Modeling the Measurements of Cochlear Microcirculation and Hearing Function after Loud Noise

Objective: Recent findings support the crucial role of microcirculatory disturbance and ischemia for hearing impairment especially after noise-induced hearing loss (NIHL). The aim of this study was to establish an animal model for in vivo analysis of cochlear microcirculation and hearing function after a loud noise to allow precise measurements of both parameters in vivo. Study Design: Randomized controlled trial. Setting: Animal study. Subjects and Methods: After assessment of normacusis (0 minutes) using evoked auditory brainstem responses (ABRs), noise (106-dB sound pressure level [SPL]) was applied to both ears in 6 guinea pigs for 30 minutes while unexposed animals served as controls. In vivo fluorescence microscopy of the stria vascularis capillaries was performed after surgical exposure of 1 cochlea. ABR measurements were derived from the contralateral ear. Results: After noise exposure, red blood cell velocity was reduced significantly by 24.3% (120 minutes) and further decreased to 44.5% at the end of the observation (210 minutes) in contrast to stable control measurements. Vessel diameters were not affected in both groups. A gradual decrease of segmental blood flow became significant (38.1%) after 150 minutes compared with controls. Hearing thresholds shifted significantly from 20.0 ± 5.5 dB SPL (0 minutes) to 32.5 ± 4.2dB SPL (60 minutes) only in animals exposed to loud noise. Conclusion: With regard to novel treatments targeting the stria vascularis in NIHL, this standardized model allows us to analyze in detail cochlear microcirculation and hearing function in vivo

Decorrelation and efficient coding by retinal ganglion cells

An influential theory of visual processing asserts that retinal center-surround receptive fields remove spatial correlations in the visual world, producing ganglion cell spike trains that are less redundant than the corresponding image pixels. For bright, high-contrast images, this decorrelation would enhance coding efficiency in optic nerve fibers of limited capacity. We tested the central prediction of the theory and found that the spike trains of retinal ganglion cells were indeed decorrelated compared with the visual input. However, most of the decorrelation was accomplished not by the receptive fields, but by nonlinear processing in the retina. We found that a steep response threshold enhanced efficient coding by noisy spike trains and that the effect of this nonlinearity was near optimal in both salamander and macaque retina. These results offer an explanation for the sparseness of retinal spike trains and highlight the importance of treating the full nonlinear character of neural codes

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms

Simultaneous bilateral total ankle replacement using a 3-component prosthesis: Outcome in 26 patients followed for 2–10 years

Total ankle replacement is an established surgical procedure in patients with end-stage ankle osteoarthritis. We analyzed complications and medium-term results in patients with simultaneous bilateral total ankle replacement

Action observation can prime visual object recognition

Observing an action activates action representations in the motor system. Moreover, the representations of manipulable objects are closely linked to the motor systems at a functional and neuroanatomical level. Here, we investigated whether action observation can facilitate object recognition using an action priming paradigm. As prime stimuli we presented short video movies showing hands performing an action in interaction with an object (where the object itself was always removed from the video). The prime movie was followed by a (briefly presented) target object affording motor interactions that are either similar (congruent condition) or dissimilar (incongruent condition) to the prime action. Participants had to decide whether an object name shown after the target picture corresponds with the picture or not (picture–word matching task). We found superior accuracy for prime–target pairs with congruent as compared to incongruent actions across two experiments. Thus, action observation can facilitate recognition of a manipulable object typically involving a similar action. This action priming effect supports the notion that action representations play a functional role in object recognition

The Conley Conjecture and Beyond

This is (mainly) a survey of recent results on the problem of the existence of infinitely many periodic orbits for Hamiltonian diffeomorphisms and Reeb flows. We focus on the Conley conjecture, proved for a broad class of closed symplectic manifolds, asserting that under some natural conditions on the manifold every Hamiltonian diffeomorphism has infinitely many (simple) periodic orbits. We discuss in detail the established cases of the conjecture and related results including an analog of the conjecture for Reeb flows, the cases where the conjecture is known to fail, the question of the generic existence of infinitely many periodic orbits, and local geometrical conditions that force the existence of infinitely many periodic orbits. We also show how a recently established variant of the Conley conjecture for Reeb flows can be applied to prove the existence of infinitely many periodic orbits of a low-energy charge in a non-vanishing magnetic field on a surface other than a sphere.Comment: 34 pages, 1 figur

Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Aβ42 reduces their differentiation potential

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several β-amyloid peptides (Aβ) are generated. In contrast to the form with 40 amino acids (Aβ₄₀), the variant with 42 amino acids (Aβ₄₂) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Aβ effects have been studied extensively, little is known about specific genome-wide effects triggered by Aβ₄₂or Aβ₄₀derived from their direct precursor C99.</p> <p>Methods</p> <p>A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Aβ peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference.</p> <p>Results</p> <p>Here we studied the transcriptomic and proteomic responses to increased or decreased Aβ₄₂and Aβ₄₀levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Aβ₄₂- and Aβ₄₀-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Aβ₄₂/Aβ₄₀ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Aβ₄₂/Aβ₄₀ratio, whereas a decreased ratio did not result in up-regulation of CRABP1.</p> <p>Conclusion</p> <p>We conclude that increasing the Aβ₄₂/Aβ₄₀ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.</p

Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study

<p>Abstract</p> <p>Background</p> <p>Cerebral malaria (CM) is associated with high mortality and morbidity caused by a high rate of transient or persistent neurological sequelae. Studies on immunomodulatory and neuroprotective drugs as ancillary treatment in murine CM indicate promising potential. The current study was conducted to evaluate the efficacy of glatiramer acetate (GA), an immunomodulatory drug approved for the treatment of relapsing remitting multiple sclerosis, in preventing the death of C57Bl/6J mice infected with <it>Plasmodium berghei </it>ANKA.</p> <p>Methods and Results</p> <p>GA treatment led to a statistically significant lower risk for developing CM (57.7% versus 84.6%) in treated animals. The drug had no effect on the course of parasitaemia. The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals. No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.</p> <p>Conclusion</p> <p>These findings support the important role of the host immune response in the pathophysiology of murine CM and might lead to the development of new adjunctive treatment strategies.</p

Effects of insurance status on children's access to specialty care: a systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>The current climate of rising health care costs has led many health insurance programs to limit benefits, which may be problematic for children needing specialty care. Findings from pediatric primary care may not transfer to pediatric specialty care because pediatric specialists are often located in academic medical centers where institutional rules determine accepted insurance. Furthermore, coverage for pediatric specialty care may vary more widely due to systematic differences in inclusion on preferred provider lists, lack of availability in staff model HMOs, and requirements for referral. Our objective was to review the literature on the effects of insurance status on children's access to specialty care.</p> <p>Methods</p> <p>We conducted a systematic review of original research published between January 1, 1992 and July 31, 2006. Searches were performed using Pubmed.</p> <p>Results</p> <p>Of 30 articles identified, the majority use number of specialty visits or referrals to measure access. Uninsured children have poorer access to specialty care than insured children. Children with public coverage have better access to specialty care than uninsured children, but poorer access compared to privately insured children. Findings on the effects of managed care are mixed.</p> <p>Conclusion</p> <p>Insurance coverage is clearly an important factor in children's access to specialty care. However, we cannot determine the structure of insurance that leads to the best use of appropriate, quality care by children. Research about specific characteristics of health plans and effects on health outcomes is needed to determine a structure of insurance coverage that provides optimal access to specialty care for children.</p

Direct Visualization of Protease Action on Collagen Triple Helical Structure

Enzymatic processing of extracellular matrix (ECM) macromolecules by matrix metalloproteases (MMPs) is crucial in mediating physiological and pathological cell processes. However, the molecular mechanisms leading to effective physiological enzyme-ECM interactions remain elusive. Only scant information is available on the mode by which matrix proteases degrade ECM substrates. An example is the enzymatic degradation of triple helical collagen II fragments, generated by the collagenase MMP-8 cleavage, during the course of acute inflammatory conditions by gelatinase B/MMP-9. As is the case for many other matrix proteases, it is not clear how MMP-9 recognizes, binds and digests collagen in this important physiological process. We used single molecule imaging to directly visualize this protease during its interaction with collagen fragments. We show that the initial binding is mediated by the diffusion of the protease along the ordered helix on the collagen ¾ fragment, with preferential binding of the collagen tail. As the reaction progressed and prior to collagen degradation, gelatin-like morphologies resulting from the denaturation of the triple helical collagen were observed. Remarkably, this activity was independent of enzyme proteolysis and was accompanied by significant conformational changes of the working protease. Here we provide the first direct visualization of highly complex mechanisms of macromolecular interactions governing the enzymatic processing of ECM substrates by physiological protease