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The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P(3). Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P(3)-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
Background: Evidence that home telemonitoring for patients with chronic heart failure (CHF) offers clinical benefit over usual care is controversial as is evidence of a health economic advantage.
Methods: Between January 2010 and June 2013, patients with a confirmed diagnosis of CHF were enrolled and randomly assigned to 2 study groups comprising usual care with and without an interactive bi-directional remote monitoring system (Motiva (R)). The primary endpoint in CardioBBEAT is the Incremental Cost-Effectiveness Ratio (ICER) established by the groups' difference in total cost and in the combined clinical endpoint "days alive and not in hospital nor inpatient care per potential days in study" within the follow-up of 12 months.
Results: A total of 621 predominantly male patients were enrolled, whereof 302 patients were assigned to the intervention group and 319 to the control group. Ischemic cardiomyopathy was the leading cause of heart failure. Despite randomization, subjects of the control group were more often in NYHA functional class III-IV, and exhibited peripheral edema and renal dysfunction more often. Additionally, the control and intervention groups differed in heart rhythm disorders. No differences existed regarding risk factor profile, comorbidities, echocardiographic parameters, especially left ventricular and diastolic diameter and ejection fraction, as well as functional test results, medication and quality of life. While the observed baseline differences may well be a play of chance, they are of clinical relevance. Therefore, the statistical analysis plan was extended to include adjusted analyses with respect to the baseline imbalances.
Conclusions: CardioBBEAT provides prospective outcome data on both, clinical and health economic impact of home telemonitoring in CHF. The study differs by the use of a high evidence level randomized controlled trial (RCT) design along with actual cost data obtained from health insurance companies. Its results are conducive to informed political and economic decision-making with regard to home telemonitoring solutions as an option for health care. Overall, it contributes to developing advanced health economic evaluation instruments to be deployed within the specific context of the German Health Care System.
While zwitterionic interfaces are known for their excellent low-fouling properties, the underlying molecular principles are still under debate. In particular, the role of the zwitterion orientation at the interface has been discussed recently. For elucidation of the effect of this parameter, self-assembled monolayers (SAMs) on gold were prepared from stoichiometric mixtures of oppositely charged alkyl thiols bearing either a quaternary ammonium or a carboxylate moiety. The alkyl chain length of the cationic component (11-mercaptoundecyl)-N,N,N-trimethylammonium, which controls the distance of the positively charged end group from the substrate's surface, was kept constant. In contrast, the anionic component and, correspondingly, the distance of the negatively charged carboxylate groups from the surface was varied by changing the alkyl chain length in the thiol molecules from 7 (8-mercaptooctanoic acid) to 11 (12-mercaptododecanoic acid) to 15 (16-mercaptohexadecanoic acid). In this way, the charge neutrality of the coating was maintained, but the charged groups exposed at the interface to water were varied, and thus, the orientation of the dipoles in the SAMs was altered. In model biofouling studies, protein adsorption, diatom accumulation, and the settlement of zoospores were all affected by the altered charge distribution. This demonstrates the importance of the dipole orientation in mixed-charged SAMs for their inertness to nonspecific protein adsorption and the accumulation of marine organisms. Overall, biofouling was lowest when both the anionic and the cationic groups were placed at the same distance from the substrate's surface.