The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets

Background The malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention. Design and Methods We compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia. Results Functional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia. Conclusions Aurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.

Clinical trial design in non-invasive brain stimulation psychiatric research

Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non-invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them. Copyright (C) 2011 John Wiley & Sons, Ltd.

Hypotheses, rationale, design, and methods for prognostic evaluation of cardiac biomarker elevation after percutaneous and surgical revascularization in the absence of manifest myocardial infarction. A comparative analysis of biomarkers and cardiac magnetic resonance. The MASS-V Trial

Background: Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis. Methods/Design: The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR. Discussion: The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass.

Optimized Duration of Clopidogrel Therapy Following Treatment with the Endeavor Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) Trial: Rationale and design of a large-scale, randomized, multicenter study

Background Current recommendations for antithrombotic therapy after drug-eluting stent (DES) implantation include prolonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel >= 12 months. However, the impact of such a regimen for all patients receiving any DES system remains unclear based on scientific evidence available to date. Also, several other shortcomings have been identified with prolonged DAPT, including bleeding complications, compliance, and cost. The second-generation Endeavor zotarolimus-eluting stent (E-ZES) has demonstrated efficacy and safety, despite short duration DAPT (3 months) in the majority of studies. Still, the safety and clinical impact of short-term DAPT with E-ZES in the real world is yet to be determined. Methods The OPTIMIZE trial is a large, prospective, multicenter, randomized (1: 1) non-inferiority clinical evaluation of short-term (3 months) vs long-term (12-months) DAPT in patients undergoing E-ZES implantation in daily clinical practice. Overall, 3,120 patients were enrolled at 33 clinical sites in Brazil. The primary composite endpoint is death (any cause), myocardial infarction, cerebral vascular accident, and major bleeding at 12-month clinical follow-up post-index procedure. Conclusions The OPTIMIZE clinical trial will determine the clinical implications of DAPT duration with the second generation E-ZES in real-world patients undergoing percutaneous coronary intervention. (Am Heart J 2012;164:810-816.e3.)

Intervention Based Exclusively on Stage- Matched Printed EducationalMaterials Regarding Healthy Eating Does Not Result in Changes to Adolescents' Dietary Behavior

Purpose. To assess the impact of a six-month stage-based intervention on fruit and vegetable intake, regarding perceived benefits and barriers, and self-efficacy among adolescents. Design. Randomized treatment-control, pre-post design. Subjects/ Setting. Schools were randomized between control and experimental groups. 860 adolescents from ten public schools in Bras ' ilia, Federal District, Brazil were evaluated at baseline; 771 (81%) completed the study. Intervention. Experimental group received monthly magazines and newsletters aimed at promotion of healthy eating. Measures. Self-reported fruit and vegetable intake, stages of change, self-efficacy and decisional balance scores were evaluated at baseline and post-intervention in both groups. Analysis. The effectiveness of the intervention was evaluated using the analysis of covariance model (ANCOVA) and repeated measurement analysis by means of weighted least squares. Comparison between the proportions of adolescents who advanced through the stages during the intervention was performed using the Mantel-Haenszel chi-square test. Results. After adjusting for sex and age, study variables showed no modifications through the proposed intervention. There was no statistical difference in participant mobility in the intervention and control groups between the stages of change, throughout the study. Conclusion. A nutritional intervention based exclusively on distribution of stage-matched printed educational materials was insufficient to change adolescents' dietary behavior.

Effectiveness of low-level laser therapy for patients with carpal tunnel syndrome: design of a randomized single-blinded controlled trial

Background: Carpal tunnel syndrome is the most common neuropathy in the upper extremity, resulting from the compression of the median nerve at wrist level. Clinical studies are essentials to present evidence on therapeutic resources use at early restoration on peripheral nerve functionality. Low-level laser therapy has been widely investigated in researches related to nerve regeneration. Therefore, it is suggested that the effect of low-level laser therapy associated with other conservative rehabilitation techniques may positively affect symptoms and overall hand function in compressive neuropathies such as carpal tunnel syndrome. The aim of this study is to evaluate the effectiveness of low-level laser therapy in addition to orthoses therapy and home orientations in patients with carpal tunnel syndrome. Methods/Design: Patients older than 18 years old will be included, with clinical diagnosis of carpal tunnel syndrome, excluding comorbidies. A physiotherapist will conduct intervention, with a blinding evaluator. Randomization will be applied to allocate the patients in each group: with association or not to low-level laser therapy. All of them will be submitted to orthoses therapy and home orientations. Outcome will be assessed through: pain visual analogic scale, Semmes Weinstein monofilaments (TM) threshold sensibility test, Pinch Gauge T, Boston Carpal Tunnel Questionnaire and two point discrimination test. Discussion: This paper describes the design of a randomized controlled trial, which aim to assess the effectiveness of conservative treatment added to low-level laser therapy for patients with carpal tunnel syndrome. Trial registration: Brazilian Clinical Trials Registry (ReBec) - 75ddtf / Universal Trial Number: U1111-1121-5184

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.

Health education intervention in early and late postmenopausal Brazilian women

Aim To identify aspects of health in postmenopausal Brazilian women using a health-related educational program provided by a multidisciplinary team as part of the primary care approach for early and late postmenopausal symptoms. Design A prospective cohort was formed with 69 postmenopausal women; they were divided into groups corresponding to early (n = 32) and late postmenopause (n = 37) through gynecological and clinical evaluations. We administered the Kuppermann-Blatt Menopausal Index and the Women's Health Questionnaire before and after health education instructions. Results The average age for the onset of menopause was 47.9 years (n = 69). Fifty women (72.5%) in this study had completed their primary education, 78.3% (n = 54) performed manual labor, and 60.9% (n = 42) showed concomitant chronic illnesses. After attending a series of health-related presentations, the mean weight of the women was reduced by 3.54% in early postmenopausal women (p < 0.001) and by 2.06% in the late postmenopausal group (p < 0.001). The mean abdominal circumference was reduced by 1.75% (p < 0.001) in the early postmenopausal group. In addition, the total score in the Kuppermann-Blatt Menopausal Index decreased by 34.38% in the early and by 33.33% in the late postmenopausal groups. According to the Women's Health Questionnaire, there was a decrease in the domain Depressive mood by 0.839 to 0.700 (p < 0.001) in the early and by 0.814 to 0.648 (p < 0.001) in the late postmenopausal groups. Conclusion Regardless of improving menopausal symptoms and anthropometric parameters, the effects of the multidisciplinary team activities in early postmenopausal women may be similar to those in late postmenopausal women.

Evaluation of the effects of hyperbaric oxygen therapy for spinal cord lesion in correlation with the moment of intervention

Study design: Experimental, controlled, animal study. Objectives: To evaluate the functional effect of hyperbaric oxygen therapy administered shortly, one day after, and no intervention (control) in standardized experimental spinal cord lesions in Wistar rats. Setting: Sao Paulo, Brazil. Methods: In all, 30 Wistar rats with spinal cord lesions were divided into three groups: one group was submitted to hyperbaric oxygen therapy beginning half an hour after the lesion and with a total of 10 one-hour sessions, one session per day, at 2 atm; the second received the same treatment, but beginning on the day after the lesion; and the third received no treatment (control). The Basso, Beattie and Bresnahan scales were used for functional evaluation on the second day after the lesion and then weekly, until being killed 1 month later. Results: There were no significant differences between the groups in the functional analysis on the second day after the lesion. There was no functional difference comparing Groups 1 and 2 (treated shortly after or one day after) in any evaluation moment. On the 7th day, as well as on the 21st and 28th postoperative days, the evaluation showed that Groups 1 and 2 performed significantly better than the control group (receiving no therapy). Conclusion: Hyperbaric chamber therapy is beneficial in the functional recovery of spinal cord lesions in rats, if it is first administered just after spinal cord injury or within 24 h. Spinal Cord (2012) 50, 502-506; doi: 10.1038/sc.2012.16; published online 6 March 2012