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Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy
No full textAbstract
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (\u3b1-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting \u3b1-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-\u3b1-syn transgenic mouse model of MSA. While the use of either CD5-D5 or lenalidomide alone had positive effects on neuroinflammation and/or \u3b1-syn accumulation in this mouse model of MSA, the combination of both approaches yielded better results than each single treatment. The combined treatment reduced astrogliosis, microgliosis, soluble and aggregated \u3b1-syn levels, and partially improved behavioral deficits in MBP-\u3b1-syn transgenic mice. These effects were associated with an activation of the Akt signaling pathway, which may mediate cytoprotective effects downstream tumor necrosis factor alpha (TNF\u3b1). These results suggest that a strategic combination of treatments may improve the therapeutic outcome in trials for MSA and related neurodegenerative disorders
Quantitative myocardial blood flow imaging with integrated time-of-flight PET-MR
No full textAbstract
Background
The use of integrated PET-MR offers new opportunities for comprehensive assessment of cardiac morphology and function. However, little is known on the quantitative accuracy of cardiac PET imaging with integrated time-of-flight PET-MR. The aim of the present work was to validate the GE Signa PET-MR scanner for quantitative cardiac PET perfusion imaging. Eleven patients (nine male; mean age 59\ua0years; range 46\u201374\ua0years) with known or suspected coronary artery disease underwent
15
O-water PET scans at rest and during adenosine-induced hyperaemia on a GE Discovery ST PET-CT and a GE Signa PET-MR scanner. PET-MR images were reconstructed using settings recommended by the manufacturer, including time-of-flight (TOF). Data were analysed semi-automatically using Cardiac VUer software, resulting in both parametric myocardial blood flow (MBF) images and segment-based MBF values. Correlation and agreement between PET-CT-based and PET-MR-based MBF values for all three coronary artery territories were assessed using regression analysis and intra-class correlation coefficients (ICC). In addition to the cardiac PET-MR reconstruction protocol as recommended by the manufacturer, comparisons were made using a PET-CT resolution-matched reconstruction protocol both without and with TOF to assess the effect of time-of-flight and reconstruction parameters on quantitative MBF values.
Results
Stress MBF data from one patient was excluded due to movement during the PET-CT scanning. Mean MBF values at rest and stress were (0.92\u2009\ub1\u20090.12) and (2.74\u2009\ub1\u20091.37) mL/g/min for PET-CT and (0.90\u2009\ub1\u20090.23) and (2.65\u2009\ub1\u20091.15) mL/g/min for PET-MR ( p \u2009=\u20090.33 and p \u2009=\u20090.74). ICC between PET-CT-based and PET-MR-based regional MBF was 0.98. Image quality was improved with PET-MR as compared to PET-CT. ICC between PET-MR-based regional MBF with and without TOF and using different filter and reconstruction settings was 1.00.
Conclusions
PET-MR-based MBF values correlated well with PET-CT-based MBF values and the parametric PET-MR images were excellent. TOF and reconstruction settings had little impact on MBF values
Rebound hyperkalemia after cessation of ritodrine in a parturient undergoing cesarean section
No full textAbstract
A 36-year-old parturient with a suspicion of placenta accreta under tocolytic therapy with ritodrine infusion underwent emergency cesarean section under general anesthesia with propofol, ketamine, and remifentanil because massive bleeding was anticipated. The ritodrine infusion was discontinued 1\ua0h before cesarean section. The baby was delivered 6\ua0min after induction of anesthesia. However, after the manual removal of the placenta from the uterus, the bleeding was massive and uncontrollable. We rapidly transfused crystalloid, colloid, and red blood cells through potassium removal filter. Hyperkalemia (5.8\ua0mmol/L) was detected just before blood transfusion. One hour later, hemostasis was still difficult, and hyperkalemia was promoted (6.1\ua0mmol/L). Thus, glucose insulin therapy started with intravenous furosemide to treat hyperkalemia. Gynecologists decided to induce the Bakri balloon tamponade for the treatment of postpartum hemorrhage. At the end of surgery, plasma potassium level also reduced to 5.5\ua0mmol/L. In the ICU, the bleeding still continued, and then radiologists performed bilateral internal iliac artery embolization for full hemostasis. Postoperative plasma potassium level was stable and 3.3\ua0mmol/L in the next morning. Although one of the common adverse reactions of ritodrine is hypokalemia, we should also beware of a rebound hyperkalemia after its cessation
A change in brain white matter after shunt surgery in idiopathic normal pressure hydrocephalus: a tract-based spatial statistics study
No full textAbstract
Background
The aim of this study was to elucidate changes in cerebral white matter after shunt surgery in idiopathic normal pressure hydrocephalus (INPH) using diffusion tensor imaging (DTI).
Methods
Twenty-eight consecutive INPH patients whose symptoms were followed for 1\ua0year after shunt placement and 10 healthy control (HC) subjects were enrolled. Twenty of the initial 28 INPH patients were shunt-responsive (SR) and the other 8 patients were non-responsive (SNR). The cerebral white matter integrity was detected by assessing fractional anisotropy (FA) and mean diffusivity (MD). The mean hemispheric DTI indices and the ventricular sizes were calculated, and a map of these DTI indices was created for each subject. The DTI maps were analysed to compare preshunt INPH with HC and preshunt INPH with 1\ua0year after shunt placement in each INPH group, using tract-based spatial statistics. We restricted analyses to the left hemisphere because of shunt valve artefacts.
Results
The ventricles became significantly smaller after shunt placement both in the SR and SNR groups. In addition, there was a significant interaction between clinical improvement after shunt and decrease in ventricular size. Although the hemispheric DTI indices were not significantly changed after shunt placement, there was a significant interaction between clinical improvement and increase in hemispheric MD. Compared with the HC group, FA in the corpus callosum and in the subcortical white matter of the convexity and the occipital cortex was significantly lower in SR at baseline, whereas MD in the periventricular and peri-Sylvian white matter was significantly higher in the SR group. Compared with the pre-operative images, the post-operative FA was only decreased in the corona radiata and only in the SR group. There were no significant regions in which DTI indices were altered after shunt placement in the SNR group.
Conclusions
Brain white matter regions in which FA was decreased after shunt placement were in the corona radiata between the lateral ventricles and the Sylvian fissures. This finding was observed only in shunt-responsive INPH patients and might reflect the plasticity of the brain for mechanical pressure changes from the cerebrospinal fluid system
Criteria to assess potential reverse innovations: opportunities for shared learning between high- and low-income countries
No full textAbstract
Background
Low- and middle-income countries (LMICs) are developing novel approaches to healthcare that may be relevant to high-income countries (HICs). These include products, services, organizational processes, or policies that improve access, cost, or efficiency of healthcare. However, given the challenge of replication, it is difficult to identify innovations that could be successfully adapted to high-income settings. We present a set of criteria for evaluating the potential impact of LMIC innovations in HIC settings.
Methods
An initial framework was drafted based on a literature review, and revised iteratively by applying it to LMIC examples from the Center for Health Market Innovations (CHMI) program database. The resulting criteria were then reviewed using a modified Delphi process by the Reverse Innovation Working Group, consisting of 31 experts in medicine, engineering, management and political science, as well as representatives from industry and government, all with an expressed interest in reverse innovation.
Results
The resulting 8 criteria are divided into two steps with a simple scoring system. First, innovations are assessed according to their success within the LMIC context according to metrics of improving accessibility, cost-effectiveness, scalability, and overall effectiveness. Next, they are scored for their potential for spread to HICs, according to their ability to address an HIC healthcare challenge, compatibility with infrastructure and regulatory requirements, degree of novelty, and degree of current collaboration with HICs. We use examples to illustrate where programs which appear initially promising may be unlikely to succeed in a HIC setting due to feasibility concerns.
Conclusions
This study presents a framework for identifying reverse innovations that may be useful to policymakers and funding agencies interested in identifying novel approaches to addressing cost and access to care in HICs. We solicited expert feedback and consensus on an empirically-derived set of criteria to create a practical tool for funders that can be used directly and tested prospectively using current databases of LMIC programs
Anastomosing hemangioma: report of two renal cases and analysis of the literature
No full textAbstract
Background
Anastomosing hemangioma (AH) is a very rare vascular tumor mimicking angiosarcoma, predominately observed in kidney and less frequently in other organs. We present two new renal cases of AH at opposite ends of the clinical presentation spectrum, provide review of the literature and compare the epidemiological, clinical and pathological profiles of renal and non-renal cases.
Case presentation
The first occurred in a 64-year-old woman presented with back pain and the second, a multifocal lesion, in a 47-year-old man with end stage renal disease (ESRD). Histology disclosed a vascular tumor with striking anastomosing pattern, minimal nuclear atypia and locally infiltrative pattern, mimicking superficially angiosarcoma. Extramedullary hematopoiesis, extensive perirenal fat entrapment and increased number of mast cells were additional features in the second lesion. Both patients are well, without disease, 25 and 14\ua0months after diagnosis.
Conclusion
Comprehensive review and analysis of the published literature show that the growing number of non-renal AHs exhibits similar epidemiologic, clinical, biologic and histologic characteristics with renal AHs and most mild differences vanish after exclusion of cases associated with ESRD. Better understanding of AH pathogenesis will contribute to optimal treatment choices
A carbon balance model for the great dismal swamp ecosystem
No full textAbstract
Background
Carbon storage potential has become an important consideration for land management and planning in the United States. The ability to assess ecosystem carbon balance can help land managers understand the benefits and tradeoffs between different management strategies. This paper demonstrates an application of the Land Use and Carbon Scenario Simulator (LUCAS) model developed for local-scale land management at the Great Dismal Swamp National Wildlife Refuge. We estimate the net ecosystem carbon balance by considering past ecosystem disturbances resulting from storm damage, fire, and land management actions including hydrologic inundation, vegetation clearing, and replanting.
Results
We modeled the annual ecosystem carbon stock and flow rates for the 30-year historic time period of 1985\u20132015, using age-structured forest growth curves and known data for disturbance events and management activities. The 30-year total net ecosystem production was estimated to be a net sink of 0.97\ua0Tg\ua0C. When a hurricane and six historic fire events were considered in the simulation, the Great Dismal Swamp became a net source of 0.89\ua0Tg\ua0C. The cumulative above and below-ground carbon loss estimated from the South One and Lateral West fire events totaled 1.70\ua0Tg\ua0C, while management activities removed an additional 0.01\ua0Tg\ua0C. The carbon loss in below-ground biomass alone totaled 1.38\ua0Tg\ua0C, with the balance (0.31\ua0Tg\ua0C) coming from above-ground biomass and detritus.
Conclusions
Natural disturbances substantially impact net ecosystem carbon balance in the Great Dismal Swamp. Through alternative management actions such as re-wetting, below-ground biomass loss may have been avoided, resulting in the added carbon storage capacity of 1.38\ua0Tg. Based on two model assumptions used to simulate the peat system, (a burn scar totaling 70\ua0cm in depth, and the soil carbon accumulation rate of 0.36\ua0t\ua0C/ha
\u22121
/year
\u22121
for Atlantic white cedar), the total soil carbon loss from the South One and Lateral West fires would take approximately 1740\ua0years to re-amass. Due to the impractical time horizon this presents for land managers, this particular loss is considered permanent. Going forward, the baseline carbon stock and flow parameters presented here will be used as reference conditions to model future scenarios of land management and disturbance
Correcting for cell-type effects in DNA methylation studies: reference-based method outperforms latent variable approaches in empirical studies
No full textAbstract
Based on an extensive simulation study, McGregor and colleagues recently recommended the use of surrogate variable analysis (SVA) to control for the confounding effects of cell-type heterogeneity in DNA methylation association studies in scenarios where no cell-type proportions are available. As their recommendation was mainly based on simulated data, we sought to replicate findings in two large-scale empirical studies. In our empirical data, SVA did not fully correct for cell-type effects, its performance was somewhat unstable, and it carried a risk of missing true signals caused by removing variation that might be linked to actual disease processes. By contrast, a reference-based correction method performed well and did not show these limitations. A disadvantage of this approach is that if reference methylomes are not (publicly) available, they will need to be generated once for a small set of samples. However, given the notable risk we observed for cell-type confounding, we argue that, to avoid introducing false-positive findings into the literature, it could be well worth making this investment.
Please see related Correspondence article: https://genomebiology.biomedcentral.com/articles/10/1186/s13059-017-1149-7 and related Research article: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0935-
Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy
No full textAbstract
Background
Canakinumab is a human anti-interleukin-1\u3b2 (IL-1\u3b2) monoclonal antibody neutralizing IL-1\u3b2-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA).
Methods
Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197.
Results
Microarray analysis identified 984 probe sets differentially expressed (\u22652-fold difference; P \u2009<\u20090.05) in patients versus controls. Over 50% of patients with \u226550 a ACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving \u226550 a ACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (\u22652-fold difference; P \u2009<\u20090.05) on day 3 versus baseline, including IL-1\u3b2, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (\u22658-fold decline; P \u2009<\u20090.0001) and remained suppressed. IL-18 declined on day 57 (\u22651.5-fold decline, P ..
A metadata-driven approach to data repository design
No full textAbstract
The design and use of a metadata-driven data repository for research data management is described. Metadata is collected automatically during the submission process whenever possible and is registered with DataCite in accordance with their current metadata schema, in exchange for a persistent digital object identifier. Two examples of data preview are illustrated, including the demonstration of a method for integration with commercial software that confers rich domain-specific data analytics without introducing customisation into the repository itself