Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing.

Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.

Using a smartphone application (PocketCPR) to determine CPR quality in a bystander CPR scenario - A manikin trial.

PURPOSE OF THE STUDY: Feedback devices and dispatcher assistance increase CPR quality in bystander resuscitation. Yet, there is no data comparing both approaches with uninstructed CPR. The present prospective, randomized, controlled, manikin trial aims to determine the effects of the use of a smartphone application (PocketCPR) on CPR quality in a bystander CPR scenario compared to dispatcher-assisted telephone CPR and uninstructed CPR. METHODS: 100 laypersons were included to perform 8-min CPR on a manikin. Volunteers were randomly assigned to one of four groups: (1) uninstructed CPR (uninstructed group), (2) dispatcher-assisted telephone CPR (telephone-group), (3) guidance and feedback through a smartphone application (app-group) and (4) dispatcher-assisted telephone CPR combined with the smartphone-app (telephone + app-group). RESULTS AND DISCUSSION: There was no significant difference in the time to first compression between the uninstructed and the app-group (p = 0.052), likewise between the telephone- and the telephone + app-group (p = 0.193). The no-flow-time of the uninstructed group was significantly longer compared to all other groups (p < 0.001). Median compression rate was significantly higher and within the recommended range in the app- and the telephone + app-group. There was no significant difference regarding correct compression depth between the four groups. Correct hand position and complete thorax release was found significantly more frequently in groups with smartphone-app support. CONCLUSIONS: Feedback by a smartphone application can improve bystander CPR quality in terms of no-flow-time, compression rate, correct hand position, thorax release and does not delay CPR onset. However, the use of a smartphone application does not improve compression depth significantly.