Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database

Therapies for osteoporosis must be taken for at least 1 year to be effective. The purpose of this study was to determine the difference in adherence to etidronate, alendronate and hormone replacement therapy in a group of patients seen at our tertiary care centres. The Canadian Database of Osteoporosis and Osteopenia (CANDOO), a prospective observational database designed to capture clinical data, was searched for patients who started therapy following entry into CANDOO. There were 1196 initiating etidronate, 477 alendronate and 294 hormone replacement therapy women and men aged (mean, SD) 65.8 (8.7) years in the study. A Cox proportional hazards regression model was used to assess differences between treatment groups in the time to discontinuation of therapy. Several potential covariates such as anthropometry, medications, illnesses, fractures and lifestyle factors were entered into the model. A forward selection technique was used to generate the final model. Hazard ratios and 95% confidence intervals (CI) were calculated. Adjusted results indicated that alendronate-treated patients were more likely to discontinue therapy as compared with etidronate-treated patients (1.404; 95% CI: 1.150, 1.714). After 1 year, 90.3% of patients were still taking etidronate compared with 77.6% for alendronate. No statistically significant differences were found between hormone replacement therapy and etidronate users (0.971; 95% CI: 0.862, 1.093) and hormone replacement therapy and alendronate users (0.824; 95% CI: 0.624, 1.088) after controlling for potential covariates. After 1 year, 80.1% of patients were still taking hormone replacement therapy, which decreased to 44.5% after 6 years. Increasing age and presence of incident non-vertebral fractures were found to be independent predictors of adherence. In conclusion, alendronate users were more likely to discontinue therapy than etidronate users over the follow-up period. Potential barriers to long-term patient adherence to osteoporosis therapies need to be evaluated.     

Cell migration and the anatomic control of thymocyte precursor differentiation

The thymus performs several essential functions during the steady-state production of T lymphocytes in adults, including expansion of the precursor pool, differentiation into multiple lineages and screening for TCRs with restricted specificities. Other than those functions attributed to the TCR, most of the factors that control these processes remain undefined. One potential mechanism for such control may be related to the movement of precursor cells between distinct anatomical compartments in the thymus. Histological studies show that the majority of CD4- CD8- cells are found in the subcapsular region. However; vascular tissues that support the migration of precursor cells into the thymus (postcapillary venules) are located deep in the tissue, near the cortico-medullary junction. This implies that blood-borne cells entering the thymus must transit outward across the cortex in order to accumulate in the SCR. Differentiation of DN cells into the CD4+ 8+ stage correlates with a reversal in polarity and migration inward, while mature cells ultimately transit the CMJ in the opposite direction of cells first entering the organ. Here we review evidence for a model in which differentiation is induced and proliferation is controlled by this progressive translocation of immature precursors through discrete stromal compartments. In addition, we attempt to summarize what is known about the molecular mechanisms that may support polarized migration of early CD4- 8- thymocytes in the adult, as well as how and where the relevant differentiative and/or proliferative signals may be compartmentalized.     

β1-Adrenoceptor stimulation suppresses endothelial IKCa-channel hyperpolarization and associated dilatation in resistance arteries

Background and Purpose

In small arteries, small conductance Ca²⁺-activated K⁺ channels (SK_Ca) and intermediate conductance Ca²⁺-activated K⁺ channels (IK_Ca) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI₂-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK_Ca channels can be negatively regulated by PKA, we investigated whether β-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.

Experimental Approach

Rat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca²⁺]_i, mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.

Key Results

Intraluminal perfusion of β-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM–10 μM) without modifying the associated changes in endothelial cell [Ca²⁺]_i. The inhibitory effect of β-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β-adrenoceptor antagonists propranolol (non-selective), atenolol (β₁) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (β₂) or glibenclamide (ATP-sensitive K⁺ channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by β-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK_Ca {with 1 μM 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34)}, but not SK_Ca (50 nM apamin) channels prevented β-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.

Conclusions and Implications

In resistance arteries, endothelial cell β₁-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK_Ca channels and may be one consequence of raised circulating catecholamines.     

Rare somatic cells from human breast tissue exhibit extensive lineage plasticity

We identified cell surface markers associated with repression of p16^INK4a/cyclin-dependent kinase inhibitor 2A(CDKN2A), a critical determinant in the acquisition of a plastic state. These cell surface markers allowed direct isolation of rare cells from healthy human breast tissue that exhibit extensive lineage plasticity. This subpopulation is poised to transcribe plasticity markers, OCT3/4, SOX2, and NANOG, at levels similar to those measured in human embryonic stem cells and to acquire a plastic state sensitive to environmental programming. In vitro, in vivo, and teratoma assays demonstrated that either a directly sorted (uncultured) or a single-cell (clonogenic) cell population from primary tissue can differentiate into functional derivatives of each germ layer, ectodermal, endodermal, and mesodermal. In contrast to other cells that express OCT3/4, SOX2, and NANOG, these human endogenous plastic somatic cells are mortal, express low telomerase activity, expand for an extensive but finite number of population doublings, and maintain a diploid karyotype before arresting in G1.