Spinal cord stimulation for predominant low back pain in failed back surgery syndrome: study protocol for an international multicenter randomized controlled trial (PROMISE study)

Background: Although results of case series support the use of spinal cord stimulation in failed back surgery syndrome patients with predominant low back pain, no confirmatory randomized controlled trial has been undertaken in this patient group to date. PROMISE is a multicenter, prospective, randomized, open-label, parallel-group study designed to compare the clinical effectiveness of spinal cord stimulation plus optimal medical management with optimal medical management alone in patients with failed back surgery syndrome and predominant low back pain. Method/Design: Patients will be recruited in approximately 30 centers across Canada, Europe, and the United States. Eligible patients with low back pain exceeding leg pain and an average Numeric Pain Rating Scale score >= 5 for low back pain will be randomized 1:1 to spinal cord stimulation plus optimal medical management or to optimal medical management alone. The investigators will tailor individual optimal medical management treatment plans to their patients. Excluded from study treatments are intrathecal drug delivery, peripheral nerve stimulation, back surgery related to the original back pain complaint, and experimental therapies. Patients randomized to the spinal cord stimulation group will undergo trial stimulation, and if they achieve adequate low back pain relief a neurostimulation system using the Specify (R) 5-6-5 multi-column lead (Medtronic Inc., Minneapolis, MN, USA) will be implanted to capture low back pain preferentially in these patients. Outcome assessment will occur at baseline (pre-randomization) and at 1, 3, 6, 9, 12, 18, and 24 months post randomization. After the 6-month visit, patients can change treatment to that received by the other randomized group. The primary outcome is the proportion of patients with >= 50% reduction in low back pain at the 6-month visit. Additional outcomes include changes in low back and leg pain, functional disability, health-related quality of life, return to work, healthcare utilization including medication usage, and patient satisfaction. Data on adverse events will be collected. The primary analysis will follow the intention-to-treat principle. Healthcare use data will be used to assess costs and long-term cost-effectiveness. Discussion: Recruitment began in January 2013 and will continue until 2016

Gut bacteria responding to dietary change encode sialidases that exhibit preference for red meat-associated carbohydrates.

Dietary habits have been associated with alterations of the human gut resident microorganisms contributing to obesity, diabetes and cancer1. In Western diets, red meat is a frequently eaten food2, but long-term consumption has been associated with increased risk of disease3,4. Red meat is enriched in N-glycolylneuraminic acid (Neu5Gc) that cannot be synthesized by humans5. However, consumption can cause Neu5Gc incorporation into cell surface glycans6, especially in carcinomas4,7. As a consequence, an inflammatory response is triggered when Neu5Gc-containing glycans encounter circulating anti-Neu5Gc antibodies8,9. Although bacteria can use free sialic acids as a nutrient source10-12, it is currently unknown if gut microorganisms contribute to releasing Neu5Gc from food. We found that a Neu5Gc-rich diet induces changes in the gut microbiota, with Bacteroidales and Clostridiales responding the most. Genome assembling of mouse and human shotgun metagenomic sequencing identified bacterial sialidases with previously unobserved substrate preference for Neu5Gc-containing glycans. X-ray crystallography revealed key amino acids potentially contributing to substrate preference. Additionally, we verified that mouse and human sialidases were able to release Neu5Gc from red meat. The release of Neu5Gc from red meat using bacterial sialidases could reduce the risk of inflammatory diseases associated with red meat consumption, including colorectal cancer4 and atherosclerosis13

Shock Generation and Control Using DBD Plasma Actuators

This report is the final report of a NASA Phase I SBIR contract, with some revisions to remove company proprietary data. The Shock Boundary Layer Interaction (SBLI) phenomena in a supersonic inlet involve mutual interaction of oblique shocks with boundary layers, forcing the boundary layer to separate from the inlet wall. To improve the inlet efficiency, it is desired to prevent or delay shock-induced boundary layer separation. In this effort, Innovative Technology Applications Company (ITAC), LLC and the University of Notre Dame (UND) jointly investigated the use of dielectric-barrier-discharge (DBD) plasma actuators for control of SBLI in a supersonic inlet. The research investigated the potential for DBD plasma actuators to suppress flow separation caused by a shock in a turbulent boundary layer. The research involved both numerical and experimental investigations of plasma flow control for a few different SBLI configurations: (a) a 12 wedge flow test case at Mach 1.5 (numerical and experimental), (b) an impinging shock test case at Mach 1.5 using an airfoil as a shock generator (numerical and experimental), and (c) a Mach 2.0 nozzle flow case in a simulated 15 X 15 cm wind tunnel with a shock generator (numerical). Numerical studies were performed for all three test cases to examine the feasibility of plasma flow control concepts. These results were used to guide the wind tunnel experiments conducted on the Mach 1.5 12 degree wedge flow (case a) and the Mach 1.5 impinging shock test case (case b) which were at similar flow conditions as the corresponding numerical studies to obtain experimental evidence of plasma control effects for SBLI control. The experiments also generated data that were used in validating the numerical studies for the baseline cases (without plasma actuators). The experiments were conducted in a Mach 1.5 test section in the University of Notre Dame Hessert Laboratory. The simulation results from cases a and b indicated that multiple spanwise actuators in series and at a voltage of 75 kVp-p could fully suppress the flow separation downstream of the shock. The simulation results from case c showed that the streamwise plasma actuators are highly effective in creating pairs of counter-rotating vortices, much like the mechanical vortex generators, and could also potentially have beneficial effects for SBLI control. However, to achieve these effects, the positioning and the quantity of the DBD actuators used must be optimized. The wind tunnel experiments mapped the baseline flow with good agreement to the numerical simulations. The experimental results were conducted with spanwise actuators for cases a and b, but were limited by the inability to generate a sufficiently high voltage due to arcing in the wind-tunnel test-section. The static pressure in the tunnel was lower than the static pressure in an inlet at flight conditions, promoting arching and degrading the actuator performance

Fifty-kDa Hyaluronic Acid Upregulates Some Epidermal Genes without Changing TNF-α Expression in Reconstituted Epidermis

Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. Methods: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-alpha expression was determined using quantitative PCR. Genonnic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. Results: LMW HA of approximately 50 kDa did not significantly alter tumor necrosis factor-alpha expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. Conclusion: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology. Copyright (C) 2011 S. Karger AG, Base

ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland

The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine

Experimental GHZ Entanglement beyond Qubits

The Greenberger-Horne-Zeilinger (GHZ) argument provides an all-or-nothing contradiction between quantum mechanics and local-realistic theories. In its original formulation, GHZ investigated three and four particles entangled in two dimensions only. Very recently, higher dimensional contradictions especially in three dimensions and three particles have been discovered but it has remained unclear how to produce such states. In this article we experimentally show how to generate a three-dimensional GHZ state from two-photon orbital-angular-momentum entanglement. The first suggestion for a setup which generates three-dimensional GHZ entanglement from these entangled pairs came from using the computer algorithm Melvin. The procedure employs novel concepts significantly beyond the qubit case. Our experiment opens up the possibility of a truly high-dimensional test of the GHZ-contradiction which, interestingly, employs non-Hermitian operators.Comment: 6+6 pages, 8 figure

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooq

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.IHD was supported by the Raymond and Beverly Sackler Foundation via the University of Cambridge MB/PhD programme; RKS, IB, DBS, and SO were supported by the Wellcome Trust (grants WT098498, WT098051, WT107064, and WT095515, respectively and Strategic Award 100574/Z/12/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The work was also supported by the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement number 115372. UK10K was funded by the Wellcome Trust under award WT091310.This is the final version of the article. It first appeared from the American Society for Clinical Investigation via https://doi.org/10.1172/jci.insight.8876

Extraction of User Navigation Pattern Based on Particle Swarm Optimization

With current projections regarding the growth of Internet sales, online retailing raises many questions about how to market on the Net. A Recommender System (RS) is a composition of software tools that provides valuable piece of advice for items or services chosen by a user. Recommender systems are currently useful in both the research and in the commercial areas. Recommender systems are a means of personalizing a site and a solution to the customer?s information overload problem. Recommender Systems (RS) are software tools and techniques providing suggestions for items and/or services to be of use to a user. These systems are achieving widespread success in e-commerce applications nowadays, with the advent of internet. This paper presents a categorical review of the field of recommender systems and describes the state-of-the-art of the recommendation methods that are usually classified into four categories: Content based Collaborative, Demographic and Hybrid systems. To build our recommender system we will use fuzzy logic and Markov chain algorithm