Patient‐Specific Analysis of Neural Activation During Spinal Cord Stimulation for Pain

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156183/2/ner13037_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156183/1/ner13037.pd

Activation of the central nervous system induced by micro-magnetic stimulation

Electrical and transcranial magnetic stimulation have proven to be therapeutically beneficial for patients suffering from neurological disorders. Moreover, these stimulation technologies have provided invaluable tools for investigating nervous system functions. Despite this success, these technologies have technical and practical limitations impeding the maximization of their full clinical and preclinical potential. Recently, micro-magnetic stimulation, which may offer advantages over electrical and transcranial magnetic stimulation, has proven effective in activating the neuronal circuitry of the retina in vitro. Here we demonstrate that this technology is also capable of activating neuronal circuitry on a systems level using an in vivo preparation. Specifically, the application of micro-magnetic fields to the dorsal cochlear nucleus activates inferior colliculus neurons. Additionally, we demonstrate the efficacy and characteristics of activation using different magnetic stimulation parameters. These findings provide a rationale for further exploration of micro-magnetic stimulation as a prospective tool for clinical and preclinical applications

Laparoendoscopic single-site (LESS) sacrocolpopexy: feasibility and efficacy of knotless procedure performed with conventional instruments

The aim of this paper was to report a case of a patient with stage IV vaginal vault prolapse treated by laparoendoscopic single-site (LESS) sacrocolpopexy using an Alexis retractor and a surgical glove attached to three trocars through a 3.5-cm umbilical incision. Only conventional laparoscopic instruments were used for intrabdominal dissection of vagina and peritoneum. The mesh was fixed to the vaginal fornix and to the sacral periosteum from the promontory using running sutures hold in the extremities by polymer clips. The posterior peritoneum was closed over the mesh. LESS sacrocolpopexy performed with conventional instruments is a difficult but feasible and efficient technique to treat vaginal vault prolapse that respects the principles of conventional laparoscopic or open repairs. Alexis retractor associated with knotless sutures are technical options that simplify LESS reconstructive surgical maneuvers

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: an inter-hemispheric inhibition study

Objective: A recent “bimodal-balance recovery” model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. Methods: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5 week-rehabilitation (n=21). Results: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM=43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM=43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n=14), more-impaired patients showed further IHI reduction. Conclusions: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. Significance: The criterion may be used to stratify patients to design targeted, precision treatments

Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies

Background: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. Methods: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. Results: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. Conclusions: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.BSF is supported by a postdoctoral scholarship and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0, both from CNPq, Brazil. CAK is a recipient of a postdoctoral fellowship from CAPES, Brazil. JCS is supported by NIMH grant R01 085667, the Dunn Foundation and the JQ are supported by research fellowship awards from CNPq (Brazil, level IA). AFC is the recipient of a research fellowship from CNPq (Brazil, level II). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. None of these agencies had any role in the design and conduct of the study, or decision to submit the manuscript for publication. We thank all authors of the included papers, particularly Drs. Natalie L. Rasgon, Deniz Ceylan, Camilla Langan, Pedro Magalhaes, Antonio L. Teixeira, Yuan-Hwa Chou, Iria Grande, Chenyu Ye, Izabela Barbosa, Menan Rabie, Ru-Band Lu, Ana Gonzales-Pinto, Reiji Yoshimura, Flavio Kapczinski, and Christoph Laske, who kindly provided unpublished data for the paper

Intradural Spinal Cord Stimulation: Performance Modeling of a New Modality

Introduction: Intradural spinal cord stimulation (SCS) may offer significant therapeutic benefits for those with intractable axial and extremity pain, visceral pain, spasticity, autonomic dysfunction and related disorders. A novel intradural electrical stimulation device, limited by the boundaries of the thecal sac, CSF and spinal cord was developed to test this hypothesis. In order to optimize device function, we have explored finite element modeling (FEM).Methods: COMSOL®Multiphysics Electrical Currents was used to solve for fields and currents over a geometric model of a spinal cord segment. Cathodic and anodic currents are applied to the center and tips of the T-cross component of the electrode array to shape the stimulation field and constrain charge-balanced cathodic pulses to the target area.Results: Currents from the electrode sites can move the effective stimulation zone horizontally across the cord by a linear step method, which can be diversified considerably to gain greater depth of penetration relative to standard epidural SCS. It is also possible to prevent spread of the target area with no off-target action potential.Conclusion: Finite element modeling of a T-shaped intradural spinal cord stimulator predicts significant gains in field depth and current shaping that are beyond the reach of epidural stimulators. Future studies with in vivo models will investigate how this approach should first be tested in humans

Data standardization of plant–pollinator interactions

Background: Animal pollination is an important ecosystem function and service, ensuring both the integrity of natural systems and human well-being. Although many knowledge shortfalls remain, some high-quality data sets on biological interactions are now available. The development and adoption of standards for biodiversity data and metadata has promoted great advances in biological data sharing and aggregation, supporting large-scale studies and science-based public policies. However, these standards are currently not suitable to fully support interaction data sharing. Results: Here we present a vocabulary of terms and a data model for sharing plant–pollinator interactions data based on the Darwin Core standard. The vocabulary introduces 48 new terms targeting several aspects of plant–pollinator interactions and can be used to capture information from different approaches and scales. Additionally, we provide solutions for data serialization using RDF, XML, and DwC-Archives and recommendations of existing controlled vocabularies for some of the terms. Our contribution supports open access to standardized data on plant–pollinator interactions. Conclusions: The adoption of the vocabulary would facilitate data sharing to support studies ranging from the spatial and temporal distribution of interactions to the taxonomic, phenological, functional, and phylogenetic aspects of plant–pollinator interactions. We expect to fill data and knowledge gaps, thus further enabling scientific research on the ecology and evolution of plant–pollinator communities, biodiversity conservation, ecosystem services, and the development of public policies. The proposed data model is flexible and can be adapted for sharing other types of interactions data by developing discipline-specific vocabularies of termsinfo:eu-repo/semantics/publishedVersio

IL28B polymorphisms are markers of therapy response and are influenced by genetic ancestry in chronic hepatitis C patients from an admixed population

Background: IL28B polymorphisms are predictors of therapy response in hepatitis C virus (HCV) patients. We do not know whether they are markers of treatment response in admixed populations or not. Aims: To determine whether IL28B polymorphisms are predictors of therapy response in patients with HCV from an admixed population and are influenced by genetic ancestry. Methods: rs12979860 and rs8099917 were genotyped in 222 HCV patients treated with pegylated interferon and ribavirin. Ancestry was determined using genetic markers. Results: IL28B rs12979860 C/C was associated with sustained virological response (SVR), whereas C/T and T/T were associated with failure to therapy (P = 1.12 x 10(-5)). IL28B rs8099917 T/T was associated with SVR, and G/G and G/T were associated with nonresponse/ relapse (NR/R) (P = 8.00 x 10(-3)). Among HCV genotype 1 patients with C/C genotype, genomic ancestry did not interfere with therapy response. Among patients with rs12979860 T/T genotype, African genetic contribution was greater in the NR/R group (P = 1.51 x 10(-3)), whereas Amerindian and European genetic ancestry contribution were higher in the SVR group (P = 3.77 x 10(-3) and P = 2.16 x 10(-2) respectively). Among HCV type 1 patients with rs8099917 T/T, African genetic contribution was significantly greater in the NR/R group (P = 5.0 x 10(-3)); Amerindian and European ancestry genetic contribution were greater in the SVR group. Conclusion: IL28B rs12979860 and rs8099917 polymorphisms were predictors of therapy response in HCV genotypes 1, 2 and 3 subjects from an admixed population. Genomic ancestry did not interfere with response to therapy in patients with rs12979860 C/C, whereas it interfered in patients with C/T and T/T genotypes. Among HCV genotype 1 rs8099917 T/T patients, genomic ancestry interfered with response to therapy.Fapesb [SUS0001/2011]Fapesp [10/10.549-1

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease