No abstract

Skeletal shape varies widely across species as adaptation to specialized modes of feeding and locomotion, but how skeletal shape is established is unknown. An example of extreme diversity in the shape of a skeletal structure can be seen in the sternum, which varies considerably across species. Here we show that the Dchs1–Fat4 planar cell polarity pathway controls cell orientation in the early skeletal condensation to define the shape and relative dimensions of the mouse sternum. These changes fit a model of cell intercalation along differential Dchs1–Fat4 activity that drives a simultaneous narrowing, thickening and elongation of the sternum. Our results identify the regulation of cellular polarity within the early pre-chondrogenic mesenchyme, when skeletal shape is established, and provide the first demonstration that Fat4 and Dchs1 establish polarized cell behaviour intrinsically within the mesenchyme. Our data also reveal the first indication that cell intercalation processes occur during ventral body wall elongation and closure.

The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4 −/− and Dchs1 −/− mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.

Objective To externally validate the RENAL, PADUA and SPARE nephrometry scoring systems for use in retroperitoneal robot‐assisted partial nephrectomy (RAPN). Materials and Methods Nephrometry scores were calculated for 322 consecutive patients receiving retroperitoneal RAPN at a tertiary referral centre from 2017. Patients with multiple tumours were excluded. Scores were correlated with peri‐operative outcomes, including the trifecta (warm ischaemia time <25 min, no peri‐operative complications and a negative surgical margin), both as continuous and categorical variables. Comparisons were performed using Spearman correlation and ability to predict the trifecta was assessed using binomial logistical regression. Results All three scoring systems correlated significantly with the main variables (operating time, warm ischaemia time and estimated blood loss), both as continuous and categorical variables. Only PADUA and SPARE were able to predict achievement of the trifecta (PADUA area under the curve [AUC] 0.623, 95% confidence interval [CI] 0.559–0.668; SPARE AUC 0.612, 95% CI 0.548–0.677). Conclusion This study validates the RENAL, PADUA and SPARE scoring systems to predict key intra‐operative outcomes in retroperitoneal RAPN. Only PADUA and SPARE were able to predict achievement of the trifecta. As a simplified version of the PADUA scoring system with comparable outcomes, we recommend using the SPARE system.

Stress urinary incontinence is the involuntary loss of urine on effort or physical exertion. It is a highly prevalent condition affecting both men and women. Treatment is performed in a step-wise approach involving conservative measures, such as weight loss and pelvic floor exercises, medical treatment with duloxetine and a variety of surgical treatment options. However, recent restrictions in the use of synthetic mesh and tape have limited the surgical treatment options, leading to the need for new and novel treatment for stress urinary incontinence. Stem cell therapy is a developing medical field and offers the potential to restore normal physiological function of the urethral sphincter. The effectiveness of stem cell therapy in stress urinary incontinence has been demonstrated in pre-clinical studies, leading to its evaluation in several clinical studies. This review assesses the current evidence for the safety and efficacy of stem cell treatment for patients with stress urinary incontinence who have failed conservative and/or medical management and have not undergone previous surgical treatment for stress urinary incontinence. Evidence Level: Not applicable