The relationship of myocardial contraction and electrical excitation—the correlation between scintigraphic phase image analysis and electrophysiologic mapping

Phase imaging derived from equilibrium radionuclide angiography presents the ventricular contraction sequence. It has been widely but only indirectly correlated with the sequence of electrical myocardial activation. We sought to determine the specific relationship between the sequence of phase progression and the sequence of myocardial activation, contraction and conduction, in order to document a noninvasive method that could monitor both. In 7 normal and 9 infarcted dogs, the sequence of phase angle was correlated with the epicardial activation map in 126 episodes of sinus rhythm and pacing from three ventricular sites. In each episode, the site of earliest phase angle was identical to the focus of initial epicardial activation. Similarly, the serial contraction pattern by phase image analysis matched the electrical epicardial activation sequence completely or demonstrated good agreement in approximately 85% of pacing episodes, without differences between normal or infarct groups. A noninvasive method to accurately determine the sequence of contraction may serve as a surrogate for the associated electrical activation sequence or be applied to identify their differences

Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders

For patients with psychiatric illnesses remaining refractory to 'standard' therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups

Comparison of tonic spinal cord stimulation, high-frequency and burst stimulation in patients with complex regional pain syndrome: a double-blind, randomised placebo controlled trial

BACKGROUND: Complex Regional Pain Syndrome (CRPS) is a disabling disease that is sometimes difficult to treat. Although spinal cord stimulation (SCS) can reduce pain in most patients with CRPS, some do not achieve the desired reduction in pain. Moreover, the pain reduction can diminish over time even after an initially successful period of SCS. Pain reduction can be regained by increasing the SCS frequency, but this has not been investigated in a prospective trial. This study compares pain reduction using five SCS frequencies (standard 40 Hz, 500 Hz, 1200 Hz, burst and placebo stimulation) in patients with CRPS to determine which of the modalities is most effective. DESIGN: All patients with a confirmed CRPS diagnosis that have unsuccessfully tried all other therapies and are eligible for SCS, can enroll in this trial (primary implantation group). CRPS patients that already receive SCS therapy, or those previously treated with SCS but with loss of therapeutic effect over time, can also participate (re-implantation group). Once all inclusion criteria are met and written informed consent obtained, patients will undergo a baseline assessment (T0). A 2-week trial with SCS is performed and, if successful, a rechargeable internal pulse generator (IPG) is implanted. For the following 3 months the patient will have standard 40 Hz stimulation therapy before a follow-up assessment (T1) is performed. Those who have completed the T1 assessment will enroll in a 10-week crossover period in which the five SCS frequencies are tested in five periods, each frequency lasting for 2 weeks. At the end of the crossover period, the patient will choose which frequency is to be used for stimulation for an additional 3 months, until the T2 assessment. DISCUSSION: Currently no trials are available that systematically investigate the importance of variation in frequency during SCS in patients with CRPS. Data from this trial will provide better insight as to whether SCS with a higher frequency, or with burst stimulation, results in more effective pain relief. TRIAL REGISTRATION: Current Controlled Trials ISRCTN3665525

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM

Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype. Altered sensitivity to apoptosis played only a minor role in this resistance mechanism. Instead, we identified the induction of autophagy to be regulated downstream of the miR-138/BIM axis and to promote cell survival following TMZ exposure. Our data thus define miR-138 as a glioblastoma cell survival-promoting miRNA associated with resistance to TMZ therapy in vitro and with tumor progression in vivo