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Introduction Increased visceral adipose tissue (VAT) has been shown to be associated with the development of insulin resistance, type 2 diabetes, stroke, and ischemic heart disease. It remains unknown whether fat distribution impacts on coagulation markers and/or the risk of venous thrombosis. This study evaluates markers of hypercoagulability in class III obesity (body mass index [BMI] >40 kg/m2) compared with nonobese controls. We further investigated whether hypercoagulability was influenced by VAT, metabolic syndrome, and metabolic markers, including adiponectin. Patients and Methods Ninety patients were recruited from the obesity clinic at King's College Hospital from November 2009 to December 2011. The inclusion criteria were class III obesity (BMI ≥40 kg/m2) and age 18 to 65 years. A control group (healthy ambulatory participants, with a BMI Results Thrombin generation revealed a significantly increased peak and endogenous thrombin potential in patients compared with controls. Lag time and time to peak (ttP) were also significantly prolonged in patients. VAT was found to have the strongest association with thrombin generation parameters: lag time (β = 0.378; p

• Weight or weight loss per se may not indicate health status or health benefit. • There is no gold standard for assessing which patients would benefit most from weight-loss interventions. • The King's Criteria is one of several recently proposed obesity classification systems.• The King's Criteria can capture health problems related to obesity and health benefits after weight loss. • The King's Criteria is a reproducible scoring system. • Using the King's Criteria may help shift the focus of patients and clinicians from weight loss to health gain.Body mass index (BMI) alone does not reflect health status in individuals. The King's Obesity Staging Criteria is a clinical tool for the assessment of patients with complex obesity. We assessed the performance of a modified version of the King's Criteria by scoring 144 obese patients before and 1 year after bariatric surgery. We also evaluated inter-observer variability by having 11 clinicians score the same 12 patients. The King's Obesity Staging Criteria comprise nine health domains: Airways, Body mass index, Cardiovascular disease, Diabetes, Economic complications, Functional limitations, Gonadal axis, Health status (perceived), and body Image. For each domain, a person's health is assigned a score of 0 ('normal health'), 1 ('at risk'), 2 ('established disease') or 3 ('advanced disease'). The patient's mean BMI decreased from 48 ± 7 to 37 ± 7 kg m(-2) post surgery. Before surgery, 84% of patients were either in stage 2 ('established disease') or stage 3 ('advanced disease') for one or more domains other than BMI. The modified King's Criteria showed significant health improvements after surgery, with a higher proportion of patients scored in stage 0 ('normal health') within each health domain (P 0.001 for all). Observers assigned the same score in75% of cases for all domains except Health status perceived (71%) and body Image (65%). In conclusion the King's Criteria captured morbidity in obese patients and health gains after weight loss. Different clinicians mostly assigned similar scores. The King's Criteria is a clinical tool that may help shift the focus of patients and clinicians towards improving health and not only losing weight.NCT01112228 (http://www.clinicaltrials.gov).

The increasing prevalence of obesity places ever-increasing cost demands on healthcare systems. One million individuals are eligible for bariatric surgery in the UK, and yet less than 6000 bariatric procedures are performed annually. Bariatric surgery reverses or improves almost all the medical and psychosocial co-morbidities associated with obesity. Although the BMI is a simple method to estimate adiposity at a population level, it is relatively inaccurate within an individual and provides little-to-no indication of overall health status or disease severity. Staging systems overcome the inherent limitations of BMI and allow highly informed decision-making for an individual. At a societal level, this helps to identify those most likely to gain and maximise economic benefit. This review summarises the co-morbidities associated with obesity and the evidence for their improvement following surgery. The rationale for new staging criteria and appropriate patient selection are discussed.

Neural cell adhesion molecules (NCAMs) are found predominantly in neural, muscle and endocrine cells. Recent interest has focused on their potential role in tumorigenesis. We have analysed the expression and secretion of NCAM in a series of 48 human pituitary adenomas. Immunocytochemical analysis of 19 adenomas demonstrated NCAM expression in all tumours with, in each case, diffuse cytoplasmic staining being found with variable membrane accentuation. There were no apparent differences in the expression of immunoreactivity seen on sections between individual tumours. Cell culture media from 43 dispersed human pituitary tumours were analysed by immunoassay for the secretion of soluble NCAM and all the pituitary hormones. In contrast to the immunocytochemical studies, soluble NCAM was released from only 27% of human pituitary tumours, but this was not related to tumour type nor was the amount of soluble NCAM released correlated with the amount of pituitary hormone secreted by each adenoma. NCAM expression is common to all human pituitary adenoma types and the observed differences in release of soluble NCAM between individual tumours may reflect different molecular mechanisms, altering adhesive interactions between normal and adenomatous tissue.

Pituitary adenylate cyclase activating polypeptide (PACAP) has been shown to increase glycoprotein hormone α-subunit synthesis and release from pituitary cells. We have used αT3–1 clonal gonadotropes to investigate the intracellular mechanisms involved in PACAP regulation of α-subunit gene transcription; and using deletion, mutation, and heterologous constructs of the α-promoter linked to a luciferase reporter gene, we have defined DNA sequences responsive to PACAP. Stimulation of αT3–1 cells for 24 h with PACAP, GnRH, or vasoactive intestinal peptide (VIP) resulted in a time- and concentration-dependent increase in α-promoter transcription at 100 nm for GnRH (17.5-fold, P < 0.001), PACAP (12.7-fold, P < 0.01), and VIP (4.1-fold, P < 0.05). Incubation of αT3–1 cells in calcium-depleted medium suggested that the transcriptional response to PACAP was less dependent on changes in intracellular calcium concentration, in contrast to the results seen with GnRH or VIP, whereα -subunit transcription was significa...

Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.

Basal expression of the glycoprotein hormone alpha-subunit gene in pituitary gonadotrophs is partially dependent on a gonadotroph specific element (GSE) which binds the nuclear receptor, steroidogenic factor-1 (SF-1). We have used surface plasmon resonance (SPR) to determine the association (kappa ass), dissociation (kappa diss) and affinity (KA) constants of SF-1 binding to immobilized oligonucleotides containing either the GSE consensus motif or a GSE mutant with a 2 bp substitution in the GSE site (GSEMUT). In vitro translated SF-1 protein bound the consensus GSE with a threefold increase in affinity constant (P

GnRH stimulates both transcription and secretion of the alpha-subunit in pituitary cells, but the precise role of the calcium- signaling mechanisms mediating these actions are unclear. We have examined the role of calcium using alpha T3-1 gonadotropes transfected with alpha-promoter constructs linked to a luciferase reporter gene and concomitant measurement of alpha-subunit secretion. The calcium channel agonist, BayK8644 (1 microM) significantly stimulated alpha-subunit transcription (4.9-fold, P0.05) but to a lesser extent than either GnRH (100 nM, 20.7-fold, P0.001) or phorbol-12-myristate-13-acetate (TPA, 100 nM, 8.7-fold, P0.05). The transcriptional response to a combination of BayK8644 and TPA was approximately additive. Despite stimulating alpha-subunit gene expression, BayK8644 had no effect on alpha-subunit secretion at 24 h, and co-addition of BayK8644 and TPA did not produce any further stimulation of alpha-subunit secretion (3.0-fold, P0.001) compared with TPA alone (3.2-fold, P0.001). Pretreatment of alpha T3-1 cells with the calcium channel blocker, nifedipine (1 microM for 5 min), essentially blocked GnRH-stimulated alpha-promoter activity without affecting GnRH-stimulated alpha-subunit release. In contrast, thapsigargin pretreatment (1 microM for 5 min), which depletes intracellular calcium stores, significantly reduced basal and GnRH-stimulated secretion without affecting the ability of GnRH to increase alpha-promoter activity. Incubation of alpha T3-1 cells in calcium-depleted media showed that the transcriptional response was dependent on extracellular calcium concentration, with maximum stimulation by GnRH seen at a calcium concentration of 1.7 mM. Deletion analysis indicated that sequences between -420 and -244 bp were involved in mediating the response to BayK8644. Constructs containing only upstream alpha-promoter sequences from -517 to -98 bp, fused to the heterologous thymidine kinase promoter, exhibited loss of responsiveness to BayK8644 below -298 bp. These upstream elements were also found to be important for basal expression of the alpha-promoter and for mediating the response to TPA but were distinct from GnRH responsiveness of the human promoter in alpha T3-1 cells. These studies suggest differential regulation of GnRH-stimulated alpha-subunit gene transcription and secretion by extracellular calcium influx and intracellular calcium mobilization. The transcriptional response to extracellular calcium influx is mediated through two or more elements between -420 and -244 bp, which are also involved in basal and TPA-stimulated expression of the alpha-subunit promoter.