Demethyl fruticulin A (SCO-1) is a compound found in Salvia corrugate leaves. SCO-1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO-1 was able to induce apoptosis also via alternative pathways.To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1 for 24 hours, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO-1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria-selective fluorescent reporter of ROS, and by the ability of N-acetyl cysteine (NAC) to inhibit apoptosis when co-administered with SOC-1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG-63 and COS-7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro-apoptotic effect induced by SCO-1. Consequently, SCO-1 may have a potential therapeutic value, which deserves further investigation in animal models.(c) 2010 Wiley-Liss, Inc.

BACKGROUND: There is no accepted consensus on the definition of high-risk patients who may benefit from the use of intraaortic balloon pump (IABP) in coronary artery bypass grafting (CABG). The aim of this study was to develop a risk model to identify high-risk patients and predict the need for IABP insertion during CABG. METHODS: From April 1996 to December 2006, 8,872 consecutive patients underwent isolated CABG; of these 182 patients (2.1%) received intraoperative or postoperative IABP. The scoring risk model was developed in 4,575 patients (derivation dataset) and validated on the remaining patients (validation dataset). Predictive accuracy was evaluated by the area under the receiver operating characteristic curve. RESULTS: Mortality was 1% in the entire cohort and 18.7%(22 patients) in the group which received IABP. Multivariable analysis showed that age greater than 70 years, moderate and poor left ventricular dysfunction, previous cardiac surgery, emergency operation, left main disease, Canadian Cardiovascular Society 3-4 class, and recent myocardial infarction were independent risk factors for the need of IABP insertion. Three risk groups were identified. The observed probability of receiving IABP and mortality in the validation dataset was 36.4% and 10% in the high-risk group (score >14), 10.9% and 2.8% in the medium-risk group (score 7 to 13), and 1.7% and 0.7% in the low-risk group (score 0 to 6). CONCLUSIONS: This simple clinical risk model based on preoperative clinical data can be used to identify high-risk patients who may benefit from elective insertion of IABP during CABG.

BACKGROUND: The opinions of relatives of patients with schizophrenia about this disorder can influence its course and outcome. AIMS: In 2003, the Italian Psychiatric Association promoted a study on family psychoeducational intervention to explore its effectiveness in improving relatives' opinions and beliefs about schizophrenia. METHODS: In each of the 10 Italian mental health centres, 30 patients with schizophrenia and 30 key relatives were randomly recruited to receive the experimental intervention or the standard care. The experimental intervention consisted of 12 manual-based informative sessions on schizophrenia. Each relative filled in the self-reported questionnaire on family opinions about schizophrenia. RESULTS: The treated sample included 107 patients and 112 relatives; the control group consisted of 105 patients and 118 relatives. In both groups, stress, traumas, heredity and family difficulties were most frequently mentioned as causing the disorder. Relatives' opinions about patients' civil rights and social competence, in particular the right to get married, to have children and to vote, improved and the belief that patients with schizophrenia are unpredictable decreased at the end of the intervention. CONCLUSIONS: These results confirm that relatives of patients with schizophrenia should receive psychoeducational interventions, particularly in Italy where family involvement in schizophrenia care is particularly frequent.

Cardiac resynchronization therapy by biventricular pacemaker/ICD implantation is a validated therapy for patients affected by heart failure with asynchrony of ventricular contraction. Considering the large number of parameters which play a role in cardiac resynchronization therapy, a comprehensive numerical model of cardiocirculatory system could be a useful tool to support clinical decisions. A variable elastance model of ventricles was updated to model the interventricular septum and to simulate the interventricular and the intraventricular desynchrony, and the effect of the biventricular stimulation. In addition, a numerical model of the biventricular pacemaker, which drives the beginning of the heart chambers and interventricular septum contraction, was also developed. In order to validate the model, five patients affected by dilated cardiomyopathy were analysed by echocardiography and electrocardiography before implantation, 24 h and 3 months after the implantation. The developed numerical model permits to reproduce clinical data and to estimate the trend of parameters that are difficult to measure (i.e. left ventricular systolic elastance). Furthermore, the model permits to study the effect of different biventricular pacemaker temporizations on hemodynamic variables.

BACKGROUND AND STUDY AIM: Endoscopic treatment of Zenker's diverticulum has been successfully reported over the last 10 years using different approaches. The hook-knife is a new device originally developed for endoscopic submucosal dissection procedures. This study aimed to investigate the safety and efficacy of endoscopic myotomy performed with the hook-knife. PATIENTS AND METHOD: From July 2005, 32 consecutive patients (23-male, mean age 74.8 years) with dysphagia secondary to the presence of Zenker's diverticulum were prospectively enrolled. Myotomy was performed using a straight-end transparent hood to the tip of the scope and the hook-knife for the incision of the bridge between the Zenker's diverticulum and the esophagus. Clinical outcome was evaluated assigning a dysphagia symptom score from 0 (symptoms absent) to 4 (inability to swallow saliva). RESULTS: General anesthesia was used in 4 patients, deep sedation with propofol in 23 patients, while midazolam was used in 5 patients. The mean procedural time was 28 minutes. Complications occurred in 2 patients (6.25 %). At 1 month follow-up, the mean dysphagia score was significantly improved from 2.9 to 0.6 ( P < 0.001) with 87.5 % of patients free of symptoms and 4 patients with dysphagia that was persistent but milder than before the treatment. Three of these 4 patients underwent a successful second endoscopic treatment with complete relief of dysphagia; one was not re-treated because of advanced age (92 years). During the follow-up period (23.87 +/- 9.6 months), 2 patients developed dysphagia recurrence. The overall success rate was 90.6 %. CONCLUSIONS: Diverticulectomy with a flexible scope and the hook-knife may represent a safe and effective alternative treatment for patients with Zenker's diverticulum.

OBJECTIVE: The role of inflammatory adipokines has clear mechanistic effects in the promotion of both DM2 and cardiovascular diseases (CVDs), but it is unknown to what extent atherosclerosis-related inflammation might promote defects of glucose metabolism. The purpose of this study was to test the hypothesis that in subjects with atherosclerotic vascular disease and no previous medical record of type 2 diabetes mellitus (DM2), the diagnosis of occult impaired glucose regulation (IGR) is related to the severity of atherosclerosis, measured as the single or combined presence of an history of coronary artery disease (CAD), carotid atherosclerosis (Car-ATS) and peripheral artery disease (PAD). METHODS: In a population of 551 subjects (440 men and 111 women) with a previous history of atherosclerosis, we investigated the presence of IGR (including both impaired glucose tolerance and DM2). To test the correlation between conventional and non-conventional risk factors for cardiovascular disease and diabetes we used logistic and regression analysis models. RESULTS: IGR was more prevalent in patients with a documented vascular disease in two or three vessel districts compared with patients with only one symptomatic district (p=0.016). Among classic risk factors we found that waist circumference was correlated neither to IGR nor to symptomatic vascular disease extension. By contrast, adiponectin level was independently associated to vascular and glucose regulation status (p=0.012 and p<0.001, respectively). CONCLUSION: In subjects affected by atherosclerotic vascular diseases, the presence of impaired glucose regulation is associated to the number of vascular districts affected and to a reduced adiponectin level.

BACKGROUND: Although endoscopic submucosal dissection (ESD) is becoming accepted as an established treatment for superficial esophageal squamous cell neoplasia, the majority of data on this endoscopic modality has been provided by Japanese series. OBJECTIVE: To assess the efficacy and safety of ESD for esophageal squamous cell neoplasia in a consecutive series of patients treated in a Western setting. DESIGN AND SETTING: Single-center, prospective observational study. PATIENTS AND INTERVENTION: From January 2005 to July 2008, 20 patients with superficial esophageal squamous cell neoplasia were treated by ESD. MAIN OUTCOME MEASUREMENTS: Rates of en bloc resection, complete resection, and complications were evaluated as short-term outcomes. Overall survival, local or distant recurrence, and postoperative stricture rates were evaluated as long-term outcomes. RESULTS: ESD was performed in 20 patients (mean age 64 years, range 46-81 years; 16 men). The mean size of the lesion was 32 mm (range 15-60 mm); it was 30 mm or larger in 14 patients (70%). The mean time of ESD was 89 minutes (range 58-180 minutes). En bloc resection with resection-free margins was achieved in 18 patients (90%), whereas 2 patients presented with incomplete or indeterminate resection. Two cases (10%) of mediastinal emphysema without overt perforation and 1 case (5%) of post-ESD symptomatic stricture were reported. No local or distant post-ESD recurrence occurred in those with resection-free margins at a median follow-up of 18 months. LIMITATIONS: Small number of patients and limited follow-up. CONCLUSION: This Western series study confirms that ESD is a potentially curative treatment for superficial esophageal squamous cell neoplasia. Early and late complication rates were comparable to those of Japanese series. ESD should be probably considered as the treatment of choice in all large lesions amenable to endoscopic treatment.

BACKGROUND: A new pacing system has been designed and pre-clinically tested for safe use in the MRI environment. However, no previous experience with this innovative system has yet been reported. OBJECTIVE: This study aims to verify the safety and effectiveness of this newly designed system compared to conventional DDD implant outcomes. METHODS: Over a period of 11 months, 107 consecutive patients (71 males, age 72.6 +/- 8.5) were implanted either with the MRI-system (n=50; MRI group) or with a dual-chamber and active-fixation leads (Medtronic 4076) non-MRI system (n=57; DDD group). Data were collected at implant and during postoperative follow-up at 1,3, 6 and 12 months. Procedural and fluoroscopic time at implant, as well as lead measurements, handling characteristics and procedural-related complications were prospectively analyzed. RESULTS: The implantation success rate in both groups was 100%. Cephalic access was 63% for MRI patients and 70% for DDD patients (p=NS). Follow-up was obtained in all patients (median 6.8 months; range 3 to 12). At implant and at the end of follow-up, we found acceptable stimulation thresholds, sensing, and impedance. There were no cases of high pacing thresholds or inadequate sensing. There were no complications and no patient experienced subsequent lead displacement. CONCLUSIONS: This prospective, controlled study provides strong evidence that feasibility and safety of this novel technology compares favorably with the conventional technique.

We fully agree with the statement that "targeted cancer stem cell therapies start with proper identification of the target." However, we wish to point out that in our study (1), we state clearly that the cells used were obtained as previously reported (2), maintained in serum-free medium, and that "under these conditions, TICs [tumor-initiating cells] grown as a monolayer in flasks coated with Matrigel (BD Biosciences) expressed stem cell markers, maintained intact self-renewal capacity, maintained partial multilineage differentiation ability, and gave rise to tumor when injected ortho-topically in nude mice"(2). Ample details were also reported about the generation and characterization of these long-term expanding cultures in this article (2). Therefore, the statements made by Erina Vlashi and Frank Pajonk that "freshly isolated glioma samples were treated with LLNle immediately after glioma tissue digestion, and the drug effect was assessed 24 to 48 hours later" and that our cultures contained "bulk of glioma cells obtained after tumor digestion" are untrue. Why do our data disagree with those obtained by Vlashi and colleagues (3)? One possibility is that the cell models and the drugs used were different. The glioma cells that they used were the U87MG cell line. This line was established 41 years ago (4) and cultured with 10% fetal bovine serum for an unknown number of passages since then (and also by Vlashi and colleagues; ref. 3). Both the use of this cell line and the conditions used for their maintenance raise large concerns over the possibility that they may indeed represent a reliable in vitro model for glioblastoma (GBM) TICs. This concern is based on the very valuable data published in 2006 (5). Once the issue about which culture systems more closely recapitulate the biology of the GBM TICs in the in vivo context is set, we think that Vlashi and Pajonk in their letter forward an interesting methodological approach about the way to establish sensitivity and/or resistance of GBM TICs to a given substance by comparison of the effects on cell growth induced by the drug, in both proliferative and differentiating conditions. This strategy may help in addressing whether a drug has a TIC-specific toxic effect in vitro and we will certainly adopt it in our future studies. We regret we missed the opportunity to properly discuss these issues in our article by citing the article by Vlashi and colleagues (3). Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.