11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.Estimates suggest that 1–2% of the population of the United States and United Kingdom take prescribed glucocorticoids (GCs) for the treatment of a broad spectrum of inflammatory and autoimmune diseases (1, 2). Despite the efficacy of GCs, 70% of patients experience an adverse systemic side-effect profile. The resultant Cushingoid features include central obesity, proximal myoatrophy, hypertension, skin thinning, osteoporosis, hepatic steatosis, insulin resistance, and type 2 diabetes (3, 4). Collectively, this contributes to increased risk of cardiovascular morbidity and mortality (5, 6). These features are replicated in patients with much rarer endogenous GC excess (Cushing syndrome), as first described by Harvey Cushing in 1932 (7). Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited.GC availability and action depend not only upon circulating levels but also on tissue-specific intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). Key metabolic tissues including liver, adipose tissue, and skeletal muscle express 11β-HSD type 1 (11β-HSD1), which coverts inactive cortisone to active cortisol [11-dehydrocorticosterone (11DHC) and corticosterone (CORT) in rodents, respectively] (8). In the setting of GC excess, the relative contribution to the metabolic effects induced by GCs of simple delivery of active GCs (cortisol or CORT) to a target tissue, compared with the regeneration of active GCs by 11β-HSD1 within the tissue, has not been determined.Type 2 11β-HSD (11β-HSD2) is predominately expressed in the kidney, colon, and salivary gland and catalyzes the inactivation of cortisol to cortisone (CORT to 11DHC in rodents). This not only protects the mineralocorticoid receptor from occupancy by cortisol but also crucially provides substrate for 11β-HSD1 in peripheral tissues.Transgenic animal models have highlighted the critical role of 11β-HSD1 in the regulation of metabolic phenotype in individual tissues. Mice overexpressing 11β-HSD1, specifically in adipose tissue, develop visceral obesity, insulin resistance, dyslipidemia, and hypertension (9, 10). Similarly, liver-specific 11β-HSD1 overexpression results in insulin resistance and hypertension, but not obesity (11). Importantly, circulating CORT levels were not elevated in either model, suggesting increased intracellular GC availability underpins the observed phenotypes. Indeed, this was confirmed in the adipose-specific 11β-HSD1–overexpressing mice, where twofold higher intraadipose CORT levels were recorded in comparison with WT controls (9). Ultimately, this has led to the development of selective 11β-HSD1 inhibitors as a potential treatment for patients with diabetes, obesity, and hypertension (12, 13).Although it is clear that 11β-HSD1 has a critical role to play in governing GC availability, its potential dynamic role in the setting of GC excess has not been fully explored (14–16). We have previously reported a patient with Cushing disease who was protected from the classic Cushing phenotype, owing to a functional defect in 11β-HSD1 activity, as evidenced by serum and urinary biomarkers (17). Based on this observation, we have hypothesized that tissue intrinsic 11β-HSD1 activity is the major determinant of the manifestations of GC excess and that 11β-HSD1 deletion will ameliorate the associated metabolic abnormalities. To determine the relative tissue-specific contribution to this effect, we have generated tissue-specific 11β-HSD1 deletions in liver and adipose tissue.     

Single incision laparoscopic adjustable gastric band: technique,feasibility, safety and learning curve

Introduction

Single incision laparoscopic surgery (SILS) is established in many procedures but not in bariatric surgery. One explanation may be that SILS is technically demanding in morbidly obese patients. This report describes our technique and experience with single incision laparoscopic adjustable gastric banding (SILAGB).

Methods

Prospective data collection was performed on consecutive obese patients who underwent SILAGB between November 2009 and February 2011. A single 3cm transverse incision in the right upper quadrant was used for a Covidien SILS^™ multichannel access port. The technique is described with a standard pars flaccida approach and the ‘tips and tricks’ needed for a wide range of candidates using standard laparoscopic equipment.

Results

A total of 29 patients (27 female) with a median body mass index of 41kg/m² (range: 35–52kg/m²) and median age of 44 years (range: 22–57 years) underwent SILAGB. There were no ‘conversions’ to a standard laparoscopic technique. Two cases required the addition of one single 5mm port. The only complications were two postoperative wound infections (one with a port site infection requiring replacement of the port) and one faulty band requiring replacement. There were therefore two returns to theatre and no 30-day deaths. All patients were discharged on the first postoperative day. In this series, operative times reduced significantly to be comparable with the conventional laparoscopic approach.

Conclusions

SILAGB is safe and feasible in the morbidly obese. Proficiency in this technique using conventional laparoscopic equipment can be achieved with a short learning curve.     

Thoracic surgical management of colorectal lung metastases: a questionnaire survey of members of the Society for Cardiothoracic Surgery in great Britain and Ireland

Introduction

Distant metastases to liver and lung are not uncommon in colorectal cancer. Resection of metastases is accepted widely as the standard of care. However, there is no firm evidence base for this. This questionnaire survey was carried out to assess the current practice preferences of cardiothoracic surgeons in Great Britain and Ireland.

Methods

An online questionnaire survey was emailed to cardiothoracic surgeons in Great Britain and Ireland. The survey was live for 12 weeks. Responses were collated with SurveyMonkey^®.

Results

Overall, there were 75 respondents. The majority (83%) indicated thoracic surgery as a specialist interest. Almost all (99%) used thoracic computed tomography (CT) for staging; 70% added liver CT and 51% added pelvic CT. Fluorodeoxyglucose positron emission tomography was used by 86%. The most frequent indication for pulmonary resection (97%) was solitary lung metastasis without extrathoracic disease. Video assisted thoracoscopic surgery (VATS) was used by 85%. In addition, thoracotomy was used by 96%. A third (33%) used radiofrequency ablation. Synchronous liver and lung resection was contraindicated for 83% of respondents. Over three-quarters (77%) thought that scientific equipoise exists presently for lung resection for colorectal lung metastases but only 21% supported a moratorium on this type of surgery until further evidence becomes available.

Conclusions

The results confirm that the majority of respondents use conventional cross-sectional imaging and either VATS or formal thoracotomy for resection. The results emphasise the continuing need for formal randomised trials to provide evidence of any survival benefit from pulmonary metastasectomy for colorectal lung metastases.     

Agreement and reproducibility of gray‐scale intravascular ultrasound and optical coherence tomography for the analysis of the bioresorbable vascular scaffold

Objective : To report the agreement between gray‐scale intravascular ultrasound (GS‐IVUS) and optical coherence tomography (OCT) in assessing the bioresorbable vascular scaffolds (BVS) structures and their respective reproducibility. Background : BVS are composed of an erodible polymer. Ultrasound and light signals backscattered from polymeric material differs from metallic stents using GS‐IVUS and OCT. Methods : Forty‐five patients included in the ABSORB trial were treated with a 3.0 × 18 mm BVS and imaged with GS‐IVUS 20 MHz and OCT post‐implantation. Qualitative (ISA, side‐branch struts, protrusion, and dissections) and quantitative (number of struts, lumen, and scaffold area) measurements were assessed by two investigators. The agreement and the inter‐ and intraobserver reproducibility were investigated using the kappa (κ) and the interclass correlation coefficient (ICC). Results : GS‐IVUS and OCT agreement was predominantly poor at a lesion, frame, and strut level analysis (κ and ICC <0.4) for qualitative measurements. GS‐IVUS demonstrated a reduced ability to detect cross‐sections with ISA (4.5% vs. 20.6%), side‐branch (SB) struts (6.3% vs. 7.8%), protrusions (3.2% vs. 9.6%), and dissections (0.2% vs. 9.0%) compared with OCT. GS‐IVUS reproducibility was poor–moderate (κ and ICC <0.6) except for ISA and SB‐struts (κ and ICC between 0.2 and 0.75). OCT showed an excellent reproducibility (κ and ICC > 0.75) except for the assessment of tissue protrusion (κ and ICC between 0.47 and 0.94). GS‐IVUS reproducibility was poor–moderate (ICC ≤ 0.5) in assessing the number of struts but excellent with OCT (ICC > 0.85). The reproducibility to assess lumen and scaffold areas was excellent using both techniques (ICC > 0.85). Conclusions : GS‐IVUS has a poor capacity to detect qualitative findings post‐BVS implantation and its reproducibility is low compared with OCT. The use of GS‐IVUS should be limited when assessing lumen and scaffold areas. © 2011 Wiley Periodicals, Inc.     

Optimal projection for transcatheter aortic valve implantation determined from the reference projection angles

Introduction : An optimal fluoroscopic working view projection (OP) with all three aortic sinuses aligned is crucial during trans‐catheter aortic valve implantation (TAVI). The aim of this study was to identify simple reference projection angles, which would act as a starting point for the operator to help determine OP for patients undergoing TAVI. Methods : During the period under consideration, 50 patients underwent TAVI. Procedural data and outcomes were collected prospectively on a dedicated database. Optimal angiographic deployment angles were achieved for all patients by starting in an anteroposterior caudal 15 degrees projection and then adjusting according to the initial image, with multiple small volume contrast injections undertaken to determine when all three aortic cusps were aligned (OP). Results : OP angles for the 50 cases were plotted on a graph. After normality testing confirmed that all angles were normally distributed, regression analysis enabled a regression line to be calculated. The equation for the regression line was defined as cranial/caudal intercept ?16.4 ± 1.5 (SE of the coefficient), P < 0.0001, slope of regression line LAO/RAO + 0.53 ± 0.1 (SE of the coefficient SE), P < 0.0001). Conclusions : As the regression line and its equation represents an acceptable estimate of the true relationship between Cranial/Caudal and LAO/RAO, to determine OP while remaining close to the regression line we suggest starting in LAO = 8.9, Caudal = ?11.4 (which represent the mean values of these two variables), and then increasing the caudal angle by approximately 0.5 degrees for every increase of 1 degree of the LAO angle or decreasing the caudal angle by 0.53 degrees for every decrease of 1 degree in LAO until all three aortic sinuses are in line which represents OP. © 2012 Wiley Periodicals, Inc.