Endoscopic ultrasonography is an independent predictive factor of prognosis in locally advanced esophageal cancer. Results from the randomized FFCD 9102 study from the Fédération Francophone de Cancérologie Digestive

BACKGROUND: No multivariate study has assessed the independent prognostic role of endoscopic ultrasonography (EUS) in esophageal cancer, even when considering computed tomography (CT). OBJECTIVE: To evaluate the prognostic value of EUS in esophageal cancer before exclusive or preoperative radiochemotherapy. METHODS: From 1993 to 1999, the FFCD 9102 study enrolled 444 patients who had cancer of the thoracic esophagus, stages T3-4, N0-1 and M0 on CT. The patients received two sessions of chemotherapy in addition to radiotherapy. The 259 patients with objective response and no contraindications for further treatment were randomized to undergo surgery or to continue with radiochemotherapy. EUS was performed in 174 patients enrolled in the trial (mean age: 59 years). Tumor characteristics and lymph node status were prospectively recorded. A Cox statistical model was used to identify any predictive prognostic factors among the clinical, EUS and CT data. RESULTS: In the multivariate analysis, three factors were associated with a poor prognosis: inability to ingest solid food (OR: 1.98; P=0.0008); more than three neoplastic subdiaphragmatic lymph nodes (LN) on EUS (OR: 2.41; P<0.0045) and age>65 (OR: 1.53; P<0.056). Their prognostic value persisted after adjustment for type of treatment given. Two- and five- year survival rates were 21.5 and 10.5%, respectively, in the presence of three neoplastic subdiaphragmatic LN, and 43 and 30%, respectively, in all other cases. CONCLUSION: Degree of dysphagia, age and presence of neoplastic subdiaphragmatic LN on EUS were independently predictive of the prognosis for locally advanced esophageal cancer. EUS results should be taken into account in future trials.     

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.The uremic syndrome is attributed to the progressive retention of numerous compounds, which in healthy individuals are normally excreted by the kidneys. At least 90 compounds, often referred to as uremic toxins, were described to accumulate in ESRD¹ and to be harmful for biologic systems. In recent years, the dialysis community has paid great attention to improve clearance of water-soluble molecules, such as urea. Unfortunately, several studies, including the HEMO study in hemodialysis,² and the ADEMEX study (Adequacy of Peritoneal Dialysis in Mexico),³ failed to significantly improve patient outcome. Protein-bound uremic toxins especially exert major toxic effects because of poor removal by the common dialysis techniques.^4,5 p-Cresol is the mother compound of an important group of protein-bound retention solutes.⁶ It is produced in the gut from the metabolism of aromatic amino acids by putrefactive bacteria of the gut microbiota.^7,8 As it crosses through the intestinal mucosa, p-cresol is then metabolized by a cytoplasmic sulfotransferase and therefore mainly circulates in blood as its sulfate conjugate, p-cresyl sulfate (PCS) (Supplemental Figure 1). PCS is excreted by the kidney mainly through proximal tubular secretion and therefore accumulates in serum of patients with renal dysfunction. Of note, p-cresol/PCS has been shown to be independently associated with mortality and cardiovascular disease in patients with CKD.^9–11 There are now accumulating in vitro data on the harmful effects of p-cresol/PCS and related protein-bound retention solutes.^7,9,12–15CKD is associated with a large range of metabolic alterations.¹⁶ As established by the pioneering work of DeFronzo et al., insulin resistance is a well documented feature of CKD.^17,18 Among patients with ESRD, insulin resistance is associated with higher prevalence of vascular diseases.¹⁹ Although the causes of CKD-associated insulin resistance remain poorly identified,²⁰ several abnormalities associated with renal dysfunction were reported to interfere with insulin signaling.^21,22 The exact mechanisms underlying insulin resistance in patients with CKD have not been clearly elucidated, but growing evidence suggests that the progressive retention of a large number of compounds, which under normal conditions are excreted by the healthy kidneys, could play a key role. In a recent study, D’Apolito et al.²³ demonstrated that increased urea levels in CKD could induce insulin resistance. However, to date no study has ruled out the role of protein-bound uremic toxins in the development of insulin resistance and metabolic disturbances in CKD. We hypothesized that increased concentrations of PCS associated with CKD might drive insulin resistance and metabolic disturbances associated with CKD. In this study, we demonstrate that PCS administrated to mice with normal renal function induces insulin resistance and metabolic disturbances mimicking those reported in CKD. We further show that the reduction of p-cresol intestinal production (and thus plasma PCS) by the use of a prebiotic (arabino-xylo-oligosaccharide [AXOS]) prevented insulin resistance and dyslipidemia in a mouse model of CKD.     

An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three‐generation family at serious risk for aortic dissection

Several genes involved in the familial appearance of thoracic aortic aneurysms and dissections (FTAAD) have been characterized recently, one of which is SMAD3. Mutations of SMAD3 cause a new syndromic form of aortic aneurysms and dissections associated with skeletal abnormalities. We discovered a small interstitial deletion of chromosome 15, leading to disruption of SMAD3, in a boy with mild mental retardation, behavioral problems and revealed features of the aneurysms‐osteoarthritis syndrome (AOS). Several family members carried the same deletion and showed features including aortic aneurysms and a dissection. This finding demonstrates that haploinsufficiency of SMAD3 leads to development of both thoracic aortic aneurysms and dissections, and the skeletal abnormalities that form part of the aneurysms‐osteoarthritis syndrome. Interestingly, the identification of this familial deletion is an example of an unanticipated result of a genomic microarray and led to the discovery of important but unrelated serious aortic disease in the proband and family members.     

Citizenship and Recovery for Everyone: A Global Model of Public Mental Health

A systematic review of the literature on health promotion as conveyed by the Ottawa Charter for Health Promotion yielded two major findings: health promotion and recovery in mental health have many values and features in common, and health promotion and recovery in mental health do not refer very much to one another. A global model of public mental health is therefore needed to bring recovery and health promotion together, to clarify the boundaries of mental health promotion and to promote citizenship for everyone. Inspired and adapted from the ecological approach initially developed on the basis of health promotion programs, the model introduced here addresses mainly the issue of recovery, which has been neglected recently in the literature on both public health and mental health promotion. It advocates the idea that recovery can explicitly be related to mental health promotion through the Ottawa Charter for health promotion. Many issues and sub-issues are addressed, and the global model suggests keeping track of various activities unfolding at five levels, with examples of citizen psychiatry. The uniqueness and additional contribution of this model to already existing literature are that the supranational level is a key component of an approach that would truly be global.