BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Current view: intestinal stem cells and signaling.

Studies using mice have yielded significant amounts of information regarding signaling pathways, such as Wnt, bone morphogenic protein, PtdIns(3,4,5) kinase, and Notch, involved in intestinal development and homeostasis, including stem cell regulation and lineage specification and maturation. However, attempts to model signals definitively that control intestinal stem cells have been difficult because of a long-standing and recently reenergized debate surrounding their location. Although crypt-based columnar cells have been recently shown to display self-renewal and multipotential capacity, a large body of evidence supports long-term label-retaining cells, located on average at the +4 position just above the Paneth cells, as putative stem cells. Herein, we propose that both these cell types represent true intestinal stem cells maintained in different states (quiescent vs actively cycling), presumably via interactions with different microenvironments. Finally, we review current findings regarding the roles of Wnt, bone morphogenic protein, PtdIns(3,4,5) kinase, and Notch pathways within the intestine.

Tricuspid leaflet repair: innovative solutions.

Tricuspid regurgitation (TR) represents a significant disease process and when severe, is associated with increased mortality. Recent guidelines support a more aggressive approach to tricuspid valve (TV) surgery, especially when encountered with left-sided valvular pathology. While annuloplasty has been the standard treatment for TR, it may not provide as effective or durable a repair compared to annuloplasty combined with TV repair techniques. Several of these approaches are discussed including bicuspidalization, anterior leaflet augmentation, edge to edge repair, neochords, leaflet resection and combined approaches. Although patient cohorts in most of the studies examining these techniques are small, the long-term durability of TV repair is significant.

Surgical Unroofing of Hemodynamically Significant Left Anterior Descending Myocardial Bridges.

BACKGROUND: Left anterior descending artery myocardial bridges (MBs) range from clinically insignificant incidental angiographic findings to a potential cause of sudden cardiac death. Within this spectrum, a group of patients with isolated, symptomatic, and hemodynamically significant MBs despite maximally tolerated medical therapy exist for whom the optimal treatment is controversial. We evaluated supraarterial myotomy, or surgical unroofing, of the left anterior descending MBs as an isolated procedure in these patients. METHODS: In 50 adult patients, we prospectively evaluated baseline clinical characteristics, risk factors, and medications for coronary artery disease, relevant diagnostic data (stress echocardiography, computed tomography angiography, stress coronary angiogram with dobutamine challenge for measurement of diastolic fractional flow reserve, and intravascular ultrasonography), and anginal symptoms using the Seattle Angina Questionnaire. These patients then underwent surgical unroofing of their left anterior descending artery MBs followed by readministration of the Seattle Angina Questionnaire at 6.6-month (range, 2 to 13) follow-up after surgery. RESULTS: Dramatic improvements were noted in physical limitation due to angina (52.0 versus 87.1, p < 0.001), anginal stability (29.6 versus 66.4, p < 0.001), anginal frequency (52.1 versus 84.7, p < 0.001), treatment satisfaction (76.1 versus 93.9, p < 0.001), and quality of life (25.0 versus 78.9, p < 0.001), all five dimensions of the Seattle Angina Questionnaire. There were no major complications or deaths. CONCLUSIONS: Surgical unroofing of carefully selected patients with MBs can be performed safely as an independent procedure with significant improvement in symptoms postoperatively. It is the optimal treatment for isolated, symptomatic, and hemodynamically significant MBs resistant to maximally tolerated medical therapy.

A novel approach to ischemic mitral regurgitation (IMR).

Ischemic mitral regurgitation (IMR) is a complicated medical condition with varying degrees of coronary artery disease and mitral regurgitation (MR). The traditional surgical treatment option for those with indications for intervention is coronary artery bypass grafting (CABG) plus or minus mitral valve repair or replacement (MVR). Percutaneous coronary intervention, hybrid coronary revascularization (HCR), and conventional CABG are three techniques available to address coronary artery disease (CAD). Percutaneous edge-to-edge repair, minimally invasive, and traditional sternotomy are accepted approaches for the treatment of MR. When taken in combination, there are nine methods available to revascularize the myocardium and restore competency to the mitral valve. While most of these treatment options have not been studied in detail, they may offer novel solutions to a widely variable and complex IMR patient population. Thus, a comparative analysis including an examination of potential benefits and risks will be helpful and potentially allow for more patient-specific treatment strategies.

Surface area determination of a polystyrene-divinylbenzene chromatographic packing material via ionic amphiphile adsorption from aqueous mobile phases and application of Gouy-Chapman theory.

A method for the determination of the chromatographically accessible area of a reversed-phase column similar to the method of Hägglund and Ståhlberg [J. Chromatogr. A 761 (1997) 13] is applied to a column containing a polystyrene-divinylbenzene resin. Its theoretical basis is Gouy-Chapman theory in combination with an electrostatically modified linear adsorption isotherm. The surface area value determined for the resin, 96 m2/g, is much less than the reported surface area value, 400 m2/g, determined by N2 sorptometry and application of Branauer-Emmett-Teller (BET) theory. The method also provides a value for the number of moles of native anionic sites present on the column.