The Uniformed Services Constipation Action Plan: An Effective Tool for the Management of Children with Functional Constipation.

OBJECTIVE: To implement and to evaluate the effectiveness of the Uniformed Services Constipation Action Plan (USCAP) in our gastroenterology clinic for children with functional constipation. STUDY DESIGN: This implementation science study included toilet-trained subjects aged 4 years and older who met the Rome IV criteria for functional constipation. Children were block randomized to receive either the USCAP or control. All clinic functional constipation plans recommended subjects continue pharmacotherapy for 4 months. Endpoints measured were clinical outcomes (resolution of functional constipation and achievement of a Pediatric Bristol Stool Form Scale [PBSFS] score of 3 or 4), patient-related outcomes (health-related quality of life [HRQoL] total scale score), and health confidence outcomes (Health Confidence Score [HCS]). RESULTS: Fifty-seven treatment group subjects (44%) received a USCAP (52% male; mean age, 10.9 [4.9] years) compared with 73 controls (56%; 48% male; mean age,10.9 [5.3] years). A PBSFS score of 3 or 4 was achieved by 77% of the treatment group compared with 59% of controls (P = .03). Subjects from the treatment group were more likely than the controls to endorse adherence to the 4-month course of pharmacotherapy (P < .001). Subjects who received a USCAP had greater improvements in HRQoL total scale score by the end of the project (P = .04). CONCLUSIONS: The USCAP is a simple, inexpensive tool that has the potential to improve global outcomes for functional constipation in children and should be recommended as standard clinical practice.

Cdk5r1 Overexpression Induces Primary ß-Cell Proliferation.

Decreased ß-cell mass is a hallmark of type 1 and type 2 diabetes. Islet transplantation as a method of diabetes therapy is hampered by the paucity of transplant ready islets. Understanding the pathways controlling islet proliferation may be used to increase functional ß-cell mass through transplantation or by enhanced growth of endogenous ß-cells. We have shown that the transcription factor Nkx6.1 induces ß-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to define Nkx6.1-independent mechanisms by which Nr4a1 and Nr4a3 induce ß-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 but not by Nkx6.1. Overexpression of Cdk5r1 is sufficient to induce primary rat ß-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 in ß-cells confers protection against apoptosis induced by etoposide and thapsigargin, but not camptothecin. The Cdk5 kinase complex inhibitor roscovitine blocks islet proliferation, suggesting that Cdk5r1 mediated ß-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 kinase complex is sufficient to induce ß-cell proliferation while maintaining glucose stimulated insulin secretion.