MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT–PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.     

Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos

We carried out a meta-analysis of 22 trials to determine the comparative placebo effect of (a) subcutaneous vs. oral and (b) in-hospital vs. at-home administration in the treatment of migraine. The headache relief rates were combined from the placebo arms of these randomised clinical trials assessing the value of sumatriptan in acute treatment of migraine. The main outcome measure was the proportion of patients reclassified from severe or moderate headache severity to no or mild headache severity 2 h after the beginning of treatment. In the oral regimen 222 of 865 patients (25.7%) reported no or mild headache severity after 2 h, compared to 279 of 862 patients (32.4%) of those receiving subcutaneous placebo (6.7% difference; 95% CI 2.4-11.0%). Adjusting for treatment setting and severity of headache at baseline did not change the observed difference. After placebo treatment at home 285 of 1,054 patients (27.0%) reported no or mild headache severity after 2 h, compared to 216 of 673 patients (32.1%) among those receiving placebo in hospital (5.1 % difference; 95% CI 0.6-9.5%). When adjusted for route of administration and severity of headache at baseline, the difference in relief rates between home and hospital setting disappeared. These findings indicate that subcutaneous administration enhances the placebo effect of acute treatment of migraine. Future trials of antimigraine drugs assessing the relative efficacy of various routes of administration should use a double-dummy technique. The interpreting of placebo-controlled trial results must therefore consider that the effect in the drug arm of the trial depends in part on the route of administration.     

Spinal dural arteriovenous fistulas: long-term follow-up of 44 treated patients

To assess the long-term clinical course of 44 patients treated for a spinal dural arteriovenous fistula, patients were re-examined after a median follow-up of 5.7 years. In total, 70% of patients rated their activities of daily life as better or much better than before treatment. In most patients, gait disturbances and muscle strength had improved after treatment, with reduced disability; problems with micturition, defecation, and erection tended to remain unchanged.     

Generation of platelet-derived microparticles in patients undergoing cardiac surgery is not affected by complement activation

OBJECTIVE: The mechanisms causing the presence of platelet-derived microparticles in the circulation are unknown. In vitro platelets release platelet-derived microparticles in response to complement activation. This study evaluates the relationship between complement activation and levels of circulating platelet-derived microparticles in patients undergoing cardiac surgery. METHODS: Prospectively, 71 patients were included who underwent elective coronary artery bypass grafting with cardiopulmonary bypass. The patients were randomly allocated to one of the 3 groups: uncoated oxygenator, UnModified Surface (n = 25) or oxygenator coated with either BioPassive Surface (n = 25) or BioActive Surface (n = 21). Platelet-derived microparticles and terminal complement complexes were determined before bypass and after induction of anesthesia, 15 minutes after the start of cardiopulmonary bypass, at the end of cardiopulmonary bypass, and 30 minutes after administration of protamine sulfate. RESULTS: Demographic and cardiopulmonary bypass data were similar for the 3 groups. At the end of cardiopulmonary bypass, platelet-derived microparticle numbers were decreased in all 3 groups. No significant differences were observed among the groups at any sampling point. At the end of cardiopulmonary bypass, terminal complement complex concentrations were increased in all groups (P <.001), and significant differences among the groups were present (P =.002). CONCLUSIONS: Despite significant complement activation, no increase in numbers of circulating platelet-derived microparticles was found in the systemic blood of patients undergoing cardiac surgery with cardiopulmonary bypass. Thus complement activation in vivo does not necessarily affect generation of platelet-derived microparticles.     

Twin-twin transfusion syndrome: etiology, severity and rational management

The twin-twin transfusion syndrome is a serious complication of monochorionic twin pregnancies. Partly as a result of an inadequate understanding of the pathophysiology of the syndrome, there is a lack of consensus in clinical management. We sought to review the available information on the etiology of twin-twin transfusion syndrome, to identify parameters that contribute to the severity of the syndrome, and propose a rational management plan based on pathophysiology, clinical presentation and the efficacy of therapies. We therefore amalgamated recent advances in twin-twin transfusion syndrome computer modelling and clinical studies, particularly on therapeutic outcomes. We found that the oligo-polyhydramnios sequence that defines twin-twin transfusion syndrome prenatally represents a wide continuum of severity in the imbalance between the fetoplacental circulations of both twins. In severe twin-twin transfusion syndrome cases, in which the circulatory imbalance deteriorates beyond fetal control, fetoscopic laser therapy of all anastomoses along the placental vascular equator is predicted to have significantly better survival rates and fewer neurological sequelae than amnioreduction. In contrast, mild twin-twin transfusion syndrome cases have better outcomes after one or at most a few amnioreductions than laser therapy, as a result of significantly fewer procedure-related risks. In conclusion, optimal individual therapy may possibly achieve an 85% survival rate in twin-twin transfusion syndrome, but requires advancement in non-invasive criteria that predict the severity of the syndrome. Identifying such criteria is a future challenge. For the interim, twin-twin transfusion syndrome diagnosed before 26 weeks' gestation has significantly better survival rates and fewer neurological sequelae after laser therapy than amnioreduction. Twin-twin transfusion syndrome diagnosed after 26 weeks can best be treated by amnioreduction, or delivery. Contrary to previous claims, fetoscopic laser therapy has outgrown its experimental status. Although improvements in technique and technology are likely, laser placental ablation has a firm scientific and clinical basis.