Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis

Objective To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function. Design Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information. Data sources PubMed and Embase from inception to April 2013. Eligibility for selecting studies Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction. Results There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman’s r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of −0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%. Conclusions Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero

Massive Young Stellar Objects in the Galactic Center. I. Spectroscopic Identification from Spitzer/IRS Observations

We present results from our spectroscopic study, using the Infrared Spectrograph (IRS) onboard the Spitzer Space Telescope, designed to identify massive young stellar objects (YSOs) in the Galactic Center (GC). Our sample of 107 YSO candidates was selected based on IRAC colors from the high spatial resolution, high sensitivity Spitzer/IRAC images in the Central Molecular Zone (CMZ), which spans the central ~300 pc region of the Milky Way Galaxy. We obtained IRS spectra over 5um to 35um using both high- and low-resolution IRS modules. We spectroscopically identify massive YSOs by the presence of a 15.4um shoulder on the absorption profile of 15um CO2 ice, suggestive of CO2 ice mixed with CH3OH ice on grains. This 15.4um shoulder is clearly observed in 16 sources and possibly observed in an additional 19 sources. We show that 9 massive YSOs also reveal molecular gas-phase absorption from CO2, C2H2, and/or HCN, which traces warm and dense gas in YSOs. Our results provide the first spectroscopic census of the massive YSO population in the GC. We fit YSO models to the observed spectral energy distributions and find YSO masses of 8 - 23 Msun, which generally agree with the masses derived from observed radio continuum emission. We find that about 50% of photometrically identified YSOs are confirmed with our spectroscopic study. This implies a preliminary star formation rate of ~0.07 Msun/yr at the GC.Comment: Accepted for publication in Ap

The Na+ Channel Inactivation Gate Is a Molecular Complex: A Novel Role of the COOH-terminal Domain

Electrical activity in nerve, skeletal muscle, and heart requires finely tuned activity of voltage-gated Na+ channels that open and then enter a nonconducting inactivated state upon depolarization. Inactivation occurs when the gate, the cytoplasmic loop linking domains III and IV of the α subunit, occludes the open pore. Subtle destabilization of inactivation by mutation is causally associated with diverse human disease. Here we show for the first time that the inactivation gate is a molecular complex consisting of the III-IV loop and the COOH terminus (C-T), which is necessary to stabilize the closed gate and minimize channel reopening. When this interaction is disrupted by mutation, inactivation is destabilized allowing a small, but important, fraction of channels to reopen, conduct inward current, and delay cellular repolarization. Thus, our results demonstrate for the first time that physiologically crucial stabilization of inactivation of the Na+ channel requires complex interactions of intracellular structures and indicate a novel structural role of the C-T domain in this process

A Biomechanical Comparison of Intralaminar C7 Screw Constructs with and without Offset Connector Used for C6-7 Cervical Spine Immobilization : A Finite Element Study

Objective: The offset connector can allow medial and lateral variability and facilitate intralaminar screw incorporation into the construct. The aim of this study was to compare the biomechanical characteristics of C7 intralaminar screw constructs with and without offset connector using a three dimensional finite element model of a C6-7 cervical spine segment. Methods: Finite element models representing C7 intralaminar screw constructs with and without the offset connector were developed. Range of motion (ROM) and maximum von Mises stresses in the vertebra for the two techniques were compared under pure moments in flexion, extension, lateral bending and axial rotation. Results: ROM for intralaminar screw construct with offset connector was less than the construct without the offset connector in the three principal directions. The maximum von Misses stress was observed in the C7 vertebra around the pedicle in both constructs. Maximum von Mises stress in the construct without offset connector was found to be 12-30% higher than the corresponding stresses in the construct with offset connector in the three principal directions. Conclusion: This study demonstrated that the intralaminar screw fixation with offset connector is better than the construct without offset connector in terms of biomechanical stability. Construct with the offset connector reduces the ROM of C6-7 segment more significantly compared to the construct without the offset connector and causes lower stresses around the C7 pedicle-vertebral body complex

The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain

INTRODUCTION: Degeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats. METHODS: Disk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model. RESULTS: After removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model. CONCLUSIONS: Although similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration

First Spectroscopic Identification of Massive Young Stellar Objects in the Galactic Center

We report the detection of several molecular gas-phase and ice absorption features in three photometrically-selected young stellar object (YSO) candidates in the central 280 pc of the Milky Way. Our spectra, obtained with the Infrared Spectrograph (IRS) onboard the Spitzer Space Telescope, reveal gas- phase absorption from CO_2 (15.0 μm), C_2H_2 (13.7 μm) and HCN (14.0 μm). We attribute this absorption to warm, dense gas in massive YSOs. We also detect strong and broad 15 μm CO_2 ice absorption features, with a remarkable double- peaked structure. The prominent long-wavelength peak is due to CH_3OH-rich ice grains, and is similar to those found in other known massive YSOs. Our IRS observations demonstrate the youth of these objects, and provide the first spectroscopic identification of massive YSOs in the Galactic Center

Model Independent Approach to Focus Point Supersymmetry: from Dark Matter to Collider Searches

The focus point region of supersymmetric models is compelling in that it simultaneously features low fine-tuning, provides a decoupling solution to the SUSY flavor and CP problems, suppresses proton decay rates and can accommodate the WMAP measured cold dark matter (DM) relic density through a mixed bino-higgsino dark matter particle. We present the focus point region in terms of a weak scale parameterization, which allows for a relatively model independent compilation of phenomenological constraints and prospects. We present direct and indirect neutralino dark matter detection rates for two different halo density profiles, and show that prospects for direct DM detection and indirect detection via neutrino telescopes such as IceCube and anti-deuteron searches by GAPS are especially promising. We also present LHC reach prospects via gluino and squark cascade decay searches, and also via clean trilepton signatures arising from chargino-neutralino production. Both methods provide a reach out to m_{\tg}\sim 1.7 TeV. At a TeV-scale linear e^+e^- collider (LC), the maximal reach is attained in the \tz_1\tz_2 or \tz_1\tz_3 channels. In the DM allowed region of parameter space, a \sqrt{s}=0.5 TeV LC has a reach which is comparable to that of the LHC. However, the reach of a 1 TeV LC extends out to m_{\tg}\sim 3.5 TeV.Comment: 34 pages plus 36 eps figure

Learning to live with nephrotic syndrome: experiences of adult patients and parents of children with nephrotic syndrome

People living with nephrotic syndrome (NS) need to develop an in-depth understanding of their condition in order to participate in treatment decisions, develop self-management skills and integrate illness into daily life. However, the learning needs of adult patients and parents of children with NS are unknown. We therefore explored patient and parent perspectives on learning needs related to NS as part of a larger study to develop a shared learning tool for NS