LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the Bmp System in Endothelial Cells and in Angiogenesis

Rationale: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism. Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. Methods and Results: Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.     

Pediatric ambulatory blood pressure monitoring: indications and interpretations

The prevalence of hypertension in children and adolescents is increasing, especially in obese and ethnic children. The adverse long-term effects of hypertension beginning in youth are known; therefore, it is important to identify young patients who need intervention. Unfortunately, measuring blood pressure (BP) is difficult due to the variety of techniques available and innate biologic variation in BP levels. Ambulatory BP monitoring may overcome some of the challenges clinicians face when attempting to categorize a young patient's BP levels. In this article, the authors review the use of ambulatory BP monitoring in pediatrics, discuss interpretation of ambulatory BP monitoring, and discuss gaps in knowledge in usage of this technique in the management of pediatric hypertension.     

The Specialist Surgeon Workforce in East,Central and Southern Africa: A Situation Analysis

Background

In East, Central and Southern Africa accurate data on the current surgeon workforce have previously been limited. In order to ensure that the workforce required for sustainable delivery of surgical care is put in place, accurate data on the number, specialty and distribution of specialist-trained surgeons are crucial for all stakeholders in surgery and surgical training in the region.

Methods

The surgical workforce in each of the ten member countries of the College of Surgeons of East, Central and Southern Africa (COSECSA) was determined by gathering and crosschecking data from multiple sources including COSECSA records, medical council registers, local surgical societies records, event attendance lists and interviews of Members and Fellows of COSECSA, and validating this by direct contact with the surgeons identified. This data was recorded and analysed in a cloud-based computerised database, developed as part of a collaboration programme with the Royal College of Surgeons in Ireland.

Results

A total of 1690 practising surgeons have been identified yielding a regional ratio of 0.53 surgeons per 100,000 population. A majority of surgeons (64 %) practise in the main commercial city of their country of residence and just 9 % of surgeons are female. More than half (53 %) of surgeons in the region are general surgeons.

Conclusions

While there is considerable geographic variation between countries, the regional surgical workforce represents less than 4 % of the equivalent number in developed countries indicating the magnitude of the human resource challenge to be addressed.

     

Dynamic changes in conjunctival dendritic cell numbers, anatomical position and phenotype during experimental allergic conjunctivitis

Dendritic cells (DCs) are a subset of antigen-presenting cells (APCs) that are involved in the initiation and control of the immune response to antigens present at the interface with the environment. A limited number of groups have studied DCs in human and animal conjunctiva but no data is available concerning the different DC subsets present in the conjunctival tissue. The aims of this study are to characterize the phenotypes and numbers of DCs present in the murine model of allergic conjunctivitis using the technique of immunohistochemistry so as to aid the understanding of the mechanisms involved in allergic eye disease. A double immunofluorescence method was used to analyze the phenotypic distribution and density of DC subsets in the mouse conjunctival tissues of the allergic model using a panel of antibodies: CD11c, as a general marker of DCs, coupled with another DC subset marker such as Langerin for Langerhans cells (LCs), CD11b for myeloid DCs (mDCs) and mPDCA-1 for plasmacytoid DCs (pDCs). In the na?ve conjunctiva, mDCs were consistently detected in the subepithelial layer and substantia propria. In the epithelium and the subepithelial layer, very few LCs and virtually no pDCs were observed. Following allergen challenge, there was a marked influx of mDCs and pDCs, but no LCs, into the subepithelial layer and throughout the substantia propria. These results indicate that conjunctival DC subsets may play an important role in the immune-regulatory processes involved in the inflammatory component of allergic conjunctivitis.     

What makes a man a man? The lived experience of male breast cancer

Male breast cancer is a rare condition with scant research into its psychosocial impact. This phenomenologic study sought to elicit its lived experience. Following analysis of interview data, 4 key themes emerged: Living with male breast cancer, concealment as a strategy for managing the diagnosis, a contested masculinity, interacting with health services. Male breast cancer constitutes a unique lived experience for men that is unparalleled in other disease profiles. The idea of living with a feminized illness was very distressing and stigmatizing for some men. Furthermore, treatment resulted in a profound change to the concept of their embodied selves and constituted a significant change to body image and sexuality. This was reinforced in participants who experienced erectile dysfunction related to tamoxifen therapy. Sadly, some health professionals were unable to offer specific psychosocial support, and participants felt marginalized from the potential benefits of the treatment environment. However, participants adapted to the illness by reasserting and renegotiating masculinity and finding ways to accommodate life with a stigmatizing condition and an altered body image.     

Are There Identifiable Risk Factors and Causes Associated with Unplanned Readmissions Following Total Knee Arthroplasty?

We conducted a retrospective review of 3218 primary total knee arthroplasties (TKA) performed over two years at an urban academic hospital network using clinical and administrative data. Increased length of stay (LOS) was associated with readmission (P < 0.001). Readmission was not associated with age (P = 0.100), gender (P = 0.608), body mass index (P = 0.329), or staged bilateral procedures (P = 0.420). The most common readmitting diagnoses were post-operative infection (22.5%), hematoma (10.1%), pulmonary embolus (7.9%) and deep vein thrombosis (5.6%). Of readmissions, 53.9% were for surgical reasons and 46.1% were for medical reasons. Certain interventions described in previous literature may be more successful in minimizing unplanned readmissions by focusing on patients with extended LOS, elevated infection risk and low socioeconomic status.     

Open reconstruction of recurrent vesicourethral anastomotic stricture after radical prostatectomy

Objectives

To determine the outcomes of open vesicourethral anastomotic reconstruction (VUAR) for outlet stenosis following radical prostatectomy (RP).

Methods

Review of all cases of VUAR within an IRB-approved database was performed. Preoperative factors assessed included cancer treatment modality, duration of symptoms, prior treatments, and length of defect. Outcomes reviewed included length-of-stay (LOS), complications, maintenance of patency, continence, and need for additional procedures.

Results

Twelve cases of VUAR performed by a single surgeon (BJF) from 2004 to 2012 were identified. Surgical approaches were either abdominal (7), perineal (3), or abdominoperineal (2). All patients underwent prior RP, with 25 % having subsequent radiotherapy. Among patients with stenosis, 43 % were completely obliterated. Two cases had prior anastomotic disruption in the early postoperative period after RP. The median length of stenosis was 2.5 cm (range 1–5 cm) and median LOS was 3.0 days (range 1–7 days). At a median follow-up of 75.5 months (range 14–120 months), 92 % of men retained patency; only 25 % were continent.

Conclusion

In experienced hands, VUAR can restore durable patency for men afflicted with outlet stenosis after RP. Despite anatomic restoration, incontinence is likely.