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Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres.

PURPOSE: To evaluate (i) the appropriateness, safety, and patient outcomes after placement of the VenaTech LP caval filter and (ii) the success of filter insertion through various venous access routes. MATERIALS AND METHODS: An open multicenter prospective observational study was conducted in 12 European centers, including an initial part limited to four centers. Patients with common indications were eligible for inclusion after approval by an independent ethics committee. Over a 42-month period, 106 patients (46 men [43.4%], 60 women [56.6%]), 72.2 years +/- 13.3 of age (range, 37-97 y), with poor prognoses were included. Patients were examined 2-5 days after the procedure, then at 30 days +/- 5 and 90 days +/- 15 for clinical follow-up and filter assessment. Evaluation criteria were based on occurrence of pulmonary embolism (PE), adverse events, death, filter position, and caval patency. Data were available in 101 case report forms at days 2-5, in 75 at day 30 +/- 5, and in 60 at day 90 +/- 15. Two patients (1.9%) were lost to follow-up. RESULTS: The overall mortality rate was 20.8%. PE was present in 71 patients (67.0%). History of venous thromboembolic disease (VTED) was noted in 32 patients (30.2%), and recently diagnosed VTED was present in 101 patients (95.3%). Partial caval thrombosis was present before the procedure. Filter tilting of 10-45 degrees was seen in 3.9% of cases at days 2-5, 4.3% of cases at day 30 +/- 5, and 1.9% of cases at day 90 +/- 15. Follow-up evidenced neither clinical signs of PE nor significant device-related events. CONCLUSIONS: In a prospective patient cohort with a projected 3-month mortality rate of nearly 21.0% as a result of severe prognoses, the success of insertion via various venous access routes and the appropriateness and safety of the VenaTech LP caval filter were assessed. Findings at 90-day follow-up were free of symptomatic PE and device-related adverse effects

Pancreatic adenocarcinomas are among the most aggressive types of cancer with an extremely poor diagnosis. Since this type of cancer is not well amenable to chemo- and radiotherapy or immunotherapy, surgical resection remains the only feasible treatment to date. Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10 are potent immunomodulators that have been shown to suppress several aspects of the immune response. Vascular Endothelial Growth Factor (VEGF) is a powerful angiogenic factor, recently thought to be involved in neoangiogenesis and metastasis spreading. Therefore the three cytokines may contribute, by different pathways, to immune escape and growth of tumor. This study was conducted to determine the possible significance of TGF-beta1, IL-10 and VEGF as markers for monitoring the clinical course of pancreatic adenocarcinoma patients.Cytokine serum levels were measured in 30 pancreatic cancer patients and in 30 age and sex-matched healthy subjects.In comparison to serum concentrations in controls, TGF-beta1, IL-10 and VEGF levels were significantly elevated in all patients. Where the patients were divided by groups on the basis of the clinical stage of the disease, no differences were observed in TGF-beta1 levels among the groups. On the contrary, IL-10 and VEGF were more represented in stage IV patients than in stage II and III patients. In addition, the 14 patients who underwent surgical resection had postoperative cytokine serum levels markedly lower than those observed at diagnosis.Overall, the results suggest the importance of these markers in predicting the biological activity of the disease and suggest new targets for future rational therapies.

Background Available information on normal bowel habits was mainly gathered by means of telephone interviews or mailed questionnaires. Aims We undertook a prospective study to evaluate the defecatory habits in subjects perceiving themselves as normal concerning this function. Subjects and Methods A questionnaire (4-week diary with “yes–no” daily answers to six questions concerning bowel habits) was distributed to 204 subjects perceiving their defecation behaviour as normal. Results The completed questionnaire was returned by 140 subjects. No significant differences were found between sexes or age groups for any variable, even though straining at stool and feeling of incomplete and/or difficult evacuation showed a trend to increase with age. No subject had less than three bowel movements per week or more than three per day. The percentage of symptoms linked to an abnormal defecatory behaviour was well below 10%. Fifty-five percent of subjects reported at least one parameter of abnormal functioning; the most frequent was straining at stool and the rarer was the manual manoeuvres to help defecation. Conclusions In normal subjects the prevalence of symptoms considered in Rome II criteria as part of an abnormal defecatory behaviour (in more than 25% of defecations) is well below 10%, manual manoeuvres are almost never used to help defecation, and the frequency of defecations is at least three per week.

Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones.To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis.Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks.After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse.Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.

Programmed cell death, also known as apoptosis, is a normal physiologic process which occurs during embryonic development as well as in maintenance of tissue homeostasis. Increasing evidence suggests that alterations in cell death contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases and acquired immunodeficiency syndrome (AIDS). The extraordinary research activity of the past few years has resulted in the characterization of the principal proteins involved in the apoptosis machinery. An area of particular interest has been the induction of apoptosis by two death receptor/ligand pairs, Fas/Fas Ligand and DR4-DR5/TRAIL. The identification of these molecules with the recruited signaling pathways could clarify their physiopathological implications, having a significant impact upon potential therapeutic interventions in diseases associated with cell survival alterations.

The aim of this review is to summarize the current concepts concerning the active role of the endothelium in the pathogenesis of atherosclerosis. Activated endothelium may promote the adhesion of monocytes and their transmigration into the intima. The coordinated expression of adhesion molecules of the selectin, integrin or immunoglobulin superfamily on the surface of endothelial cells and of monocytes modulates these events. The role of lipoproteins and their oxidative derivatives as well as that of selected cytokines and platelet activated factor in initiating changes on the endothelial cell surface has been investigated: these events are associated with an increased endothelial permeability to lipids and lipoproteins with their accumulation in the subendothelium. Once migrated into the intima, monocytes undergo morphological and functional modifications leading to the generation of a polypeptide mediator network which is instrumental in the migration, differentiation and proliferation of smooth muscle cells. Mediators produced by macrophages infiltrating the atherosclerotic plaque and by the endothelium may render the surface of the endothelial cells thrombogenic thus favoring thrombotic occlusion. In conclusion, the most recent studies suggest that the endothelium plays an active role in the pathogenesis of atherosclerosis.

This study investigated the role of platelet-activating factor in the recruitment of polymorphonuclear neutrophils (PMN) in a rabbit model of cardiac ischemia and reperfusion. The accumulation of PMN was evaluated 2 and 24 hours after removal of 40 minutes of coronary occlusion by morphometric analysis and 111In-labeled PMN infiltration. The administration of two structurally unrelated platelet-activating factor-receptor antagonists (SDZ 63-675, 5 mg/kg body weight, and WEB 2170, 5 mg/kg body weight) before reperfusion significantly reduced the accumulation of PMN, as well as the hemodynamic alterations and the size of necrotic area. Two hours after reperfusion, the percentage of increase of 111In-labeled PMN in transmural central ischemic zone was significantly reduced in rabbits pretreated with SDZ 63-675 (51.4 +/- 7.9) or WEB 2170 (32.4 +/- 8.8) with respect to untreated rabbits (107.6 +/- 13.5). The morphometric analysis of myocardial sections confirmed the reduction of PMN infiltration at 2 hours and demonstrated that at 24 hours the phenomenon was even more significant. In addition, SDZ 63-675 and WEB 2170 prevented early transient bradycardia and hypotension and reduced the infarct size, judged by staining with tetrazolium at 2 and 24 hours after reperfusion, and by histological examination at 24 hours. These results suggest that platelet-activating factor is involved in the accumulation of PMN in the reperfused ischemic myocardium and contributes to the evolution of myocardial injury.