adiponectin multimerization but rather to an increment in intracellular localization at the ER and plasma membrane. Thus, when rats consumed a HFD, the type of dietary fat differentially affected the abundance of endoplasmic reticulum resident protein 44 kDa (ERp44), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ (PPARγ) mRNAs, all of which are involved in the post-translational processing of adiponectin required for its secretion.Leptin, RBP-4, resistin and visfatin serum concentrations did not change during fasting, whereas modest alterations were observed after refeeding. CONCLUSIONS: The short-term consumption of a HFD affected adiponectin localization in adipose tissue, thereby decreasing its secretion to a different magnitude depending on the dietary fat source. Evaluating the fasting serum concentration of adipokines was not sufficient to identify alterations in their secretion, whereas postprandial values provided additional information as dynamic indicators.

Treatment and outcomes for patients with depression who are partial responders to SSRI treatment: post-hoc analysis findings from the FINDER European observational study.

BACKGROUND: Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and subsequent outcomes of partial responder patients. METHODS: Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score >10 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort (n=1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months. RESULTS: At 3 months, 29.4% of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI(s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission (p<0.05). LIMITATIONS: FINDER was an observational study; the current analysis was conducted post-hoc. Multivariable methods were not applied and findings are primarily descriptive and exploratory. CONCLUSIONS: Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission.

Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis.

Expansion of human stem cells before cell therapy is typically performed at 20% O(2). Growth in these pro-oxidative conditions can lead to oxidative stress and genetic instability. Here, we demonstrate that culture of human mesenchymal stem cells at lower, physiological O(2) concentrations significantly increases lifespan, limiting oxidative stress, DNA damage, telomere shortening and chromosomal aberrations. Our gene expression and bioenergetic data strongly suggest that growth at reduced oxygen tensions favors a natural metabolic state of increased glycolysis and reduced oxidative phosphorylation. We propose that this balance is disturbed at 20% O(2), resulting in abnormally increased levels of oxidative stress. These observations indicate that bioenergetic pathways are intertwined with the control of lifespan and decisively influence the genetic stability of human primary stem cells. We conclude that stem cells for human therapy should be grown under low oxygen conditions to increase biosafety.

miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells.

In spite of the extensive potential of human mesenchymal stem cells (hMSCs) in cell therapy, little is known about the molecular mechanisms that regulate their therapeutic properties. We aimed to identify microRNAs (miRNAs) involved in controlling the transition between the resting and reparative phenotypes of hMSCs, hypothesizing that these miRNAs must be present in the undifferentiated cells and downregulated to allow initiation of distinct activation/differentiation programs. Differential miRNA expression analyses revealed that miR-335 is significantly downregulated upon hMSC differentiation. In addition, hMSCs derived from a variety of tissues express miR-335 at a higher level than human skin fibroblasts, and overexpression of miR-335 in hMSCs inhibited their proliferation and migration, as well as their osteogenic and adipogenic potential. Expression of miR-335 in hMSCs was upregulated by the canonical Wnt signaling pathway, a positive regulator of MSC self-renewal, and downregulated by interferon-γ (IFN-γ), a pro-inflammatory cytokine that has an important role in activating the immunomodulatory properties of hMSCs. Differential gene expression analyses, in combination with computational searches, defined a cluster of 62 putative target genes for miR-335 in hMSCs. Western blot and 3'UTR reporter assays confirmed RUNX2 as a direct target of miR-335 in hMSCs. These results strongly suggest that miR-335 downregulation is critical for the acquisition of reparative MSC phenotypes.

Comparing alternative definitions of the contemporary group effect in Avilena Negra Iberica beef cattle using classical and Bayesian criteria.

Data on weaning weight from 12,740 animals were used to compare different definitions of contemporary groups (CG) for the genetic evaluation of the Avilena Negra Iberica beef cattle breed. Six alternative definitions for the CG effect were considered: herd-year-season of calving (HYS), with seasons defined according to the four natural seasons; herd-year-month of calving (HYM); herd clusters of 30 d (HC30-30) or 90 d (HC90-90); and adaptive herd clusters with two time limits, 30 and 90 d (HC30-90), and 30 and 180 d (HC30-180). A minimum of five observations in each CG class was required. This rendered substantial differences in loss of information, ranging from 0.7% of the total number of records for HC30-180 to 14% for HYM. Several classical statistics and Bayesian criteria for statistical model comparison were used. The use of classical criteria, such as the between- and within-CG variation and the accuracy of prediction, can be controversial because of their dependency on the unknown variance components. Residual variance decreased with the decrease in time span associated with the definition of CG. This was expected in this population because environmental conditions are highly variable throughout the year. However, estimates of the additive genetic variance for direct effects, which should not be affected by the definition of CG, were substantially larger for definitions involving larger time periods (HYS, HC90-90). When parameters used in the current evaluation procedure were used with all data sets, CG involving 30 d (HYM and HC30-30) were optimal in terms of providing the lowest/largest within-/between-CG variation. On the other hand, CG involving 90 d (HYS and HC90-90) yielded the poorest within-/between CG variation, with only a slight improvement of accuracy of prediction of direct genetic values over the other definitions. Bayes factors and cross-validation predictive densities allowed for improved discrimination among models. Models including CG spanning 30 d were more plausible and showed better predicting ability than models spanning 90 d. Adaptive CG showed intermediate results. Overall, it seems that average time span rendered by the different definitions had a major effect on the ranking of models. However, from the breeder's point of view, the loss of information associated with definitions involving shorter periods of time, such as HYM or HC30-30, might be unacceptable.

Assessment of homogeneity vs. heterogeneity of residual variance in random regression test-day models in a Bayesian analysis.

Test-day first-lactation milk yields from Holstein cows were analyzed with a set of random regression models based on Legendre polynomials of varying order on additive genetic and permanent environmental effects. Homogeneity and heterogeneity of residual variance, assuming three and 30 arbitrary measurement error classes of different length were considered. Unknown parameters were estimated within a Bayesian framework. Bayes factors and a checking function for the cross-validation predictive densities of the data were the tools chosen for selecting among competing models. Residual variances obtained from 30 arbitrary intervals were nearly constant between d 70 and 300 and tended to increase towards the extremes of the lactation, especially at the onset. In early lactation, the temporary measurement errors were found to be larger and highly variable. A high order of the regression submodels employed for modeling the permanent environmental deviations tended to strongly correct the heterogeneity of the residual variance. Accordingly, the assumption of homogeneity of residual variance was the most plausible specification under both comparison criteria when the number of random regression coefficients was set to five. Otherwise, the heterogeneity assumption, using three or 30 error classes, was better supported, depending on the criterion and on the order of the submodel fitted for the permanent environmental effect.