Identification of flow structures in fully developed canonical and wavy channels by means of modal decomposition techniques

NASA Astrophysics Data System (ADS)

Ghebali, Sacha; Garicano-Mena, Jesús; Ferrer, Esteban; Valero, Eusebio

2018-04-01

A Dynamic Mode Decomposition (DMD) of Direct Numerical Simulations (DNS) of fully developed channel flows is undertaken in order to study the main differences in flow features between a plane-channel flow and a passively “controlled” flow wherein the mean friction was reduced relative to the baseline by modifying the geometry in order to generate a streamwise-periodic spanwise pressure gradient, as is the case for an oblique wavy wall. The present analysis reports POD and DMD modes for the plane channel, jointly with the application of a sparsity-promoting method, as well as a reconstruction of the Reynolds shear stress with the dynamic modes. Additionally, a dynamic link between the streamwise velocity fluctuations and the friction on the wall is sought by means of a composite approach both in the plane and wavy cases. One of the DMD modes associated with the wavy-wall friction exhibits a meandering motion which was hardly identifiable on the instantaneous friction fluctuations.

Delayed-onset descemet membrane detachment after uneventful cataract surgery treated by corneal venting incision with air tamponade: a case report.

PubMed

Bhatia, Harsimran Kaur; Gupta, Rakesh

2016-04-04

Descemet membrane detachment (DMD) is a significant complication noted during or early after cataract surgery. Review of literature revealed a few cases of delayed-onset DMD with presentation ranging from weeks to months after cataract surgery but most of them were treated with pneumatic descemetopexy and a few ended in penetrating keratoplasty. We report this case, to highlight the usefulness of corneal venting incision with air tamponade in late-onset DMD cases not responding to pneumatic descemetopexy. A retrospective case review of a 66 year old male who presented with diminution of vision in right eye 17 days after uneventful cataract surgery was done. Visual acuity in this eye was 20/200 at presentation. DMD was noted 3 days later (approximately 3 weeks post-operatively) and Anterior Segment Optical Coherence Tomography & Scheimpflug imaging were done in view of diffuse corneal edema. Pneumatic descemetopexy was attempted thrice (twice with SF6, once with air) over a week's span with limited success at re-attaching the DM. Finally, corneal venting incision with air tamponade was done resulting in egress of supra-descemet's fluid and DM appeared apposed to stroma. Bandage contact lens (BCL) was applied at the end of the procedure. DM was seen attached the next day. Corneal edema cleared completely in 1 week. Best corrected visual acuity (BCVA) at 6 weeks follow-up was 20/30. Delayed-onset DMD should be considered as a differential diagnosis in cases with late-onset corneal edema post-cataract surgery. Anterior segment Optical Coherence Tomography (AS-OCT) and Scheimpflug Imaging are useful tools in cases with dense corneal edema. Corneal venting incision with air tamponade is an option in cases where methods like pneumatic descemetopexy fail.

Profile of cognitive function in adults with duchenne muscular dystrophy.

PubMed

Ueda, Yukihiko; Suwazono, Shugo; Maedo, Sino; Higuchi, Itsuro

2017-03-01

Several studies have examined intellectual functioning of boys with duchenne muscular dystrophy (DMD). However, little is known about the remaining cognitive weaknesses in adults with DMD. The purpose of this study was to investigate the profile of cognitive functioning that is characteristics of adults with DMD. Twenty-four subscales from the Wechsler Adult Intelligence Scale III (WAIS-III), the Clinical Assessment for Attention (CAT), and the Wechsler Memory Scale Revised (WMS-R) were used to assess participants with DMD (N=15; mean age=30.4years). Scores for Picture Completion, Arithmetic, Matrix Reasoning, Symbol Search, Letter-Number Sequencing, and Digit Span of the WAIS-III; all CAT scores, and Logical Memory and Delayed Logical Memory from the WMS-R were significantly deficient in adults with DMD in comparison to the normal population. The ability to sequentially process auditory and visual information remains impaired in adults with DMD. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Dynamic Data-Driven Reduced-Order Models of Macroscale Quantities for the Prediction of Equilibrium System State for Multiphase Porous Medium Systems

NASA Astrophysics Data System (ADS)

Talbot, C.; McClure, J. E.; Armstrong, R. T.; Mostaghimi, P.; Hu, Y.; Miller, C. T.

2017-12-01

Microscale simulation of multiphase flow in realistic, highly-resolved porous medium systems of a sufficient size to support macroscale evaluation is computationally demanding. Such approaches can, however, reveal the dynamic, steady, and equilibrium states of a system. We evaluate methods to utilize dynamic data to reduce the cost associated with modeling a steady or equilibrium state. We construct data-driven models using extensions to dynamic mode decomposition (DMD) and its connections to Koopman Operator Theory. DMD and its variants comprise a class of equation-free methods for dimensionality reduction of time-dependent nonlinear dynamical systems. DMD furnishes an explicit reduced representation of system states in terms of spatiotemporally varying modes with time-dependent oscillation frequencies and amplitudes. We use DMD to predict the steady and equilibrium macroscale state of a realistic two-fluid porous medium system imaged using micro-computed tomography (µCT) and simulated using the lattice Boltzmann method (LBM). We apply Koopman DMD to direct numerical simulation data resulting from simulations of multiphase fluid flow through a 1440x1440x4320 section of a full 1600x1600x5280 realization of imaged sandstone. We determine a representative set of system observables via dimensionality reduction techniques including linear and kernel principal component analysis. We demonstrate how this subset of macroscale quantities furnishes a representation of the time-evolution of the system in terms of dynamic modes, and discuss the selection of a subset of DMD modes yielding the optimal reduced model, as well as the time-dependence of the error in the predicted equilibrium value of each macroscale quantity. Finally, we describe how the above procedure, modified to incorporate methods from compressed sensing and random projection techniques, may be used in an online fashion to facilitate adaptive time-stepping and parsimonious storage of system states over time.

Shaping Laguerre-Gaussian laser modes with binary gratings using a digital micromirror device.

PubMed

Lerner, Vitaly; Shwa, David; Drori, Yehonathan; Katz, Nadav

2012-12-01

Laguerre-Gaussian (LG) beams are used in many research fields, including microscopy, laser cavity modes, and optical tweezing. We developed a holographic method to generate pure LG modes (amplitude and phase) with a binary amplitude-only digital micromirror device (DMD) as an alternative to the commonly used phase-only spatial light modulator. The advantages of such a DMD include very high frame rates, low cost, and high damage thresholds. We have shown that the propagating shaped beams are self-similar and their phase fronts are of helical shape as demanded. We estimate the purity of the resultant beams to be above 94%.

Fast parallel 3D profilometer with DMD technology

NASA Astrophysics Data System (ADS)

Hou, Wenmei; Zhang, Yunbo

2011-12-01

Confocal microscope has been a powerful tool for three-dimensional profile analysis. Single mode confocal microscope is limited by scanning speed. This paper presents a 3D profilometer prototype of parallel confocal microscope based on DMD (Digital Micromirror Device). In this system the DMD takes the place of Nipkow Disk which is a classical parallel scanning scheme to realize parallel lateral scanning technique. Operated with certain pattern, the DMD generates a virtual pinholes array which separates the light into multi-beams. The key parameters that affect the measurement (pinhole size and the lateral scanning distance) can be configured conveniently by different patterns sent to DMD chip. To avoid disturbance between two virtual pinholes working at the same time, a scanning strategy is adopted. Depth response curve both axial and abaxial were extract. Measurement experiments have been carried out on silicon structured sample, and axial resolution of 55nm is achieved.

Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications

PubMed Central

Aartsma-Rus, Annemieke; van Ommen, Gert-Jan B.

2007-01-01

Antisense-mediated modulation of splicing is one of the few fields where antisense oligonucleotides (AONs) have been able to live up to their expectations. In this approach, AONs are implemented to restore cryptic splicing, to change levels of alternatively spliced genes, or, in case of Duchenne muscular dystrophy (DMD), to skip an exon in order to restore a disrupted reading frame. The latter allows the generation of internally deleted, but largely functional, dystrophin proteins and would convert a severe DMD into a milder Becker muscular dystrophy phenotype. In fact, exon skipping is currently one of the most promising therapeutic tools for DMD, and a successful first-in-man trial has recently been completed. In this review the applicability of exon skipping for DMD and other diseases is described. For DMD AONs have been designed for numerous exons, which has given us insight into their mode of action, splicing in general, and splicing of the DMD gene in particular. In addition, retrospective analysis resulted in guidelines for AON design for DMD and most likely other genes as well. This knowledge allows us to optimize therapeutic exon skipping, but also opens up a range of other applications for the exon skipping approach. PMID:17684229

Ultra-high enhancement of light focusing through disordered media controlled by mega-pixel modes (Conference Presentation)

NASA Astrophysics Data System (ADS)

Yu, Hyeonseung; Lee, KyeoReh; Park, YongKeun

2017-02-01

Developing an efficient strategy for light focusing through scattering media is an important topic in the study of multiple light scattering. The enhancement factor of the light focusing, defined as the ratio between the optimized intensity and the background intensity is proportional to the number of controlling modes in a spatial light modulator (SLM). The demonstrated enhancement factors in previous studies are typically less than 1,000 due to several limiting factors, such as the slow refresh rate of a LCoS SLM, long optimization time, and lack of an efficient algorithm for high controlling modes. A digital micro-mirror device is an amplitude modulator, which is recently widely used for fast optimization through dynamic biological tissues. The fast frame rate of the DMD up to 16 kHz can also be exploited for increasing the number of controlling modes. However, the manipulation of large pattern data and efficient calculation of the optimized pattern remained as an issue. In this work, we demonstrate the enhancement factor more than 100,000 in focusing through scattering media by using 1 Mega controlling modes of a DMD. Through careful synchronization between a DMD, a photo-detector and an additional computer for parallel optimization, we achieved the unprecedented enhancement factor with 75 mins of the optimization time. We discuss the design principles of the system and the possible applications of the enhanced light focusing.

An electrochemically-driven dual-mode display device with both reflective and emissive modes using poly(p-phenylenevinylene) derivatives

NASA Astrophysics Data System (ADS)

Tsuneyasu, Shota; Jin, Lu; Nakamura, Kazuki; Kobayashi, Norihisa

2016-04-01

We demonstrate a novel electrochemical dual-mode displaying (DMD) device, which enables control of both coloration and light emission using an electrochemical reaction. The coloration control of the DMD device was based on an electrochromic (EC) reaction, whereas the light emission of the device was caused by an electrochemiluminescence (ECL) mechanism. This novel DMD device consisted of a pair of facing conductive polymer-modified electrodes: comb-shaped interdigitated Au electrodes modified with poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) layers and poly(2,3-dihydrothieno-1,4-dioxin)-poly(styrene sulfonate) (PEDOT/PSS) film-modified indium tin oxide (ITO) electrodes. When a bias voltage was applied between the PEDOT/PSS film-modified ITO electrode and the comb-shaped electrodes, a color change of the device was observed by the EC reaction of the MEH-PPV and PEDOT/PSS. On the other hand, an emission was obtained when the bias voltage was applied between two comb-shaped interdigitated electrodes. The orange emission was ascribed to the ECL reaction of the MEH-PPV layer, which resulted from the formation of a p-i-n junction in this layer.

A MEMS and agile optics-based dual-mode variable optical power splitter with no moving parts

NASA Astrophysics Data System (ADS)

Khwaja, Tariq S.; Suleman, Hamid; Reza, Syed Azer

2017-06-01

In this paper, we present a novel design of an optical power splitter. Owing to the inherent variable power split ratios that the proposed design delivers, it is ideal for use in communications, sensing and signal processing applications where variable power splitting is often quintessential. The proposed power splitter module is dual mode as it combines the use of a Micro-Electro-Mechanical Systems (MEMS) based Digital Micro-mirror Device (DMD) and an Electronically Controlled Tunable Lens (ECTL) to split the power of an input optical signal between two output ports - the designated port and the surplus port. The use of a reflective Digital Spatial Light Modulator (DSLM) such as the DMD provides a motion-free digital control of the split ratio between the two output ports. Although the digital step between two possible successive split ratios can be fairly minimal with the use of a high resolution DMD but it is a challenge to correctly ascertain the exact image pattern on the DMD to obtain any desired specific split ratio. To counter this challenge, we propose the synchronized use of a circular pattern on the DMD, which serves as a circular clear aperture with a tunable radius, and an ECTL. The radius of the circular pattern on the DMD provides a digital control of the split ratio between the two ports whereas the ECTL, depending on its controller, can provide either an analog or a digital control by altering the beam radius which is incident at the DMD circular pattern. The radius of the circular pattern on the DMD can be minimally changed by one micro-pixel thickness. Setting the radius of the circular pattern on the DMD to an appropriate value provides the closest "ball-park" split ratio whereas further tuning the ECTL aids in slightly altering from this digitally set value to obtain the exact desired split ratio in-between any two digitally-set successive split ratios that correspond to any clear aperture radius of the DMD pattern and its incremental minimal allowable change of one micropixel. We provide a detailed scheme to calculate the desired DMD aperture radius as well as the focal length setting of the ECTL to obtain any given split ratio. By setting tolerance limits on the split ratio, we also show that our method affords diversity by providing multiple possible solutions to achieve a desired optical power split ratio within the specified tolerances. We also demonstrate the validation of the proposed concept with initial experimental results and discussions. These experimental results show a repeatable splitter operation and the resulting power split ratios according to the theoretical predictions. With the experimental data, we also demonstrate the effectiveness of the method in obtaining any particular split ratio through different DMD and ECTL configurations with specific split ratio tolerance values.

On the need of mode interpolation for data-driven Galerkin models of a transient flow around a sphere

NASA Astrophysics Data System (ADS)

Stankiewicz, Witold; Morzyński, Marek; Kotecki, Krzysztof; Noack, Bernd R.

2017-04-01

We present a low-dimensional Galerkin model with state-dependent modes capturing linear and nonlinear dynamics. Departure point is a direct numerical simulation of the three-dimensional incompressible flow around a sphere at Reynolds numbers 400. This solution starts near the unstable steady Navier-Stokes solution and converges to a periodic limit cycle. The investigated Galerkin models are based on the dynamic mode decomposition (DMD) and derive the dynamical system from first principles, the Navier-Stokes equations. A DMD model with training data from the initial linear transient fails to predict the limit cycle. Conversely, a model from limit-cycle data underpredicts the initial growth rate roughly by a factor 5. Key enablers for uniform accuracy throughout the transient are a continuous mode interpolation between both oscillatory fluctuations and the addition of a shift mode. This interpolated model is shown to capture both the transient growth of the oscillation and the limit cycle.

Dual-mode optical microscope based on single-pixel imaging

NASA Astrophysics Data System (ADS)

Rodríguez, A. D.; Clemente, P.; Tajahuerce, E.; Lancis, J.

2016-07-01

We demonstrate an inverted microscope that can image specimens in both reflection and transmission modes simultaneously with a single light source. The microscope utilizes a digital micromirror device (DMD) for patterned illumination altogether with two single-pixel photosensors for efficient light detection. The system, a scan-less device with no moving parts, works by sequential projection of a set of binary intensity patterns onto the sample that are codified onto a modified commercial DMD. Data to be displayed are geometrically transformed before written into a memory cell to cancel optical artifacts coming from the diamond-like shaped structure of the micromirror array. The 24-bit color depth of the display is fully exploited to increase the frame rate by a factor of 24, which makes the technique practicable for real samples. Our commercial DMD-based LED-illumination is cost effective and can be easily coupled as an add-on module for already existing inverted microscopes. The reflection and transmission information provided by our dual microscope complement each other and can be useful for imaging non-uniform samples and to prevent self-shadowing effects.

Diagnosis of Duchenne Muscular Dystrophy in Italy in the last decade: Critical issues and areas for improvements.

PubMed

D'Amico, Adele; Catteruccia, Michela; Baranello, Giovanni; Politano, Luisa; Govoni, Alessandra; Previtali, Stefano Carlo; Pane, Marika; D'Angelo, Maria Grazia; Bruno, Claudio; Messina, Sonia; Ricci, Federica; Pegoraro, Elena; Pini, Antonella; Berardinelli, Angela; Gorni, Ksenjia; Battini, Roberta; Vita, Gianluca; Trucco, Federica; Scutifero, Marianna; Petillo, Roberta; D'Ambrosio, Paola; Ardissone, Anna; Pasanisi, Barbara; Vita, Giuseppe; Mongini, Tiziana; Moggio, Maurizio; Comi, Giacomo Pietro; Mercuri, Eugenio; Bertini, Enrico

2017-05-01

Despite all the advances in diagnosis and management of Duchenne muscular dystrophy over the past 50 years, the average age at diagnosis in most countries in the world around is still around 4-5 years. This retrospective study investigates the age at diagnosis in Italy in the past 10 years. We report findings from 384 boys who were diagnosed with DMD from 2005 to 2014. The mean age at first medical contact, which raised the suspicion of DMD, was 31 months. The mean age at diagnosis was 41 months. The finding that more frequently brought to suspect a DMD was the incidental finding of consistent elevated creatine kinase serum level detected during routine assessments in children undergoing general anesthesia or with intercurrent illness. This was followed by motor delay and signs of muscle weakness. Initial concerns were raised by general pediatricians (29%), specialists at tertiary centers (35%) or first level hospitals (23%). In children presenting incidental elevated creatine kinase values the diagnosis was achieved earlier than in children presenting a developmental delay. The mean age at diagnosis in our cohort was about 10-12 months lower than that reported in other countries. Copyright © 2017 Elsevier B.V. All rights reserved.

Generation of cylindrically polarized vector vortex beams with digital micromirror device

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Lei; Liu, Weiwei; Wang, Meng

We propose a novel technique to directly transform a linearly polarized Gaussian beam into vector-vortex beams with various spatial patterns. Full high-quality control of amplitude and phase is implemented via a Digital Micro-mirror Device (DMD) binary holography for generating Laguerre-Gaussian, Bessel-Gaussian, and helical Mathieu–Gaussian modes, while a radial polarization converter (S-waveplate) is employed to effectively convert the optical vortices into cylindrically polarized vortex beams. Additionally, the generated vector-vortex beams maintain their polarization symmetry after arbitrary polarization manipulation. Due to the high frame rates of DMD, rapid switching among a series of vector modes carrying different orbital angular momenta paves themore » way for optical microscopy, trapping, and communication.« less

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frydman, M.; Straussberg, R.; Shomrat, R.

1995-09-11

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. {open_quotes}Idiopathic{close_quotes} hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggestmore » that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia. 13 refs., 3 figs., 1 tab.« less

Diagnosis of becker muscular dystrophy: Results of Re-analysis of DNA samples.

PubMed

Straathof, Chiara S M; Van Heusden, Dave; Ippel, Pieternella F; Post, Jan G; Voermans, Nicol C; De Visser, Marianne; Brusse, Esther; Van Den Bergen, Janneke C; Van Der Kooi, Anneke J; Verschuuren, Jan J G M; Ginjaar, Hendrika B

2016-01-01

The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995. All requests for DNA analysis of the DMD gene in probands with suspected BMD were re-evaluated. If the phenotype was compatible with BMD, and no deletions or duplications were detected, DNA samples were screened for small mutations. In 79 of 185 referrals, no mutation was found. Analysis could be performed on 31 DNA samples. Seven different mutations, including 3 novel ones, were found. Long-term clinical follow-up is described. Refining DNA analysis in previously undiagnosed cases can identify mutations in the DMD gene and provide genetic diagnosis of BMD. A delayed diagnosis can still be valuable for the proband or the relatives of BMD patients. © 2015 Wiley Periodicals, Inc.

Superpixel-based spatial amplitude and phase modulation using a digital micromirror device.

PubMed

Goorden, Sebastianus A; Bertolotti, Jacopo; Mosk, Allard P

2014-07-28

We present a superpixel method for full spatial phase and amplitude control of a light beam using a digital micromirror device (DMD) combined with a spatial filter. We combine square regions of nearby micromirrors into superpixels by low pass filtering in a Fourier plane of the DMD. At each superpixel we are able to independently modulate the phase and the amplitude of light, while retaining a high resolution and the very high speed of a DMD. The method achieves a measured fidelity F = 0.98 for a target field with fully independent phase and amplitude at a resolution of 8 × 8 pixels per diffraction limited spot. For the LG10 orbital angular momentum mode the calculated fidelity is F = 0.99993, using 768 × 768 DMD pixels. The superpixel method reduces the errors when compared to the state of the art Lee holography method for these test fields by 50% and 18%, with a comparable light efficiency of around 5%. Our control software is publicly available.

Bone health measured using quantitative ultrasonography in adult males with muscular dystrophy

PubMed Central

Morse, C.I.; Smith, J.; Denny, A.; Tweedale, J.; Searle, N.D.; Winwood, K.; Onambele-Pearson, G.L.

2016-01-01

Objectives: To compare muscle and bone health markers in adult males (aged 20-59 yrs) with and without muscular dystrophy (MD). Methods: Participants included 11 Fascioscapulohumeral (FSH), 11 Becker’s (Be), 9 limb girdle (LG), 11 Duchenne (DMD), and 14 non-dystrophic controls (CTRL). Physical activity was assessed using Bone (BPAQ) and disability specific (PASIPD) questionnaires. Bone QUS provided T- and Z scores from the Distal Radius (DR) and Mid-shaft tibia (MST). Tibialis anterior cross sectional area (TAACSA) was measured using B-mode ultrasound. Grip strength was measured in all but DMD. Results: Physical activity was lower in DMD, FSH and BeMD than CTRL (P<0.05), and lower in DMD than other MDs (P<0.01). T and Z scores were lower in DMD and Be than CTRL (DR, P<0.05); and lower in DMD than CTRL, LG, and FSH (MST, P<0.01). TAACSA and grip strength was 35-59% and 50-58% smaller in MD than CTRL, respectively (P<0.01). Within MD, BPAQ correlated with bone QUS measures (r=0.42-0.38, P<0.01). PASIPD correlated with grip strength (r=0.65, P<0.01) and TAACSA (r=0.46, P<0.01). Conclusion: Muscle size, strength, and bone health was lower in adult males with MD compared to adult males without MD, the extent of this is partially determined by physical activity. PMID:27973386

Bone health measured using quantitative ultrasonography in adult males with muscular dystrophy.

PubMed

Morse, C I; Smith, J; Denny, A; Tweedale, J; Searle, N D; Winwood, K; Onambele-Pearson, G L

2016-12-14

To compare muscle and bone health markers in adult males (aged 20-59 yrs) with and without muscular dystrophy (MD). Participants included 11 Fascioscapulohumeral (FSH), 11 Becker's (Be), 9 limb girdle (LG), 11 Duchenne (DMD), and 14 non-dystrophic controls (CTRL). Physical activity was assessed using Bone (BPAQ) and disability specific (PASIPD) questionnaires. Bone QUS provided T- and Z scores from the Distal Radius (DR) and Mid-shaft tibia (MST). Tibialis anterior cross sectional area (TA ACSA ) was measured using B-mode ultrasound. Grip strength was measured in all but DMD. Physical activity was lower in DMD, FSH and BeMD than CTRL (P<0.05), and lower in DMD than other MDs (P<0.01). T and Z scores were lower in DMD and Be than CTRL (DR, P<0.05); and lower in DMD than CTRL, LG, and FSH (MST, P<0.01). TA ACSA and grip strength was 35-59% and 50-58% smaller in MD than CTRL, respectively (P<0.01). Within MD, BPAQ correlated with bone QUS measures (r=0.42-0.38, P<0.01). PASIPD correlated with grip strength (r=0.65, P<0.01) and TA ACSA (r=0.46, P<0.01). Muscle size, strength, and bone health was lower in adult males with MD compared to adult males without MD, the extent of this is partially determined by physical activity.

Interrogating the viscoelastic properties of tissue using viscoelastic response (VISR) ultrasound

NASA Astrophysics Data System (ADS)

Selzo, Mallory Renee

Affecting approximately 1 in 3,500 newborn males, Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders in humans. Boys with DMD suffer progressive loss of muscle strength and function, leading to wheelchair dependence, cardiac and respiratory compromise, and death during young adulthood. There are currently no treatments that can halt or reverse the disease progression, and translating prospective treatments into clinical trials has been delayed by inadequate outcome measures. Current outcome measures, such as functional and muscle strength assessments, lack sensitivity to individual muscles, require subjective effort of the child, and are impacted by normal childhood growth and development. The goal of this research is to develop Viscoelastic Response (VisR) ultrasound which can be used to delineate compositional changes in muscle associated with DMD. In VisR, acoustic radiation force (ARF) is used to produce small, localized displacements within the muscle. Using conventional ultrasound to track the motion, the displacement response of the tissue can be evaluated against a mechanical model. In order to develop signal processing techniques and assess mechanical models, finite element method simulations are used to model the response of a viscoelastic material to ARF excitations. Results are then presented demonstrating VisR differentiation of viscoelastic changes with progressive dystrophic degeneration in a dog model of DMD. Finally, clinical feasibility of VisR imaging is demonstrated in two boys with DMD.

Design and Parametric Study of the Magnetic Sensor for Position Detection in Linear Motor Based on Nonlinear Parametric Model Order Reduction

PubMed Central

Paul, Sarbajit; Chang, Junghwan

2017-01-01

This paper presents a design approach for a magnetic sensor module to detect mover position using the proper orthogonal decomposition-dynamic mode decomposition (POD-DMD)-based nonlinear parametric model order reduction (PMOR). The parameterization of the sensor module is achieved by using the multipolar moment matching method. Several geometric variables of the sensor module are considered while developing the parametric study. The operation of the sensor module is based on the principle of the airgap flux density distribution detection by the Hall Effect IC. Therefore, the design objective is to achieve a peak flux density (PFD) greater than 0.1 T and total harmonic distortion (THD) less than 3%. To fulfill the constraint conditions, the specifications for the sensor module is achieved by using POD-DMD based reduced model. The POD-DMD based reduced model provides a platform to analyze the high number of design models very fast, with less computational burden. Finally, with the final specifications, the experimental prototype is designed and tested. Two different modes, 90° and 120° modes respectively are used to obtain the position information of the linear motor mover. The position information thus obtained are compared with that of the linear scale data, used as a reference signal. The position information obtained using the 120° mode has a standard deviation of 0.10 mm from the reference linear scale signal, whereas the 90° mode position signal shows a deviation of 0.23 mm from the reference. The deviation in the output arises due to the mechanical tolerances introduced into the specification during the manufacturing process. This provides a scope for coupling the reliability based design optimization in the design process as a future extension. PMID:28671580

Design and Parametric Study of the Magnetic Sensor for Position Detection in Linear Motor Based on Nonlinear Parametric model order reduction.

PubMed

Paul, Sarbajit; Chang, Junghwan

2017-07-01

This paper presents a design approach for a magnetic sensor module to detect mover position using the proper orthogonal decomposition-dynamic mode decomposition (POD-DMD)-based nonlinear parametric model order reduction (PMOR). The parameterization of the sensor module is achieved by using the multipolar moment matching method. Several geometric variables of the sensor module are considered while developing the parametric study. The operation of the sensor module is based on the principle of the airgap flux density distribution detection by the Hall Effect IC. Therefore, the design objective is to achieve a peak flux density (PFD) greater than 0.1 T and total harmonic distortion (THD) less than 3%. To fulfill the constraint conditions, the specifications for the sensor module is achieved by using POD-DMD based reduced model. The POD-DMD based reduced model provides a platform to analyze the high number of design models very fast, with less computational burden. Finally, with the final specifications, the experimental prototype is designed and tested. Two different modes, 90° and 120° modes respectively are used to obtain the position information of the linear motor mover. The position information thus obtained are compared with that of the linear scale data, used as a reference signal. The position information obtained using the 120° mode has a standard deviation of 0.10 mm from the reference linear scale signal, whereas the 90° mode position signal shows a deviation of 0.23 mm from the reference. The deviation in the output arises due to the mechanical tolerances introduced into the specification during the manufacturing process. This provides a scope for coupling the reliability based design optimization in the design process as a future extension.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

PubMed

Bosley, Thomas M; Salih, Mustafa A; Alkhalidi, Hisham; Oystreck, Darren T; El Khashab, Heba Y; Kondkar, Altaf A; Abu-Amero, Khaled K

2016-09-01

We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems. The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene. The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene. This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

Characterization of the low-frequency unsteadines in LES data of supersonic and hypersonic STBLI

NASA Astrophysics Data System (ADS)

Helm, Clara; Martin, Pino

2016-11-01

In a recent study, Priebe et al. (JFM 2016) used Dynamic Mode Decomposition (DMD) to analyze DNS data of a Mach 3 ramp-generated shock and turbulent boundary layer interaction (STBLI). The authors found that the reconstructed low-frequency DMD modes took on the form of Görtler-like vortices downstream of separation. The five reconstructed modes reproduced the low-frequency dynamics of the separation bubble accurately. Martín et al. (AIAA2016-3341) and Martín et al. (APS, DFD 2016) show that the low-frequency unsteadiness in STBLI results from an inviscid centrifugal instability similar to that found in separated subsonic and laminar flows, and that the turbulence is modulated but passive to the global mode. In this work we further characterize the Görtler-like vortices using LES data of Mach 3 and Mach 7 separated STBLIs. We find that the Görtler-like vortices are unsteady, and we quantify the wavelength, amplitude and the aperiodic development of these structures. This work is supported by the Air Force Office of Scientific Research under Grant AF9550-15-1-0284.

Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of α1-syntrophin and PLC/PKC in SOCE regulation.

PubMed

Harisseh, Rania; Chatelier, Aurélien; Magaud, Christophe; Déliot, Nadine; Constantin, Bruno

2013-05-01

Calcium homeostasis is critical for several vital functions in excitable and nonexcitable cells and has been shown to be impaired in many pathologies including Duchenne muscular dystrophy (DMD). Various studies using murine models showed the implication of calcium entry in the dystrophic phenotype. However, alteration of store-operated calcium entry (SOCE) and transient receptor potential vanilloid 2 (TRPV2)-dependant cation entry has not been investigated yet in human skeletal muscle cells. We pharmacologically characterized basal and store-operated cation entries in primary cultures of myotubes prepared from muscle of normal and DMD patients and found, for the first time, an increased SOCE in DMD myotubes. Moreover, this increase cannot be explained by an over expression of the well-known SOCE actors: TRPC1/4, Orai1, and stromal interaction molecule 1 (STIM1) mRNA and proteins. Thus we investigated the modes of regulation of this cation entry. We firstly demonstrated the important role of the scaffolding protein α1-syntrophin, which regulates SOCE in primary human myotubes through its PDZ domain. We also studied the implication of phospholipase C (PLC) and protein kinase C (PKC) in SOCE and showed that their inhibition restores normal levels of SOCE in DMD human myotubes. In addition, the involvement of TRPV2 in calcium deregulation in DMD human myotubes was explored. We showed an abnormal elevation of TRPV2-dependant cation entry in dystrophic primary human myotubes compared with normal ones. These findings show that calcium homeostasis mishandling in DMD myotubes depends on SOCE under the influence of Ca(2+)/PLC/PKC pathway and α1-syntrophin regulation as well as on TRPV2-dependant cation influx.

Performance of flapping airfoil propulsion with LBM method and DMD analysis

NASA Astrophysics Data System (ADS)

Li, Bing-Hua; Huang, Xian-Wen; Zheng, Yao; Xie, Fang-Fang; Wang, Jing; Zou, Jian-Feng

2018-05-01

In this work, the performance of flapping airfoil propulsion at low Reynolds number of Re = 100-400 is studied numerically with the lattice Boltzmann method (LBM). Combined with immersed boundary method (IBM), the LBM has been widely used to simulate moving boundary problems. The influences of the reduced frequency on the plunging and pitching airfoil are explored. It is found that the leading-edge vertex separation and inverted wake structures are two main coherent structures, which dominate the flapping airfoil propulsion. However, the two structures play different roles in the flow and the combination effects on the propulsion need to be clarified. To do so, we adopt the dynamic mode decomposition (DMD) algorithm to reveal the underlying physics. The DMD has been proven to be very suitable for analyzing the complex transient systems like the vortex structure of flapping flight.

A novel automotive headlight system based on digital micro-mirror devices and diffractive optical elements

NASA Astrophysics Data System (ADS)

Su, Ping; Song, Yuming; Ma, Jianshe

2018-01-01

The DMD (Digital Micro-mirror Device) has the advantages of high refresh rate and high diffraction efficiency, and these make it become an ideal loader of multiple modes illumination. DOEs (Diffractive Optical Element) have the advantages of high degree of freedom, light weight, easy to copy, low cost etc., and can be used to reduce the weight, complexity, cost of optical system. A novel automotive headlamp system using DMD as the light distribution element and a DOE as the light field modulation device is proposed in this paper. The pure phase DOE is obtained by the GS algorithm using Rayleigh-Sommerfeld diffraction integral model. Based on the standard automotive headlamp light intensity distribution in the target plane, the amplitude distribution of DMD is obtained by numerical simulation, and the grayscale diagram loaded on the DMD can be obtained accordingly. Finally, according to simulation result, the light intensity distribution in the target plane is proportional to the national standard, hence verifies the validity of the novel system. The novel illumination system proposed in this paper provides a reliable hardware platform for the intelligent headlamps.

Rocuronium-induced neuromuscular block and sugammadex in pediatric patient with duchenne muscular dystrophy

PubMed Central

Kim, Ji Eun; Chun, Hea Rim

2017-01-01

Abstract Introduction: Anesthetic management of patients with Duchenne muscular dystrophy (DMD) is complicated because these patients are more sensitive to nondepolarizing neuromuscular blocking agents (NMBAs) and are vulnerable to postoperative complications, such as postoperative residual curarization and respiratory failure. Sugammadex is a new reversal agent for aminosteroidal NMBAs, but its safety in children is controversial. Clinical features: An 11-year-old boy with DMD underwent general anesthesia for a percutaneous nephrolithotomy. We used rocuronium bromide and sugammadex to reverse the deep neuromuscular block. Reversal of neuromuscular block was done 15 minutes after administration of 2 mg/kg of sugammadex. The patient's recovery from anesthesia was uneventful, and he was discharged to the postoperative recovery ward. Conclusion: A delayed recovery was achieved, but no adverse events were observed, such as recurarization or hypersensitivity to sugammadex. We report safe use of 2 mg/kg of sugammadex to reverse a deep neuromuscular block in a child with DMD. PMID:28353578

Rocuronium-induced neuromuscular block and sugammadex in pediatric patient with duchenne muscular dystrophy: A case Report.

PubMed

Kim, Ji Eun; Chun, Hea Rim

2017-03-01

Anesthetic management of patients with Duchenne muscular dystrophy (DMD) is complicated because these patients are more sensitive to nondepolarizing neuromuscular blocking agents (NMBAs) and are vulnerable to postoperative complications, such as postoperative residual curarization and respiratory failure. Sugammadex is a new reversal agent for aminosteroidal NMBAs, but its safety in children is controversial. An 11-year-old boy with DMD underwent general anesthesia for a percutaneous nephrolithotomy. We used rocuronium bromide and sugammadex to reverse the deep neuromuscular block. Reversal of neuromuscular block was done 15 minutes after administration of 2 mg/kg of sugammadex. The patient's recovery from anesthesia was uneventful, and he was discharged to the postoperative recovery ward. A delayed recovery was achieved, but no adverse events were observed, such as recurarization or hypersensitivity to sugammadex. We report safe use of 2 mg/kg of sugammadex to reverse a deep neuromuscular block in a child with DMD.

Demonstration of the CDMA-mode CAOS smart camera.

PubMed

Riza, Nabeel A; Mazhar, Mohsin A

2017-12-11

Demonstrated is the code division multiple access (CDMA)-mode coded access optical sensor (CAOS) smart camera suited for bright target scenarios. Deploying a silicon CMOS sensor and a silicon point detector within a digital micro-mirror device (DMD)-based spatially isolating hybrid camera design, this smart imager first engages the DMD starring mode with a controlled factor of 200 high optical attenuation of the scene irradiance to provide a classic unsaturated CMOS sensor-based image for target intelligence gathering. Next, this CMOS sensor provided image data is used to acquire a focused zone more robust un-attenuated true target image using the time-modulated CDMA-mode of the CAOS camera. Using four different bright light test target scenes, successfully demonstrated is a proof-of-concept visible band CAOS smart camera operating in the CDMA-mode using up-to 4096 bits length Walsh design CAOS pixel codes with a maximum 10 KHz code bit rate giving a 0.4096 seconds CAOS frame acquisition time. A 16-bit analog-to-digital converter (ADC) with time domain correlation digital signal processing (DSP) generates the CDMA-mode images with a 3600 CAOS pixel count and a best spatial resolution of one micro-mirror square pixel size of 13.68 μm side. The CDMA-mode of the CAOS smart camera is suited for applications where robust high dynamic range (DR) imaging is needed for un-attenuated un-spoiled bright light spectrally diverse targets.

Generation-3 programmable array microscope (PAM) with digital micro-mirror device (DMD)

NASA Astrophysics Data System (ADS)

De Beule, Pieter A. A.; de Vries, Anthony H. B.; Arndt-Jovin, Donna J.; Jovin, Thomas M.

2011-03-01

We report progress on the construction of an optical sectioning programmable array microscope (PAM) implemented with a digital micro-mirror device (DMD) spatial light modulator (SLM) utilized for both fluorescence illumination and detection. The introduction of binary intensity modulation at the focal plane of a microscope objective in a computer controlled pixilated mode allows the recovery of an optically sectioned image. Illumination patterns can be changed very quickly, in contrast to static Nipkow disk or aperture correlation implementations, thereby creating an optical system that can be optimized to the optical specimen in a convenient manner, e.g. for patterned photobleaching, photobleaching reduction, or spatial superresolution. We present a third generation (Gen-3) dual path PAM module incorporating the 25 kHz binary frame rate TI 1080p DMD and a newly developed optical system that offers diffraction limited imaging with compensation of tilt angle distortion.

Investigation of coherent structures in a superheated jet using decomposition methods

NASA Astrophysics Data System (ADS)

Sinha, Avick; Gopalakrishnan, Shivasubramanian; Balasubramanian, Sridhar

2016-11-01

A superheated turbulent jet, commonly encountered in many engineering flows, is complex two phase mixture of liquid and vapor. The superposition of temporally and spatially evolving coherent vortical motions, known as coherent structures (CS), govern the dynamics of such a jet. Both POD and DMD are employed to analyze such vortical motions. PIV data is used in conjunction with the decomposition methods to analyze the CS in the flow. The experiments were conducted using water emanating into a tank containing homogeneous fluid at ambient condition. Three inlet pressure were employed in the study, all at a fixed inlet temperature. 90% of the total kinetic energy in the mean flow is contained within the first five modes. The scatterplot for any two POD coefficients predominantly showed a circular distribution, representing a strong connection between the two modes. We speculate that the velocity and vorticity contours of spatial POD basis functions show presence of K-H instability in the flow. From DMD, eigenvalues away from the origin is observed for all the cases indicating the presence of a non-oscillatory structure. Spatial structures are also obtained from DMD. The authors are grateful to Confederation of Indian Industry and General Electric India Pvt. Ltd. for partial funding of this project.

Towards DMD-Based Estimation and Control of Flow Separation using an Array of Surface Pressure Sensors

NASA Astrophysics Data System (ADS)

Deem, Eric; Cattafesta, Louis; Zhang, Hao; Rowley, Clancy

2016-11-01

Closed-loop control of flow separation requires the spatio-temporal states of the flow to be fed back through the controller in real time. Previously, static and dynamic estimation methods have been employed that provide reduced-order model estimates of the POD-coefficients of the flow velocity using surface pressure measurements. However, this requires a "learning" dataset a priori. This approach is effective as long as the dynamics during control do not stray from the learning dataset. Since only a few dynamical features are required for feedback control of flow separation, many of the details provided by full-field snapshots are superfluous. This motivates a state-observation technique that extracts key dynamical features directly from surface pressure, without requiring PIV snapshots. The results of identifying DMD modes of separated flow through an array of surface pressure sensors in real-time are presented. This is accomplished by employing streaming DMD "on the fly" to surface pressure snapshots. These modal characteristics exhibit striking similarities to those extracted from PIV data and the pressure field obtained via solving Poisson's equation. Progress towards closed-loop separation control based on the dynamic modes of surface pressure will be discussed. Supported by AFOSR Grant FA9550-14-1-0289.

Microsecond reconfigurable NxN data-communication switch using DMD

NASA Astrophysics Data System (ADS)

Blanche, Pierre-Alexandre; Miles, Alexander; Lynn, Brittany; Wissinger, John; Carothers, Daniel; Norwood, Robert A.; Peyghambarian, Nasser

2014-03-01

We present here the use the DMD as a diffraction-based optical switch, where Fourier diffraction patterns are used to steer the incoming beams to any output configuration. We have implemented a single-mode fiber coupled N X N switch and demonstrated its ability to operate over the entire telecommunication C-band centered at 1550 nm. The all-optical switch was built primarily with off-the-shelf components and a Texas Instruments DLP7000™with an array of 1024 X 768 micromirrors. This DMD is capable of switching 100 times faster than currently available technology (3D MOEMS). The switch is robust to typical failure modes, protocol and bit-rate agnostic, and permits full reconfigurable optical add drop multiplexing (ROADM). The switch demonstrator was inserted into a networking testbed for the majority of the measurements. The testbed assembled under the Center for Integrated Access Networks (ClAN), a National Science Foundation (NSF) Engineering Research Center (ERC), provided an environment in which to simulate and test the data routing functionality of the switch. A Fujitsu Flashwave 9500 PS was used to provide the data signal, which was sent through the switch and received by a second Flashwave node. We successfully transmitted an HD video stream through a switched channel without any measurable data loss.

A current approach to heart failure in Duchenne muscular dystrophy.

PubMed

D'Amario, Domenico; Amodeo, Antonio; Adorisio, Rachele; Tiziano, Francesco Danilo; Leone, Antonio Maria; Perri, Gianluigi; Bruno, Piergiorgio; Massetti, Massimo; Ferlini, Alessandra; Pane, Marika; Niccoli, Giampaolo; Porto, Italo; D'Angelo, Gianluca A; Borovac, Josip Anđelo; Mercuri, Eugenio; Crea, Filippo

2017-11-01

Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular condition that is marked by the long-term muscle deterioration with significant implications of pulmonary and cardiac dysfunction. As such, end-stage heart failure (HF) in DMD is increasingly becoming the main cause of death in this population. The early detection of cardiomyopathy is often challenging, due to a long subclinical phase of ventricular dysfunction and difficulties in assessment of cardiovascular symptomatology in these patients who usually loose ambulation during the early adolescence. However, an early diagnosis of cardiovascular disease in patients with DMD is decisive since it allows a timely initiation of cardioprotective therapies that can mitigate HF symptoms and delay detrimental heart muscle remodelling. Echocardiography and ECG are standardly used for screening and detection of cardiovascular abnormalities in these patients, although these tools are not always adequate to detect an early, clinically asymptomatic phases of disease progression. In this regard, cardiovascular magnetic resonance (CMR) with late gadolinium enhancement is emerging as a promising method for the detection of early cardiac involvement in patients with DMD. The early detection of cardiac dysfunction allows the therapeutic institution of various classes of drugs such as corticosteroids, beta-blockers, ACE inhibitors, antimineralocorticoid diuretics and novel pharmacological and surgical solutions in the multimodal and multidisciplinary care for this group of patients. This review will focus on these challenges and available options for HF in patients with DMD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Stability and modal analysis of shock/boundary layer interactions

NASA Astrophysics Data System (ADS)

Nichols, Joseph W.; Larsson, Johan; Bernardini, Matteo; Pirozzoli, Sergio

2017-02-01

The dynamics of oblique shock wave/turbulent boundary layer interactions is analyzed by mining a large-eddy simulation (LES) database for various strengths of the incoming shock. The flow dynamics is first analyzed by means of dynamic mode decomposition (DMD), which highlights the simultaneous occurrence of two types of flow modes, namely a low-frequency type associated with breathing motion of the separation bubble, accompanied by flapping motion of the reflected shock, and a high-frequency type associated with the propagation of instability waves past the interaction zone. Global linear stability analysis performed on the mean LES flow fields yields a single unstable zero-frequency mode, plus a variety of marginally stable low-frequency modes whose stability margin decreases with the strength of the interaction. The least stable linear modes are grouped into two classes, one of which bears striking resemblance to the breathing mode recovered from DMD and another class associated with revolving motion within the separation bubble. The results of the modal and linear stability analysis support the notion that low-frequency dynamics is intrinsic to the interaction zone, but some continuous forcing from the upstream boundary layer may be required to keep the system near a limit cycle. This can be modeled as a weakly damped oscillator with forcing, as in the early empirical model by Plotkin (AIAA J 13:1036-1040, 1975).

A spectrally tunable calibration source using Ebert-Fastie configuration

NASA Astrophysics Data System (ADS)

Wang, Xiaoxu; Li, Zhigang

2018-03-01

A novel spectrally tunable calibration source based on a digital micromirror device (DMD) and Ebert-Fastie optical configuration with two working modes (narrow-band mode and broad-band mode) was designed. The DMD is set on the image plane of the first spectral tuner, and controls the wavelength and intensity of the light reflected into the second spectral tuner by switching the micromirror array’s condition, which in turn controls the working mode of the spectrally tunable source. When working in narrow-band mode, the spectrally tunable source can be calibrated by a Gershun tube radiant power radiometer and a spectroradiometer. In broad-band mode, it can be used to calibrate optical instruments as a standard spectral radiance source. When using a xenon lamp as a light source, the stability of the spectrally tunable source is better than 0.5%, the minimum spectral bandwidth is 7 nm, and the uncertainty of the spectral radiance of the spectrally tunable source is estimated as 14.68% at 450 nm, 1.54% at 550 nm, and 1.48% at 654.6 nm. The uncertainty of the spectral radiance of the spectrally tunable source calibrated by the Gershun tube radiometer and spectroradiometer can be kept low during the radiometric calibration procedure so that it can meet the application requirement of optical quantitative remote sensing calibration.

Conceptual design for an AIUC multi-purpose spectrograph camera using DMD technology

NASA Astrophysics Data System (ADS)

Rukdee, S.; Bauer, F.; Drass, H.; Vanzi, L.; Jordan, A.; Barrientos, F.

2017-02-01

Current and upcoming massive astronomical surveys are expected to discover a torrent of objects, which need groundbased follow-up observations to characterize their nature. For transient objects in particular, rapid early and efficient spectroscopic identification is needed. In particular, a small-field Integral Field Unit (IFU) would mitigate traditional slit losses and acquisition time. To this end, we present the design of a Digital Micromirror Device (DMD) multi-purpose spectrograph camera capable of running in several modes: traditional longslit, small-field patrol IFU, multi-object and full-field IFU mode via Hadamard spectra reconstruction. AIUC Optical multi-purpose CAMera (AIUCOCAM) is a low-resolution spectrograph camera of R 1,600 covering the spectral range of 0.45-0.85 μm. We employ a VPH grating as a disperser, which is removable to allow an imaging mode. This spectrograph is envisioned for use on a 1-2 m class telescope in Chile to take advantage of good site conditions. We present design decisions and challenges for a costeffective robotized spectrograph. The resulting instrument is remarkably versatile, capable of addressing a wide range of scientific topics.

Printing line/space patterns on nonplanar substrates using a digital micromirror device-based point-array scanning technique

NASA Astrophysics Data System (ADS)

Kuo, Hung-Fei; Kao, Guan-Hsuan; Zhu, Liang-Xiu; Hung, Kuo-Shu; Lin, Yu-Hsin

2018-02-01

This study used a digital micromirror device (DMD) to produce point-array patterns and employed a self-developed optical system to define line-and-space patterns on nonplanar substrates. First, field tracing was employed to analyze the aerial images of the lithographic system, which comprised an optical system and the DMD. Multiobjective particle swarm optimization was then applied to determine the spot overlapping rate used. The objective functions were set to minimize linewidth and maximize image log slope, through which the dose of the exposure agent could be effectively controlled and the quality of the nonplanar lithography could be enhanced. Laser beams with 405-nm wavelength were employed as the light source. Silicon substrates coated with photoresist were placed on a nonplanar translation stage. The DMD was used to produce lithographic patterns, during which the parameters were analyzed and optimized. The optimal delay time-sequence combinations were used to scan images of the patterns. Finally, an exposure linewidth of less than 10 μm was successfully achieved using the nonplanar lithographic process.

Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options

PubMed Central

LoMauro, Antonella; D’Angelo, Maria Grazia; Aliverti, Andrea

2015-01-01

Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting in progressive weakness and wasting of all the striated muscles including the respiratory muscles. The consequences are loss of ambulation before teen ages, cardiac involvement and breathing difficulties, the main cause of death. A cure for DMD is not currently available. In the last decades the survival of patients with DMD has improved because the natural history of the disease can be changed thanks to a more comprehensive therapeutic approach. This comprises interventions targeted to the manifestations and complications of the disease, particularly in the respiratory care. These include: 1) pharmacological intervention, namely corticosteroids and idebenone that significantly reduce the decline of spirometric parameters; 2) rehabilitative intervention, namely lung volume recruitment techniques that help prevent atelectasis and slows the rate of decline of pulmonary function; 3) scoliosis treatment, namely steroid therapy that is used to reduce muscle inflammation/degeneration and prolong ambulation in order to delay the onset of scoliosis, being an additional contribution to the restrictive lung pattern; 4) cough assisted devices that improve airway clearance thus reducing the risk of pulmonary infections; and 5) non-invasive mechanical ventilation that is essential to treat nocturnal hypoventilation, sleep disordered breathing, and ultimately respiratory failure. Without any intervention death occurs within the first 2 decades, however, thanks to this multidisciplinary therapeutic approach life expectancy of a newborn with DMD nowadays can be significantly prolonged up to his fourth decade. This review is aimed at providing state-of-the-art methods and techniques for the assessment and management of respiratory function in DMD patients. PMID:26451113

DMD-based LED-illumination super-resolution and optical sectioning microscopy.

PubMed

Dan, Dan; Lei, Ming; Yao, Baoli; Wang, Wen; Winterhalder, Martin; Zumbusch, Andreas; Qi, Yujiao; Xia, Liang; Yan, Shaohui; Yang, Yanlong; Gao, Peng; Ye, Tong; Zhao, Wei

2013-01-01

Super-resolution three-dimensional (3D) optical microscopy has incomparable advantages over other high-resolution microscopic technologies, such as electron microscopy and atomic force microscopy, in the study of biological molecules, pathways and events in live cells and tissues. We present a novel approach of structured illumination microscopy (SIM) by using a digital micromirror device (DMD) for fringe projection and a low-coherence LED light for illumination. The lateral resolution of 90 nm and the optical sectioning depth of 120 μm were achieved. The maximum acquisition speed for 3D imaging in the optical sectioning mode was 1.6×10(7) pixels/second, which was mainly limited by the sensitivity and speed of the CCD camera. In contrast to other SIM techniques, the DMD-based LED-illumination SIM is cost-effective, ease of multi-wavelength switchable and speckle-noise-free. The 2D super-resolution and 3D optical sectioning modalities can be easily switched and applied to either fluorescent or non-fluorescent specimens.

DMD-based LED-illumination Super-resolution and optical sectioning microscopy

PubMed Central

Dan, Dan; Lei, Ming; Yao, Baoli; Wang, Wen; Winterhalder, Martin; Zumbusch, Andreas; Qi, Yujiao; Xia, Liang; Yan, Shaohui; Yang, Yanlong; Gao, Peng; Ye, Tong; Zhao, Wei

2013-01-01

Super-resolution three-dimensional (3D) optical microscopy has incomparable advantages over other high-resolution microscopic technologies, such as electron microscopy and atomic force microscopy, in the study of biological molecules, pathways and events in live cells and tissues. We present a novel approach of structured illumination microscopy (SIM) by using a digital micromirror device (DMD) for fringe projection and a low-coherence LED light for illumination. The lateral resolution of 90 nm and the optical sectioning depth of 120 μm were achieved. The maximum acquisition speed for 3D imaging in the optical sectioning mode was 1.6×107 pixels/second, which was mainly limited by the sensitivity and speed of the CCD camera. In contrast to other SIM techniques, the DMD-based LED-illumination SIM is cost-effective, ease of multi-wavelength switchable and speckle-noise-free. The 2D super-resolution and 3D optical sectioning modalities can be easily switched and applied to either fluorescent or non-fluorescent specimens. PMID:23346373

Quasi-interferometric scheme improved by fiber Bragg grating written on macrostructure defect in silica multimode optical fiber operating in a few-mode regime

NASA Astrophysics Data System (ADS)

Evtushenko, Alexander S.; Faskhutdinov, Lenar M.; Kafarova, Anastasia M.; Kuznetzov, Artem A.; Minaeva, Alina Yu.; Sevruk, Nikita L.; Nureev, Ilnur I.; Vasilets, Alexander A.; Andreev, Vladimir A.; Morozov, Oleg G.; Burdin, Vladimir A.; Bourdine, Anton V.

2017-04-01

This work presents results of experimental approbation of earlier on proposed modified fiber optic stress sensor based on a few-mode effects occurring during laser-excited optical signal propagation over silica multimode optical fiber (MMF). Modification is concerned with a passage to quasi-interferometric scheme realized by two multimode Y-couplers with equalized arm lengths improved by fiber Bragg grating (FBG) written on preliminary formed precision macrostructure defects in silica multimode graded-index optical fibers and special offset launching conditions providing laser-based excitation of higher-order modes. The "arms" of quasi-interferometer are two equalized lengths of MMF Cat. OM2 with great central dip of refractive index profile and strong pulse splitting due to high differential mode delay (DMD). We tested FBGs with Bragg wavelength both 1310 nm and 1550 nm written over tapers or up-tapers preliminary formed in short pieces of MMF Cat. OM2+/OM3 and further jointed to the end of one of the arms before output Y-coupler. Researches were focused on comparison analysis of pulse responses under changing of selected excited mode mixing and power diffusion processes due to stress distributed action to sensor fiber depending. Here we considered FBGs not only as particular wavelength reflector during spectral response measurement but also as local periodic microstructure defect which strongly effects on few-mode signal components mixing process also improved by combination with macro-defect like taper or up-taper that should provide response variation. Some results pulse response measurements produced for different scheme configuration and their comparison analysis are represented.

Dynamic mode decomposition of Fontan hemodynamics in an idealized total cavopulmonary connection

NASA Astrophysics Data System (ADS)

Delorme, Yann T.; Kerlo, Anna-Elodie M.; Anupindi, Kameswararao; Rodefeld, Mark D.; Frankel, Steven H.

2014-08-01

Univentricular heart disease is the leading cause of death from any birth defect in the first year of life. Typically, patients have to undergo three open heart surgical procedures within the first few years of their lives to eventually directly connect the superior and inferior vena cavae to the left and right pulmonary arteries forming the total cavopulmonary connection (TCPC). The end result is a weak circulation where the single working ventricle pumps oxygenated blood to the body and de-oxygenated blood flows passively through the TCPC into the lungs. The fluid dynamics of the TCPC junction involve confined impinging jets resulting in a highly unstable flow, significant mechanical energy dissipation and undesirable pressure loss. Understanding and predicting such flows is important for improving the surgical procedure and for the design of mechanical cavopulmonary assist devices. In this study, dynamic mode decomposition (DMD) is used to analyze previously obtained stereoscopic particle imaging velocimetry (SPIV) data and large eddy simulation (LES) results for an idealized TCPC. Analysis of the DMD modes from the SPIV and LES serves to both highlight the unsteady vortical dynamics and the qualitative agreement between measurements and simulations.

Relationship Between Audio-Vestibular Functional Tests and Inner Ear MRI in Meniere's Disease.

PubMed

Quatre, Raphaële; Attyé, Arnaud; Karkas, Alexandre; Job, Agnès; Dumas, Georges; Schmerber, Sébastien

2018-04-25

Meniere's disease is an inner ear disorder generally attributed to an endolymphatic hydrops. Different electrophysiological tests and imaging techniques have been developed to improve endolymphatic hydrops diagnosis. The goal of our study was to compare the sensitivity and the specificity of delayed inner ear magnetic resonance imaging (MRI) after intravenous injection of gadolinium with extratympanic clicks electrocochleography (EcochG), phase shift of distortion product otoacoustic emissions (shift-DPOAEs), and cervical vestibular-evoked myogenic potentials (cVEMP) for the diagnosis of Meniere's disease. Forty-one patients, with a total of 50 affected ears, were included prospectively from April 2015 to April 2016 in our institution. Patients included had definite or possible Meniere's disease based on the latest American Academy of Otolaryngology-Head and Neck Surgery guidelines revised in 2015. All patients went through delayed inner ear MRI after intravenous injection of gadolinium (three dimension-fluid attenuated inversion recovery sequences), pure-tone audiometry, extratympanic clicks EcochG, shift-DPOAEs, and cVEMP on the same day. Endolymphatic hydrops was graded on MRI using the saccule to utricle ratio inversion defined as when the saccule appeared equal or larger than the utricle. Abnormal EcochG and shift-DPOAEs in patients with definite Meniere's disease (DMD) were found in 68 and 64.5%, respectively. The two methods were significantly associated in DMD group. In DMD group, 25.7% had a positive MRI. The correlation between MRI versus EcochG and MRI versus shift-DPOAEs was not significant. MRI hydrops detection was correlated with hearing loss. Finally, 22.9% of DMD group had positive cVEMP. EcochG and shift-DPOAEs were both well correlated with clinical criteria of Meniere's disease. Inner ear MRI showed hydrops when hearing loss was higher than 35 dB. The shift-DPOAEs presented the advantage of a rapid and easy measurement if DPOAEs could be recorded (i.e., hearing threshold <60dB). In contrast, EcochG can be performed regardless of hearing loss. In combination with shift-DPOAEs, it enhances the chances to confirm the diagnosis with a better confidence.

Early limited instrumentation of scoliosis in Duchenne muscular dystrophy: is a single-rod construct sufficient?

PubMed

Cawley, Derek T; Carmody, Olan; Dodds, Michael K; McCormack, Damian

2015-10-01

Correction of scoliotic deformity in Duchenne muscular dystrophy (DMD) is performed to maintain adequate seating posture and facilitate comfort. Delaying surgery can predispose to greater morbidity as DMD exhibits progressive cardiorespiratory compromise. Early limited instrumentation may provide a solution to optimize patients with this condition. The aim was to assess outcomes for a cohort of DMD patients who had posterior single-rod instrumentation and bilateral spinal fusion of their neuromuscular scoliotic deformity. This was a retrospective cohort study. Forty-one consecutive patients were included. Perioperative morbidity, seating outcomes, pulmonary function, deformity correction, and instrumentation integrity were assessed. Clinical and radiographic review was performed. No perioperative mortality or neurologic deterioration was encountered. Total surgical time was 96 minutes, mean total blood loss was 2.3l, mean intensive care unit stay was 41 hours, and overall length of stay was 11 days. Mean Cobb angle improved from 24.3° to 15.6°, pelvic obliquity improved from 7° preoperatively to 5° postoperatively. Three patients had failure of fixation at a mean of 3.5 years. Forced vital capacity was 60% preoperatively and 56% at 1 year, forced expiratory volume/1 second was 67% and 62% at 1 year postoperatively. Seating and posture was satisfactory in all these patients. The authors advocate early operative intervention using a limited instrumentation technique in patients with DMD to maintain seating balance and minimize perioperative morbidity. Copyright © 2015 Elsevier Inc. All rights reserved.

Reversal of rocuronium-induced neuromuscular blockade by pyridostigmine in patients with Duchenne muscular dystrophy.

PubMed

Muenster, Tino; Forst, Juergen; Goerlitz, Peter; Schmitt, Hubert J

2008-03-01

The aim of this study was to investigate the effect and safety of pyridostigmine for the reversal of a neuromuscular block (NMB) in patients with Duchenne muscular dystrophy (DMD). In patients with DMD recovery from a rocuronium-induced NMB is markedly delayed. Fourteen DMD patients (aged between 11 and 19 years) scheduled for elective scoliosis repair were studied. Following tracheal intubation without muscle relaxant, all patients received a single dose of rocuronium 0.6 mg.kg(-1). NMB was monitored by acceleromyography at the adductor pollicis muscle. When the first twitch height (T1) of the train-of-four (TOF) had recovered to 25% seven patients received either pyridostigmine 0.1 mg.kg(-1) (the anticholinergic drug with a long duration of action) or saline in a blinded manner. The times to attain TOF ratio of 0.9 were recorded. For comparison the Mann-Whitney U-test was used. Recovery to TOF ratio of 0.9 was significantly (P < 0.05) accelerated by pyridostigmine [84 (median), 57-141(range)] compared with controls (148, 84-243 min). The recovery time (time between T1 of 25% and TOF of 90%) was also significantly (P < 0.01) shortened by pyridostigmine (15, 8-49 vs 76, 43-144 min, respectively). Time to recovery of T(1) to 90% was not different between the groups (108, 63-134 vs 169. 61-208 min, respectively). Pyridostigmine 0.1 mg.kg(-1) effectively reversed a rocuronium-induced NMB in DMD patients.

BATMAN: a DMD-based MOS demonstrator on Galileo Telescope

NASA Astrophysics Data System (ADS)

Zamkotsian, Frédéric; Spanò, Paolo; Bon, William; Riva, Marco; Lanzoni, Patrick; Nicastro, Luciano; Molinari, Emilio; Cosentino, Rosario; Ghedina, Adriano; Gonzalez, Manuel; Di Marcantonio, Paolo; Coretti, Igor; Cirami, Roberto; Manetta, Marco; Zerbi, Filippo; Tresoldi, Daniela; Valenziano, Luca

2012-09-01

Multi-Object Spectrographs (MOS) are the major instruments for studying primary galaxies and remote and faint objects. Current object selection systems are limited and/or difficult to implement in next generation MOS for space and groundbased telescopes. A promising solution is the use of MOEMS devices such as micromirror arrays which allow the remote control of the multi-slit configuration in real time. We are developing a Digital Micromirror Device (DMD) - based spectrograph demonstrator called BATMAN. We want to access the largest FOV with the highest contrast. The selected component is a DMD chip from Texas Instruments in 2048 x 1080 mirrors format, with a pitch of 13.68μm. Our optical design is an all-reflective spectrograph design with F/4 on the DMD component. This demonstrator permits the study of key parameters such as throughput, contrast and ability to remove unwanted sources in the FOV (background, spoiler sources), PSF effect, new observational modes. This study will be conducted in the visible with possible extension in the IR. A breadboard on an optical bench, ROBIN, has been developed for a preliminary determination of these parameters. The demonstrator on the sky is then of prime importance for characterizing the actual performance of this new family of instruments, as well as investigating the operational procedures on astronomical objects. BATMAN will be placed on the Nasmyth focus of Telescopio Nazionale Galileo (TNG) during next year.

Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies

PubMed Central

Kornegay, Joe N.; Bogan, Janet R.; Bogan, Daniel J.; Childers, Martin K.; Li, Juan; Nghiem, Peter; Detwiler, David A.; Larsen, C. Aaron; Grange, Robert W.; Bhavaraju-Sanka, Ratna K.; Tou, Sandra; Keene, Bruce P.; Howard, James F.; Wang, Jiahui; Fan, Zheng; Schatzberg, Scott J.; Styner, Martin A.; Flanigan, Kevin M.; Xiao, Xiao; Hoffman, Eric P.

2013-01-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID:22218699

Photobiomodulation therapy protects skeletal muscle and improves muscular function of mdx mice in a dose-dependent manner through modulation of dystrophin.

PubMed

Albuquerque-Pontes, Gianna Móes; Casalechi, Heliodora Leão; Tomazoni, Shaiane Silva; Serra, Andrey Jorge; Ferreira, Cheila de Sousa Bacelar; Brito, Rodrigo Barbosa de Oliveira; de Melo, Brunno Lemes; Vanin, Adriane Aver; Monteiro, Kadma Karênina Damasceno Soares; Dellê, Humberto; Frigo, Lucio; Marcos, Rodrigo Labat; de Carvalho, Paulo de Tarso Camillo; Leal-Junior, Ernesto Cesar Pinto

2018-05-01

This study aimed to analyze the protective effects of photobiomodulation therapy (PBMT) with combination of low-level laser therapy (LLLT) and light emitting diode therapy (LEDT) on skeletal muscle tissue to delay dystrophy progression in mdx mice (DMD mdx ). To this aim, mice were randomly divided into five different experimental groups: wild type (WT), placebo-control (DMD mdx ), PBMT with doses of 1 J (DMD mdx ), 3 J (DMD mdx ), and 10 J (DMD mdx ). PBMT was performed employing a cluster probe with 9 diodes (1 x 905nm super-pulsed laser diode; 4 x 875nm infrared LEDs; and 4 x 640nm red LEDs, manufactured by Multi Radiance Medical®, Solon - OH, USA), 3 times a week for 14 weeks. PBMT was applied on a single point (tibialis anterior muscle-bilaterally). We analyzed functional performance, muscle morphology, and gene and protein expression of dystrophin. PBMT with a 10 J dose significantly improved (p < 0.001) functional performance compared to all other experimental groups. Muscle morphology was improved by all PBMT doses, with better outcomes with the 3 and 10 J doses. Gene expression of dystrophin was significantly increased with 3 J (p < 0.01) and 10 J (p < 0.01) doses when compared to placebo-control group. Regarding protein expression of dystrophin, 3 J (p < 0.001) and 10 J (p < 0.05) doses also significantly showed increase compared to placebo-control group. We conclude that PBMT can mainly preserve muscle morphology and improve muscular function of mdx mice through modulation of gene and protein expression of dystrophin. Furthermore, since PBMT is a non-pharmacological treatment which does not present side effects and is easy to handle, it can be seen as a promising tool for treating Duchenne's muscular dystrophy.

Absolute detector-based spectrally tunable radiant source using digital micromirror device and supercontinuum fiber laser.

PubMed

Li, Zhigang; Wang, Xiaoxu; Zheng, Yuquan; Li, Futian

2017-06-10

High-accuracy absolute detector-based spectroradiometric calibration techniques traceable to cryogenic absolute radiometers have made progress rapidly in recent decades under the impetus of atmospheric quantitative spectral remote sensing. A high brightness spectrally tunable radiant source using a supercontinuum fiber laser and a digital micromirror device (DMD) has been developed to meet demands of spectroradiometric calibrations for ground-based, aeronautics-based, and aerospace-based remote sensing instruments and spectral simulations of natural scenes such as the sun and atmosphere. Using a supercontinuum fiber laser as a radiant source, the spectral radiance of the spectrally tunable radiant source is 20 times higher than the spectrally tunable radiant source using conventional radiant sources such as tungsten halogen lamps, xenon lamps, or LED lamps, and the stability is better than ±0.3%/h. Using a DMD, the spectrally tunable radiant source possesses two working modes. In narrow-band modes, it is calibrated by an absolute detector, and in broad-band modes, it can calibrate for remote sensing instrument. The uncertainty of the spectral radiance of the spectrally tunable radiant source is estimated at less than 1.87% at 350 nm to 0.85% at 750 nm, and compared to only standard lamp-based calibration, a greater improvement is gained.

Clinical Manifestations and Overall Management Strategies for Duchenne Muscular Dystrophy.

PubMed

Tsuda, Takeshi

2018-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that causes progressive weakness and wasting of skeletal muscular and myocardium in boys due to mutation of dystrophin. The structural integrity of each individual skeletal and cardiac myocyte is significantly compromised upon physical stress due to the absence of dystrophin. The progressive destruction of systemic musculature and myocardium causes affected patients to develop multiple organ disabilities, including loss of ambulation, physical immobility, neuromuscular scoliosis, joint contracture, restrictive lung disease, obstructive sleep apnea, and cardiomyopathy. There are some central nervous system-related medical problems, as dystrophin is also expressed in the neuronal tissues. Although principal management is to mainly delay the pathological process, an enhanced understanding of underlying pathological processes has significantly improved quality of life and longevity for DMD patients. Future research in novel molecular approach is warranted to answer unanswered questions.

Modal analysis of passive flow control for the turbulent wake of a generic planar space launcher

NASA Astrophysics Data System (ADS)

Loosen, S.; Statnikov, V.; Meinke, M.; Schröder, W.

2018-06-01

The turbulent wake of a generic planar space launcher equipped with two passive flow control devices is simulated using a zonal RANS-LES method and analyzed by dynamic mode decomposition (DMD). In the first approach, the effect of a classical boat tail on the wake is examined. In the second concept, a flow control device consisting of semi-circular lobes integrated at the base shoulder of the main body is used. The objective of the two concepts is to reduce the reattachment length and thus the lever arm of the forces as well as to stabilize the separated shear layer. Using a boat tail, the reattachment length can be reduced by 50%. Furthermore, it is shown that the semi-circular lobes enhance the turbulent mixing and the shear layer growth rate. Hence, they significantly reduce the reattachment length by about 75%. The semi-circular lobes partially reduce undesired low-frequency pressure fluctuations on the nozzle surface. However, this reduction is achieved at the expense of an increase of high-frequency pressure fluctuations due to intensified small turbulent scales. The DMD analysis of the velocity field reveals that the large-scale coherent structures featuring a wave length of two step heights observed in the reference configuration without flow control can be suppressed by the lobes. The spanwise wave length of the coherent structures seems to depend on the geometry of the lobes, since all detected spatial DMD modes show a spanwise periodicity being equal to the distance between two lobes.

Modal analysis of passive flow control for the turbulent wake of a generic planar space launcher

NASA Astrophysics Data System (ADS)

Loosen, S.; Statnikov, V.; Meinke, M.; Schröder, W.

2017-12-01

The turbulent wake of a generic planar space launcher equipped with two passive flow control devices is simulated using a zonal RANS-LES method and analyzed by dynamic mode decomposition (DMD). In the first approach, the effect of a classical boat tail on the wake is examined. In the second concept, a flow control device consisting of semi-circular lobes integrated at the base shoulder of the main body is used. The objective of the two concepts is to reduce the reattachment length and thus the lever arm of the forces as well as to stabilize the separated shear layer. Using a boat tail, the reattachment length can be reduced by 50%. Furthermore, it is shown that the semi-circular lobes enhance the turbulent mixing and the shear layer growth rate. Hence, they significantly reduce the reattachment length by about 75%. The semi-circular lobes partially reduce undesired low-frequency pressure fluctuations on the nozzle surface. However, this reduction is achieved at the expense of an increase of high-frequency pressure fluctuations due to intensified small turbulent scales. The DMD analysis of the velocity field reveals that the large-scale coherent structures featuring a wave length of two step heights observed in the reference configuration without flow control can be suppressed by the lobes. The spanwise wave length of the coherent structures seems to depend on the geometry of the lobes, since all detected spatial DMD modes show a spanwise periodicity being equal to the distance between two lobes.

Extended dynamic mode decomposition with dictionary learning: A data-driven adaptive spectral decomposition of the Koopman operator

NASA Astrophysics Data System (ADS)

Li, Qianxiao; Dietrich, Felix; Bollt, Erik M.; Kevrekidis, Ioannis G.

2017-10-01

Numerical approximation methods for the Koopman operator have advanced considerably in the last few years. In particular, data-driven approaches such as dynamic mode decomposition (DMD)51 and its generalization, the extended-DMD (EDMD), are becoming increasingly popular in practical applications. The EDMD improves upon the classical DMD by the inclusion of a flexible choice of dictionary of observables which spans a finite dimensional subspace on which the Koopman operator can be approximated. This enhances the accuracy of the solution reconstruction and broadens the applicability of the Koopman formalism. Although the convergence of the EDMD has been established, applying the method in practice requires a careful choice of the observables to improve convergence with just a finite number of terms. This is especially difficult for high dimensional and highly nonlinear systems. In this paper, we employ ideas from machine learning to improve upon the EDMD method. We develop an iterative approximation algorithm which couples the EDMD with a trainable dictionary represented by an artificial neural network. Using the Duffing oscillator and the Kuramoto Sivashinsky partical differential equation as examples, we show that our algorithm can effectively and efficiently adapt the trainable dictionary to the problem at hand to achieve good reconstruction accuracy without the need to choose a fixed dictionary a priori. Furthermore, to obtain a given accuracy, we require fewer dictionary terms than EDMD with fixed dictionaries. This alleviates an important shortcoming of the EDMD algorithm and enhances the applicability of the Koopman framework to practical problems.

Extended dynamic mode decomposition with dictionary learning: A data-driven adaptive spectral decomposition of the Koopman operator.

PubMed

Li, Qianxiao; Dietrich, Felix; Bollt, Erik M; Kevrekidis, Ioannis G

2017-10-01

Numerical approximation methods for the Koopman operator have advanced considerably in the last few years. In particular, data-driven approaches such as dynamic mode decomposition (DMD) 51 and its generalization, the extended-DMD (EDMD), are becoming increasingly popular in practical applications. The EDMD improves upon the classical DMD by the inclusion of a flexible choice of dictionary of observables which spans a finite dimensional subspace on which the Koopman operator can be approximated. This enhances the accuracy of the solution reconstruction and broadens the applicability of the Koopman formalism. Although the convergence of the EDMD has been established, applying the method in practice requires a careful choice of the observables to improve convergence with just a finite number of terms. This is especially difficult for high dimensional and highly nonlinear systems. In this paper, we employ ideas from machine learning to improve upon the EDMD method. We develop an iterative approximation algorithm which couples the EDMD with a trainable dictionary represented by an artificial neural network. Using the Duffing oscillator and the Kuramoto Sivashinsky partical differential equation as examples, we show that our algorithm can effectively and efficiently adapt the trainable dictionary to the problem at hand to achieve good reconstruction accuracy without the need to choose a fixed dictionary a priori. Furthermore, to obtain a given accuracy, we require fewer dictionary terms than EDMD with fixed dictionaries. This alleviates an important shortcoming of the EDMD algorithm and enhances the applicability of the Koopman framework to practical problems.

Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy

PubMed Central

Gloss, David; Moxley, Richard T.; Ashwal, Stephen; Oskoui, Maryam

2016-01-01

Objective: To update the 2005 American Academy of Neurology (AAN) guideline on corticosteroid treatment of Duchenne muscular dystrophy (DMD). Methods: We systematically reviewed the literature from January 2004 to July 2014 using the AAN classification scheme for therapeutic articles and predicated recommendations on the strength of the evidence. Results: Thirty-four studies met inclusion criteria. Recommendations: In children with DMD, prednisone should be offered for improving strength (Level B) and pulmonary function (Level B). Prednisone may be offered for improving timed motor function (Level C), reducing the need for scoliosis surgery (Level C), and delaying cardiomyopathy onset by 18 years of age (Level C). Deflazacort may be offered for improving strength and timed motor function and delaying age at loss of ambulation by 1.4–2.5 years (Level C). Deflazacort may be offered for improving pulmonary function, reducing the need for scoliosis surgery, delaying cardiomyopathy onset, and increasing survival at 5–15 years of follow-up (Level C for each). Deflazacort and prednisone may be equivalent in improving motor function (Level C). Prednisone may be associated with greater weight gain in the first years of treatment than deflazacort (Level C). Deflazacort may be associated with a greater risk of cataracts than prednisone (Level C). The preferred dosing regimen of prednisone is 0.75 mg/kg/d (Level B). Over 12 months, prednisone 10 mg/kg/weekend is equally effective (Level B), with no long-term data available. Prednisone 0.75 mg/kg/d is associated with significant risk of weight gain, hirsutism, and cushingoid appearance (Level B). PMID:26833937

Particle Tracking Simulation of Collective Modes. Parametric Landau Damping Off Coupling Resonance.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macridin, Alexandru; Burov, Alexey; Stern, Eric

Employing Synergia simulations with the DMD method we investigate the Landau damping of space charge modes in bunched beams. The simulations reveal two instances of the parametric damping mechanism in bunched beams. The first example occurs in the proximity of coupling resonance and is due to the oscillation of particles’ amplitudes in the transverse plane. This oscillation modulates the modeparticle coupling with particle dependent trapping frequency. The second example is due to the modulation of the modeparticle coupling in one transverse plane by the oscillatory motion in the other plane.

Dynamic generation of Ince-Gaussian modes with a digital micromirror device

NASA Astrophysics Data System (ADS)

Ren, Yu-Xuan; Fang, Zhao-Xiang; Gong, Lei; Huang, Kun; Chen, Yue; Lu, Rong-De

2015-04-01

Ince-Gaussian (IG) beam with elliptical profile, as a connection between Hermite-Gaussian (HG) and Laguerre-Gaussian (LG) beams, has showed unique advantages in some applications such as quantum entanglement and optical micromanipulation. However, its dynamic generation with high switching frequency is still challenging. Here, we experimentally reported the quick generation of Ince-Gaussian beam by using a digital micro-mirror device (DMD), which has the highest switching frequency of 5.2 kHz in principle. The configurable properties of DMD allow us to observe the quasi-smooth variation from LG (with ellipticity ɛ = 0 ) to IG and HG ( ɛ = ∞ ) beam. This approach might pave a path to high-speed quantum communication in terms of IG beam. Additionally, the characterized axial plane intensity distribution exhibits a 3D mould potentially being employed for optical micromanipulation.

Topics in Modeling of Cochlear Dynamics: Computation, Response and Stability Analysis

NASA Astrophysics Data System (ADS)

Filo, Maurice G.

This thesis touches upon several topics in cochlear modeling. Throughout the literature, mathematical models of the cochlea vary according to the degree of biological realism to be incorporated. This thesis casts the cochlear model as a continuous space-time dynamical system using operator language. This framework encompasses a wider class of cochlear models and makes the dynamics more transparent and easier to analyze before applying any numerical method to discretize space. In fact, several numerical methods are investigated to study the computational efficiency of the finite dimensional realizations in space. Furthermore, we study the effects of the active gain perturbations on the stability of the linearized dynamics. The stability analysis is used to explain possible mechanisms underlying spontaneous otoacoustic emissions and tinnitus. Dynamic Mode Decomposition (DMD) is introduced as a useful tool to analyze the response of nonlinear cochlear models. Cochlear response features are illustrated using DMD which has the advantage of explicitly revealing the spatial modes of vibrations occurring in the Basilar Membrane (BM). Finally, we address the dynamic estimation problem of BM vibrations using Extended Kalman Filters (EKF). Due to the limitations of noninvasive sensing schemes, such algorithms are inevitable to estimate the dynamic behavior of a living cochlea.

Application of Dynamic Mode Decomposition: Temporal Evolution of Flow Structures in an Aneurysm

NASA Astrophysics Data System (ADS)

Conlin, William; Yu, Paulo; Durgesh, Vibhav

2017-11-01

An aneurysm is an enlargement of a weakened arterial wall that can be fatal or debilitating on rupture. Aneurysm hemodynamics is integral to developing an understanding of aneurysm formation, growth, and rupture. The flow in an aneurysm exhibits complex fluid dynamics behavior due to an inherent unsteady inflow condition and its interactions with large-scale flow structures present in the aneurysm. The objective of this study is to identify the large-scale structures in the aneurysm, study temporal behavior, and quantify their interaction with the inflow condition. For this purpose, detailed Particle Image Velocimetry (PIV) measurements were performed at the center plane of an idealized aneurysm model for a range of inflow conditions. Inflow conditions were precisely controlled using a ViVitro SuperPump system. Dynamic Modal Decomposition (DMD) of the velocity field was used to identify coherent structures and their temporal behavior. DMD was successful in capturing the large-scale flow structures and their temporal behavior. A low dimensional approximation to the flow field was obtained with the most relevant dynamic modes and was used to obtain temporal information about the coherent structures and their interaction with the inflow, formation, evolution, and growth.

Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle.

PubMed

Klymiuk, Nikolai; Blutke, Andreas; Graf, Alexander; Krause, Sabine; Burkhardt, Katinka; Wuensch, Annegret; Krebs, Stefan; Kessler, Barbara; Zakhartchenko, Valeri; Kurome, Mayuko; Kemter, Elisabeth; Nagashima, Hiroshi; Schoser, Benedikt; Herbach, Nadja; Blum, Helmut; Wanke, Rüdiger; Aartsma-Rus, Annemieke; Thirion, Christian; Lochmüller, Hanns; Walter, Maggie C; Wolf, Eckhard

2013-11-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness and a maximum life span of 3 months due to respiratory impairment. Unlike human DMD patients, some DMD pigs die shortly after birth. To address the accelerated development of muscular dystrophy in DMD pigs when compared with human patients, we performed a genome-wide transcriptome study of biceps femoris muscle specimens from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good concordance with gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis and impaired metabolic activity. In contrast, the transcriptome profile of 2-day-old DMD pigs showed similarities with transcriptome changes induced by acute exercise muscle injury. Our studies provide new insights into early changes associated with dystrophin deficiency in a clinically severe animal model of DMD.

Koopman Invariant Subspaces and Finite Linear Representations of Nonlinear Dynamical Systems for Control.

PubMed

Brunton, Steven L; Brunton, Bingni W; Proctor, Joshua L; Kutz, J Nathan

2016-01-01

In this wIn this work, we explore finite-dimensional linear representations of nonlinear dynamical systems by restricting the Koopman operator to an invariant subspace spanned by specially chosen observable functions. The Koopman operator is an infinite-dimensional linear operator that evolves functions of the state of a dynamical system. Dominant terms in the Koopman expansion are typically computed using dynamic mode decomposition (DMD). DMD uses linear measurements of the state variables, and it has recently been shown that this may be too restrictive for nonlinear systems. Choosing the right nonlinear observable functions to form an invariant subspace where it is possible to obtain linear reduced-order models, especially those that are useful for control, is an open challenge. Here, we investigate the choice of observable functions for Koopman analysis that enable the use of optimal linear control techniques on nonlinear problems. First, to include a cost on the state of the system, as in linear quadratic regulator (LQR) control, it is helpful to include these states in the observable subspace, as in DMD. However, we find that this is only possible when there is a single isolated fixed point, as systems with multiple fixed points or more complicated attractors are not globally topologically conjugate to a finite-dimensional linear system, and cannot be represented by a finite-dimensional linear Koopman subspace that includes the state. We then present a data-driven strategy to identify relevant observable functions for Koopman analysis by leveraging a new algorithm to determine relevant terms in a dynamical system by ℓ1-regularized regression of the data in a nonlinear function space; we also show how this algorithm is related to DMD. Finally, we demonstrate the usefulness of nonlinear observable subspaces in the design of Koopman operator optimal control laws for fully nonlinear systems using techniques from linear optimal control.ork, we explore finite-dimensional linear representations of nonlinear dynamical systems by restricting the Koopman operator to an invariant subspace spanned by specially chosen observable functions. The Koopman operator is an infinite-dimensional linear operator that evolves functions of the state of a dynamical system. Dominant terms in the Koopman expansion are typically computed using dynamic mode decomposition (DMD). DMD uses linear measurements of the state variables, and it has recently been shown that this may be too restrictive for nonlinear systems. Choosing the right nonlinear observable functions to form an invariant subspace where it is possible to obtain linear reduced-order models, especially those that are useful for control, is an open challenge. Here, we investigate the choice of observable functions for Koopman analysis that enable the use of optimal linear control techniques on nonlinear problems. First, to include a cost on the state of the system, as in linear quadratic regulator (LQR) control, it is helpful to include these states in the observable subspace, as in DMD. However, we find that this is only possible when there is a single isolated fixed point, as systems with multiple fixed points or more complicated attractors are not globally topologically conjugate to a finite-dimensional linear system, and cannot be represented by a finite-dimensional linear Koopman subspace that includes the state. We then present a data-driven strategy to identify relevant observable functions for Koopman analysis by leveraging a new algorithm to determine relevant terms in a dynamical system by ℓ1-regularized regression of the data in a nonlinear function space; we also show how this algorithm is related to DMD. Finally, we demonstrate the usefulness of nonlinear observable subspaces in the design of Koopman operator optimal control laws for fully nonlinear systems using techniques from linear optimal control.

[Preimplantation genetic diagnosis of Duchenne muscular dystrophy by single cell triplex PCR].

PubMed

Wu, Yue-Li; Wu, Ling-Qian; Li, Yan-Ping; Liu, Dong-E; Zeng, Qiao; Zhu, Hai-Yan; Pan, Qian; Liang, De-Sheng; Hu, Hao; Long, Zhi-Gao; Li, Juan; Dai, He-Ping; Xia, Kun; Xia, Jia-Hui

2007-04-01

To detect two exons of Duchenne muscular dystrophy (DMD) gene and a gender discrimination locus amelogenin gene by single cell triplex PCR, and to evaluate the possibility of this technique for preimplantation genetic diagnosis (PGD) in DMD family with DMD deletion mutation. Single lymphocytes from a normal male, a normal female, two DMD patients (exon 8 and 47 deleted, respectively) and single blastomeres from the couples treated by the in vitro fertilization pre-embryo transfer (IVF-ET) and without family history of DMD were obtained. Exons 8 and 47 of DMD gene were amplified by a triplex PCR assay, the amelogenin gene on X and Y chromosomes were co-amplified to analyze the correlation between embryo gender and deletion status. In the normal single lymphocytes, the amplification rate of exons 8 and 47 of DMD and amelogenin gene were 93.8%, 93.8%, and 95.3% respectively. The false positive rate was 3.3%. In the exon 8 deleted DMD patient, the amplification rate of exon 47 of DMD and amelogenin gene was 95.8%, and the false positive rate was 3.3%. In the exon 47 deleted DMD patient, the amplification rate of exon 8 of DMD and amelogenin gene was 95.8%, and the false positive rate was 0. In the single blastomeres, the amplification rate of exons 8 and 47 of DMD and amelogenin gene was 82.5%, 80.0% and 77.5%, respectively, and the false positive rate was 0. The single cell triplex PCR protocol for the detection of DMD and amelogenin gene is highly sensitive, specific and reliable, and can be used for PGD in those DMD families with DMD deletion mutation.

Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology.

PubMed

Gloss, David; Moxley, Richard T; Ashwal, Stephen; Oskoui, Maryam

2016-02-02

To update the 2005 American Academy of Neurology (AAN) guideline on corticosteroid treatment of Duchenne muscular dystrophy (DMD). We systematically reviewed the literature from January 2004 to July 2014 using the AAN classification scheme for therapeutic articles and predicated recommendations on the strength of the evidence. Thirty-four studies met inclusion criteria. In children with DMD, prednisone should be offered for improving strength (Level B) and pulmonary function (Level B). Prednisone may be offered for improving timed motor function (Level C), reducing the need for scoliosis surgery (Level C), and delaying cardiomyopathy onset by 18 years of age (Level C). Deflazacort may be offered for improving strength and timed motor function and delaying age at loss of ambulation by 1.4-2.5 years (Level C). Deflazacort may be offered for improving pulmonary function, reducing the need for scoliosis surgery, delaying cardiomyopathy onset, and increasing survival at 5-15 years of follow-up (Level C for each). Deflazacort and prednisone may be equivalent in improving motor function (Level C). Prednisone may be associated with greater weight gain in the first years of treatment than deflazacort (Level C). Deflazacort may be associated with a greater risk of cataracts than prednisone (Level C). The preferred dosing regimen of prednisone is 0.75 mg/kg/d (Level B). Over 12 months, prednisone 10 mg/kg/weekend is equally effective (Level B), with no long-term data available. Prednisone 0.75 mg/kg/d is associated with significant risk of weight gain, hirsutism, and cushingoid appearance (Level B). © 2016 American Academy of Neurology.

Data-driven sensor placement from coherent fluid structures

NASA Astrophysics Data System (ADS)

Manohar, Krithika; Kaiser, Eurika; Brunton, Bingni W.; Kutz, J. Nathan; Brunton, Steven L.

2017-11-01

Optimal sensor placement is a central challenge in the prediction, estimation and control of fluid flows. We reinterpret sensor placement as optimizing discrete samples of coherent fluid structures for full state reconstruction. This permits a drastic reduction in the number of sensors required for faithful reconstruction, since complex fluid interactions can often be described by a small number of coherent structures. Our work optimizes point sensors using the pivoted matrix QR factorization to sample coherent structures directly computed from flow data. We apply this sampling technique in conjunction with various data-driven modal identification methods, including the proper orthogonal decomposition (POD) and dynamic mode decomposition (DMD). In contrast to POD-based sensors, DMD demonstrably enables the optimization of sensors for prediction in systems exhibiting multiple scales of dynamics. Finally, reconstruction accuracy from pivot sensors is shown to be competitive with sensors obtained using traditional computationally prohibitive optimization methods.

Data-based adjoint and H2 optimal control of the Ginzburg-Landau equation

NASA Astrophysics Data System (ADS)

Banks, Michael; Bodony, Daniel

2017-11-01

Equation-free, reduced-order methods of control are desirable when the governing system of interest is of very high dimension or the control is to be applied to a physical experiment. Two-phase flow optimal control problems, our target application, fit these criteria. Dynamic Mode Decomposition (DMD) is a data-driven method for model reduction that can be used to resolve the dynamics of very high dimensional systems and project the dynamics onto a smaller, more manageable basis. We evaluate the effectiveness of DMD-based forward and adjoint operator estimation when applied to H2 optimal control approaches applied to the linear and nonlinear Ginzburg-Landau equation. Perspectives on applying the data-driven adjoint to two phase flow control will be given. Office of Naval Research (ONR) as part of the Multidisciplinary University Research Initiatives (MURI) Program, under Grant Number N00014-16-1-2617.

Dynamic generation of Ince-Gaussian modes with a digital micromirror device

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Yu-Xuan, E-mail: yxren@ustc.edu.cn; Fang, Zhao-Xiang; Chen, Yue

Ince-Gaussian (IG) beam with elliptical profile, as a connection between Hermite-Gaussian (HG) and Laguerre-Gaussian (LG) beams, has showed unique advantages in some applications such as quantum entanglement and optical micromanipulation. However, its dynamic generation with high switching frequency is still challenging. Here, we experimentally reported the quick generation of Ince-Gaussian beam by using a digital micro-mirror device (DMD), which has the highest switching frequency of 5.2 kHz in principle. The configurable properties of DMD allow us to observe the quasi-smooth variation from LG (with ellipticity ε=0) to IG and HG (ε=∞) beam. This approach might pave a path to high-speedmore » quantum communication in terms of IG beam. Additionally, the characterized axial plane intensity distribution exhibits a 3D mould potentially being employed for optical micromanipulation.« less

Demonstration of multi-wavelength tunable fiber lasers based on a digital micromirror device processor.

PubMed

Ai, Qi; Chen, Xiao; Tian, Miao; Yan, Bin-bin; Zhang, Ying; Song, Fei-jun; Chen, Gen-xiang; Sang, Xin-zhu; Wang, Yi-quan; Xiao, Feng; Alameh, Kamal

2015-02-01

Based on a digital micromirror device (DMD) processor as the multi-wavelength narrow-band tunable filter, we demonstrate a multi-port tunable fiber laser through experiments. The key property of this laser is that any lasing wavelength channel from any arbitrary output port can be switched independently over the whole C-band, which is only driven by single DMD chip flexibly. All outputs display an excellent tuning capacity and high consistency in the whole C-band with a 0.02 nm linewidth, 0.055 nm wavelength tuning step, and side-mode suppression ratio greater than 60 dB. Due to the automatic power control and polarization design, the power uniformity of output lasers is less than 0.008 dB and the wavelength fluctuation is below 0.02 nm within 2 h at room temperature.

Prenatal diagnosis for a Chinese family with a de novo DMD gene mutation

PubMed Central

Li, Tao; Zhang, Zhao-jing; Ma, Xin; Lv, Xue; Xiao, Hai; Guo, Qian-nan; Liu, Hong-yan; Wang, Hong-dan; Wu, Dong; Lou, Gui-yu; Wang, Xin; Zhang, Chao-yang; Liao, Shi-xiu

2017-01-01

Abstract Background: Patients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis. Methods: First, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified. Results: MLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient. Conclusion: The pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic. PMID:29390271

Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy.

PubMed

Lin, Bo; Li, Yang; Han, Lu; Kaplan, Aaron D; Ao, Ying; Kalra, Spandan; Bett, Glenna C L; Rasmusson, Randall L; Denning, Chris; Yang, Lei

2015-05-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca(2+), mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca(2+) level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients. © 2015. Published by The Company of Biologists Ltd.

Using dynamic mode decomposition for real-time background/foreground separation in video

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kutz, Jose Nathan; Grosek, Jacob; Brunton, Steven

The technique of dynamic mode decomposition (DMD) is disclosed herein for the purpose of robustly separating video frames into background (low-rank) and foreground (sparse) components in real-time. Foreground/background separation is achieved at the computational cost of just one singular value decomposition (SVD) and one linear equation solve, thus producing results orders of magnitude faster than robust principal component analysis (RPCA). Additional techniques, including techniques for analyzing the video for multi-resolution time-scale components, and techniques for reusing computations to allow processing of streaming video in real time, are also described herein.

The Fundamentals of Using the Digital Micromirror Device (DMD(TM)) for Projection Display

NASA Technical Reports Server (NTRS)

Yoder, Lars A.

1995-01-01

Developed by Texas Instruments (TI) the digital micromirror device (DMD(tm)) is a quickly emerging and highly useful micro-electro-mechanical structures (MEMS) device. Using standard semiconductor fabrication technology, the DMD's simplicity in concept and design will provide advantageous solutions for many different applications. At the rudimentary level, the DMD is a precision, semiconductor light switch. In the initial commercial development of DMD technology, TI has concentrated on projection display and hardcopy. This paper will focus on how the DMD is used for projection display. Other application areas are being explored and evaluated to find appropriate and beneficial uses for the DMD.

Fundamental Insights into Combustion Instability Predictions in Aerospace Propulsion

NASA Astrophysics Data System (ADS)

Huang, Cheng

Integrated multi-fidelity modeling has been performed for combustion instability in aerospace propulsion, which includes two levels of analysis: first, computational fluid dynamics (CFD) using hybrid RANS/LES simulations for underlying physics investigations (high-fidelity modeling); second, modal decomposition techniques for diagnostics (analysis & validation); third, development of flame response model using model reduction techniques for practical design applications (low-order model). For the high-fidelity modeling, the relevant CFD code development work is moving towards combustion instability prediction for liquid propulsion system. A laboratory-scale single-element lean direct injection (LDI) gas turbine combustor is used for configuration that produces self-excited combustion instability. The model gas turbine combustor is featured with an air inlet section, air plenum, swirler-venturi-injector assembly, combustion chamber, and exit nozzle. The combustor uses liquid fuel (Jet-A/FT-SPK) and heated air up to 800K. Combustion dynamics investigations are performed with the same geometry and operating conditions concurrently between the experiment and computation at both high (φ=0.6) and low (φ=0.36) equivalence ratios. The simulation is able to reach reasonable agreement with experiment measurements in terms of the pressure signal. Computational analyses are also performed using an acoustically-open geometry to investigate the characteristic hydrodynamics in the combustor with both constant and perturbed inlet mass flow rates. Two hydrodynamic modes are identified by using Dynamic Mode Decomposition (DMD) analysis: Vortex Breakdown Bubble (VBB) and swirling modes. Following that, the closed geometry simulation results are analyzed in three steps. In step one, a detailed cycle analysis shows two physically important couplings in the combustor: first, the acoustic compression enhances the spray drop breakup and vaporization, and generates more gaseous fuel for reaction; second, the acoustic compression couples with the unsteady hydrodynamics found in the open-geometry simulation, enhances the fuel/air mixing, and triggers a large amount of heat addition. In step two, a modal analysis using DMD extracts the dynamic features of important modes in the combustor, and identifies the presence of Precessing Vortex Core (PVC) mode and its nonlinear interactions with acoustic modes. Moreover, the DMD analysis helps to establish the couplings between the hydrodynamics and acoustics in terms of frequencies. In step 3, Rayleigh index analysis provides a quantitative assessment of acoustics/combustion couplings and identifies local regions for instability driving/damping. Two modal decomposition techniques, Proper Orthogonal Decomposition (POD) and Dynamic Mode Decomposition (DMD), are assessed in terms of their capabilities in extracting important information from the original simulation dataset and in validating the computational results using the experiment measurement. A POD analysis provides a series of modes with decreasing energy content and it offers an efficient and optimized way to represent a large dataset. The frequency-based DMD technique provides modes that correspond to all single frequencies. For the low-order modeling, fundamental aspects are examined to study necessary conditions, criteria and approaches to develop a reduced-order model (ROM) that is able to represent generic combustion/flame responses, which then can be used in an engineering level tool to provide efficient predictions of combustion instability for practical design applications. Explorations are focused on model reduction techniques by using the so-called POD/Galerkin method. The method uses the numerical solutions of the model equations as the database for building a set of POD eigen-bases. Specifically, the numerical solutions are calculated by perturbing quantities of interest such as the inlet conditions. The POD-derived eigen-bases are, in turn, used in conjunction with a Galerkin procedure to reduce the governing partial differential equation to an ordinary differential equation, which constitutes the ROM. Once the ROM is established, it can then be used as a lower-order test-bed to predict detailed results within certain parametric ranges at a fraction of the cost of solving the full governing equations. A detailed assessment is performed on the method in two parts. In part one, a one-dimensional scalar reaction-advection model equation is used for fundamental investigations, which include verification of the POD eigen-basis calculation and of the ROM development procedure. Moreover, certain criteria during ROM development are established: 1. a necessary number of POD modes that should be included to guarantee a stable ROM; 2. the need for the numerical discretization scheme to be consistent between the original CFD and the developed ROM. Furthermore, the predictive capabilities of the resulting ROM are evaluated to test its limits and to validate the values of applying broadband forcing in improving the ROM performance. In part two, the exploration is extended to a vector system of equations. Using the one-dimensional Euler equation is used as a model equation. A numerical stability issue is identified during the ROM development, the cause of which is further studied and attributed to the normalization methods implemented to generate coupled POD eigen-bases for vector variables. (Abstract shortened by UMI.).

Optical joint transform correlation on the DMD. [deformable mirror device

NASA Technical Reports Server (NTRS)

Knopp, Jerome; Juday, Richard D.

1989-01-01

Initial experimental investigation of the deformable mirror device (DMD) in a joint optical transform correlation is reported. The inverted cloverleaf version of the DMD, in which form the DMD is phase-mostly but of limited phase range, is used. Binarized joint Fourier transforms were calculated for similar and dissimilar objects and written onto the DMD. Inverse Fourier transform was done in a diffraction order for which the DMD shows phase-mostly modulation. Matched test objects produced sharp correlation, distinct objects did not. Further studies are warranted and they are outlined.

Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus.

PubMed

Yue, Yongping; Pan, Xiufang; Hakim, Chady H; Kodippili, Kasun; Zhang, Keqing; Shin, Jin-Hong; Yang, Hsiao T; McDonald, Thomas; Duan, Dongsheng

2015-10-15

The ultimate goal of muscular dystrophy gene therapy is to treat all muscles in the body. Global gene delivery was demonstrated in dystrophic mice more than a decade ago using adeno-associated virus (AAV). However, translation to affected large mammals has been challenging. The only reported attempt was performed in newborn Duchenne muscular dystrophy (DMD) dogs. Unfortunately, AAV injection resulted in growth delay, muscle atrophy and contracture. Here we report safe and bodywide AAV delivery in juvenile DMD dogs. Three ∼2-m-old affected dogs received intravenous injection of a tyrosine-engineered AAV-9 reporter or micro-dystrophin (μDys) vector at the doses of 1.92-6.24 × 10(14) viral genome particles/kg under transient or sustained immune suppression. DMD dogs tolerated injection well and their growth was not altered. Hematology and blood biochemistry were unremarkable. No adverse reactions were observed. Widespread muscle transduction was seen in skeletal muscle, the diaphragm and heart for at least 4 months (the end of the study). Nominal expression was detected in internal organs. Improvement in muscle histology was observed in μDys-treated dogs. In summary, systemic AAV gene transfer is safe and efficient in young adult dystrophic large mammals. This may translate to bodywide gene therapy in pediatric patients in the future. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain

NASA Astrophysics Data System (ADS)

Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas

1988-03-01

Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

PubMed Central

McGreevy, Joe W.; Hakim, Chady H.; McIntosh, Mark A.; Duan, Dongsheng

2015-01-01

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs. PMID:25740330

Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy.

PubMed

Yu, Hong-Hao; Zhao, Heng; Qing, Yu-Bo; Pan, Wei-Rong; Jia, Bao-Yu; Zhao, Hong-Ye; Huang, Xing-Xu; Wei, Hong-Jiang

2016-10-09

Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD . Two piglets were obtained after embryo transfer, one of piglets was identified as DMD -modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD -modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD -modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig.

Trans-Interface Optical Communication (TIOC)

DTIC Science & Technology

2008-01-01

communication interface 4. Bitmap stream creation 5. Display thread 6. DMD activeX control 7. DMD communication 8. System timing/control 9...o DMD activeX control o DMD communication o System timing/control o Graphical user interface (GUI) • All components are available for

Dynamic mode decomposition of separated flow over a finite blunt plate: time-resolved particle image velocimetry measurements

NASA Astrophysics Data System (ADS)

Liu, Yingzheng; Zhang, Qingshan

2015-07-01

Dynamic mode decomposition (DMD) analysis was performed on a large number of realizations of the separated flow around a finite blunt plate, which were determined by using planar time-resolved particle image velocimetry (TR-PIV). Three plates with different chord-to-thickness ratios corresponding to globally different flow patterns were particularly selected for comparison: L/D = 3.0, 6.0 and 9.0. The main attention was placed on dynamic variations in the dominant events and their interactive influences on the global fluid flow in terms of the DMD analysis. Toward this end, a real-time data transfer from the high-speed camera to the arrayed disks was built to enable continuous sampling of the spatiotemporally varying flows at the frequency of 250 Hz for a long run. The spectra of the wall-normal velocity fluctuation, the energy spectra of the DMD modes, and their spatial patterns convincingly determined the energetic unsteady events, i.e., St = 0.051 (Karman vortex street), 0.109 (harmonic event of Karman vortex street) and 0.197 (leading-edge vortex) in the shortest system L/D = 3.0, St = 0.159 (Karman vortex street) and 0.242 (leading-edge vortex) in the system L/D = 6.0, and St = 0.156 (Karman vortex street) and 0.241 (leading-edge vortex) in the longest system L/D = 9.0. In the shortest system L/D = 3.0, the first DMD mode pattern demonstrated intensified entrainment of the massive fluid above and below the whole plate by the Karman vortex street. The phase-dependent variation in the low-order flow field elucidated that this motion was sustained by the consecutive mechanisms of the convective leading-edge vortices near the upper and lower trailing edges, and the large-scale vortical structures occurring immediately behind the trailing edge, whereas the leading-edge vortices were entrained and decayed into the near wake. For the system L/D = 6.0, the closely approximated energy spectra at St = 0.159 and 0.242 indicated the balanced dominance of dual unsteady events in the measurement region. The Karman vortex street was found to induce considerable localized movement of the fluid near the trailing edges of the plate. However, the leading-edge vortices near the trailing edge were found to detach away from the plate and fully decay around 0.5 D behind the trailing edge, where a well-ordered origination of the downstream large-scale vortical structures (the Karman vortex street) was established and might be locally energized by the decayed leading-edge vortex. In the longest system L/D = 9.0, the phase-dependent variations in the low-order flow disclosed a rapid decay of the leading-edge vortices beyond the reattachment zone, reaching the fully diffused state near the trailing edges. Accordingly, no clear signature of the interaction between the Karman vortex street and the leading-edge vortex could be found in the dynamic process of the leading-edge vortex.

Generation of muscular dystrophy model rats with a CRISPR/Cas system.

PubMed

Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

2014-07-09

Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, H. D.; Fiorito, R. B.; Corbett, J.

The 3GeV SPEAR3 synchrotron light source operates in top-up injection mode with up to 500 mA circulating in the storage ring (equivalently 392 nC). Each injection pulse contains 40–80 pC producing a contrast ratio between total stored charge and injected charge of about 6500:1. In order to study transient injected beam dynamics during user operations, it is desirable to optically image the injected pulse in the presence of the bright stored beam. In the present work this is done by imaging the visible component of the synchrotron radiation onto a digital micro-mirror-array device (DMD), which is then used as anmore » optical mask to block out light from the bright central core of the stored beam. The physical masking, together with an asynchronously-gated, ICCD imaging camera, makes it possible to observe the weak injected beam component on a turn-by-turn basis. The DMD optical masking system works similar to a classical solar coronagraph but has some distinct practical advantages: i.e. rapid adaption to changes in the shape of the stored beam, a high extinction ratio for unwanted light and minimum scattering from the primary beam into the secondary optics. In this paper we describe the DMD masking method, features of the high dynamic range point spread function for the SPEAR3 optical beam line and measurements of the injected beam in the presence of the stored beam.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hao; Fiorito, Ralph; Corbett, Jeff

The 3GeV SPEAR3 synchrotron light source operates in top-up injection mode with up to 500mA circulating in the storage ring (equivalently 392nC). Each injection pulse contains only 40-80 pC producing a contrast ratio between total stored charge and injected charge of about 6500:1. In order to study transient injected beam dynamics during User operations, it is desirable to optically image the injected pulse in the presence of the bright stored beam. In the present work this is done by re-imaging visible synchrotron radiation onto a digital micro-mirror-array device (DMD), which is then used as an optical mask to block outmore » light from the bright central core of the stored beam. The physical masking, together with an asynchronously-gated, ICCD imaging camera makes it is possible to observe the weak injected beam component on a turn-by-turn basis. The DMD optical masking system works similar to a classical solar coronagraph but has some distinct practical advantages: i.e. rapid adaption to changes in the shape of the stored beam, high extinction ratio for unwanted light and minimum scattering from the primary beam into the secondary optics. In this paper we describe the DMD masking method, features of the high dynamic range point spread function for the SPEAR3 optical beam line and measurements of the injected beam in the presence of the stored beam.« less

Opportunities to Enhance Multimode Fiber Links by Application of Overfilled Launch

NASA Astrophysics Data System (ADS)

Onlagic, Denis

2005-11-01

This paper investigates possibilities for the practical design of high-performance multimode fibers (MMFs) that can provide bandwidths in excess of 10 GHz ...km in an overfilled regime of operation. Analysis of standard MMF in an overfilled launch demonstrates that the theoretical bandwidth limitations arise from the influence of cladding on the propagation of the highest order modes. Practical MMF profile designs that overcome this problem are investigated. The standard 50-and 62.5- μm fiber profiles are redesigned first to allow for the performance in an overfilled launch with the differential mode delays (DMDs) below 0.055 and 0.250 ns/km, respectively. It is shown that such fibers can exhibit the same or better theoretical bandwidth in an overfilled launch when compared to standard fiber under restricted launch. Elimination of the need for the restricted mode launch in high-performance multimode transmission systems can improve reliability issues and can relax the range of tolerance requirements imposed on terminal equipment, optical components, and link installation. Furthermore, MMFs that can be operated in an overfilled launched are compatible with emerging vertical cavity surface emitting laser (VCSEL) wavelength division multiplexing (WDM) array technologies. A successfully controlled higher order mode DMD also allows for the reduction of MMF core size and mit Delta that can be beneficial for low-cost high-performance single-channel links. It is demonstrated that properly designed reduced core fibers can achieve theoretical DMDs in the range of 0.005-0.02 ns/km. The bend loss properties of redesigned fibers are investigated in detail, showing that the proposed modifications do not lead to significant degradation of bend loss performance. Moreover, they can be manufactured at considerably lower cost while utilizing commercially readily available low-cost VCSELs. Even where the theoretical limit is not achieved by practical fiber making, the reduced core size and mit Delta MMF can provide higher production yield, lower cost, and higher average bandwidth.

The importance of genetic diagnosis for Duchenne muscular dystrophy

PubMed Central

Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

2016-01-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

Emerging digital micromirror device (DMD) applications

NASA Astrophysics Data System (ADS)

Dudley, Dana; Duncan, Walter M.; Slaughter, John

2003-01-01

For the past six years, Digital Light Processing technology from Texas Instruments has made significant inroads in the projection display market. With products enabling the world"s smallest data and video projectors, HDTVs, and digital cinema, DLP technology is extremely powerful and flexible. At the heart of these display solutions is Texas Instruments Digital Micromirror Device (DMD), a semiconductor-based "light switch" array of thousands of individually addressable, tiltable, mirror-pixels. With success of the DMD as a spatial light modulator for projector applications, dozens of new applications are now being enabled by general-use DMD products that are recently available to developers. The same light switching speed and "on-off" (contrast) ratio that have resulted in superior projector performance, along with the capability of operation outside the visible spectrum, make the DMD very attractive for many applications, including volumetric display, holographic data storage, lithography, scientific instrumentation, and medical imaging. This paper presents an overview of past and future DMD performance in the context of new DMD applications, cites several examples of emerging products, and describes the DMD components and tools now available to developers.

Scattered light in a DMD based multi-object spectrometer

NASA Astrophysics Data System (ADS)

Fourspring, Kenneth D.; Ninkov, Zoran; Kerekes, John P.

2010-07-01

The DMD (Digital Micromirror Device) has an important future in both ground and space based multi-object spectrometers. A series of laboratory measurements have been performed to determine the scattered light properties of a DMD. The DMD under test had a 17 μm pitch and 1 μm gap between adjacent mirrors. Prior characterization of this device has focused on its use in DLP (TI Digital Light Processing) projector applications in which a whole pixel is illuminated by a uniform collimated source. The purpose of performing these measurements is to determine the limiting signal to noise ratio when utilizing the DMD as a slit mask in a spectrometer. The DMD pixel was determined to scatter more around the pixel edge and central via, indicating the importance of matching the telescope point spread function to the DMD. Also, the generation of DMD tested here was determined to have a significant mirror curvature. A maximum contrast ratio was determined at several wavelengths. Further measurements are underway on a newer generation DMD device, which has a smaller mirror pitch and likely different scatter characteristics. A previously constructed instrument, RITMOS (RIT Multi-Object Spectrometer) will be used to validate these scatter models and signal to noise ratio predications through imaging a star field.

Computer task performance by subjects with Duchenne muscular dystrophy.

PubMed

Malheiros, Silvia Regina Pinheiro; da Silva, Talita Dias; Favero, Francis Meire; de Abreu, Luiz Carlos; Fregni, Felipe; Ribeiro, Denise Cardoso; de Mello Monteiro, Carlos Bandeira

2016-01-01

Two specific objectives were established to quantify computer task performance among people with Duchenne muscular dystrophy (DMD). First, we compared simple computational task performance between subjects with DMD and age-matched typically developing (TD) subjects. Second, we examined correlations between the ability of subjects with DMD to learn the computational task and their motor functionality, age, and initial task performance. The study included 84 individuals (42 with DMD, mean age of 18±5.5 years, and 42 age-matched controls). They executed a computer maze task; all participants performed the acquisition (20 attempts) and retention (five attempts) phases, repeating the same maze. A different maze was used to verify transfer performance (five attempts). The Motor Function Measure Scale was applied, and the results were compared with maze task performance. In the acquisition phase, a significant decrease was found in movement time (MT) between the first and last acquisition block, but only for the DMD group. For the DMD group, MT during transfer was shorter than during the first acquisition block, indicating improvement from the first acquisition block to transfer. In addition, the TD group showed shorter MT than the DMD group across the study. DMD participants improved their performance after practicing a computational task; however, the difference in MT was present in all attempts among DMD and control subjects. Computational task improvement was positively influenced by the initial performance of individuals with DMD. In turn, the initial performance was influenced by their distal functionality but not their age or overall functionality.

PubMed Central

D'ANGELO, MARIA GRAZIA; VITA, GIUSEPPE; PANE, MARIKA; D'AMICO, ADELE; BALOTTIN, UMBERTO; ANGELINI, CORRADO; BATTINI, ROBERTA; POLITANO, LUISA; PATALANO, MELANIA

2014-01-01

This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease. PMID:25873782

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

PubMed

Thayer, Sarah; Bell, Christopher; McDonald, Craig M

2017-06-01

A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones. DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars). The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001). In the United States, resource use and medical costs of DMD are substantial and increase with age. Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

Digital micromirror devices: principles and applications in imaging.

PubMed

Bansal, Vivek; Saggau, Peter

2013-05-01

A digital micromirror device (DMD) is an array of individually switchable mirrors that can be used in many advanced optical systems as a rapid spatial light modulator. With a DMD, several implementations of confocal microscopy, hyperspectral imaging, and fluorescence lifetime imaging can be realized. The DMD can also be used as a real-time optical processor for applications such as the programmable array microscope and compressive sensing. Advantages and disadvantages of the DMD for these applications as well as methods to overcome some of the limitations will be discussed in this article. Practical considerations when designing with the DMD and sample optical layouts of a completely DMD-based imaging system and one in which acousto-optic deflectors (AODs) are used in the illumination pathway are also provided.

Direct Observation of a Majorana Quasiparticle Heat Capacity in 3He

NASA Astrophysics Data System (ADS)

Bunkov, Y. M.

2014-04-01

The Majorana fermion, which acts as its own antiparticle, was suggested by Majorana in 1937 (Nuovo Cimento 14:171). While no stable particle with Majorana properties has yet been observed, Majorana quasiparticles (QP) may exist at the boundaries of topological insulators. Here we report the preliminary results of direct observation of Majorana QPs by a precise measurements of superfluid 3He heat capacity. The bulk superfluid 3He heat capacity falls exponentially with cooling at the temperatures significantly below the energy gap. Owing to the zero energy gap mode the Majorana heat capacity falls in a power law. The Majorana heat capacity can be larger than bulk one at some temperature, which depends on surface to volume ratio of the experimental cell. Some times ago we developed the Dark matter particles detector (DMD) on a basis of superfluid 3He which is working at the frontier of extremely low temperatures (Winkelmann et al., Nucl. Instrum. Meth. A 559:384-386, 2006). Here we report the observation of zero gap mode of Majorana, follows from the new analyses of DMD heat capacity, published early. We have found a 10 % deviation from the bulk superfluid 3He heat capacity at the temperature of 135 μK. This deviation corresponds well to the theoretical value for Majorana heat capacity at such low temperature. (Note, there were no fitting parameters).

A hypothalamic circuit that controls body temperature.

PubMed

Zhao, Zheng-Dong; Yang, Wen Z; Gao, Cuicui; Fu, Xin; Zhang, Wen; Zhou, Qian; Chen, Wanpeng; Ni, Xinyan; Lin, Jun-Kai; Yang, Juan; Xu, Xiao-Hong; Shen, Wei L

2017-02-21

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.

Psychological and practical difficulties among parents and healthy siblings of children with Duchenne vs. Becker muscular dystrophy: an Italian comparative study.

PubMed

Magliano, Lorenza; D'Angelo, Maria Grazia; Vita, Giuseppe; Pane, Marika; D'Amico, Adele; Balottin, Umberto; Angelini, Corrado; Battini, Roberta; Politano, Luisa; Patalano, Melania; Sagliocchi, Alessandra; Civati, Federica; Brighina, Erika; Vita, Gian Luca; Messina, Sonia; Sframeli, Maria; Lombardo, Maria Elena; Scalise, Roberta; Colia, Giulia; Catteruccia, Maria; Berardinelli, Angela; Motta, Maria Chiara; Gaiani, Alessandra; Semplicini, Claudio; Bello, Luca; Astrea, Guja; Zaccaro, Antonella; Scutifero, Marianna

2014-12-01

This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease.

Skeletal muscle water T2 as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy.

PubMed

Mankodi, Ami; Azzabou, Noura; Bulea, Thomas; Reyngoudt, Harmen; Shimellis, Hirity; Ren, Yupeng; Kim, Eunhee; Fischbeck, Kenneth H; Carlier, Pierre G

2017-08-01

The purpose of this study was to examine exercise effects on muscle water T 2 in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T 2 and R 2 (1/T 2 ) by the tri-exponential model. Muscle water R 2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p < .001) except in the tibialis posterior muscle. Muscle water T 2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T 2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p < .001). DMD participants had a lower muscle torque (p < .001) and exerted less power (p < .01) during exercise than controls. Nevertheless, muscle water R 2 decreased (T 2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantarflexor muscles. Skeletal muscle water T 2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls. Published by Elsevier B.V.

A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20.

PubMed

Mata López, Sara; Hammond, James J; Rigsby, Madison B; Balog-Alvarez, Cynthia J; Kornegay, Joe N; Nghiem, Peter P

2018-05-29

Boys with Duchenne muscular dystrophy (DMD) have DMD gene mutations, with associated loss of the dystrophin protein and progressive muscle degeneration and weakness. Corticosteroids and palliative support are currently the best treatment options. The long-term benefits of recently approved compounds such as eteplirsen and ataluren remain to be seen. Dogs with naturally occurring dystrophinopathies show progressive disease akin to that of DMD. Accordingly, canine DMD models are useful for studies of pathogenesis and preclinical therapy development. A dystrophin-deficient, male border collie dog was evaluated at the age of 5 months for progressive muscle weakness and dysphagia. Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L) were seen on a biochemistry panel. Histopathologic changes characteristic of dystrophinopathy were seen. Dystrophin was absent in the skeletal muscle on immunofluorescence microscopy and western blot. Whole genome sequencing, polymerase chain reaction, and Sanger sequencing revealed a frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream. Semen was archived for future line perpetuation. This spontaneous canine dystrophinopathy occurred due to a novel mutation in the minor DMD mutation hotspot (between exons 2 through 20). Perpetuating this line could allow for preclinical testing of genetic therapies targeted to this area of the DMD gene.

Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

PubMed Central

2015-01-01

Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

Koopman Invariant Subspaces and Finite Linear Representations of Nonlinear Dynamical Systems for Control

PubMed Central

Brunton, Steven L.; Brunton, Bingni W.; Proctor, Joshua L.; Kutz, J. Nathan

2016-01-01

In this work, we explore finite-dimensional linear representations of nonlinear dynamical systems by restricting the Koopman operator to an invariant subspace spanned by specially chosen observable functions. The Koopman operator is an infinite-dimensional linear operator that evolves functions of the state of a dynamical system. Dominant terms in the Koopman expansion are typically computed using dynamic mode decomposition (DMD). DMD uses linear measurements of the state variables, and it has recently been shown that this may be too restrictive for nonlinear systems. Choosing the right nonlinear observable functions to form an invariant subspace where it is possible to obtain linear reduced-order models, especially those that are useful for control, is an open challenge. Here, we investigate the choice of observable functions for Koopman analysis that enable the use of optimal linear control techniques on nonlinear problems. First, to include a cost on the state of the system, as in linear quadratic regulator (LQR) control, it is helpful to include these states in the observable subspace, as in DMD. However, we find that this is only possible when there is a single isolated fixed point, as systems with multiple fixed points or more complicated attractors are not globally topologically conjugate to a finite-dimensional linear system, and cannot be represented by a finite-dimensional linear Koopman subspace that includes the state. We then present a data-driven strategy to identify relevant observable functions for Koopman analysis by leveraging a new algorithm to determine relevant terms in a dynamical system by ℓ1-regularized regression of the data in a nonlinear function space; we also show how this algorithm is related to DMD. Finally, we demonstrate the usefulness of nonlinear observable subspaces in the design of Koopman operator optimal control laws for fully nonlinear systems using techniques from linear optimal control. PMID:26919740

Brain-related comorbidities in boys and men with Duchenne Muscular Dystrophy: A descriptive study.

PubMed

Hendriksen, Ruben G F; Vles, Johan S H; Aalbers, Marlien W; Chin, Richard F M; Hendriksen, Jos G M

2018-05-01

Duchenne Muscular Dystrophy (DMD) is more than a muscle disease since there is a higher prevalence of neuropsychological comorbidities. Similarly, the prevalence of epilepsy is increased. Given the nowadays-increasing interest in brain-related comorbidities in DMD, this study aimed to evaluate the relationship between DMD, epilepsy, and associated neurodevelopmental disorders in an international sample of DMD patients. Using a questionnaire-based study we investigated the occurrence of self/by-proxy reported brain-related comorbidities in a group of 228 DMD patients. We evaluated the presence of epilepsy and other brain-related comorbidities, but also the specific mutation in the dystrophin gene. With respect to epilepsy, all individually reported epilepsy cases as based on the questionnaire results including information provided on epilepsy treatment, EEG abnormalities, and a description of how a typical seizure would look like, were independently and blindly re-assessed by two external paediatric neurologists (Cohen's kappa of 0.85). Based on the latter, 18 (7.9%) DMD patients were considered to have epilepsy. In patients with both DMD and epilepsy, certain other brain-related comorbidities (i.e. attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety disorders and sleep disorders) were significantly more prevalent. This study is supportive of a high occurrence of epilepsy and other brain-related comorbidities in DMD. Furthermore this study shows for the first time that the frequency of some of these disorders appear to be further increased when epilepsy is present next to DMD. As this study is limited by the self/by proxy setup and the lack of response rates, future studies should elucidate the true incidence of the (triangular) cooccurrence between epilepsy, neurodevelopmental deficits, and DMD. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Central Arterial Function Measured by Non-invasive Pulse Wave Analysis is Abnormal in Patients with Duchenne Muscular Dystrophy.

PubMed

Ryan, Thomas D; Parent, John J; Gao, Zhiqian; Khoury, Philip R; Dupont, Elizabeth; Smith, Jennifer N; Wong, Brenda; Urbina, Elaine M; Jefferies, John L

2017-08-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutation of dystrophin. Cardiovascular involvement includes dilated cardiomyopathy. Non-invasive assessment of vascular function has not been evaluated in DMD. We hypothesize arterial wave reflection is abnormal in patients with DMD. Pulse wave analysis was performed on DMD patients with a SphygmoCor SCOR-PVx System to determine central blood pressure and augmentation index (AIx) as an assessment of arterial wave reflection. Results were compared to a control group. A total of 43 patients with DMD were enrolled, and compared to 43 normal controls. Central systolic blood pressure was lower, while both AIx-75 (7.8 ± 9.6% vs. 2.1 ± 10.4%, p 0.01, DMD vs. normal) and AIx-not corrected (16.8 ± 10.1% vs. -3.6 ± 10.9, p < 0.001, DMD vs. normal) were higher in the DMD compared to control. Using multivariable linear regression model, the variables found to have a significant effect on AIx-not corrected included diagnosis of DMD, height, and heart rate (r 2  = 0.257). The current data suggest that, despite lower central systolic blood pressure, patients with DMD have higher wave reflection when compared to normal controls, which may represent increased arterial stiffness. Overall there appears to be no effect on ventricular systolic function, however the long-term consequence in this group is unknown. Further study is required to determine the mechanism of these differences, which may be related to the effects of systemic steroids or the role of dystrophin in vascular function.

The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD.

PubMed

Wang, Jing-Zhang; Wu, Peng; Shi, Zhi-Min; Xu, Yan-Li; Liu, Zhi-Jun

2017-08-01

Mutations in the dystrophin gene (Dmd) result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which afflict many newborn boys. In 2016, Brain and Development published several interesting articles on DMD treatment with antisense oligonucleotide, kinase inhibitor, and prednisolone. Even more strikingly, three articles in the issue 6271 of Science in 2016 provide new insights into gene therapy of DMD and BMD via the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). In brief, adeno-associated virus (AAV) vectors transport guided RNAs (gRNAs) and Cas9 into mdx mouse model, gRNAs recognize the mutated Dmd exon 23 (having a stop codon), and Cas9 cut the mutated exon 23 off the Dmd gene. These manipulations restored expression of truncated but partially functional dystrophin, improved skeletal and cardiac muscle function, and increased survival of mdx mice significantly. This review concisely summarized the related advancements and discussed their primary implications in the future gene therapy of DMD, including AAV-vector selection, gRNA designing, Cas9 optimization, dystrophin-restoration efficiency, administration routes, and systemic and long-term therapeutic efficacy. Future orientations, including off-target effects, safety concerns, immune responses, precision medicine, and Dmd-editing in the brain (potentially blocked by the blood-brain barrier) were also elucidated briefly. Collectively, the AAV-mediated and RNA-guided CRISPR/Cas9 system has major superiorities compared with traditional gene therapy, and might contribute to the treatment of DMD and BMD substantially in the near future. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

The HDAC Inhibitor TSA Ameliorates a Zebrafish Model of Duchenne Muscular Dystrophy.

PubMed

Johnson, Nathan M; Farr, Gist H; Maves, Lisa

2013-09-17

Zebrafish are an excellent model for Duchenne muscular dystrophy. In particular, zebrafish provide a system for rapid, easy, and low-cost screening of small molecules that can ameliorate muscle damage in dystrophic larvae. Here we identify an optimal anti-sense morpholino cocktail that robustly knocks down zebrafish Dystrophin (dmd-MO). We use two approaches, muscle birefringence and muscle actin expression, to quantify muscle damage and show that the dmd-MO dystrophic phenotype closely resembles the zebrafish dmd mutant phenotype. We then show that the histone deacetylase (HDAC) inhibitor TSA, which has been shown to ameliorate the mdx mouse Duchenne model, can rescue muscle fiber damage in both dmd-MO and dmd mutant larvae. Our study identifies optimal morpholino and phenotypic scoring approaches for dystrophic zebrafish, further enhancing the zebrafish dmd model for rapid and cost-effective small molecule screening.

Dystrophin-deficient large animal models: translational research and exon skipping

PubMed Central

Yu, Xinran; Bao, Bo; Echigoya, Yusuke; Yokota, Toshifumi

2015-01-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene. Affecting approximately 1 in 3,600-9337 boys, DMD patients exhibit progressive muscle degeneration leading to fatality as a result of heart or respiratory failure. Despite the severity and prevalence of the disease, there is no cure available. While murine models have been successfully used in illustrating the mechanisms of DMD, their utility in DMD research is limited due to their mild disease phenotypes such as lack of severe skeletal muscle and cardiac symptoms. To address the discrepancy between the severity of disease displayed by murine models and human DMD patients, dystrophin-deficient dog models with a splice site mutation in intron 6 were established. Examples of these are Golden Retriever muscular dystrophy and beagle-based Canine X-linked muscular dystrophy. These large animal models are widely employed in therapeutic DMD research due to their close resemblance to the severity of human patient symptoms. Recently, genetically tailored porcine models of DMD with deleted exon 52 were developed by our group and others, and can potentially act as a new large animal model. While therapeutic outcomes derived from these large animal models can be more reliably extrapolated to DMD patients, a comprehensive understanding of these models is still needed. This paper will discuss recent progress and future directions of DMD studies with large animal models such as canine and porcine models. PMID:26396664

Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy.

PubMed

Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A; Blutke, Andreas; Krause, Sabine; Walter, Maggie C; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J

2016-09-16

Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials.

Muscle ultrasound quantifies disease progression over time in infants and young boys with duchenne muscular dystrophy.

PubMed

Zaidman, Craig M; Malkus, Elizabeth C; Connolly, Anne M

2015-09-01

Quantitative muscle ultrasound (QUS) in boys with Duchenne muscular dystrophy (DMD) shows increased echointensity as muscle is replaced with fat and fibrosis. Studies of quantitative ultrasound in infants/young boys with DMD over time have not been reported. We used calibrated muscle backscatter (cMB), a reproducible measure of ultrasound echointensity, to quantify muscle pathology in 5 young boys with DMD (ages 0.5-2.8 years) over 17-29 months. We compared the results with repeated assessments of function (n = 4) and with muscle ultrasound images from a cross-section of 6 male controls (0.6-3.1 years). cMB in boys with DMD increased (worsened) over time (P < 0.001), whereas function improved. After age 2 years, cMB in most (4 of 5) boys with DMD was higher than in any control. QUS measures disease progression in young boys with DMD despite functional improvements. QUS could be employed as an outcome measure for serial assessment of young boys with DMD. © 2015 Wiley Periodicals, Inc.

Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history.

PubMed

Arora, Harneet; Willcocks, Rebecca J; Lott, Donovan J; Harrington, Ann T; Senesac, Claudia R; Zilke, Kirsten L; Daniels, Michael J; Xu, Dandan; Tennekoon, Gihan I; Finanger, Erika L; Russman, Barry S; Finkel, Richard S; Triplett, William T; Byrne, Barry J; Walter, Glenn A; Sweeney, H Lee; Vandenborne, Krista

2018-05-09

Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). The ImagingDMD study has generated a large data set using these tests, which can describe the contemporary natural history of DMD in 5-12.9 year olds. 92 corticosteroid treated boys with DMD and 45 controls participated in this longitudinal study. Subjects performed the 6 minute walk test (6MWT) and timed function tests (TFTs: 10m walk/run, 4 stairs, supine to stand). Boys with DMD had impaired functional performance even at 5-6.9 years. Boys older than 7 had significant declines in function over 1 year for 10m walk/run and 6MWT. 80% of subjects could perform all functional tests at 9 years old. TFTs appear to be slightly more responsive and predictive of disease progression than 6MWT in 7-12.9 year olds. This study provides insight into the contemporary natural history of key functional endpoints in DMD. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Satellite Cells in Muscular Dystrophy - Lost in Polarity

PubMed Central

Chang, Natasha C.; Chevalier, Fabien P.; Rudnicki, Michael A.

2016-01-01

Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem cell divisions and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility, but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review, we highlight recent research advances in DMD and discuss the current state of treatment and importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD. PMID:27161598

Parental attitudes toward newborn screening for Duchenne/Becker muscular dystrophy and spinal muscular atrophy.

PubMed

Wood, Molly F; Hughes, Sarah C; Hache, Lauren P; Naylor, Edwin W; Abdel-Hamid, Hoda Z; Barmada, M Michael; Dobrowolski, Steven F; Stickler, David E; Clemens, Paula R

2014-06-01

Disease inclusion in the newborn screening (NBS) panel should consider the opinions of those most affected by the outcome of screening. We assessed the level and factors that affect parent attitudes regarding NBS panel inclusion of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and spinal muscular atrophy (SMA). The attitudes toward NBS for DMD, BMD, and SMA were surveyed and compared for 2 categories of parents, those with children affected with DMD, BMD, or SMA and expectant parents unselected for known family medical history. The level of support for NBS for DMD, BMD, and SMA was 95.9% among parents of children with DMD, BMD, or SMA and 92.6% among expectant parents. There was strong support for NBS for DMD, BMD, and SMA in both groups of parents. Given advances in diagnostics and promising therapeutic approaches, discussion of inclusion in NBS should continue. Copyright © 2013 Wiley Periodicals, Inc.

PubMed Central

DE LOS ANGELES BEYTÍA, MARIA; VRY, JULIA; KIRSCHNER, JANBERND

2012-01-01

Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3,600-6,000 newborn males. It is manifested by the absence of the dystrophin protein in muscle fibres, which causes progressive damage leading to death in the third decade of life. The only medication so far shown to be effective in delaying the progression of this illness are corticosteroids, which have been shown to increase muscle strength in randomised controlled studies; long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction, dilated cardiomyopathy and scoliosis. Several potential drugs are now being investigated. Genetic therapy, involving the insertion of a dystrophin gene through a vector, has proven effective in animals but not humans. Currently under clinical study is Ataluren, a molecule that binds with ribosomes and may allow the insertion of an aminoacid in the premature termination codon, and exon-skipping, which binds with RNA and excludes specific sites of RNA splicing, producing a dystrophin that is smaller but functional. There are also studies attempting to modulate other muscular proteins, such as myostatin and utrophin, to reduce symptoms. This paper does not address cardiomyopathy treatment in DMD patients. PMID:22655510

Image fusion in craniofacial virtual reality modeling based on CT and 3dMD photogrammetry.

PubMed

Xin, Pengfei; Yu, Hongbo; Cheng, Huanchong; Shen, Shunyao; Shen, Steve G F

2013-09-01

The aim of this study was to demonstrate the feasibility of building a craniofacial virtual reality model by image fusion of 3-dimensional (3D) CT models and 3 dMD stereophotogrammetric facial surface. A CT scan and stereophotography were performed. The 3D CT models were reconstructed by Materialise Mimics software, and the stereophotogrammetric facial surface was reconstructed by 3 dMD patient software. All 3D CT models were exported as Stereo Lithography file format, and the 3 dMD model was exported as Virtual Reality Modeling Language file format. Image registration and fusion were performed in Mimics software. Genetic algorithm was used for precise image fusion alignment with minimum error. The 3D CT models and the 3 dMD stereophotogrammetric facial surface were finally merged into a single file and displayed using Deep Exploration software. Errors between the CT soft tissue model and 3 dMD facial surface were also analyzed. Virtual model based on CT-3 dMD image fusion clearly showed the photorealistic face and bone structures. Image registration errors in virtual face are mainly located in bilateral cheeks and eyeballs, and the errors are more than 1.5 mm. However, the image fusion of whole point cloud sets of CT and 3 dMD is acceptable with a minimum error that is less than 1 mm. The ease of use and high reliability of CT-3 dMD image fusion allows the 3D virtual head to be an accurate, realistic, and widespread tool, and has a great benefit to virtual face model.

Current Translational Research and Murine Models For Duchenne Muscular Dystrophy

PubMed Central

Rodrigues, Merryl; Echigoya, Yusuke; Fukada, So-ichiro; Yokota, Toshifumi

2016-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah-deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52, which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx), mdx52, dystrophin/utrophin double-deficient (dko), mdxβgeo, Dmd-null, humanized DMD (hDMD), mdx on DBA/2 background (DBA/2-mdx), Cmah-mdx, and mdx/mTRKO murine models. PMID:27854202

Growth and psychomotor development of patients with Duchenne muscular dystrophy.

PubMed

Sarrazin, Elisabeth; von der Hagen, Maja; Schara, Ulrike; von Au, Katja; Kaindl, Angela M

2014-01-01

Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Cryo Power and Heat Transfer

DTIC Science & Technology

2004-09-01

of DMD ...........................................................................................47 Figure 3.15: Lens used for intensity...51 Figure 3.18: Imaging system for DMD ...temperatures, converts to a ceramic material Digital Micromirror Device ( DMD ) – A MEMS device that consists of tiny mirror used for light modulation

Biochemical markers of bone metabolism and risk of dorsal metacarpal disease in 2-year-old Thoroughbreds.

PubMed

Jackson, B F; Lonnell, C; Verheyen, K L P; Dyson, P; Pfeiffer, D U; Price, J S

2005-01-01

Dorsal metacarpal disease (DMD) is a common problem in 2-year-old racehorses and results in loss of a significant number of days from training. Biochemical markers of bone cell activity measured early in the training season could have value for identifying 2-year-old Thoroughbred racehorses that develop DMD. To determine the association between serum concentrations of osteocalcin, the carboxyterminal propeptide of type I collagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) measured early in the training season and the risk of DMD. Blood samples were collected from 165 two-year-old Thoroughbreds during late November/early December. Osteocalcin and PICP were measured as markers of bone formation, and ICTP as a marker of bone resorption. Training and veterinary records for each horse were monitored over the following training/racing season (10 months). Cases were defined as an episode where signs of DMD were sufficiently severe for a horse to miss at least 5 consecutive days of training. Classification tree and logistic regression analysis were used to identify the most important factors suitable for prediction of DMD risk. There were 24 cases of DMD during the season (14.6% cumulative incidence), with an average time to recognition of approximately 6 months (May). The earliest recognised case was in February and the latest in September. Osteocalcin and ICTP concentrations in the early stages of the training season were significantly higher in horses that subsequently developed DMD (P = 0.017 and 0.019, respectively). DMD cases were also significantly older compared to noncases (21.04 vs. 20.44 months, P = 0.023). Using a multivariable logistic regression model, it was possible to postulate a set of diagnostic rules to predict the likelihood of DMD injury during the season. This suggested that horses with ICTP concentrations above 12365 ug/l and older than 20.5 months are 2.6 times more likely to develop DMD. The measurement of the bone resorption marker ICTP could be useful for identification of 2-year-olds at increased risk of developing DMD. These findings, together with other strategies such as modification of training regimens, e.g. early introduction of short distances of high-speed exercise into the training programme, could help reduce the days lost to training as a result of DMD.

Translocation (X;6) in a female with Duchenne muscular dystrophy: implications for the localisation of the DMD locus.

PubMed Central

Zatz, M; Vianna-Morgante, A M; Campos, P; Diament, A J

1981-01-01

A female with Duchenne muscular dystrophy who was a carrier of a balanced translocation t(X;6)(p21;q21) is reported. Four other previously described (X;A) translocations associated with DMD share with the present case a breakpoint at Xp21. The extremely low probability of five independent (X;A) translocations having a breakpoint at Xp21 points to a non-rand association of this site with the DMD phenotype. A DMD locus at Xp21 could be damaged by the translocation, giving rise to Duchenne muscular dystrophy. Alternatively, a pre-existing DMD gene could weaken the chromosome, favouring breaks at Xp21. Images PMID:7334502

Serum miR-206 and other muscle-specific microRNAs as non-invasive biomarkers for Duchenne muscular dystrophy.

PubMed

Hu, Jun; Kong, Min; Ye, Yuanzhen; Hong, Siqi; Cheng, Li; Jiang, Li

2014-06-01

Creatine kinase has been utilized as a diagnostic marker for Duchenne muscular dystrophy (DMD), but it correlates less well with the DMD pathological progression. In this study, we hypothesized that muscle-specific microRNAs (miR-1, -133, and -206) in serum may be useful for monitoring the DMD pathological progression, and explored the possibility of these miRNAs as potential non-invasive biomarkers for the disease. By using real-time quantitative reverse transcription-polymerase chain reaction in a randomized and controlled trial, we detected that miR-1, -133, and -206 were significantly over-expressed in the serum of 39 children with DMD (up to 3.20 ± 1.20, 2(-ΔΔCt) ): almost 2- to 4-fold enriched in comparison to samples from the healthy controls (less than 1.15 ± 0.34, 2(-ΔΔCt) ). To determine whether these miRNAs were related to the clinical features of children with DMD, we analyzed the associations compared to creatine kinase. There were very good inverse correlations between the levels of these miRNAs, especially miR-206, and functional performances: high levels corresponded to low muscle strength, muscle function, and quality of life. Moreover, by receiver operating characteristic curves analyses, we revealed that these miRNAs, especially miR-206, were able to discriminate DMD from controls. Thus, miR-206 and other muscle-specific miRNAs in serum are useful for monitoring the DMD pathological progression, and hence as potential non-invasive biomarkers for the disease. There has been a long-standing need for reliable, non-invasive biomarkers for Duchenne muscular dystrophy (DMD). We found that the levels of muscle-specific microRNAs, especially miR-206, in the serum of DMD were 2- to 4-fold higher than in the controls. High levels corresponded to low muscle strength, muscle function, and quality of life (QoL). These miRNAs were able to discriminate DMD from controls by receiver operating characteristic (ROC) curves analyses. Thus, miR-206 and other muscle-specific miRNAs are useful as non-invasive biomarkers for DMD. © 2014 International Society for Neurochemistry.

Verbal and memory skills in males with Duchenne muscular dystrophy

PubMed Central

Hinton, V J; BA, R J Fee; Goldstein, E M; De Vivo, D C

2007-01-01

Duchenne muscular dystrophy (DMD) is a progressive pediatric disorder that affects both muscle and brain. Children with DMD have mean IQ scores that are about one standard deviation lower than population means, with lower Verbal IQ than Performance IQ scores. For the present study, verbal skills and verbal memory skills were examined in males with DMD with the Clinical Evaluation of Language Fundamentals, 3rd edition, and the California Verbal Learning Test for Children. Performance of 50 males with DMD (age range 6–14y, mean 9y 4mo [SD 2y 1mo]) was compared to normative values. Two subsets of the probands were also compared with two comparison groups: unaffected siblings (n=24; DMD group age range 6–12y, mean 9y 1mo [SD 1y 8mo]; sibling age range 6–15y, mean 9y 11mo [SD 2y 4mo]) and males with cerebral palsy (CP); (n=23; DMD group age range 6–9y, mean 7y 8mo [SD 1y 2mo]; CP age range 6–8y, mean 6y 8mo [SD 0y 8mo]). Results demonstrated that although males with DMD performed slightly more poorly than normative values, they performed comparably to the controls on most measures. Consistent deficits were observed only on tests requiring immediate repetition for verbal material (Recalling Sentences, and Concepts and Directions). On other language tasks, including tests of understanding and use of grammar, and understanding of semantic relationships, the males with DMD performed well. Moreover, the males with DMD performed well on multiple indices of verbal recall, and there was no evidence of declarative memory deficits. DMD is a single-gene disorder that is selectively associated with decreased verbal span capacity, but not impaired recall. PMID:17254000

System Biology Approach: Gene Network Analysis for Muscular Dystrophy.

PubMed

Censi, Federica; Calcagnini, Giovanni; Mattei, Eugenio; Giuliani, Alessandro

2018-01-01

Phenotypic changes at different organization levels from cell to entire organism are associated to changes in the pattern of gene expression. These changes involve the entire genome expression pattern and heavily rely upon correlation patterns among genes. The classical approach used to analyze gene expression data builds upon the application of supervised statistical techniques to detect genes differentially expressed among two or more phenotypes (e.g., normal vs. disease). The use of an a posteriori, unsupervised approach based on principal component analysis (PCA) and the subsequent construction of gene correlation networks can shed a light on unexpected behaviour of gene regulation system while maintaining a more naturalistic view on the studied system.In this chapter we applied an unsupervised method to discriminate DMD patient and controls. The genes having the highest absolute scores in the discrimination between the groups were then analyzed in terms of gene expression networks, on the basis of their mutual correlation in the two groups. The correlation network structures suggest two different modes of gene regulation in the two groups, reminiscent of important aspects of DMD pathogenesis.

The use of field-inversion gel electrophoresis for deletion detection in Duchenne muscular dystrophy.

PubMed Central

Chen, J D; Denton, M J; Morgan, G; Pearn, J H; Mackinlay, A G

1988-01-01

Deletion is a common cause of Duchenne muscular dystrophy (DMD). Field-inversion gel electrophoresis, in conjunction with Southern blot hybridization, was used to detect large SfiI DNA fragments in the DMD locus. Two unrelated boys with DMD were found to have abnormal sized DNA fragments resulting from deletions. Some of the female relatives of these patients were also shown by this method to have deletions in the DMD locus. Images Figure 1 PMID:3358426

Abnormal Collagen Metabolism in Cultured Skin Fibroblasts from Patients with Duchenne Muscular Dystrophy

NASA Astrophysics Data System (ADS)

Rodemann, H. Peter; Bayreuther, Klaus

1984-08-01

Total collagen synthesis is decreased by about 29% (P < 0.01) in skin fibroblasts established in vitro from male patients with Duchenne muscular dystrophy (DMD) as compared with that in normal male skin fibroblasts in vitro. The reduction in collagen synthesis is associated with an approximately 2-fold increase in collagen degradation in DMD fibroblasts. Correlated to these alterations in the metabolism of collagen, DMD fibroblasts express a significantly higher hydroxyproline/proline ratio (DMD: 1.36-1.45; P < 0.01) than do normal fibroblasts (controls: 0.86-0.89). The increased hydroxylation of proline residues of collagen (composed of type I and type III) could be the cause for the enhanced degradation of collagen in DMD fibroblasts.

Diffraction of digital micromirror device gratings and its effect on properties of tunable fiber lasers.

PubMed

Chen, Xiao; Yan, Bin-bin; Song, Fei-jun; Wang, Yi-quan; Xiao, Feng; Alameh, Kamal

2012-10-20

A digital micromirror device (DMD) is a kind of widely used spatial light modulator. We apply DMD as wavelength selector in tunable fiber lasers. Based on the two-dimensional diffraction theory, the diffraction of DMD and its effect on properties of fiber laser parameters are analyzed in detail. The theoretical results show that the diffraction efficiency is strongly dependent upon the angle of incident light and the pixel spacing of DMD. Compared with the other models of DMDs, the 0.55 in. DMD grating is an approximate blazed state in our configuration, which makes most of the diffracted radiation concentrated into one order. It is therefore a better choice to improve the stability and reliability of tunable fiber laser systems.

Special Technology Area Review on Micro-Opto-Electro-Mechanical-Systems (MOEMS)

DTIC Science & Technology

1997-12-01

Optical Interference in Night Vision Systems "* DMD Assisted Intelligent Manufacturing of ................................................... SRI...CONCEPT ......................................... p. 8 FIGURE 3(a): DMD LIGHT SWITCHES...p. 9 FIGURE 3(b): SEM PHOTOMICROGRAPHS OF DMD CHIPS ........................................ p. 9 FIGURE 4: MULTI-USER MEMS PROJECTS (MUMPS

A Detailed Study of Transom Breaking Waves

DTIC Science & Technology

2009-05-01

be effectively mapped over a desired area. The novel projection optics of the DLP-enhanced QViz system used a Digital Micromirror Device (DMD), an...optical semiconductor instrument. The DMD device (Texas Instruments, DMD Discovery 1100) contains an array of 1024 by 768 micromirrors . In the

Quantitative muscle ultrasound in Duchenne muscular dystrophy: a comparison of techniques.

PubMed

Shklyar, Irina; Geisbush, Tom R; Mijialovic, Aleksandar S; Pasternak, Amy; Darras, Basil T; Wu, Jim S; Rutkove, Seward B; Zaidman, Craig M

2015-02-01

Muscle pathology in Duchenne muscular dystrophy (DMD) can be quantified using ultrasound by measuring either the amplitudes of sound-waves scattered back from the tissue [quantitative backscatter analysis (QBA)] or by measuring these backscattered amplitudes after compression into grayscale levels (GSL) obtained from the images. We measured and compared QBA and GSL from 6 muscles of 25 boys with DMD and 25 healthy subjects, aged 2-14 years, with age and, in DMD, with function (North Star Ambulatory Assessment). Both QBA and GSL were measured reliably (intraclass correlation ≥ 0.87) and were higher in DMD than controls (P < 0.0001). In DMD, average QBA and GSL measured from superficial regions of muscle increased (rho ≥ 0.47, P < 0.05) with both higher age and worse function; in contrast, GSL measured from whole regions of muscle did not. QBA and GSL measured from superficial regions of muscle can similarly quantify muscle pathology in DMD. © 2014 Wiley Periodicals, Inc.

Parallel detection experiment of fluorescence confocal microscopy using DMD.

PubMed

Wang, Qingqing; Zheng, Jihong; Wang, Kangni; Gui, Kun; Guo, Hanming; Zhuang, Songlin

2016-05-01

Parallel detection of fluorescence confocal microscopy (PDFCM) system based on Digital Micromirror Device (DMD) is reported in this paper in order to realize simultaneous multi-channel imaging and improve detection speed. DMD is added into PDFCM system, working to take replace of the single traditional pinhole in the confocal system, which divides the laser source into multiple excitation beams. The PDFCM imaging system based on DMD is experimentally set up. The multi-channel image of fluorescence signal of potato cells sample is detected by parallel lateral scanning in order to verify the feasibility of introducing the DMD into fluorescence confocal microscope. In addition, for the purpose of characterizing the microscope, the depth response curve is also acquired. The experimental result shows that in contrast to conventional microscopy, the DMD-based PDFCM system has higher axial resolution and faster detection speed, which may bring some potential benefits in the biology and medicine analysis. SCANNING 38:234-239, 2016. © 2015 Wiley Periodicals, Inc. © Wiley Periodicals, Inc.

PMO Delivery System Using Bubble Liposomes and Ultrasound Exposure for Duchenne Muscular Dystrophy Treatment.

PubMed

Negishi, Yoichi; Ishii, Yuko; Nirasawa, Kei; Sasaki, Eri; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo

2018-01-01

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration, caused by nonsense or frameshift mutations in the dystrophin (DMD) gene. Antisense oligonucleotides can be used to induce specific exon skipping; recently, a phosphorodiamidate morpholino oligomer (PMO) has been approved for clinical use in DMD. However, an efficient PMO delivery strategy is required to improve the therapeutic efficacy in DMD patients. We previously developed polyethylene glycol (PEG)-modified liposomes containing ultrasound contrast gas, "Bubble liposomes" (BLs), and found that the combination of BLs with ultrasound exposure is a useful gene delivery tool. Here, we describe an efficient PMO delivery strategy using the combination of BLs and ultrasound exposure to treat muscles in a DMD mouse model (mdx). This ultrasound-mediated BL technique can increase the PMO-mediated exon-skipping efficiency, leading to significantly increased dystrophin expression. Thus, the combination of BLs and ultrasound exposure may be a feasible PMO delivery method to improve therapeutic efficacy and reduce the PMO dosage for DMD treatment.

Design of a high-numerical-aperture digital micromirror device camera with high dynamic range.

PubMed

Qiao, Yang; Xu, Xiping; Liu, Tao; Pan, Yue

2015-01-01

A high-NA imaging system with high dynamic range is presented based on a digital micromirror device (DMD). The DMD camera consists of an objective imaging system and a relay imaging system, connected by a DMD chip. With the introduction of a total internal reflection prism system, the objective imaging system is designed with a working F/# of 1.97, breaking through the F/2.45 limitation of conventional DMD projection lenses. As for the relay imaging system, an off-axis design that could correct off-axis aberrations of the tilt relay imaging system is developed. This structure has the advantage of increasing the NA of the imaging system while maintaining a compact size. Investigation revealed that the dynamic range of a DMD camera could be greatly increased, by 2.41 times. We built one prototype DMD camera with a working F/# of 1.23, and the field experiments proved the validity and reliability our work.

Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy.

PubMed

Viggiano, Emanuela; Ergoli, Manuela; Picillo, Esther; Politano, Luisa

2016-07-01

Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate-severe muscle involvement.

[Study on correlation between HLA-A, B, DR alleles and Duchenne muscular dystrophy].

PubMed

Chen, Wei; Xiao, Lulu; Zhang, Cheng; Wu, Hong-ling

2007-10-01

To analyze the polymorphism of HLA-A, B and DR alleles of Duchenne muscular dystrophy (DMD) patients in Han nationality of South China and to discuss the role of immune and genetic factors in the pathogenesis of DMD and muscular fiber necrosis. Polymerase chain reaction-reverse sequence specific oligonucleotide (PCR-RSSO) and National Marrow Donor Program (NMDP) were used to analyze the polymorphism of HLA-A,B and DR alleles of 113 DMD patients and 406 normal controls in Han nationality of South China. The frequencies of HLA-A24, A30 alleles in DMD group were 11.25% and 5.46% respectively, indicating notable difference (P=0.001, < 0.01) from 22.16% and 0.87% of control group; the frequencies of HLA-B13, B15, B61 and B62 alleles in DMD group were 12.26%, 16.92%, 0.44% and 0.44%, indicating a notable difference (P=0.016, < 0.01, 0.001) from 6.76%, 1.49%, 4.79% and 5.05% of control group; the frequencies of HLA-DR04, DR07, DR12 alleles in DMD group were 17.45%, 6.40% and 19.62%, indicating a notable difference (P=0.018, < 0.01, 0.012) from 10.67%, 2.24% and 11.92% of control group. There are significant differences in the HLA gene frequencies between DMD patients and normal controls. These results suggest that HLA genotype relates to the muscular necrosis and the pathogenesis of DMD.

Patients with Duchenne muscular dystrophy are significantly shorter than those with Becker muscular dystrophy, with the higher incidence of short stature in Dp71 mutated subgroup.

PubMed

Matsumoto, Masaaki; Awano, Hiroyuki; Lee, Tomoko; Takeshima, Yasuhiro; Matsuo, Masafumi; Iijima, Kazumoto

2017-11-01

Duchenne and Becker muscular dystrophy (DMD/BMD) are caused by mutations in the dystrophin gene and are characterized by severe and mild progressive muscle wasting, respectively. Short stature has been reported as a feature of DMD in the Western hemisphere, but not yet confirmed in Orientals. Height of young BMD has not been fully characterized. Here, height of ambulant and steroid naive Japanese 179 DMD and 42 BMD patients between 4 and 10 years of age was retrospectively examined using height standard deviation score (SDS). The mean height SDS of DMD was -1.08 SD that was significantly smaller than normal (p < 0.001), indicating short stature of Japanese DMD. Furthermore, the mean height SDS of BMD was -0.27 SD, suggesting shorter stature than normal. Remarkably, the mean height SDS of DMD was significantly smaller than that of BMD (p < 0.0001). In DMD higher incidence of short stature (height SDS < -2.5 SD) was observed in Dp71 subgroup having mutations in dystrophin exons 63-79 than others having mutations in exons 1-62 (27.8% vs. 7.5%, p = 0.017). These suggested that height is influenced by dystrophin in not only DMD but also BMD and that dystrophin Dp71 has a role in height regulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Stroke in Duchenne Muscular Dystrophy: A Retrospective Longitudinal Study in 54 Patients.

PubMed

Winterholler, Martin; Holländer, Christian; Kerling, Frank; Weber, Irina; Dittrich, Sven; Türk, Matthias; Schröder, Rolf

2016-08-01

Duchenne muscular dystrophy (DMD) is the most frequent skeletal muscle myopathy. Nearly all patients develop cardiomyopathy in their second decade of life. The purpose of this study was to evaluate the frequency, cause, and outcome of stroke in a German cohort of patients with DMD. Retrospective analysis of medical records of 54 DMD patients, who lived in a regional facility for handicapped people (Wichernhaus Altdorf, Germany) between 1963 and 2013. Fifty-four DMD patients were followed up for 7.4 years on average. Mean age at admission and discharge from the long-term care facility or death were 11.4 and 18.8 years, respectively. Covering a total observation period of 400 patient-years, we identified 4 DMD patients with juvenile arterial ischemic strokes. Off-label systemic thrombolysis in 2 patients resulted in a nearly complete regression of stroke-related symptoms, but 1 patient died of septic pneumonia and cardiac failure 24 days after thrombolysis therapy. In the other 2 patients, who had their ischemic strokes in 1994 and 1998, severe infarction-related symptoms persisted, and 1 patient died 13 days later. DMD-associated cardiomyopathy without evidence of atrial fibrillation was the only risk factor for ischemic stroke in all patients. This study indicates an increased risk for ischemic strokes in DMD patients. Regular cardiological assessment of all DMD patients is mandatory to evaluate the individual risk profile for cardioembolic events and to adapt therapeutic strategies. © 2016 American Heart Association, Inc.

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

PubMed

Hathout, Yetrib; Brody, Edward; Clemens, Paula R; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H Lee; Williams, Steve; Gold, Larry

2015-06-09

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

PubMed

Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

2016-01-01

Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

Stomatognathic function in Duchenne muscular dystrophy: a case-control study.

PubMed

Ferreira, Bruno; Da Silva, Gabriel Pádua; Gonçalves, Camila Rosa; Arnoni, Veridiana Wanshi; Siéssere, Selma; Semprini, Marisa; Verri, Edson Donizetti; Chaves, Thais Cristina; Regalo, Simone Cecilio Hallak

2016-05-01

This study aimed to analyse electromyographic activity, masticatory efficiency, muscle thickness, and bite force of individuals with Duchenne muscular dystrophy (DMD). Forty males aged 4-15 years, 20 with DMD and 20 healthy age-, height-, and weight-matched controls, underwent electromyography and ultrasonography of temporalis, masseter, and sternocleidomastoid muscles during postural control of the jaw, mastication, and maximal molar bite force. The normalized electromyography signals showed higher activity in masseter and temporal muscles at rest, during protrusion, left and right laterality, and fatigue condition in the group with DMD than in the comparison group (p≤0.05). For masticatory efficiency of cycles, in analysis of non-habitual chewing of flavourless gum, and habitual chewing of peanuts and raisins, the group with DMD presented lower averages (p≤0.05). For the muscle thickness, the results showed that there was a lower muscle thickness in the group with DMD for all muscles during the rest and maximal voluntary contraction, except for masseter and sternocleidomastoid in the maximal voluntary contraction. In the maximal molar bite force, the group with DMD presented higher values for both sides than the comparison group (p≤0.05). Patients with DMD show muscle changes related to the stomatognathic system, in their activity, bite force, and muscle thickness. © 2016 Mac Keith Press.

Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression.

PubMed

Pescatori, Mario; Broccolini, Aldobrando; Minetti, Carlo; Bertini, Enrico; Bruno, Claudio; D'amico, Adele; Bernardini, Camilla; Mirabella, Massimiliano; Silvestri, Gabriella; Giglio, Vincenzo; Modoni, Anna; Pedemonte, Marina; Tasca, Giorgio; Galluzzi, Giuliana; Mercuri, Eugenio; Tonali, Pietro A; Ricci, Enzo

2007-04-01

Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMP-are progressively induced or repressed in the natural history of DMD.

Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

PubMed Central

Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin’ichi; Aoki, Yoshitsugu

2016-01-01

Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. PMID:27621596

Prevalence and Genetic Profile of Duchene and Becker Muscular Dystrophy in Puerto Rico.

PubMed

Ramos, Edwardo; Conde, José G; Berrios, Rafael Arias; Pardo, Sherly; Gómez, Omar; Mas Rodríguez, Manuel F

2016-05-27

Duchenne and Becker Muscular Dystrophy (DMD and BMD, respectively), are common forms of inherited muscle disease. Information regarding the epidemiology of these conditions, including genotype, is still sparse. To establish the prevalence and genetic profile of DMD and BMD in Puerto Rico. We collected data from medical records in all Muscular Dystrophy Association (MDA) clinics in Puerto Rico in order to estimate the prevalence of DMD and BMD and to describe the genotypic profile of these patients. Patients selected for data analysis matched "definite", "probable" and "possible" case definitions as established by MD STARnet. A total of 141 patients matched the inclusion criteria, with 64.5% and 35.5% being categorized into DMD and BMD, respectively. DMD and BMD prevalence in Puerto Rico was estimated at 5.18 and 2.84 per 100,000 males, respectively. Deletion was the most common form of mutation (66.7%) in the dystrophin gene, with exons in segment 45 to 47 being the most frequently affected. This is the first report of the prevalence and genetic profile characteristics of DMD and BMD in Puerto Rico. Prevalence of DMD was similar to that reported worldwide, while prevalence of BMD was higher. Genetic profile was consistent with that reported in the literature.

Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

PubMed

Ricotti, Valeria; Evans, Matthew R B; Sinclair, Christopher D J; Butler, Jordan W; Ridout, Deborah A; Hogrel, Jean-Yves; Emira, Ahmed; Morrow, Jasper M; Reilly, Mary M; Hanna, Michael G; Janiczek, Robert L; Matthews, Paul M; Yousry, Tarek A; Muntoni, Francesco; Thornton, John S

2016-01-01

A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function. 15 non-ambulant DMD boys (mean age 13.3 y) and 10 age-gender matched healthy controls (mean age 14.6 y) were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.). Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation. Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001). A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7), accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9) and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8). These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

Influenza A Virus Infection Damages Zebrafish Skeletal Muscle and Exacerbates Disease in Zebrafish Modeling Duchenne Muscular Dystrophy

PubMed Central

Goody, Michelle; Jurczyszak, Denise; Kim, Carol; Henry, Clarissa

2017-01-01

INTRODUCTION: Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases. METHODS: We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD. RESULTS: We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic. DISCUSSION: These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging. PMID:29188128

Influenza A Virus Infection Damages Zebrafish Skeletal Muscle and Exacerbates Disease in Zebrafish Modeling Duchenne Muscular Dystrophy.

PubMed

Goody, Michelle; Jurczyszak, Denise; Kim, Carol; Henry, Clarissa

2017-10-25

Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases. We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD. We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic. These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging.

The golden retriever model of Duchenne muscular dystrophy.

PubMed

Kornegay, Joe N

2017-05-19

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about the poor rate of translation of animal model preclinical studies to humans with analogous diseases. Accordingly, in performing GRMD trials, special attention must be paid to experimental design to align with the approach used in DMD clinical trials. This review provides context for the GRMD model, beginning with its original description and extending to its use in preclinical trials.

Corneal edema after phacoemulsification

PubMed Central

Sharma, Namrata; Singhal, Deepali; Nair, Sreelakshmi P; Sahay, Pranita; Sreeshankar, SS; Maharana, Prafulla Kumar

2017-01-01

Phacoemulsification is the most commonly performed cataract surgery in this era. With all the recent advances in investigations and management of cataract through phacoemulsification, most of the patients are able to achieve excellent visual outcome. Corneal edema after phacoemulsification in the immediate postoperative period often leads to patient dissatisfaction and worsening of outcome. Delayed onset corneal edema often warrants endothelial keratoplasty. This review highlights the etiopathogenesis, risk factors, and management of corneal edema in the acute phase including descemet's membrane detachment (DMD) and toxic anterior segment syndrome. Various investigative modalities such as pachymetry, specular microscopy, anterior segment optical coherence tomography, and confocal microscopy have been discussed briefly. PMID:29208818

Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.

PubMed

Wein, Nicolas; Alfano, Lindsay; Flanigan, Kevin M

2015-06-01

Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades. Copyright © 2015 Elsevier Inc. All rights reserved.

Use of the six-minute walk test to characterize golden retriever muscular dystrophy.

PubMed

Acosta, Austin R; Van Wie, Emiko; Stoughton, William B; Bettis, Amanda K; Barnett, Heather H; LaBrie, Nicholas R; Balog-Alvarez, Cynthia J; Nghiem, Peter P; Cummings, Kevin J; Kornegay, Joe N

2016-12-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which loss of the dystrophin protein causes progressive skeletal/cardiac muscle degeneration and death within the third decade. For clinical trials and supportive animal studies, DMD disease progression and response to treatment must be established using outcome parameters (biomarkers). The 6-minute walk test (6MWT), defined as the distance an individual can walk in 6 minutes, is commonly used in DMD clinical trials and has been employed in dogs to characterize cardiac and respiratory disease severity. Building on methods established in DMD and canine clinical studies, we assessed the 6MWT in dogs with the DMD genetic homolog, golden retriever muscular dystrophy (GRMD). Twenty-one cross-bred golden retrievers were categorized as affected (DMD mutation and GRMD phenotype), carrier (female heterozygous for DMD mutation and no phenotype), and normal (wild type DMD gene and normal phenotype). When compared to grouped normal/carrier dogs, GRMD dogs walked shorter height-adjusted distances at 6 and 12 months of age and their distances walked declined with age. Percent change in creatine kinase after 6MWT was greater in GRMD versus normal/carrier dogs at 6 months, providing another potential biomarker. While these data generally support use of the 6MWT as a biomarker for preclinical GRMD treatment trials, there were certain limitations. Results of the 6MWT did not correlate with other outcome parameters for GRMD dogs when considered alone and an 80% increase in mean distance walked would be necessary to achieve satisfactory power. Copyright © 2016 Elsevier B.V. All rights reserved.

Gait patterns comparison of children with Duchenne muscular dystrophy to those of control subjects considering the effect of gait velocity.

PubMed

Gaudreault, Nathaly; Gravel, Denis; Nadeau, Sylvie; Houde, Sylvie; Gagnon, Denis

2010-07-01

3D analysis of the gait of children with Duchenne muscular dystrophy (DMD) was the topic of only a few studies and none of these considered the effect of gait velocity on the gait parameters of children with DMD. Gait parameters of 11 children with DMD were compared to those of 14 control children while considering the effect of gait velocity using 3D biomechanical analysis. Kinematic and kinetic gait parameters were measured using an Optotrak motion analysis system and AMTI force plates embedded in the floor. The data profiles of children with DMD walking at natural gait velocity were compared to those of the control children who walked at both natural and slow gait velocities. When both groups walked at similar velocity, children with DMD had higher cadence and shorter step length. They demonstrated a lower hip extension moment as well as a minimal or absent knee extension moment. At the ankle, a dorsiflexion moment was absent at heel strike due to the anterior location of the center of pressure. The magnitude of the medio-lateral ground reaction force was higher in children with DMD. Despite this increase, the hip abductor moment was lower. Hip power generation was also observed at the mid-stance in DMD children. These results suggest that most of the modifications observed are strategies used by children with DMD to cope with possible muscle weakness in order to provide support, propulsion and balance of the body during gait. Copyright © 2010 Elsevier B.V. All rights reserved.

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

PubMed Central

Koeks, Zaïda; Bladen, Catherine L.; Salgado, David; van Zwet, Erik; Pogoryelova, Oksana; McMacken, Grace; Monges, Soledad; Foncuberta, Maria E.; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Bellgard, Matthew I.; Roy, Anna J.; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Barišić, Nina; Brabec, Petr; Lähdetie, Jaana; Walter, Maggie C.; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Herczegfalvi, Agnes; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Ferlini, Alessandra; Kimura, En; van den Bergen, Janneke C.; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Klein, Andrea; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A. Ayşe; Oznur, Tunca; Topaloğlu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V.; Martin, Ann S.; Peay, Holly L.; Kirschner, Jan; Flanigan, Kevin M.; Straub, Volker; Bushby, Kate; Béroud, Christophe; Verschuuren, Jan J.; Lochmüller, Hanns

2017-01-01

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. PMID:29125504

Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy

PubMed Central

Mankodi, Ami; Bishop, Courtney A.; Auh, Sungyoung; Newbould, Rexford D.; Fischbeck, Kenneth H.; Janiczek, Robert

2016-01-01

Purpose To explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction (AFF) and water T2 (T2,w) in patients with Duchenne muscular dystrophy (DMD). Materials and Methods In twenty healthy volunteer (HV) boys and thirteen subjects with DMD, thigh muscle AFF was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. The study was in compliance with the Patient Privacy Act and approved by the Institutional Review Board. Results AFF in the thigh muscles of subjects with DMD was significantly increased compared to HV boys (p < 0.001). Dixon and IDEAL-CPMG AFF strongly correlated (r = 0.92) and were in good agreement. Muscle T2,w measured by IDEAL-CPMG was independent of changes in AFF. Muscle T2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p < 0.05). There was a strong correlation (p < 0.004) between AFF in all thigh muscles and six-minute walk distance (6MWD) in subjects with DMD. Conclusions IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG AFF and T2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes. PMID:27593185

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

PubMed

Koeks, Zaïda; Bladen, Catherine L; Salgado, David; van Zwet, Erik; Pogoryelova, Oksana; McMacken, Grace; Monges, Soledad; Foncuberta, Maria E; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Bellgard, Matthew I; Roy, Anna J; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Barišić, Nina; Brabec, Petr; Lähdetie, Jaana; Walter, Maggie C; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Herczegfalvi, Agnes; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Ferlini, Alessandra; Kimura, En; van den Bergen, Janneke C; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Klein, Andrea; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A Ayşe; Oznur, Tunca; Topaloğlu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V; Martin, Ann S; Peay, Holly L; Kirschner, Jan; Flanigan, Kevin M; Straub, Volker; Bushby, Kate; Béroud, Christophe; Verschuuren, Jan J; Lochmüller, Hanns

2017-01-01

Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy.

PubMed

van den Bergen, J C; Schade van Westrum, S M; Dekker, L; van der Kooi, A J; de Visser, M; Wokke, B H A; Straathof, C S; Hulsker, M A; Aartsma-Rus, A; Verschuuren, J J; Ginjaar, H B

2014-01-01

Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.

Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

ERIC Educational Resources Information Center

Waring, Phoebe; Woodyatt, Gail

2011-01-01

Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results…

WHOLE-BODY VIBRATION EXERCISE IS WELL TOLERATED IN PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY: A SYSTEMATIC REVIEW.

PubMed

Moreira-Marconi, Eloá; Sá-Caputo, Danubia C; Dionello, Carla F; Guedes-Aguiar, Eliane O; Sousa-Gonçalves, Cintia R; Morel, Danielle S; Paineiras-Domingos, Laisa L; Souza, Patricia L; Kütter, Cristiane R; Costa-Cavalcanti, Rebeca G; Costa, Glenda; Paiva, Patricia C; Figueiredo, Claudia; Brandão-Sobrinho-Neto, Samuel; Stark, Christina; Unger, Marianne; Bernardo-Filho, Mario

2017-01-01

Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X-chromosome, responsible for the production of the dystrophin protein. Complications in the musculoskeletal system have been previously described in DMD patients. Whole body vibration exercise (WBVE) is a treatment that improves musculoskeletal function in movement disorders. The aim of this study was to review the effects of WBVE on functional mobility, bone and muscle in DMD patients. Four databases were searched. Three eligible studies were found; all three conclude the management of DMD patients with WBV was clinically well tolerated. The studies used a side-alternating WBV system, frequencies 7 - 24 Hz; and amplitudes 2 - 4 mm. A work indicates that a temporary increase in creatine kinase in DMD during the first days of WBV was observed, but other authors did not find changes. No significant changes in bone mass, muscle strength or bone markers. Some patients reported subjective functional improvement during training. Interpretation. It is concluded that WBV seems to be a feasible and well tolerated exercise modality in DMD patients.

Femtosecond laser pulse shaping at megahertz rate via a digital micromirror device.

PubMed

Gu, Chenglin; Chang, Yina; Zhang, Dapeng; Cheng, Jiyi; Chen, Shih-Chi

2015-09-01

In this Letter, we present a scanner and digital micromirror device (DMD)-based ultrafast pulse shaper, i.e., S-DUPS, for programmable ultrafast pulse modulation, achieving a shaping rate of 2 MHz. To our knowledge, the S-DUPS is the fastest programmable pulse shaper reported to date. In the S-DUPS, the frequency spectrum of the input pulsed laser is first spread horizontally, and then mapped to a thin stripe on the DMD programmed with phase modulation patterns. A galvanometric scanner, synchronized with the DMD, subsequently scans the spectrum vertically on the DMD to achieve a shaping rate up to 10 s MHz. A grating pair and a cylindrical lens in front of the DMD compensate for the temporal and spatial dispersion of the system. To verify the concept, experiments were conducted with the DMD and the galvanometric scanner operated at 2 kHz and 1 kHz, respectively, achieving a 2 MHz speed for continuous group velocity dispersion tuning, as well as 2% efficiency. Up to 5% efficiency of S-DUPS can be expected with high efficiency gratings and optical components of proper coatings.

Longitudinal Evaluation of Muscle Composition Using Magnetic Resonance in 4 Boys With Duchenne Muscular Dystrophy: Case Series.

PubMed

Senesac, Claudia R; Lott, Donovan J; Forbes, Sean C; Mathur, Sunita; Arpan, Ishu; Senesac, Emily S; Walter, Glenn A; Vandenborne, Krista

2015-07-01

Duchenne muscular dystrophy (DMD), an inherited recessive X chromosome-linked disease, is the most severe childhood form of muscular dystrophy. Boys with DMD experience muscle loss, with infiltration of intramuscular fat into muscles. This case series describes the progression of DMD in boys using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Magnetic resonance results are then compared with an established functional timed test. Four boys with DMD and 4 healthy age-matched controls were chosen from a larger cohort. Boys with DMD were assessed at 4 time points over 2 years, with controls assessed at baseline only. Progression of the disease was documented by assessing the plantar flexors using MRI and MRS techniques and by assessing ambulation using the 30-Foot Fast Walk Test. Transverse relaxation time (T2) values were elevated in all boys with DMD at baseline. The lipid ratio increased rapidly as the disease progressed in 2 boys. Discrete changes in T2 in the other 2 boys with DMD indicated a slower disease progression. Magnetic resonance imaging and MRS allowed monitoring of the disease over all time periods regardless of ambulation status. The magnetic resonance data were collected with 2 different magnets at 2 different field strengths (1.5 and 3.0 T). Although we corrected for this difference, care must be taken in interpreting data when different image collection systems are used. This was a case series of 4 boys with DMD taken from a larger cohort study. Magnetic resonance imaging and MRS are objective, noninvasive techniques for measuring muscle pathology and can be used to detect discrete changes in both people who are ambulatory and those who are nonambulatory. These techniques should be considered when monitoring DMD progression and assessing efficacy of therapeutic interventions. © 2015 American Physical Therapy Association.

PDGFRα signalling promotes fibrogenic responses in collagen-producing cells in Duchenne muscular dystrophy.

PubMed

Ieronimakis, Nicholas; Hays, Aislinn; Prasad, Amalthiya; Janebodin, Kajohnkiart; Duffield, Jeremy S; Reyes, Morayma

2016-12-01

Fibrosis is a characteristic of Duchenne muscular dystrophy (DMD), yet the cellular and molecular mechanisms responsible for DMD fibrosis are poorly understood. Utilizing the Collagen1a1-GFP transgene to identify cells producing Collagen-I matrix in wild-type mice exposed to toxic injury or those mutated at the dystrophin gene locus (mdx) as a model of DMD, we studied mechanisms of skeletal muscle injury/repair and fibrosis. PDGFRα is restricted to Sca1+, CD45- mesenchymal progenitors. Fate-mapping experiments using inducible CreER/LoxP somatic recombination indicate that these progenitors expand in injury or DMD to become PDGFRα+, Col1a1-GFP+ matrix-forming fibroblasts, whereas muscle fibres do not become fibroblasts but are an important source of the PDGFRα ligand, PDGF-AA. While in toxin injury/repair of muscle PDGFRα, signalling is transiently up-regulated during the regenerative phase in the DMD model and in human DMD it is chronically overactivated. Conditional expression of the constitutively active PDGFRα D842V mutation in Collagen-I+ fibroblasts, during injury/repair, hindered the repair phase and instead promoted fibrosis. In DMD, treatment of mdx mice with crenolanib, a highly selective PDGFRα/β tyrosine kinase inhibitor, reduced fibrosis, improved muscle strength, and was associated with decreased activity of Src, a downstream effector of PDGFRα signalling. These observations are consistent with a model in which PDGFRα activation of mesenchymal progenitors normally regulates repair of the injured muscle, but in DMD persistent and excessive activation of this pathway directly drives fibrosis and hinders repair. The PDGFRα pathway is a potential new target for treatment of progressive DMD. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Longitudinal Evaluation of Muscle Composition Using Magnetic Resonance in 4 Boys With Duchenne Muscular Dystrophy: Case Series

PubMed Central

Lott, Donovan J.; Forbes, Sean C.; Mathur, Sunita; Arpan, Ishu; Senesac, Emily S.; Walter, Glenn A.; Vandenborne, Krista

2015-01-01

Background Duchenne muscular dystrophy (DMD), an inherited recessive X chromosome-linked disease, is the most severe childhood form of muscular dystrophy. Boys with DMD experience muscle loss, with infiltration of intramuscular fat into muscles. Objectives This case series describes the progression of DMD in boys using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Magnetic resonance results are then compared with an established functional timed test. Methods Four boys with DMD and 4 healthy age-matched controls were chosen from a larger cohort. Boys with DMD were assessed at 4 time points over 2 years, with controls assessed at baseline only. Progression of the disease was documented by assessing the plantar flexors using MRI and MRS techniques and by assessing ambulation using the 30-Foot Fast Walk Test. Results Transverse relaxation time (T2) values were elevated in all boys with DMD at baseline. The lipid ratio increased rapidly as the disease progressed in 2 boys. Discrete changes in T2 in the other 2 boys with DMD indicated a slower disease progression. Magnetic resonance imaging and MRS allowed monitoring of the disease over all time periods regardless of ambulation status. Limitations The magnetic resonance data were collected with 2 different magnets at 2 different field strengths (1.5 and 3.0 T). Although we corrected for this difference, care must be taken in interpreting data when different image collection systems are used. This was a case series of 4 boys with DMD taken from a larger cohort study. Conclusions Magnetic resonance imaging and MRS are objective, noninvasive techniques for measuring muscle pathology and can be used to detect discrete changes in both people who are ambulatory and those who are nonambulatory. These techniques should be considered when monitoring DMD progression and assessing efficacy of therapeutic interventions. PMID:25592189

Compact multichannel MEMS based spectrometer for FBG sensing

NASA Astrophysics Data System (ADS)

Ganziy, D.; Rose, B.; Bang, O.

2017-04-01

We propose a novel type of compact multichannel MEMS based spectrometer, where we replace the linear detector with a Digital Micromirror Device (DMD). The DMD is typically cheaper and has better pixel sampling than an InGaAs detector used in the 1550 nm range, which leads to cost reduction and better performance. Moreover, the DMD is a 2D array, which means that multichannel systems can be implemented without any additional optical components in the spectrometer. This makes the proposed interrogator highly cost-effective. The digital nature of the DMD also provides opportunities for advanced programmable spectroscopy.

Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy.

PubMed

Rodríguez-Cruz, Maricela; Sanchez, Raúl; Escobar, Rosa E; Cruz-Guzmán, Oriana Del Rocío; López-Alarcón, Mardia; Bernabe García, Mariela; Coral-Vázquez, Ramón; Matute, Guadalupe; Velázquez Wong, Ana Claudia

2015-01-01

Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16-74.69) and 50 (OR = 8.73; 95% CI = 1.17-65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR.

Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

PubMed Central

Rodríguez-Cruz, Maricela; Sanchez, Raúl; Escobar, Rosa E.; Cruz-Guzmán, Oriana del Rocío; López-Alarcón, Mardia; Bernabe García, Mariela; Coral-Vázquez, Ramón; Matute, Guadalupe; Velázquez Wong, Ana Claudia

2015-01-01

Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69) and 50 (OR = 8.73; 95% CI = 1.17–65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR. PMID:26089900

Ultrafast axial scanning for two-photon microscopy via a digital micromirror device and binary holography.

PubMed

Cheng, Jiyi; Gu, Chenglin; Zhang, Dapeng; Wang, Dien; Chen, Shih-Chi

2016-04-01

In this Letter, we present an ultrafast nonmechanical axial scanning method for two-photon excitation (TPE) microscopy based on binary holography using a digital micromirror device (DMD), achieving a scanning rate of 4.2 kHz, scanning range of ∼180  μm, and scanning resolution (minimum step size) of ∼270  nm. Axial scanning is achieved by projecting the femtosecond laser to a DMD programmed with binary holograms of spherical wavefronts of increasing/decreasing radii. To guide the scanner design, we have derived the parametric relationships between the DMD parameters (i.e., aperture and pixel size), and the axial scanning characteristics, including (1) maximum optical power, (2) minimum step size, and (3) scan range. To verify the results, the DMD scanner is integrated with a custom-built TPE microscope that operates at 60 frames per second. In the experiment, we scanned a pollen sample via both the DMD scanner and a precision z-stage. The results show the DMD scanner generates images of equal quality throughout the scanning range. The overall efficiency of the TPE system was measured to be ∼3%. With the high scanning rate, the DMD scanner may find important applications in random-access imaging or high-speed volumetric imaging that enables visualization of highly dynamic biological processes in 3D with submillisecond temporal resolution.

Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

PubMed

Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

2015-03-01

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

78 FR 36591 - David M. Lewis, D.M.D., Dismissal of Proceeding

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration David M. Lewis, D.M.D., Dismissal of Proceeding On December 5, 2012, the Deputy Assistant Administrator, Office of Diversion Control, Drug Enforcement Administration (DEA), issued an Order to Show Cause to David M. Lewis, D.M.D. (Registrant), of Sacramento, California. The Show Cause Order...

General relation between the group delay and dwell time in multicomponent electron systems

NASA Astrophysics Data System (ADS)

Zhai, Feng; Lu, Junqiang

2016-10-01

For multicomponent electron scattering states, we derive a general relation between the Wigner group delay and the Bohmian dwell time. It is found that the definition of group delay should account for the phase of the spinor wave functions of propagating modes. The difference between the group delay and dwell time comes from both the interference delay and the decaying modes. For barrier tunneling of helical electrons on a surface of topological insulators, our calculations including the trigonal-warping term show that the decaying modes can contribute greatly to the group delay. The derived relation between the group delay and the dwell time is helpful to unify the two definitions of tunneling time in a quite general situation.

Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy.

PubMed

Mankodi, Ami; Bishop, Courtney A; Auh, Sungyoung; Newbould, Rexford D; Fischbeck, Kenneth H; Janiczek, Robert L

2016-10-01

The purpose of this study was to explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction and water T 2 (T 2,w ) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer boys and thirteen subjects with DMD, thigh muscle apparent fat fraction was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T 2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. The study was in compliance with the Patient Privacy Act and approved by the Institutional Review Board. Apparent fat fraction in the thigh muscles of subjects with DMD was significantly increased compared to healthy volunteer boys (p <0.001). There was a strong correlation between Dixon and IDEAL-CPMG apparent fat fraction. Muscle T 2,w measured by IDEAL-CPMG was independent of changes in apparent fat fraction. Muscle T 2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p <0.05). There was a strong correlation (p <0.004) between apparent fat fraction in all thigh muscles and six-minute walk distance (6MWD) in subjects with DMD. IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG apparent fat fraction and T 2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes. Published by Elsevier B.V.

A retrospective study on the incidence of post-cataract surgery Descemet's membrane detachment and outcome of air descemetopexy.

PubMed

Odayappan, Annamalai; Shivananda, Narayana; Ramakrishnan, Seema; Krishnan, Tiruvengada; Nachiappan, Sivagami; Krishnamurthy, Smitha

2018-02-01

To study the anatomic and functional outcome of air descemetopexy in postcataract surgery Descemet's membrane detachment (DMD). Retrospective study. Setting: Institutional. Records of 112 patients who underwent air descemetopexy for postcataract surgery sight-threatening DMD at Aravind Eye Hospital, Pondicherry, between January 2013 and December 2015 were studied. Anatomical outcome refers to reattachment of the Descemet's membrane (DM). Functional outcome was given by the best-corrected visual acuity. The mean age was 66.47±8.46 (SD) years, the male to female ratio was 45:67. The incidence of DMD was more in extracapsular cataract extraction (0.26%) and manual small incision cataract surgery (0.11%) than phacoemulsification (0.04%) (p=0.005 and p<0.0001). DMD was more common among surgical trainees (0.17%) than consultants (0.07%) (p≤0.0001). After primary air descemetopexy, 78 (71%) out of the 110 patients had DM reattachment. The complications noted after descemetopexy include persistent DMD (21.8%), corneal decompensation (7.3%), appositional angle closure (18%), pupillary block with air (2.7%) and uveitis (2.7%). Age, sex and timing of intervention did not influence the reattachment rate. Fifteen patients underwent repeat air descemetopexy for persistent DMD among whom nine (60%) had successful reattachment. Almost 75% of patients had vision better than 6/18 1 month after anatomically successful descemetopexy. Air descemetopexy is a safe and efficient modality of treatment of DMD and should be tried even in patients with severe DMD before planning a major surgery like endothelial keratoplasty. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Genomics and cure: understanding narratives of patients with Duchenne muscular dystrophy in Japan.

PubMed

Kato, Masae

2018-04-01

Globally, genomics research is expected to enhance the health of patients with intractable diseases such as Duchenne muscular dystrophy (DMD). But how do patients perceive medical and scientific attempts at creating drugs and finding cure, and why? Since the 1990s, a number of clinical trials for patients of DMD have been organized. Among them are a gene therapy and exon skipping, and they indicate the possibility of finding therapies for DMD patients. Since 2011, Japanese medical institutions have been participating in Global Clinical Trials so that Japanese DMD patients can have access to them once developed. Despite ongoing global clinical trials, however, field research shows that the DMD patients the author encountered were neither enthusiastic nor well informed about gene therapies developed in Japan or elsewhere. Why not? The author observed that the desire for a cure among DMD patients is not self-evident, but is framed by sociocultural conditions surrounding the patients, the local history of discrimination against genetic disorders, and the way care is organised. These factors further interplay with physical and mental conditions particular to DMD, affecting patients' desire for a cure. This paper discusses the perception of genomics research and the possibility of a cure of DMD patients the author encountered in Japan, indicating that such perceptions are a result of the deeply-related interactions of the conditions in which patients live. Finally, the author suggests how commonly held views of patients and patients' desire for cure need to be nuanced in genomic medicine. Data in this paper were collected between April and July 2014, and between 1996 and 2005 in Japan.

Equalizer tap length requirement for mode group delay-compensated fiber link with weakly random mode coupling.

PubMed

Bai, Neng; Li, Guifang

2014-02-24

The equalizer tap length requirement is investigated analytically and numerically for differential modal group delay (DMGD) compensated fiber link with weakly random mode coupling. Each span of the DMGD compensated link comprises multiple pairs of fibers which have opposite signs of DMGD. The result reveals that under weak random mode coupling, the required tap length of the equalizer is proportional to modal group delay of a single DMGD compensated pair, instead of the total modal group delay (MGD) of the entire link. By using small DMGD compensation step sizes, the required tap length (RTL) can be potentially reduced by 2 orders of magnitude.

Simulation of the effect of incline incident angle in DMD Maskless Lithography

NASA Astrophysics Data System (ADS)

Liang, L. W.; Zhou, J. Y.; Xiang, L. L.; Wang, B.; Wen, K. H.; Lei, L.

2017-06-01

The aim of this study is to provide a simulation method for investigation of the intensity fluctuation caused by the inclined incident angle in DMD (digital micromirror device) maskless lithography. The simulation consists of eight main processes involving the simplification of the DMD aperture function and light propagation utilizing the non-parallel angular spectrum method. These processes provide a possibility of co-simulation in the spatial frequency domain, which combines the microlens array and DMD in the maskless lithography system. The simulation provided the spot shape and illumination distribution. These two parameters are crucial in determining the exposure dose in the existing maskless lithography system.

Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy.

PubMed

Ropars, Juliette; Lempereur, Mathieu; Vuillerot, Carole; Tiffreau, Vincent; Peudenier, Sylviane; Cuisset, Jean-Marie; Pereon, Yann; Leboeuf, Fabien; Delporte, Ludovic; Delpierre, Yannick; Gross, Raphaël; Brochard, Sylvain

2016-01-01

The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity.

PubMed Central

Bello, Luca

2016-01-01

Accurate definition of genetic mutations causing Duchenne muscular dystrophy (DMD) has always been relevant in order to provide genetic counseling to patients and families, and helps to establish the prognosis in the case where the distinction between Duchenne, Becker, or intermediate muscular dystrophy is not obvious. As molecular treatments aimed at dystrophin restoration in DMD are increasingly available as commercialized drugs or within clinical trials, genetic diagnosis has become an indispensable tool in order to determine eligibility for these treatments. DMD patients in which multiplex ligation-dependent probe amplification (MLPA) or similar techniques show a deletion suitable to exon skipping of exons 44, 45, 51, or 53, may be currently treated with AONs targeting these exons, in the context of clinical trials, or, as is the case for exon 51 skipping in the United States, with the first commercialized drug (eteplirsen). Patients who test negative at MLPA, but in whom DMD gene sequencing shows a nonsense mutation, may be amenable for treatment with stop codon readthrough compounds such as ataluren. Novel molecular approaches such as CRISPR-Cas9 targeting of specific DMD mutations are still in the preclinical stages, but appear promising. In conclusion, an accurate genetic diagnosis represents the entrance into a new scenario of personalized medicine in DMD. PMID:28484312

Utility of Cystatin C to monitor renal function in Duchenne muscular dystrophy

PubMed Central

Viollet, Laurence; Gailey, Susan; Thornton, David J.; Friedman, Neil R.; Flanigan, Kevin M.; Mahan, John D.; Mendell, Jerry R.

2009-01-01

Introduction: Creatinine as a marker of renal function has limited value in Duchenne muscular dystrophy (DMD) because of reduced muscle mass. Alternative methods of assessing renal function are sorely needed. Cystatin C, a nonglycosylated protein unaffected by muscle mass, is potentially an ideal biomarker of nephrotoxicity for this population but requires validation. Methods: 75 subjects were recruited: 35 DMD (mean age 10.8 ± 5.4 years, corticosteroids n = 19, ambulatory n = 26), 29 healthy controls, 10 with renal disease, and one DMD with renal failure. Results: Cystatin C levels in DMD were normal irrespective of age, ambulation or corticosteroid treatment. Serum cystatin C was 0.67 ± 0.11 mg/L compared to normal controls 0.69 ± 0.09. mg/L. In these same individuals serum creatinine was severely reduced (0.27 ± 0.12 mg/dL) versus normals (0.75 ± 0.15 mg/dL, p < 0.01). In one DMD subject in renal failure, cystatin C was elevated. Discussion: This study demonstrates the potential value of cystatin C as a biomarker for monitoring renal function in DMD. Its applicability extends to other neuromuscular diseases. PMID:19623638

Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model.

PubMed

Choi, In Young; Lim, HoTae; Estrellas, Kenneth; Mula, Jyothi; Cohen, Tatiana V; Zhang, Yuanfan; Donnelly, Christopher J; Richard, Jean-Philippe; Kim, Yong Jun; Kim, Hyesoo; Kazuki, Yasuhiro; Oshimura, Mitsuo; Li, Hongmei Lisa; Hotta, Akitsu; Rothstein, Jeffrey; Maragakis, Nicholas; Wagner, Kathryn R; Lee, Gabsang

2016-06-07

Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our "chemical-compound-based" strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFβ signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological "dual-SMAD" inhibition, the DMD-hiPSC-derived myoblasts and genetically corrected isogenic myoblasts form "rescued" multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human "DMD-in-a-dish" model using hiPSC-based disease modeling. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

PubMed Central

Amoasii, Leonela; Long, Chengzu; Li, Hui; Mireault, Alex A.; Shelton, John M.; Sanchez-Ortiz, Efrain; McAnally, John R.; Bhattacharyya, Samadrita; Schmidt, Florian; Grimm, Dirk; Hauschka, Stephen D.; Bassel-Duby, Rhonda; Olson, Eric N.

2017-01-01

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle disease caused by mutations in the dystrophin gene. The majority of DMD mutations are deletions that prematurely terminate the dystrophin protein. Deletions of exon 50 of the dystrophin gene are among the most common single exon deletions causing DMD. Such mutations can be corrected by skipping exon 51, thereby restoring the dystrophin reading frame. Using clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9), we generated a DMD mouse model by deleting exon 50. These ΔEx50 mice displayed severe muscle dysfunction, which was corrected by systemic delivery of adeno-associated virus encoding CRISPR/Cas9 genome editing components. We optimized the method for dystrophin reading frame correction using a single guide RNA that created reframing mutations and allowed skipping of exon 51. In conjunction with muscle-specific expression of Cas9, this approach restored up to 90% of dystrophin protein expression throughout skeletal muscles and the heart of ΔEx50 mice. This method of permanently bypassing DMD mutations using a single cut in genomic DNA represents a step toward clinical correction of DMD mutations and potentially those of other neuromuscular disorders. PMID:29187645

Genetic therapeutic approaches for Duchenne muscular dystrophy.

PubMed

Foster, Helen; Popplewell, Linda; Dickson, George

2012-07-01

Despite an expansive wealth of research following the discovery of the DMD gene 25 years ago, there is still no curative treatment for Duchenne muscular dystrophy. However, there are currently many promising lines of research, including cell-based therapies and pharmacological reagents to upregulate dystrophin via readthrough of nonsense mutations or by upregulation of the dystrophin homolog utrophin. Here we review genetic-based therapeutic strategies aimed at the amelioration of the DMD phenotype. These include the reintroduction of a copy of the DMD gene into an affected tissue by means of a viral vector; correction of the mutated DMD transcript by antisense oligonucleotide-induced exon skipping to restore the open reading frame; and direct modification of the DMD gene at a chromosomal level through genome editing. All these approaches are discussed in terms of the more recent advances, and the hurdles to be overcome if a comprehensive and effective treatment for DMD is to be found. These hurdles include the need to target all musculature of the body. Therefore any potential treatment would need to be administered systemically. In addition, any treatment needs to have a long-term effect, with the possibility of readministration, while avoiding any potentially detrimental immune response to the vector or transgene.

WHOLE-BODY VIBRATION EXERCISE IS WELL TOLERATED IN PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY: A SYSTEMATIC REVIEW

PubMed Central

Moreira-Marconi, Eloá; Sá-Caputo, Danubia C; Dionello, Carla F; Guedes-Aguiar, Eliane O; Sousa-Gonçalves, Cintia R; Morel, Danielle S; Paineiras-Domingos, Laisa L; Souza, Patricia L; Kütter, Cristiane R; Costa-Cavalcanti, Rebeca G; Costa, Glenda; Paiva, Patricia C; Figueiredo, Claudia; Brandão-Sobrinho-Neto, Samuel; Stark, Christina; Unger, Marianne; Bernardo-Filho, Mario

2017-01-01

Background: Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X-chromosome, responsible for the production of the dystrophin protein. Complications in the musculoskeletal system have been previously described in DMD patients. Whole body vibration exercise (WBVE) is a treatment that improves musculoskeletal function in movement disorders. The aim of this study was to review the effects of WBVE on functional mobility, bone and muscle in DMD patients. Materials and Methods: Four databases were searched. Three eligible studies were found; all three conclude the management of DMD patients with WBV was clinically well tolerated. The studies used a side-alternating WBV system, frequencies 7 - 24 Hz; and amplitudes 2 - 4 mm. Results: A work indicates that a temporary increase in creatine kinase in DMD during the first days of WBV was observed, but other authors did not find changes. No significant changes in bone mass, muscle strength or bone markers. Some patients reported subjective functional improvement during training. Interpretation: Conclusion: It is concluded that WBV seems to be a feasible and well tolerated exercise modality in DMD patients. PMID:28740938

Separation control in a hypersonic shock wave / turbulent boundary-layer interaction

NASA Astrophysics Data System (ADS)

Schreyer, Anne-Marie; Bermejo-Moreno, Ivan; Kim, Jeonglae; Urzay, Javier

2016-11-01

Hypersonic vehicles play a key role for affordable access to space. The associated flow fields are strongly affected by shock wave/turbulent boundary-layer interactions, and the inherent separation causes flow distortion and low-frequency unsteadiness. Microramp sub-boundary layer vortex generators are a promising means to control separation and diminish associated detrimental effects. We investigate the effect of a microramp on the low-frequency unsteadiness in a fully separated interaction. A large eddy simulation of a 33 ∘ -compression-ramp interaction was performed for an inflow Mach number of 7.2 and a Reynolds number based on momentum thickness of Reθ = 3500 , matching the experiment of Schreyer et al. (2011). For the control case, we introduced a counter-rotating vortex pair, as induced by a single microramp, into the boundary layer through the inflow conditions. We applied a dynamic mode decomposition (DMD) on both cases to identify coherent structures that are responsible for the dynamic behavior. Based on the DMD, we discuss the reduction of the separation zone and the stabilization of the shock motion achieved by the microramp, and contribute to the description of the governing mechanisms. Pursued during the 2016 CTR Summer Program at Stanford University.

Motor and Cognitive Assessment of Infants and Young Boys with Duchenne Muscular Dystrophy; Results from the Muscular Dystrophy Association DMD Clinical Research Network

PubMed Central

Connolly, Anne M.; Florence, Julaine M.; Cradock, Mary M.; Malkus, Elizabeth C.; Schierbecker, Jeanine R.; Siener, Catherine A.; Wulf, Charlie O.; Anand, Pallavi; Golumbek, Paul T.; Zaidman, Craig M; Miller, J Philip; Lowes, Linda P; Alfano, Lindsay N.; Viollet-Callendret, Laurence; Flanigan, Kevin M.; Mendell, Jerry R.; McDonald, Craig M.; Goude, Erica; Johnson, Linda; Nicorici, Alina; Karachunski, Peter I.; Day, John W.; Dalton, Joline C.; Farber, Janey M.; Buser, Karen K.; Darras, Basil T.; Kang, Peter B.; Riley, Susan O.; Shriber, Elizabeth; Parad, Rebecca; Bushby, Kate; Eagle, Michelle

2013-01-01

Therapeutic trials in Duchenne Muscular dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley-III Scales of Infant and Toddler Development (Bayley-III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n=24; 1.9±0.7 years) were assessed. The mean Bayley-III motor composite score was low (82.8 ± 8; p=<.0001)(normal=100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p=<.0001). The mean cognitive comprehensive (p=.0002), receptive language (p=<.0001), and expressive language (p=.0001) were also low compared to normal children. Age was negatively associated with Bayley-III gross motor (r=−0.44 p=.02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n =18 boys; 2.2 ± 0.4years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley-III. PMID:23726376

Designing, Probing, and Stabilizing Exotic Fabry-Perot Cavities for Studying Strongly Correlated Light

NASA Astrophysics Data System (ADS)

Ryou, Albert

Synthetic materials made of engineered quasiparticles are a powerful platform for studying manybody physics and strongly correlated systems due to their bottom-up approach to Hamiltonian modeling. Photonic quasiparticles called polaritons are particularly appealing since they inherit fast dynamics from light and strong interaction from matter. This thesis describes the experimental demonstration of cavity Rydberg polaritons, which are composite particles arising from the hybridization of an optical cavity with Rydberg EIT, as well as the tools for probing and stabilizing the cavity. We first describe the design, construction, and testing of a four-mirror Fabry-Perot cavity, whose small waist size on the order of 10 microns is comparable to the Rydberg blockade radius. By achieving strong coupling between the cavity photon and an atomic ensemble undergoing electromagnetically induced transparency (EIT), we observe the emergence of the dark-state polariton and characterize its single-body properties as well as the single-quantum nonlinearity. We then describe the implementation of a holographic spatial light modulator for exciting different transverse modes of the cavity, an essential tool for studying polariton-polariton scattering. For compensating optical aberrations, we employ a digital micromirror device (DMD), combining beam shaping with adaptive optics to produce diffraction-limited light. We quantitatively measure the purity of the DMD-produced Hermite-Gauss modes and confirm up to 99.2% efficiency. One application of the technique is to create Laguerre-Gauss modes, which have been used to probe synthetic Landau levels for photons in a twisted, nonplanar cavity. Finally, we describe the implementation of an FPGA-based FIR filter for stabilizing the cavity. We digitally cancel the acoustical resonances of the feedback-controlled mechanical system, thereby demonstrating an order-of-magnitude enhancement in the feedback bandwidth from 200 Hz to more than 2 kHz. Harnessing the massive processing power of a state-of-the-art FPGA, we present a novel, low-latency digital architecture for loop-shaping, with applications in atomic physics and beyond.

1000 X Difference Between Current Displays and Capability of Human Visual System: Payoff Potential for Affordable Defense Systems

DTIC Science & Technology

2000-01-01

second tier technologies: digital micromirror devices (DMD); alternating current gas plasma (ACGP); inorganic electroluminescent (EL, TFEL, AMEL... Micromirror Device (DMD) - Alternating Current Gas Plasma (ACGP) - Electroluminescent (EL, TFEL, AMEL) - Vacuum Fluorescent Display (VFD) - Inorganic Light...Instruments Digital Micromirror Device (DMD) Digital Light Processing technology and another, the Qualcomm/Hughes-JVC CRT/Liquid Crystal Light Valve

Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis.

PubMed

Srivastava, Niraj Kumar; Yadav, Ramakant; Mukherjee, Somnath; Sinha, Neeraj

2018-03-01

Muscular dystrophy is an inherited muscle disease, characterized by progressive muscle wasting and weakness of variable distribution and severity. In vitro, high-resolution proton nuclear magnetic resonance (NMR) spectroscopy based analysis was performed on perchloric acid (PCA) extract of muscle specimens of patients suffering from various types of muscular dystrophies to identify alteration in hydrophilic low-molecular weight substances (aqueous metabolites) as compared to muscle of control subjects as well as in between the types of muscular dystrophy. Muscle tissue specimens were obtained from Duchenne muscular dystrophy (DMD) [n=11], Becker muscular dystrophy (BMD) [n=12], facioscapulohumeral dystrophy (FSHD) [n=9] and limb girdle muscular dystrophy (LGMD)-2B [n=22]. Control muscle specimens [n=40] were also taken. Concentration of branched chain amino acids (BCA), glutamine/glutamate (Gln/Glu), acetate (Ace) and fumarate (Fum) was decreased and His was increased in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control subjects. Alanine (Ala) was significantly reduced in BMD, FSHD and LGMD-2B patients as compared to control subjects. Tyrosine (Tyr) was present only in the muscle tissue of control subjects. Propionate (Prop) was present in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients and was absent in muscle tissue of control subjects. Concentration of BCA and Prop is significantly reduced in patients with DMD as compared to BMD, but Glucose is significantly higher in patients with DMD as compared to BMD. Quantity of Glucose, His and Gln/glu are significantly higher in patients with DMD as compared to FSHD, but Prop is significantly reduced in patients with DMD as compared to FSHD. Concentration of Ala and His is significantly higher in patients with DMD as compared to LGMD-2B, but BCA, Glucose and Prop are significantly reduced in patients with DMD as compared to LGMD-2B. Concentration of His is significantly higher in patients with BMD as compared to FSHD. Concentration of His is significantly reduced and Glucose is higher in patients with LGMD-2B as compared to BMD. Glucose concentration is significantly reduced in patients with FSHD as compared to LGMD-2B. ROC curves supported the noticeable discrimination in between the patients with DMD and FSHD for the quantity of Gln/Glu, and patients with LGMD-2B and DMD for the quantity of Ala. Collectively, these findings showed the perturbation of muscle metabolism in muscular dystrophy. The data of presented study may be used as supporting information for existing methods of the diagnosis for patients with muscular dystrophy. Copyright © 2017 Elsevier B.V. All rights reserved.

[Advances in genome editing technologies for treating muscular dystrophy.

PubMed

Makita, Yukimasa; Hozumi, Hiroyuki; Hotta, Akitsu

Recent advances in genome editing technologies have opened the possibility for treating genetic diseases, such as Duchenne muscular dystrophy(DMD), by correcting the causing gene mutations in dystrophin gene. In fact, there are several reports that demonstrated the restoration of the mutated dystrophin gene in DMD patient-derived iPS cell or functional recovery of forelimb grip strength in DMD model mice. For future clinical applications, there are several aspects that need to be taken into consideration:efficient delivery of the genome editing components, risk of off-target mutagenesis and immunogenicity against genome editing enzyme. In this review, we summarize the current status and future prospective of the research in applying genome editing technologies to DMD.

Development of a digital-micromirror-device-based multishot snapshot spectral imaging system.

PubMed

Wu, Yuehao; Mirza, Iftekhar O; Arce, Gonzalo R; Prather, Dennis W

2011-07-15

We report on the development of a digital-micromirror-device (DMD)-based multishot snapshot spectral imaging (DMD-SSI) system as an alternative to current piezostage-based multishot coded aperture snapshot spectral imager (CASSI) systems. In this system, a DMD is used to implement compressive sensing (CS) measurement patterns for reconstructing the spatial/spectral information of an imaging scene. Based on the CS measurement results, we demonstrated the concurrent reconstruction of 24 spectral images. The DMD-SSI system is versatile in nature as it can be used to implement independent CS measurement patterns in addition to spatially shifted patterns that piezostage-based systems can offer. © 2011 Optical Society of America

Three Wishes and Psychological Functioning in Boys with Duchenne Muscular Dystrophy

PubMed Central

NEREO, NANCY E.; HINTON, VERONICA J.

2007-01-01

This study examined Three Wishes (a projective technique commonly used with children) in boys with Duchenne muscular dystrophy (DMD), a fatal, progressive illness (n = 74). A reliable and parsimonious scoring system was developed to code wish type. Probands’ responses were compared with unaffected siblings (n = 32) and a male comparison group (n = 43). Contrary to what was expected, the DMD group did not make significantly more health-related wishes than their siblings or the comparison group. Further, no association between health-related wishes and problem behaviors was observed in the DMD group. These findings indicate that, despite increased stressors, boys with DMD present wishes similar to those of their healthy peers. PMID:12692454

The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice.

PubMed

Di Certo, Maria Grazia; Corbi, Nicoletta; Strimpakos, Georgios; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Guglielmotti, Angelo; Batassa, Enrico Maria; Pisani, Cinzia; Floridi, Aristide; Benassi, Barbara; Fanciulli, Maurizio; Magrelli, Armando; Mattei, Elisabetta; Passananti, Claudio

2010-03-01

The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.

Non-invasive assessment of muscle stiffness in patients with Duchenne muscular dystrophy.

PubMed

Lacourpaille, Lilian; Hug, François; Guével, Arnaud; Péréon, Yann; Magot, Armelle; Hogrel, Jean-Yves; Nordez, Antoine

2015-02-01

Assessment of muscle mechanical properties may provide clinically valuable information for follow-up of patients with Duchenne muscular dystrophy (DMD) through the course of their disease. In this study we aimed to assess the effect of DMD on stiffness of relaxed muscles using elastography (supersonic shear imaging). Fourteen DMD patients and 13 control subjects were studied. Six muscles were measured at 2 muscle lengths (shortened and stretched): gastrocnemius medialis (GM); tibialis anterior (TA); vastus lateralis (VL); biceps brachii (BB); triceps brachii (TB); and abductor digiti minimi (ADM). Stiffness was significantly higher in DMD patients compared with controls for all the muscles (main effect for population, P < 0.033 in all cases), except for ADM. The effect size was small (d = 0.33 for ADM at both muscle lengths) to large (d = 0.86 for BB/stretched). Supersonic shear imaging is a sensitive non-invasive technique to assess the increase in muscle stiffness associated with DMD. © 2014 Wiley Periodicals, Inc.

A human in vitro model of Duchenne muscular dystrophy muscle formation and contractility.

PubMed

Nesmith, Alexander P; Wagner, Matthew A; Pasqualini, Francesco S; O'Connor, Blakely B; Pincus, Mark J; August, Paul R; Parker, Kevin Kit

2016-10-10

Tongue weakness, like all weakness in Duchenne muscular dystrophy (DMD), occurs as a result of contraction-induced muscle damage and deficient muscular repair. Although membrane fragility is known to potentiate injury in DMD, whether muscle stem cells are implicated in deficient muscular repair remains unclear. We hypothesized that DMD myoblasts are less sensitive to cues in the extracellular matrix designed to potentiate structure-function relationships of healthy muscle. To test this hypothesis, we drew inspiration from the tongue and engineered contractile human muscle tissues on thin films. On this platform, DMD myoblasts formed fewer and smaller myotubes and exhibited impaired polarization of the cell nucleus and contractile cytoskeleton when compared with healthy cells. These structural aberrations were reflected in their functional behavior, as engineered tongues from DMD myoblasts failed to achieve the same contractile strength as healthy tongue structures. These data suggest that dystrophic muscle may fail to organize with respect to extracellular cues necessary to potentiate adaptive growth and remodeling. © 2016 Nesmith et al.

Direct Metal Deposition of H13 Tool Steel on Copper Alloy Substrate: Parametric Investigation

NASA Astrophysics Data System (ADS)

Imran, M. Khalid; Masood, S. H.; Brandt, Milan

2015-12-01

Over the past decade, researchers have demonstrated interest in tribology and prototyping by the laser aided material deposition process. Laser aided direct metal deposition (DMD) enables the formation of a uniform clad by melting the powder to form desired component from metal powder materials. In this research H13 tool steel has been used to clad on a copper alloy substrate using DMD. The effects of laser parameters on the quality of DMD deposited clad have been investigated and acceptable processing parameters have been determined largely through trial-and-error approaches. The relationships between DMD process parameters and the product characteristics such as porosity, micro-cracks and microhardness have been analysed using scanning electron microscope (SEM), image analysis software (ImageJ) and microhardness tester. It has been found that DMD parameters such as laser power, powder mass flow rate, feed rate and focus size have an important role in clad quality and crack formation.

Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management

PubMed Central

Birnkrant, David J; Bushby, Katharine; Bann, Carla M; Alman, Benjamin A; Apkon, Susan D; Blackwell, Angela; Case, Laura E; Cripe, Linda; Hadjiyannakis, Stasia; Olson, Aaron K; Sheehan, Daniel W; Bolen, Julie; Weber, David R; Ward, Leanne M

2018-01-01

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients’ duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available. PMID:29395990

Parallel Discrete Molecular Dynamics Simulation With Speculation and In-Order Commitment*†

PubMed Central

Khan, Md. Ashfaquzzaman; Herbordt, Martin C.

2011-01-01

Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6× on an 8-core and over 9× on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations. PMID:21822327

Parallel Discrete Molecular Dynamics Simulation With Speculation and In-Order Commitment.

PubMed

Khan, Md Ashfaquzzaman; Herbordt, Martin C

2011-07-20

Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6× on an 8-core and over 9× on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations.

Manufacturing Methods and Engineering for TFT Addressed Display.

DTIC Science & Technology

1980-02-20

type required for the Army’s DMD (Digital Message Device), based on an active-matrix addressed electroluminescent display previously developed by...electroluminescent phosphor as the light emitter, and finally packaging or encapsulation. Because of size limitations of the pilot manufacturing facility, the DMD ...display was designed as two identical halves, which were then to be made individually in the auto- mated machine and later assembled into a single DMD

Advanced Relay Design and Technology for Energy-Efficient Electronics

DTIC Science & Technology

2011-07-07

Estimates and Unique Failure Mechanisms of the Digital Micromirror Device (DMD),” in Proceedings of the IEEE Annual International Reliability Physics...Symposium (IRPS 󈨦), pp. 9-16, March 1998. [18] A. B. Sontheimer, “Digital Micromirror Device (DMD) Hinge Memory Lifetime Reliability Modeling,” in...Mechanisms of the Digital Micromirror Device (DMD),” in Proceedings of the IEEE Annual International Reliability Physics Symposium (IRPS 󈨦), pp. 9-16

Genetic diagnosis as a tool for personalized treatment of Duchenne muscular dystrophy.

PubMed

Bello, Luca; Pegoraro, Elena

2016-12-01

Accurate definition of genetic mutations causing Duchenne muscular dystrophy (DMD) has always been relevant in order to provide genetic counseling to patients and families, and helps to establish the prognosis in the case where the distinction between Duchenne, Becker, or intermediate muscular dystrophy is not obvious. As molecular treatments aimed at dystrophin restoration in DMD are increasingly available as commercialized drugs or within clinical trials, genetic diagnosis has become an indispensable tool in order to determine eligibility for these treatments. DMD patients in which multiplex ligation-dependent probe amplification (MLPA) or similar techniques show a deletion suitable to exon skipping of exons 44, 45, 51, or 53, may be currently treated with AONs targeting these exons, in the context of clinical trials, or, as is the case for exon 51 skipping in the United States, with the first commercialized drug (eteplirsen). Patients who test negative at MLPA, but in whom DMD gene sequencing shows a nonsense mutation, may be amenable for treatment with stop codon readthrough compounds such as ataluren. Novel molecular approaches such as CRISPR-Cas9 targeting of specific DMD mutations are still in the preclinical stages, but appear promising. In conclusion, an accurate genetic diagnosis represents the entrance into a new scenario of personalized medicine in DMD.

The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

PubMed Central

Bladen, Catherine L; Salgado, David; Monges, Soledad; Foncuberta, Maria E; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Roy, Anna J; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Barišić, Nina; Brabec, Petr; Lahdetie, Jaana; Walter, Maggie C; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Kimura, En; Koeks, Zaïda; van den Bergen, Janneke C; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Zimowski, Janusz; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Jeannet, Pierre-Yves; Joncourt, Franziska; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A Ayşe; Topaloğlu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V; Martin, Ann S; Peay, Holly L; Bellgard, Matthew I; Kirschner, Jan; Flanigan, Kevin M; Straub, Volker; Bushby, Kate; Verschuuren, Jan; Aartsma-Rus, Annemieke; Béroud, Christophe; Lochmüller, Hanns

2015-01-01

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). PMID:25604253

Digital micromirror device-based common-path quantitative phase imaging.

PubMed

Zheng, Cheng; Zhou, Renjie; Kuang, Cuifang; Zhao, Guangyuan; Yaqoob, Zahid; So, Peter T C

2017-04-01

We propose a novel common-path quantitative phase imaging (QPI) method based on a digital micromirror device (DMD). The DMD is placed in a plane conjugate to the objective back-aperture plane for the purpose of generating two plane waves that illuminate the sample. A pinhole is used in the detection arm to filter one of the beams after sample to create a reference beam. Additionally, a transmission-type liquid crystal device, placed at the objective back-aperture plane, eliminates the specular reflection noise arising from all the "off" state DMD micromirrors, which is common in all DMD-based illuminations. We have demonstrated high sensitivity QPI, which has a measured spatial and temporal noise of 4.92 nm and 2.16 nm, respectively. Experiments with calibrated polystyrene beads illustrate the desired phase measurement accuracy. In addition, we have measured the dynamic height maps of red blood cell membrane fluctuations, showing the efficacy of the proposed system for live cell imaging. Most importantly, the DMD grants the system convenience in varying the interference fringe period on the camera to easily satisfy the pixel sampling conditions. This feature also alleviates the pinhole alignment complexity. We envision that the proposed DMD-based common-path QPI system will allow for system miniaturization and automation for a broader adaption.

Digital micromirror device-based common-path quantitative phase imaging

PubMed Central

Zheng, Cheng; Zhou, Renjie; Kuang, Cuifang; Zhao, Guangyuan; Yaqoob, Zahid; So, Peter T. C.

2017-01-01

We propose a novel common-path quantitative phase imaging (QPI) method based on a digital micromirror device (DMD). The DMD is placed in a plane conjugate to the objective back-aperture plane for the purpose of generating two plane waves that illuminate the sample. A pinhole is used in the detection arm to filter one of the beams after sample to create a reference beam. Additionally, a transmission-type liquid crystal device, placed at the objective back-aperture plane, eliminates the specular reflection noise arising from all the “off” state DMD micromirrors, which is common in all DMD-based illuminations. We have demonstrated high sensitivity QPI, which has a measured spatial and temporal noise of 4.92 nm and 2.16 nm, respectively. Experiments with calibrated polystyrene beads illustrate the desired phase measurement accuracy. In addition, we have measured the dynamic height maps of red blood cell membrane fluctuations, showing the efficacy of the proposed system for live cell imaging. Most importantly, the DMD grants the system convenience in varying the interference fringe period on the camera to easily satisfy the pixel sampling conditions. This feature also alleviates the pinhole alignment complexity. We envision that the proposed DMD-based common-path QPI system will allow for system miniaturization and automation for a broader adaption. PMID:28362789

Potential medical applications of TAE

NASA Technical Reports Server (NTRS)

Fahy, J. Ben; Kaucic, Robert; Kim, Yongmin

1986-01-01

In cooperation with scientists in the University of Washington Medical School, a microcomputer-based image processing system for quantitative microscopy, called DMD1 (Digital Microdensitometer 1) was constructed. In order to make DMD1 transportable to different hosts and image processors, we have been investigating the possibility of rewriting the lower level portions of DMD1 software using Transportable Applications Executive (TAE) libraries and subsystems. If successful, we hope to produce a newer version of DMD1, called DMD2, running on an IBM PC/AT under the SCO XENIX System 5 operating system, using any of seven target image processors available in our laboratory. Following this implementation, copies of the system will be transferred to other laboratories with biomedical imaging applications. By integrating those applications into DMD2, we hope to eventually expand our system into a low-cost general purpose biomedical imaging workstation. This workstation will be useful not only as a self-contained instrument for clinical or research applications, but also as part of a large scale Digital Imaging Network and Picture Archiving and Communication System, (DIN/PACS). Widespread application of these TAE-based image processing and analysis systems should facilitate software exchange and scientific cooperation not only within the medical community, but between the medical and remote sensing communities as well.

Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures.

PubMed

Segura, Leal G; Lorenz, Jessica D; Weingarten, Toby N; Scavonetto, Federica; Bojanić, Katarina; Selcen, Duygu; Sprung, Juraj

2013-09-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are associated with life-threatening perioperative complications, including rhabdomyolysis, hyperkalemia, and hyperthermia. Current recommendations contraindicate use of succinylcholine and volatile anesthetics; however, the latter recommendation remains controversial. To review the perioperative outcomes of patients with DMD and BMD. We reviewed records of patients with DMD or BMD who underwent anesthetic management at our institution from January 1990 through December 2011. We identified 47 patients (DMD, 37; BMD, 10) who underwent 117 anesthetic exposures (DMD, 101; BMD, 16). Volatile anesthetic agents were used 66 times (DMD, 59; BMD, 7). One patient with undiagnosed BMD received succinylcholine and developed acute rhabdomyolysis and hyperkalemic cardiac arrest. All other major complications were attributed to the procedure (i.e., large bleeding), to preexisting comorbidities (i.e., respiratory failure, cardiac disease), or to both. Use of succinylcholine in children with dystrophinopathy is contraindicated. These patients have significant comorbidities and are frequently undergoing extensive operations; complications related to these factors can develop, as evidenced by our series. These complications may occur with use of volatile and nonvolatile anesthetics. However, because most of our patients were older than 8 years at the time of surgery, our observation cannot be generalized to younger dystrophin-deficient children. © 2013 John Wiley & Sons Ltd.

Duchenne and Becker muscular dystrophy in adolescents: current perspectives

PubMed Central

Andrews, Jennifer G; Wahl, Richard A

2018-01-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are life-limiting and progressive neuromuscular conditions with significant comorbidities, many of which manifest during adolescence. BMD is a milder presentation of the condition and much less prevalent than DMD, making it less represented in the literature, or more severely affected individuals with BMD may be subsumed into the DMD population using clinical cutoffs. Numerous consensus documents have been published on the clinical management of DMD, the most recent of which was released in 2010. The advent of these clinical management consensus papers, particularly respiratory care, has significantly increased the life span for these individuals, and the adolescent years are now a point of transition into adult lives, rather than a period of end of life. This review outlines the literature on DMD and BMD during adolescence, focusing on clinical presentation during adolescence, impact of living with a chronic illness on adolescents, and the effect that adolescents have on their chronic illness. In addition, we describe the role that palliative-care specialists could have in improving outcomes for these individuals. The increasing proportion of individuals with DMD and BMD living into adulthood underscores the need for more research into interventions and intracacies of adolescence that can improve the social aspects of their lives. PMID:29588625

Duchenne and Becker muscular dystrophy in adolescents: current perspectives.

PubMed

Andrews, Jennifer G; Wahl, Richard A

2018-01-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are life-limiting and progressive neuromuscular conditions with significant comorbidities, many of which manifest during adolescence. BMD is a milder presentation of the condition and much less prevalent than DMD, making it less represented in the literature, or more severely affected individuals with BMD may be subsumed into the DMD population using clinical cutoffs. Numerous consensus documents have been published on the clinical management of DMD, the most recent of which was released in 2010. The advent of these clinical management consensus papers, particularly respiratory care, has significantly increased the life span for these individuals, and the adolescent years are now a point of transition into adult lives, rather than a period of end of life. This review outlines the literature on DMD and BMD during adolescence, focusing on clinical presentation during adolescence, impact of living with a chronic illness on adolescents, and the effect that adolescents have on their chronic illness. In addition, we describe the role that palliative-care specialists could have in improving outcomes for these individuals. The increasing proportion of individuals with DMD and BMD living into adulthood underscores the need for more research into interventions and intracacies of adolescence that can improve the social aspects of their lives.

Duchenne muscular dystrophy and caregiver burden: a systematic review.

PubMed

Landfeldt, Erik; Edström, Josefin; Buccella, Filippo; Kirschner, Janbernd; Lochmüller, Hanns

2018-06-14

To conduct a systematic literature review of caregiver burden in Duchenne muscular dystrophy (DMD). We searched Embase, Web of Science, and PubMed for full-text articles reporting results from studies of caregiver burden in DMD. We identified 483 unique publications. Of these, 450 were excluded after title and abstract screening, and 12 after full-text review. A total of 21 articles were included for data synthesis. Results encompassing more than 15 aspects of caregiver burden, investigated through surveys and/or interviews across 15 countries, were identified in the literature. Caregiving in DMD was frequently associated with impaired health-related quality of life, poor sleep quality, reduced family function, depression, pain, stress, sexual dysfunction, and/or lower self-esteem, as well as a considerable impact on work life and productivity. Providing informal care to a patient with DMD can be associated with a substantial burden. Yet, more research is needed to better understand the clinical implications of caregiving in DMD and the relationship between caregiver burden and the progression of the disease. Our data synthesis should be helpful in informing clinical and social support programmes directed to families caring for a patient with DMD. A substantial body of evidence describes caregiver burden in Duchenne muscular dystrophy. Little is known of the family burden beyond caregivers' self-assessments. © 2018 Mac Keith Press.

Dystrophin Expressing Chimeric (DEC) Human Cells Provide a Potential Therapy for Duchenne Muscular Dystrophy.

PubMed

Siemionow, Maria; Cwykiel, Joanna; Heydemann, Ahlke; Garcia, Jesus; Marchese, Enza; Siemionow, Krzysztof; Szilagyi, Erzsebet

2018-06-01

Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD. We introduce two Dystrophin Expressing Chimeric (DEC) cell lines created by ex vivo fusion of human myoblasts (MB) derived from two normal donors (MB N1 /MB N2 ), and normal and DMD donors (MB N /MB DMD ). The efficacy of fusion was confirmed by flow cytometry and confocal microscopy based on donor cell fluorescent labeling (PKH26/PKH67). In vitro, DEC displayed phenotype and genotype of donor parent cells, expressed dystrophin, and maintained proliferation and myogenic differentiation. In vivo, local delivery of both DEC lines (0.5 × 10 6 ) restored dystrophin expression (17.27%±8.05-MB N1 /MB N2 and 23.79%±3.82-MB N /MB DMD ) which correlated with significant improvement of muscle force, contraction and tolerance to fatigue at 90 days after DEC transplant to the gastrocnemius muscles (GM) of dystrophin-deficient mdx/scid mice. This study establishes DEC as a potential therapy for DMD and other types of muscular dystrophies.

CD133+ cells derived from skeletal muscles of Duchenne muscular dystrophy patients have a compromised myogenic and muscle regenerative capability.

PubMed

Meng, Jinhong; Muntoni, Francesco; Morgan, Jennifer

2018-05-12

Cell-mediated gene therapy is a possible means to treat muscular dystrophies like Duchenne muscular dystrophy. Autologous patient stem cells can be genetically-corrected and transplanted back into the patient, without causing immunorejection problems. Regenerated muscle fibres derived from these cells will express the missing dystrophin protein, thus improving muscle function. CD133+ cells derived from normal human skeletal muscle contribute to regenerated muscle fibres and form muscle stem cells after their intra-muscular transplantation into an immunodeficient mouse model. But it is not known whether CD133+ cells derived from DMD patient muscles have compromised muscle regenerative function. To test this, we compared CD133+ cells derived from DMD and normal human muscles. DMD CD133+ cells had a reduced capacity to undergo myogenic differentiation in vitro compared with CD133+ cells derived from normal muscle. In contrast to CD133+ cells derived from normal human muscle, those derived from DMD muscle formed no satellite cells and gave rise to significantly fewer muscle fibres of donor origin, after their intra-muscular transplantation into an immunodeficient, non-dystrophic, mouse muscle. DMD CD133+ cells gave rise to more clones of smaller size and more clones that were less myogenic than did CD133+ cells derived from normal muscle. The heterogeneity of the progeny of CD133+ cells, combined with the reduced proliferation and myogenicity of DMD compared to normal CD133+ cells, may explain the reduced regenerative capacity of DMD CD133+ cells. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

PubMed

Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

2015-10-13

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.

PubMed

Nio, Yasunori; Tanaka, Masayuki; Hirozane, Yoshihiko; Muraki, Yo; Okawara, Mitsugi; Hazama, Masatoshi; Matsuo, Takanori

2017-12-01

Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy. © FASEB.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

PubMed Central

Whitehead, Nicholas P.; Kim, Min Jeong; Bible, Kenneth L.; Adams, Marvin E.; Froehner, Stanley C.

2015-01-01

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID:26417069

A comparison of swallowing dysfunction in Becker muscular dystrophy and Duchenne muscular dystrophy.

PubMed

Yamada, Yuka; Kawakami, Michiyuki; Wada, Ayako; Otsuka, Tomoyoshi; Muraoka, Kaori; Liu, Meigen

2018-06-01

Swallowing dysfunction has been reported in Duchenne muscular dystrophy (DMD), but has not been studied in Becker muscular dystrophy (BMD). The aims of this study were to report the characteristics of swallowing dysfunction in BMD compared with DMD. The study participants were 18 patients with BMD and 18 patients with DMD. All the patients were examined using videofluorography during swallowing of 5 mL of fluid. The penetration-aspiration scale (P-A scale) and the videofluorographic dysphagia scale (VDS) were used to evaluate dysphagia. Swinyard functional ability stage was not significantly different between the BMD and DMD groups. Rate of aspiration, P-A scale score, and total VDS score did not differ across groups, but the VDS item score for laryngeal elevation was lower in the BMD group than in the DMD group (median scores 4.5 and 9, respectively; p < 0.001). In the BMD group, total VDS score significantly correlated with Swinyard stage (r = 0.78, p < 0.001), but not with age or lung function. Patients with BMD have swallowing problems similar to those observed in patients with DMD when matched according to physical functional status. These patients should be evaluated and followed-up for the duration of their disease. Implications for rehabiliation Dysphagia is one of the most critical problems in patients with progressive neuromuscular disease but dysphagia in patients with Becker muscular dystrophy (BMD) was not well known. Eighteen patients with BMD and 18 patients with Duchenne muscular dystrophy were examined with videofluorography. Patients with BMD have swallowing problems similar to those observed in patients with DMD.

Antitumor activity of 2‑[(2E)‑3,7‑dimethyl‑2,6‑octadienyl]‑6‑methyl‑2,5‑cyclohexadiene‑1,4‑dione isolated from the aerial part of Atractylodes macrocephala in hepatocellular carcinoma.

PubMed

Li, Lei; Zhao, Rui; Li, Ying; Wang, Wen-Hui

2017-11-01

2‑[(2E)‑3,7‑dimethyl‑2,6‑octadienyl]‑6‑methy l‑2,5‑cyclohexadiene‑1,4‑dione (DMD) is a compound isolated from Atractylodes macrocephala; however, its antitumor activity has not yet been investigated. Therefore, the present study aimed to investigate the antitumor activity of DMD in the H22 mouse hepatocellular carcinoma (HCC) cell line in vitro and in vivo. In the present study, the antiproliferative effects of DMD against H22 cells were evaluated using the MTT assay in vitro. Furthermore, xenograft nude mice were established to evaluate the antitumor effects of DMD on H22 cells in vivo. In addition, apoptosis of H22 cells was determined by flow cytometry with Annexin V‑fluorescein isothiocyanate/propidium iodide staining, and western blotting was subsequently performed to examine the expression levels of proteins associated with apoptosis, and c‑Jun N‑terminal kinase (JNK), p38 and extracellular signal‑regulated kinase (ERK)1/2 mitogen‑activated protein kinases (MAPKs). The results demonstrated that DMD exerts an antitumor effect against H22 cells in vitro and in vivo, and the underlying mechanism may be associated with mitochondria‑mediated apoptosis through upregulation of cytochrome c, cleaved (c)‑caspase‑3, c‑caspase‑9, c‑caspase‑7 and B‑cell lymphoma 2 (Bcl‑2)‑associated X protein, and downregulation of Bcl‑2. In addition, the antitumor effects of DMD against H22 cells may be also associated with the MAPK signaling pathway via increased p‑JNK and reduced p‑ERK1/2 expression. In conclusion, the present study demonstrated the DMD exerts antitumor effects against HCC in mice and provides a scientific basis for the clinical use of DMD for the treatment of HCC.

Dysphagia in Duchenne muscular dystrophy: practical recommendations to guide management.

PubMed

Toussaint, Michel; Davidson, Zoe; Bouvoie, Veronique; Evenepoel, Nathalie; Haan, Jurn; Soudon, Philippe

2016-10-01

Duchenne muscular dystrophy (DMD) is a rapidly progressive neuromuscular disorder causing weakness of the skeletal, respiratory, cardiac and oropharyngeal muscles with up to one third of young men reporting difficulty swallowing (dysphagia). Recent studies on dysphagia in DMD clarify the pathophysiology of swallowing disorders and offer new tools for its assessment but little guidance is available for its management. This paper aims to provide a step-by-step algorithm to facilitate clinical decisions regarding dysphagia management in this patient population. This algorithm is based on 30 years of clinical experience with DMD in a specialised Centre for Neuromuscular Disorders (Inkendaal Rehabilitation Hospital, Belgium) and is supported by literature where available. Dysphagia can worsen the condition of ageing patients with DMD. Apart from the difficulties of chewing and oral fragmentation of the food bolus, dysphagia is rather a consequence of an impairment in the pharyngeal phase of swallowing. By contrast with central neurologic disorders, dysphagia in DMD accompanies solid rather than liquid intake. Symptoms of dysphagia may not be clinically evident; however laryngeal food penetration, accumulation of food residue in the pharynx and/or true laryngeal food aspiration may occur. The prevalence of these issues in DMD is likely underestimated. There is little guidance available for clinicians to manage dysphagia and improve feeding for young men with DMD. This report aims to provide a clinical algorithm to facilitate the diagnosis of dysphagia, to identify the symptoms and to propose practical recommendations to treat dysphagia in the adult DMD population. Implications for Rehabilitation Little guidance is available for the management of dysphagia in Duchenne dystrophy. Food can penetrate the vestibule, accumulate as residue or cause aspiration. We propose recommendations and an algorithm to guide management of dysphagia. Penetration/residue accumulation: prohibit solid food and promote intake of fluids. Aspiration: if cough augmentation techniques are ineffective, consider tracheostomy.

Dysphagia in Duchenne muscular dystrophy: practical recommendations to guide management

PubMed Central

Toussaint, Michel; Davidson, Zoe; Bouvoie, Veronique; Evenepoel, Nathalie; Haan, Jurn; Soudon, Philippe

2016-01-01

Abstract Purpose: Duchenne muscular dystrophy (DMD) is a rapidly progressive neuromuscular disorder causing weakness of the skeletal, respiratory, cardiac and oropharyngeal muscles with up to one third of young men reporting difficulty swallowing (dysphagia). Recent studies on dysphagia in DMD clarify the pathophysiology of swallowing disorders and offer new tools for its assessment but little guidance is available for its management. This paper aims to provide a step-by-step algorithm to facilitate clinical decisions regarding dysphagia management in this patient population. Methods: This algorithm is based on 30 years of clinical experience with DMD in a specialised Centre for Neuromuscular Disorders (Inkendaal Rehabilitation Hospital, Belgium) and is supported by literature where available. Results: Dysphagia can worsen the condition of ageing patients with DMD. Apart from the difficulties of chewing and oral fragmentation of the food bolus, dysphagia is rather a consequence of an impairment in the pharyngeal phase of swallowing. By contrast with central neurologic disorders, dysphagia in DMD accompanies solid rather than liquid intake. Symptoms of dysphagia may not be clinically evident; however laryngeal food penetration, accumulation of food residue in the pharynx and/or true laryngeal food aspiration may occur. The prevalence of these issues in DMD is likely underestimated. Conclusions: There is little guidance available for clinicians to manage dysphagia and improve feeding for young men with DMD. This report aims to provide a clinical algorithm to facilitate the diagnosis of dysphagia, to identify the symptoms and to propose practical recommendations to treat dysphagia in the adult DMD population.Implications for RehabilitationLittle guidance is available for the management of dysphagia in Duchenne dystrophy.Food can penetrate the vestibule, accumulate as residue or cause aspiration.We propose recommendations and an algorithm to guide management of dysphagia.Penetration/residue accumulation: prohibit solid food and promote intake of fluids.Aspiration: if cough augmentation techniques are ineffective, consider tracheostomy. PMID:26728920

Gait deviations in Duchenne muscular dystrophy-Part 2. Statistical non-parametric mapping to analyze gait deviations in children with Duchenne muscular dystrophy.

PubMed

Goudriaan, Marije; Van den Hauwe, Marleen; Simon-Martinez, Cristina; Huenaerts, Catherine; Molenaers, Guy; Goemans, Nathalie; Desloovere, Kaat

2018-04-30

Prolonged ambulation is considered important in children with Duchenne muscular dystrophy (DMD). However, previous studies analyzing DMD gait were sensitive to false positive outcomes, caused by uncorrected multiple comparisons, regional focus bias, and inter-component covariance bias. Also, while muscle weakness is often suggested to be the main cause for the altered gait pattern in DMD, this was never verified. Our research question was twofold: 1) are we able to confirm the sagittal kinematic and kinetic gait alterations described in a previous review with statistical non-parametric mapping (SnPM)? And 2) are these gait deviations related to lower limb weakness? We compared gait kinematics and kinetics of 15 children with DMD and 15 typical developing (TD) children (5-17 years), with a two sample Hotelling's T 2 test and post-hoc two-tailed, two-sample t-test. We used canonical correlation analyses to study the relationship between weakness and altered gait parameters. For all analyses, α-level was corrected for multiple comparisons, resulting in α = 0.005. We only found one of the previously reported kinematic deviations: the children with DMD had an increased knee flexion angle during swing (p = 0.0006). Observed gait deviations that were not reported in the review were an increased hip flexion angle during stance (p = 0.0009) and swing (p = 0.0001), altered combined knee and ankle torques (p = 0.0002), and decreased power absorption during stance (p = 0.0001). No relationships between weakness and these gait deviations were found. We were not able to replicate the gait deviations in DMD previously reported in literature, thus DMD gait remains undefined. Further, weakness does not seem to be linearly related to altered gait features. The progressive nature of the disease requires larger study populations and longitudinal analyses to gain more insight into DMD gait and its underlying causes. Copyright © 2018 Elsevier B.V. All rights reserved.

Experimental generation of Laguerre-Gaussian beam using digital micromirror device.

PubMed

Ren, Yu-Xuan; Li, Ming; Huang, Kun; Wu, Jian-Guang; Gao, Hong-Fang; Wang, Zi-Qiang; Li, Yin-Mei

2010-04-01

A digital micromirror device (DMD) modulates laser intensity through computer control of the device. We experimentally investigate the performance of the modulation property of a DMD and optimize the modulation procedure through image correction. Furthermore, Laguerre-Gaussian (LG) beams with different topological charges are generated by projecting a series of forklike gratings onto the DMD. We measure the field distribution with and without correction, the energy of LG beams with different topological charges, and the polarization property in sequence. Experimental results demonstrate that it is possible to generate LG beams with a DMD that allows the use of a high-intensity laser with proper correction to the input images, and that the polarization state of the LG beam differs from that of the input beam.

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy.

PubMed

Marrocco, V; Fiore, P; Benedetti, A; Pisu, S; Rizzuto, E; Musarò, A; Madaro, L; Lozanoska-Ochser, B; Bouché, M

2017-02-01

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. Duchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a "cure" for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. Copyright © 2017 3-V Biosciences. Published by Elsevier B.V. All rights reserved.

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

PubMed

Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

2014-04-01

New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.

Quantitative Ultrasound Assessment of Duchenne Muscular Dystrophy Using Edge Detection Analysis.

PubMed

Koppaka, Sisir; Shklyar, Irina; Rutkove, Seward B; Darras, Basil T; Anthony, Brian W; Zaidman, Craig M; Wu, Jim S

2016-09-01

The purpose of this study was to investigate the ability of quantitative ultrasound (US) using edge detection analysis to assess patients with Duchenne muscular dystrophy (DMD). After Institutional Review Board approval, US examinations with fixed technical parameters were performed unilaterally in 6 muscles (biceps, deltoid, wrist flexors, quadriceps, medial gastrocnemius, and tibialis anterior) in 19 boys with DMD and 21 age-matched control participants. The muscles of interest were outlined by a tracing tool, and the upper third of the muscle was used for analysis. Edge detection values for each muscle were quantified by the Canny edge detection algorithm and then normalized to the number of edge pixels in the muscle region. The edge detection values were extracted at multiple sensitivity thresholds (0.01-0.99) to determine the optimal threshold for distinguishing DMD from normal. Area under the receiver operating curve values were generated for each muscle and averaged across the 6 muscles. The average age in the DMD group was 8.8 years (range, 3.0-14.3 years), and the average age in the control group was 8.7 years (range, 3.4-13.5 years). For edge detection, a Canny threshold of 0.05 provided the best discrimination between DMD and normal (area under the curve, 0.96; 95% confidence interval, 0.84-1.00). According to a Mann-Whitney test, edge detection values were significantly different between DMD and controls (P < .0001). Quantitative US imaging using edge detection can distinguish patients with DMD from healthy controls at low Canny thresholds, at which discrimination of small structures is best. Edge detection by itself or in combination with other tests can potentially serve as a useful biomarker of disease progression and effectiveness of therapy in muscle disorders.

Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy

PubMed Central

Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

2012-01-01

Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3. PMID:22876130

Genetic and Early Clinical Manifestations of Females Heterozygous for Duchenne/Becker Muscular Dystrophy.

PubMed

Papa, Riccardo; Madia, Francesca; Bartolomeo, Domenico; Trucco, Federica; Pedemonte, Marina; Traverso, Monica; Broda, Paolo; Bruno, Claudio; Zara, Federico; Minetti, Carlo; Fiorillo, Chiara

2016-02-01

Female carriers of Duchenne muscular dystrophy (DMD), although usually asymptomatic, develop muscle weakness up to 17% of the time, and a third present cardiac abnormalities or cognitive impairment. Clinical features of DMD carriers during childhood are poorly known. We describe a cohort of pediatric DMD carriers, providing clinical, genetic, and histopathologic features, with a mean follow-up of 7 years. Fifteen females with a DMD mutation (age range 5 to 18 years) were included. Seven patients (46%) presented with clinically evident symptoms and signs such as limb girdle weakness, abnormal gait, and exercise intolerance. The other eight patients (53%) were evaluated because of an incidental finding of elevated level of creatine kinase. Creatine kinase level was elevated in all, ranging from 392 to 13,000 U/L. Calf hypertrophy was observed in eight patients (53%). No patient developed respiratory or cardiac involvement. The most frequent complication was scoliosis (46%). Four patients (29%) also presented minor learning disabilities or behavioral problems. We performed electromyography in half of patients, showing myopathic pattern in four (53%). Muscle biopsy revealed a mosaic reduction of dystrophin in nine available cases. DMD gene mutations were mostly deletions (71%), resulting in loss of reading frame in five patients (36%). The three patients who experienced the most severe disease course were affected either by a nonsense or frameshift mutation. Our analysis suggests that DMD gene mutations may be suspected in a female child with persistently elevated levels of creatine kinase. Evidence of scoliosis, calf hypertrophy, or myopathic pattern at electromyography may also be helpful, and muscle biopsy is always indicative. DMD carriers should be followed for subtle orthopedic and psychiatric complications during childhood. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy.

PubMed

Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S Vasantha; Chandak, Giriraj Ratan; Kumar, Arun

2012-01-01

Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3.

Modulation of Stem Cell Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration after Injury

DTIC Science & Technology

2011-03-01

Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor...extracellular matrix, and fat, characterizes muscle dystrophy , and in particular Duchenne muscular dystrophy (DMD) (1,2), as seen also in its animal model...stem cells (MDSC) into myogenic as opposed to lipofibrogenic lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To

Near-infrared Compressive Line Sensing Imaging System using Individually Addressable Laser Diode Array

DTIC Science & Technology

2015-05-11

Micromirror Device (DMD) is a microelectromechanical (MEMS) device. A DMD consists of millions of electrostatically actuated micro- mirrors (or pixels...digital micromirror device) were analyzed. We discussed the effort of developing such a prototype by Proc. of SPIE Vol. 9484 94840I-11 Downloaded...to Digital Micromirror Device (DMD) Technology”, (n.d.) Retrieved May 1, 2011, from http://www.ti.com/lit/an/dlpa008a/dlpa008a.pdf. [16

Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy.

PubMed

Echigoya, Yusuke; Lim, Kenji Rowel Q; Trieu, Nhu; Bao, Bo; Miskew Nichols, Bailey; Vila, Maria Candida; Novak, James S; Hara, Yuko; Lee, Joshua; Touznik, Aleksander; Mamchaoui, Kamel; Aoki, Yoshitsugu; Takeda, Shin'ichi; Nagaraju, Kanneboyina; Mouly, Vincent; Maruyama, Rika; Duddy, William; Yokota, Toshifumi

2017-11-01

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Three-dimensional photography for the evaluation of facial profiles in obstructive sleep apnoea.

PubMed

Lin, Shih-Wei; Sutherland, Kate; Liao, Yu-Fang; Cistulli, Peter A; Chuang, Li-Pang; Chou, Yu-Ting; Chang, Chih-Hao; Lee, Chung-Shu; Li, Li-Fu; Chen, Ning-Hung

2018-06-01

Craniofacial structure is an important determinant of obstructive sleep apnoea (OSA) syndrome risk. Three-dimensional stereo-photogrammetry (3dMD) is a novel technique which allows quantification of the craniofacial profile. This study compares the facial images of OSA patients captured by 3dMD to three-dimensional computed tomography (3-D CT) and two-dimensional (2-D) digital photogrammetry. Measurements were correlated with indices of OSA severity. Thirty-eight patients diagnosed with OSA were included, and digital photogrammetry, 3dMD and 3-D CT were performed. Distances, areas, angles and volumes from the images captured by three methods were analysed. Almost all measurements captured by 3dMD showed strong agreement with 3-D CT measurements. Results from 2-D digital photogrammetry showed poor agreement with 3-D CT. Mandibular width, neck perimeter size and maxillary volume measurements correlated well with the severity of OSA using all three imaging methods. Mandibular length, facial width, binocular width, neck width, cranial base triangle area, cranial base area 1 and middle cranial fossa volume correlated well with OSA severity using 3dMD and 3-D CT, but not with 2-D digital photogrammetry. 3dMD provided accurate craniofacial measurements of OSA patients, which were highly concordant with those obtained by CT, while avoiding the radiation associated with CT. © 2018 Asian Pacific Society of Respirology.

The optical-mechanical design of DMD modulation imaging device

NASA Astrophysics Data System (ADS)

Li, Tianting; Xu, Xiping; Qiao, Yang; Li, Lei; Pan, Yue

2014-09-01

In order to avoid the phenomenon of some image information were lost, which is due to the jamming signals, such as incident laser, make the pixels dot on CCD saturated. In this article a device of optical-mechanical structure was designed, which utilized the DMD (Digital Micro mirror Device) to modulate the image. The DMD reflection imaging optical system adopts the telecentric light path. However, because the design is not only required to guarantee a 66° angle between the optical axis of the relay optics and the DMD, but also to ensure that the optical axis of the projection system keeps parallel with the perpendicular bisector of the micro-mirror which is in the "flat" state, so the TIR prism is introduced，and making the relay optics and the DMD satisfy the optical institution's requirements. In this paper, a mechanical structure of the imaging optical system was designed and at the meanwhile the lens assembly has been well connected and fixed and fine-tuned by detailed structural design, which included the tilt decentered lens, wedge flanges, prisms. By optimizing the design, the issues of mutual restraint between the inverting optical system and the projecting system were well resolved, and prevented the blocking of the two systems. In addition, the structure size of the whole DMD reflection imaging optical system was minimized; it reduced the energy loss and ensured the image quality.

Design method of freeform light distribution lens for LED automotive headlamp based on DMD

NASA Astrophysics Data System (ADS)

Ma, Jianshe; Huang, Jianwei; Su, Ping; Cui, Yao

2018-01-01

We propose a new method to design freeform light distribution lens for light-emitting diode (LED) automotive headlamp based on digital micro mirror device (DMD). With the Parallel optical path architecture, the exit pupil of the illuminating system is set in infinity. Thus the principal incident rays of micro lens in DMD is parallel. DMD is made of high speed digital optical reflection array, the function of distribution lens is to distribute the emergent parallel rays from DMD and get a lighting pattern that fully comply with the national regulation GB 25991-2010.We use DLP 4500 to design the light distribution lens, mesh the target plane regulated by the national regulation GB 25991-2010 and correlate the mesh grids with the active mirror array of DLP4500. With the mapping relations and the refraction law, we can build the mathematics model and get the parameters of freeform light distribution lens. Then we import its parameter into the three-dimensional (3D) software CATIA to construct its 3D model. The ray tracing results using Tracepro demonstrate that the Illumination value of target plane is easily adjustable and fully comply with the requirement of the national regulation GB 25991-2010 by adjusting the exit brightness value of DMD. The theoretical optical efficiencies of the light distribution lens designed using this method could be up to 92% without any other auxiliary lens.

Observer-based sliding mode control of Markov jump systems with random sensor delays and partly unknown transition rates

NASA Astrophysics Data System (ADS)

Yao, Deyin; Lu, Renquan; Xu, Yong; Ren, Hongru

2017-10-01

In this paper, the sliding mode control problem of Markov jump systems (MJSs) with unmeasured state, partly unknown transition rates and random sensor delays is probed. In the practical engineering control, the exact information of transition rates is hard to obtain and the measurement channel is supposed to subject to random sensor delay. Design a Luenberger observer to estimate the unmeasured system state, and an integral sliding mode surface is constructed to ensure the exponential stability of MJSs. A sliding mode controller based on estimator is proposed to drive the system state onto the sliding mode surface and render the sliding mode dynamics exponentially mean-square stable with H∞ performance index. Finally, simulation results are provided to illustrate the effectiveness of the proposed results.

THE COOPERATIVE INTERNATIONAL NEUROMUSCULAR RESEARCH GROUP DUCHENNE NATURAL HISTORY STUDY—A LONGITUDINAL INVESTIGATION IN THE ERA OF GLUCOCORTICOID THERAPY: DESIGN OF PROTOCOL AND THE METHODS USED

PubMed Central

McDonald, Craig M.; Henricson, Erik K.; Abresch, R. Ted; Han, Jay J.; Escolar, Diana M.; Florence, Julaine M.; Duong, Tina; Arrieta, Adrienne; Clemens, Paula R.; Hoffman, Eric P.; Cnaan, Avital

2014-01-01

Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. Methods The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2–28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/ health-related quality-of-life instruments. Results Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). Conclusions Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. PMID:23677550

Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice.

PubMed

Wein, Nicolas; Vulin, Adeline; Falzarano, Maria S; Szigyarto, Christina Al-Khalili; Maiti, Baijayanta; Findlay, Andrew; Heller, Kristin N; Uhlén, Mathias; Bakthavachalu, Baskar; Messina, Sonia; Vita, Giuseppe; Passarelli, Chiara; Brioschi, Simona; Bovolenta, Matteo; Neri, Marcella; Gualandi, Francesca; Wilton, Steve D; Rodino-Klapac, Louise R; Yang, Lin; Dunn, Diane M; Schoenberg, Daniel R; Weiss, Robert B; Howard, Michael T; Ferlini, Alessandra; Flanigan, Kevin M

2014-09-01

Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.

Adaptive spatiotemporal optical pulse front tilt using a digital micromirror device and its terahertz application.

PubMed

Murate, Kosuke; Roshtkhari, Mehraveh Javan; Ropagnol, Xavier; Blanchard, François

2018-05-01

We report a new method to temporally and spatially manipulate the pulse front tilt (PFT) intensity profile of an ultrashort optical pulse using a commercial microelectromechanical system, also known as a digital micromirror device (DMD). For our demonstration, we show terahertz generation in a lithium niobate crystal using the PFT pumping scheme derived from a DMD chip. The adaptive functionality of the DMD could be a convenient alternative to the more conventional grating required to generate a laser beam with a PFT intensity profile that is typically used for efficient optical rectification in noncollinear phase-matching conditions. In contrast to a grating, PFT using DMD does not suffer from wavelength dispersion, and exhibits overlap properties between grating and a stair-step echelon mirror.

Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle

NASA Astrophysics Data System (ADS)

Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.

1988-03-01

A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.

Development of a Free-Electron Laser Center and Research in Medicine, Biology and Materials Science,

DTIC Science & Technology

1992-05-14

Elastin Production in Tissue Culture", Debra A.Gonzalez MD, David L. Zealear, PhD., J.M. Davidson, PhD., Robert H. Ossoff, MD, DMD , August 1990...Otolaryngoloty-Head and Neck Surgery. K. "CO2 Laser Micromanipulator Parallax Error Resolved, Jay Werkhaven,MD, Jerri Tribble, and Robert H. Ossoff, MD, DMD ...of the Upper Aerodigestive Tract, Robert H. Ossoff, MD, DMD , Al Aly, MD, Nick Houchin, AAS, and Debra Gonzalez, MD, Vanderbilt University, Nashville

An improved algorithm for balanced POD through an analytic treatment of impulse response tails

NASA Astrophysics Data System (ADS)

Tu, Jonathan H.; Rowley, Clarence W.

2012-06-01

We present a modification of the balanced proper orthogonal decomposition (balanced POD) algorithm for systems with simple impulse response tails. In this new method, we use dynamic mode decomposition (DMD) to estimate the slowly decaying eigenvectors that dominate the long-time behavior of the direct and adjoint impulse responses. This is done using a new, low-memory variant of the DMD algorithm, appropriate for large datasets. We then formulate analytic expressions for the contribution of these eigenvectors to the controllability and observability Gramians. These contributions can be accounted for in the balanced POD algorithm by simply appending the impulse response snapshot matrices (direct and adjoint, respectively) with particular linear combinations of the slow eigenvectors. Aside from these additions to the snapshot matrices, the algorithm remains unchanged. By treating the tails analytically, we eliminate the need to run long impulse response simulations, lowering storage requirements and speeding up ensuing computations. To demonstrate its effectiveness, we apply this method to two examples: the linearized, complex Ginzburg-Landau equation, and the two-dimensional fluid flow past a cylinder. As expected, reduced-order models computed using an analytic tail match or exceed the accuracy of those computed using the standard balanced POD procedure, at a fraction of the cost.

Focusing light through strongly scattering media by controlling binary amplitude optimization using genetic algorithm

NASA Astrophysics Data System (ADS)

Liu, Zhipeng; Zhang, Bin; Feng, Qi; Chen, Zhaoyang; Lin, Chengyou; Ding, Yingchun

2017-06-01

Focusing light through strongly scattering media plays an important role in biomedical imaging and therapy. Here, we experimentally demonstrate light focusing through ZnO sample by controlling binary amplitude optimization using genetic algorithm. In the experiment, we use a Micro Electro-Mechanical System (MEMS)-based digital micromirror device (DMD) which is in amplitude-only modulation mode. The DMD consists of 1920×1080 square mirrors that can be independently controlled to reflect light to a desired position. We control only 160 thousand mirrors which are divided into 400 segments to modulate light focusing through the scattering media using advanced genetic algorithm. Light intensity at the target position is enhanced up to 50+/-5 times the average speckle intensity. The diameters of focusing spot can be changed ranging from 7 μm to 70 μm at arbitrary positions and multiple foci are obtained simultaneously. The spatial arrangement of multiple foci can be flexibly controlled. The advantage of DMDs lies in their switching speed up to 30 kHz, which has the potential to generate a focus in an ultra-short period of time. Our work provides a reference for the study of high speed wavefront shaping that is required in vivo tissues imaging.

Shaping perfect optical vortex with amplitude modulated using a digital micro-mirror device

NASA Astrophysics Data System (ADS)

Zhang, Chonglei; Min, Changjun; Yuan, X.-C.

2016-12-01

We propose a technique to generate of perfect optical vortex (POV) via Fourier transformation of Bessel-Gauss (BG) beams through encoding of the amplitude of the optical field with binary amplitude digital micro-mirrors device (DMD). Furthermore, we confirm the correct phase patterns of the POV with the method of Mach-Zehnder interferometer. Our approach to generate the POV has the advantages that rapidly switch among the different modes, wide spectral regions and high energy tolerance. Since the POV possess propagation properties that not shape-invariant, we therefore suppose that our proposed approach will find potential applications in optical microscopy, optical fabrication, and optical communication.

Three-dimensional crossbar interconnection using planar-integrated free-space optics and digital mirror-device

NASA Astrophysics Data System (ADS)

Lohmann, U.; Jahns, J.; Limmer, S.; Fey, D.

2011-01-01

We consider the implementation of a dynamic crossbar interconnect using planar-integrated free-space optics (PIFSO) and a digital mirror-device™ (DMD). Because of the 3D nature of free-space optics, this approach is able to solve geometrical problems with crossings of the signal paths that occur in waveguide optical and electrical interconnection, especially for large number of connections. The DMD device allows one to route the signals dynamically. Due to the large number of individual mirror elements in the DMD, different optical path configurations are possible, thus offering the chance for optimizing the network configuration. The optimization is achieved by using an evolutionary algorithm for finding best values for a skewless parallel interconnection. Here, we present results and experimental examples for the use of the PIFSO/DMD-setup.

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

PubMed

Nelson, Michael D; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F; Miceli, M Carrie; Elashoff, Robert M; Sweeney, H Lee; Victor, Ronald G

2014-06-10

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. © 2014 American Academy of Neurology.

Dystrophin Is Required for Proper Functioning of Luminance and Red-Green Cone Opponent Mechanisms in the Human Retina.

PubMed

Barboni, Mirella Telles Salgueiro; Martins, Cristiane Maria Gomes; Nagy, Balázs Vince; Tsai, Tina; Damico, Francisco Max; da Costa, Marcelo Fernandes; de Cassia, Rita; Pavanello, M; Lourenço, Naila Cristina Vilaça; de Cerqueira, Antonia Maria Pereira; Zatz, Mayana; Kremers, Jan; Ventura, Dora Fix

2016-07-01

Visual information is processed in parallel pathways in the visual system. Parallel processing begins at the synapse between the photoreceptors and their postreceptoral neurons in the human retina. The integrity of this first neural connection is vital for normal visual processing downstream. Of the numerous elements necessary for proper functioning of this synaptic contact, dystrophin proteins in the eye play an important role. Deficiency of muscle dystrophin causes Duchenne muscular dystrophy (DMD), an X-linked disease that affects muscle function and leads to decreased life expectancy. In DMD patients, postreceptoral retinal mechanisms underlying scotopic and photopic vision and ON- and OFF-pathway responses are also altered. In this study, we recorded the electroretinogram (ERG) while preferentially activating the (red-green) opponent or the luminance pathway, and compared data from healthy participants (n = 16) with those of DMD patients (n = 10). The stimuli were heterochromatic sinusoidal modulations at a mean luminance of 200 cd/m2. The recordings allowed us also to analyze ON and OFF cone-driven retinal responses. We found significant differences in 12-Hz response amplitudes and phases between controls and DMD patients, with conditions with large luminance content resulting in larger response amplitudes in DMD patients compared to controls, whereas responses of DMD patients were smaller when pure chromatic modulation was given. The results suggest that dystrophin is required for the proper function of luminance and red-green cone opponent mechanisms in the human retina.

Acetylcholine, GABA and neuronal networks: a working hypothesis for compensations in the dystrophic brain.

PubMed

Cohen, Erez James; Quarta, Eros; Fulgenzi, Gianluca; Minciacchi, Diego

2015-01-01

Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease's progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS. Copyright © 2014 Elsevier Inc. All rights reserved.

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

PubMed

Brinkmeyer-Langford, Candice; Balog-Alvarez, Cynthia; Cai, James J; Davis, Brian W; Kornegay, Joe N

2016-08-22

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.

Programmable spectral engine design of hyperspectral image projectors based on digital micro-mirror device (DMD)

NASA Astrophysics Data System (ADS)

Wang, Xicheng; Gao, Jiaobo; Wu, Jianghui; Li, Jianjun; Cheng, Hongliang

2017-02-01

Recently, hyperspectral image projectors (HIP) have been developed in the field of remote sensing. For the advanced performance of system-level validation, target detection and hyperspectral image calibration, HIP has great possibility of development in military, medicine, commercial and so on. HIP is based on the digital micro-mirror device (DMD) and projection technology, which is capable to project arbitrary programmable spectra (controlled by PC) into the each pixel of the IUT1 (instrument under test), such that the projected image could simulate realistic scenes that hyperspectral image could be measured during its use and enable system-level performance testing and validation. In this paper, we built a visible hyperspectral image projector also called the visible target simulator with double DMDs, which the first DMD is used to product the selected monochromatic light from the wavelength of 410 to 720 um, and the light come to the other one. Then we use computer to load image of realistic scenes to the second DMD, so that the target condition and background could be project by the second DMD with the selected monochromatic light. The target condition can be simulated and the experiment could be controlled and repeated in the lab, making the detector instrument could be tested in the lab. For the moment, we make the focus on the spectral engine design include the optical system, research of DMD programmable spectrum and the spectral resolution of the selected spectrum. The detail is shown.

Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming.

PubMed

Matsakas, Antonios; Yadav, Vikas; Lorca, Sabina; Narkar, Vihang

2013-10-01

Treatment of Duchenne muscular dystrophy (DMD) by replacing mutant dystrophin or restoring dystrophin-associated glycoprotein complex (DAG) has been clinically challenging. Instead, identifying and targeting muscle pathways deregulated in DMD will provide new therapeutic avenues. We report that the expression of nuclear receptor estrogen-related receptor-γ (ERRγ), and its metabolic and angiogenic targets are down-regulated (50-85%) in skeletal muscles of mdx mice (DMD model) vs. wild-type mice. Corelatively, oxidative myofibers, muscle vasculature, and exercise tolerance (33%) are decreased in mdx vs. wild-type mice. Overexpressing ERRγ selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERRγ enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33-66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERRγ pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERRγ did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERRγ. In summary, ERRγ-dependent metabolic and angiogenic gene program is defective in DMD, and we demonstrate that its restoration is a potential strategy for treating muscular dystrophy.

Galectin-1 Protein Therapy Prevents Pathology and Improves Muscle Function in the mdx Mouse Model of Duchenne Muscular Dystrophy.

PubMed

Van Ry, Pam M; Wuebbles, Ryan D; Key, Megan; Burkin, Dean J

2015-08-01

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by mutations in the dystrophin gene, leading to the loss of a critical component of the sarcolemmal dystrophin glycoprotein complex. Galectin-1 is a small 14 kDa protein normally found in skeletal muscle and has been shown to be a modifier of immune response, muscle repair, and apoptosis. Galectin-1 levels are elevated in the muscle of mouse and dog models of DMD. Together, these findings led us to hypothesize that Galectin-1 may serve as a modifier of disease progression in DMD. To test this hypothesis, recombinant mouse Galectin-1 was produced and used to treat myogenic cells and the mdx mouse model of DMD. Here we show that intramuscular and intraperitoneal injections of Galectin-1 into mdx mice prevented pathology and improved muscle function in skeletal muscle. These improvements were a result of enhanced sarcolemmal stability mediated by elevated utrophin and α7β1 integrin protein levels. Together our results demonstrate for the first time that Galectin-1 may serve as an exciting new protein therapeutic for the treatment of DMD.

Deletion detection for diagnosis of Duchenne muscular dystrophy in the Japanese population--comparison between the polymerase chain reaction and the Southern blot analysis.

PubMed

Katayama, S; Takeshita, N; Yano, T; Ubagai, T; Qiu, X J; Katagiri, Y; Kubo, H; Hirakawa, S

1993-06-01

We compared the efficacy of the multiplex PCR with that of the cDNA analysis for detection of deletions of the DMD gene in the Japanese patients. Thirty males with DMD from 27 Japanese families were studied by the multiplex PCR, and 24 of them were also investigated by Southern blot analysis. We used five dystrophin cDNA probes for deletion analysis. A total of 19 regions were amplified by the PCR to detect deletions, 9 regions by the method of Chamberlain et al. and another 10 regions by the method of Beggs et al. Deletions were detected in 14 (52%) out of 27 DMD families by the PCR. Southern blot analysis detected deletions in 14 (64%) out of 22 families. Thirteen (93%) of the 14 DMD families with deletions detected by Southern blotting were also confirmed by the multiplex PCR. Provided care is taken in cases where the deletion is limited to a single exon, the multiplex PCR appears to be an efficient and useful alternative to conventional Southern blot analysis for detecting deletions during the prenatal and postnatal diagnosis of DMD.

Tablet PC interaction with digital micromirror device (DMD)

NASA Astrophysics Data System (ADS)

Refai, Hakki H.; Dahshan, Mostafa H.; Sluss, James J., Jr.

2007-02-01

Digital light processing (DLP) is an innovative display technology that uses an optical switch array, known as a digital micromirror device (DMD), which allows digital control of light. To date, DMDs have been used primarily as high-speed spatial light modulators for projector applications. A tablet PC is a notebook or slate-shaped mobile PC. Its touch screen or digitizing tablet technology allows the user to operate the notebook with a stylus or digital pen instead of using a keyboard or mouse. In this paper, we describe an interface solution that translates any sketch on the tablet PC screen to an identical mirror-copy over the cross-section of the DMD micromirrors such that the image of the sketch can be projected onto a special screen. An algorithm has been created to control each single micromirror of the hundreds of thousands of micromirrors that cover the DMD surface. We demonstrate the successful application of a DMD to a high-speed two-dimensional (2D) scanning environment, acquiring the data from the tablet screen and launching its contents to the projection screen; with very high accuracy up to 13.68 μm x 13.68 μm of mirror pitch.

Impact of corticotherapy, nutrition, and sleep disorder on quality of life of patients with Duchenne muscular dystrophy.

PubMed

Jeronimo, Giovanna; Nozoe, Karen T; Polesel, Daniel N; Moreira, Gustavo A; Tufik, Sergio; Andersen, Monica L

2016-03-01

Duchenne muscular dystrophy (DMD) is the second most common hereditary genetic disease in humans and has elevated mortality. DMD is an X-linked, life-limiting progressive muscle-wasting disease found predominantly in boys and young men. One of the main treatments for patients with DMD is corticosteroids. However, long-term use may cause major side effects such as obesity, a reduction in vitamin D, and osteoporosis. Sleep-disordered breathing is a common condition among patients with DMD, especially obstructive sleep apnea (OSA). In children, OSA is associated with obesity and a reduction of vitamin D concentration. In this article we aim to explore the interrelationship that exists between corticosteroids, obesity, OSA, and the risk of osteoporosis. Our main hypothesis is that factors such as nutrition and sleep are related to obesity and OSA, respectively. In addition, the chronic use of corticosteroids, obesity, and OSA are factors that can reduce serum levels of vitamin D, triggering osteoporosis. Thus, these factors play a key role in affecting the quality of life for patients with DMD and intervention based on these aspects may improve survival. Copyright © 2016 Elsevier Inc. All rights reserved.

Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

PubMed Central

Xu, Huaigeng

2017-01-01

In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic. PMID:28607562

Observation of the asymmetric Bessel beams with arbitrary orientation using a digital micromirror device.

PubMed

Gong, Lei; Qiu, Xing-Ze; Ren, Yu-Xuan; Zhu, Hui-Qing; Liu, Wei-Wei; Zhou, Jin-Hua; Zhong, Min-Cheng; Chu, Xiu-Xiang; Li, Yin-Mei

2014-11-03

Recently, V. V. Kotlyar et al. [Opt. Lett.39, 2395 (2014)] have theoretically proposed a novel kind of three-parameter diffraction-free beam with a crescent profile, namely, the asymmetric Bessel (aB) beam. The asymmetry degree of such nonparaxial modes was shown to depend on a nonnegative real parameter c. We present a more generalized asymmetric Bessel mode in which the parameter c is a complex constant. This parameter controls not only the asymmetry degree of the mode but also the orientation of the optical crescent, and affects the energy distribution and orbital angular momentum (OAM) of the beam. As a proof of concept, the high-quality generation of asymmetric Bessel-Gauss beams was demonstrated with the super-pixel method using a digital micromirror device (DMD). We investigated the near-field properties as well as the far field features of such beams, and the experimental observations were in good agreement with the theoretical predictions. Additionally, we provided an effective way to control the beam's asymmetry and orientation, which may find potential applications in light-sheet microscopy and optical manipulation.

Complete measurement of spatiotemporally complex multi-spatial-mode ultrashort pulses from multimode optical fibers using delay-scanned wavelength-multiplexed holography.

PubMed

Zhu, Ping; Jafari, Rana; Jones, Travis; Trebino, Rick

2017-10-02

We introduce a simple delay-scanned complete spatiotemporal intensity-and-phase measurement technique based on wavelength-multiplexed holography to characterize long, complex pulses in space and time. We demonstrate it using pulses emerging from multi-mode fiber. This technique extends the temporal range and spectral resolution of the single-frame STRIPED FISH technique without using an otherwise-required expensive ultranarrow-bandpass filter. With this technique, we measured the complete intensity and phase of up to ten fiber modes from a multi-mode fiber (normalized frequency V ≈10) over a ~3ps time range. Spatiotemporal complexities such as intermodal delay, modal dispersion, and material dispersion were also intuitively displayed by the retrieved results. Agreement between the reconstructed color movies and the monitored time-averaged spatial profiles confirms the validity to this delay-scanned STRIPED FISH method.

Impact of a Comparative Study on the Management of Scoliosis in Duchenne Muscular Dystrophy: Are Corticosteroids Decreasing the Rate of Scoliosis Surgery in the United States?

PubMed

Raudenbush, Brandon L; Thirukumaran, Caroline P; Li, Yue; Sanders, James O; Rubery, Paul T; Mesfin, Addisu

2016-09-01

A cross-sectional analysis. The aim of this study was to determine whether the surgical treatment for scoliosis due to Duchenne muscular dystrophy (DMD) has decreased over a recent 11-year period, specifically, after the wide acceptance of glucocorticoid treatment for DMD. DMD can result in a flaccid neuromuscular scoliosis that has been traditionally treated surgically. In 2004, a comparative study demonstrated that glucocorticoid treatment decreased the progression of scoliosis in DMD. We used the Nationwide Inpatient Sample from 2001 to 2012 to identify patients with DMD undergoing spinal fusion. Demographic information (age, hospital size, location, geographic status) was collected. We examined the distribution of patient and hospital characteristics among cohorts undergoing spinal fusion from 2001 to 2004 (period 1; before publication of the comparative study), 2005 to 2008 (period 2; immediately following publication of the comparative study), and 2009 to 2012 (period 3; moderate duration following publication of the comparative study). We identified 1874 males undergoing spinal fusion. During this period, the overall rate of DMD surgeries declined by 48%-from 1.87 surgeries in 2001 to 0.97 surgeries in 2012 per million US males per year. This decline was significantly pronounced following the publication of the comparative study [periods 2 and 3; For period 2 vs. period 1: incidence rate ratio (IRR) = 0.71, 95% confidence interval (95% CI) = 0.56-0.91, P = 0.01; For period 3 vs. period 1: IRR = 0.77, 95% CI = 0.61-0.97, P = 0.03]. Our study demonstrates a significant decrease in the rate of scoliosis surgery for DMD from 2001 to 2012. It appears that the decline in surgical treatment could be related to the publication and landmark study demonstrating decreased progression of scoliosis with glucocorticoid treatment. 3.

Quantitative Skeletal Muscle MRI: Part 2, MR Spectroscopy and T2 Relaxation Time Mapping-Comparison Between Boys With Duchenne Muscular Dystrophy and Healthy Boys.

PubMed

Kim, Hee Kyung; Serai, Suraj; Lindquist, Diana; Merrow, Arnold C; Horn, Paul S; Kim, Dong Hoon; Wong, Brenda L

2015-08-01

The purpose of this study is to validate the use of MR spectroscopy (MRS) in measuring muscular fat and to compare it with T2 maps in differentiating boys with Duchenne muscular dystrophy (DMD) from healthy boys. Forty-two boys with DMD and 31 healthy boys were evaluated with MRI with (1)H-MRS and T2 maps. Grading of muscle fat and edema on conventional images, calculation of fat fractions ([fat / fat] + water) on MRS, and calculation of T2 fat values on T2 maps of the gluteus maximus and vastus lateralis muscles were performed. Group comparisons were made. The 95% reference interval (RI) of fat fraction for the control group was applied and compared with T2 map results. Minimal fat on T1-weighted images was seen in 90.3% (gluteus maximus) and 71.0% (vastus lateralis) of healthy boys, versus 33.3% (gluteus maximus) and 52.4% (vastus lateralis) of boys with DMD. Muscle edema was seen in none of the healthy boys versus 52.4% (gluteus maximus) and 57.1% (vastus lateralis) of the boys with DMD. Fat fractions were higher in the DMD group (52.7%, gluteus maximus; 27.3%, vastus lateralis) than in the control group (12.8%, gluteus maximus; 13.7%, vastus lateralis) (p < 0.001). The 95% RI for gluteus maximus (38.7%) resulted in 61.9% sensitivity and 100% specificity for differentiating boys with DMD from healthy boys, whereas the value for vastus lateralis (17.8%) resulted in 76.2% sensitivity and 100% specificity; both had lower accuracy than did T2 maps (100% sensitivity and specificity). There was a positive correlation between T2 fat values and fat fractions (p < 0.0001). In differentiation of the two groups, T2 maps were more accurate than MRS. Fat fractions can underestimate the actual amount of fat because of coexisting muscle edema in DMD.

Improvements in motor tasks through the use of smartphone technology for individuals with Duchenne muscular dystrophy.

PubMed

Capelini, Camila Miliani; da Silva, Talita Dias; Tonks, James; Watson, Suzanna; Alvarez, Mayra Priscila Boscolo; de Menezes, Lilian Del Ciello; Favero, Francis Meire; Caromano, Fátima Aparecida; Massetti, Thais; de Mello Monteiro, Carlos Bandeira

2017-01-01

In individuals severely affected with Duchenne muscular dystrophy (DMD), virtual reality has recently been used as a tool to enhance community interaction. Smartphones offer the exciting potential to improve communication, access, and participation, and present the unique opportunity to directly deliver functionality to people with disabilities. To verify whether individuals with DMD improve their motor performance when undertaking a visual motor task using a smartphone game. Fifty individuals with DMD and 50 healthy, typically developing (TD) controls, aged 10-34 years participated in the study. The functional characterization of the sample was determined through Vignos, Egen Klassifikation, and the Motor Function Measure scales. To complete the task, individuals moved a virtual ball around a virtual maze and the time in seconds was measured after every attempt in order to analyze improvement of performance after the practice trials. Motor performance (time to finish each maze) was measured in phases of acquisition, short-term retention, and transfer. Use of the smartphone maze game promoted improvement in performance during acquisition in both groups, which remained in the retention phase. At the transfer phases, with alternative maze tasks, the performance in DMD group was similar to the performance of TD group, with the exception of the transfer to the contralateral hand (nondominant). However, the group with DMD demonstrated longer movement time at all stages of learning, compared with the TD group. The practice of a visual motor task delivered via smartphone game promoted an improvement in performance with similar patterns of learning in both groups. Performance can be influenced by task difficulty, and for people with DMD, motor deficits are responsible for the lower speed of execution. This study indicates that individuals with DMD showed improved performance in a short-term motor learning protocol using a smartphone. We advocate that this technology could be used to promote function in this population.

Quantitative Skeletal Muscle MRI: Part 1, Derived T2 Fat Map in Differentiation Between Boys With Duchenne Muscular Dystrophy and Healthy Boys.

PubMed

Johnston, Jennifer H; Kim, Hee Kyung; Merrow, Arnold C; Laor, Tal; Serai, Suraj; Horn, Paul S; Kim, Dong Hoon; Wong, Brenda L

2015-08-01

The purpose of this study was to validate derived T2 maps as an objective measure of muscular fat for discrimination between boys with Duchenne muscular dystrophy (DMD) and healthy boys. Forty-two boys with DMD (mean age, 9.9 years) and 31 healthy boys (mean age, 11.4 years) were included in the study. Age, body mass index, and clinical function scale grade were evaluated. T1-weighted MR images and T2 maps with and without fat suppression were obtained. Fatty infiltration was graded 0-4 on T1-weighted images, and derived T2 fat values (difference between mean T2 values from T2 maps with and without fat suppression) of the gluteus maximus and vastus lateralis muscles were calculated. Group comparisons were performed. The upper limit of the 95% reference interval of T2 fat values from the control group was applied. There was no significant difference in age or body mass index between groups. All healthy boys and 19 boys (45.2%) with DMD had a normal clinical function scale grade. Grade 1 fatty infiltration was seen in 90.3% (gluteus maximus) and 71.0% (vastus lateralis) of healthy boys versus 33.3% (gluteus maximus) and 52.4% (vastus lateralis) of boys with DMD. T2 fat values of boys with DMD were significantly longer than in the control group (p < 0.001). Using a 95% reference interval for healthy boys for the gluteus maximus (28.3 milliseconds) allowed complete separation from boys with DMD (100% sensitivity, 100% specificity), whereas the values for the vastus lateralis (7.28 milliseconds) resulted in 83.3% sensitivity and 100% specificity. Measurement of muscular fat with T2 maps is accurate for differentiating boys with DMD from healthy boys.

Influence of management regime and harvest date on the forage quality of rangelands plants: the importance of dry matter content

PubMed Central

Bumb, Iris; Garnier, Eric; Bastianelli, Denis; Richarte, Jean; Bonnal, Laurent; Kazakou, Elena

2016-01-01

In spite of their recognized ecological value, relatively little is known about the nutritional value of species-rich rangelands for herbivores. We investigated the sources of variation in dry matter digestibility (DMD), neutral detergent fibre content (NDF) and nitrogen concentration (NC) in plants from species-rich Mediterranean rangelands in southern France, and tested whether the dry matter content (DMC) was a good predictor of the forage quality of different plant parts. Sixteen plant species with contrasting growth forms (rosette, tussock, extensive and stemmed-herb) were studied, representative of two management regimes imposed in these rangelands: (i) fertilization and intensive grazing and (ii) non-fertilization and moderate grazing. Among the 16 plant species, four species were found in both treatments, allowing us to assess the intraspecific variability in forage quality and DMC across the treatments. The components of nutritional value (DMD, NDF and NC) as well as the DMC of leaves, stems and reproductive plant parts, were assessed at the beginning of the growing season and at peak standing biomass. All components of nutritional value and DMC were affected by species growth form: rosettes had higher DMD and NC than tussocks; the reverse being found for NDF and DMC. As the season progressed, DMD and NC of the different plant parts decreased while NDF and DMC increased for all species. DMC was negatively related to DMD and NC and positively to NDF, regardless of the source of variation (species, harvest date, management regime or plant part). Path analysis indicated that NDF was the main determinant of DMD. Better assessment of forage quality in species-rich systems requires consideration of their growth form composition. DMC of all plant parts, which is closely related to NDF, emerged as a good predictor and easily measured trait to estimate DMD in these species-rich systems. PMID:27339049

Improvements in motor tasks through the use of smartphone technology for individuals with Duchenne muscular dystrophy

PubMed Central

Capelini, Camila Miliani; da Silva, Talita Dias; Tonks, James; Watson, Suzanna; Alvarez, Mayra Priscila Boscolo; de Menezes, Lilian Del Ciello; Favero, Francis Meire; Caromano, Fátima Aparecida; Massetti, Thais; de Mello Monteiro, Carlos Bandeira

2017-01-01

Background In individuals severely affected with Duchenne muscular dystrophy (DMD), virtual reality has recently been used as a tool to enhance community interaction. Smartphones offer the exciting potential to improve communication, access, and participation, and present the unique opportunity to directly deliver functionality to people with disabilities. Objective To verify whether individuals with DMD improve their motor performance when undertaking a visual motor task using a smartphone game. Patients and methods Fifty individuals with DMD and 50 healthy, typically developing (TD) controls, aged 10–34 years participated in the study. The functional characterization of the sample was determined through Vignos, Egen Klassifikation, and the Motor Function Measure scales. To complete the task, individuals moved a virtual ball around a virtual maze and the time in seconds was measured after every attempt in order to analyze improvement of performance after the practice trials. Motor performance (time to finish each maze) was measured in phases of acquisition, short-term retention, and transfer. Results Use of the smartphone maze game promoted improvement in performance during acquisition in both groups, which remained in the retention phase. At the transfer phases, with alternative maze tasks, the performance in DMD group was similar to the performance of TD group, with the exception of the transfer to the contralateral hand (nondominant). However, the group with DMD demonstrated longer movement time at all stages of learning, compared with the TD group. Conclusion The practice of a visual motor task delivered via smartphone game promoted an improvement in performance with similar patterns of learning in both groups. Performance can be influenced by task difficulty, and for people with DMD, motor deficits are responsible for the lower speed of execution. This study indicates that individuals with DMD showed improved performance in a short-term motor learning protocol using a smartphone. We advocate that this technology could be used to promote function in this population. PMID:28860778

An Overview of Recent Therapeutics Advances for Duchenne Muscular Dystrophy.

PubMed

Mah, Jean K

2018-01-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.

Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy.

PubMed

Hu, Xiao; Blemker, Silvia S

2015-08-01

Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research. © 2015 Wiley Periodicals, Inc.

DMD mutation spectrum analysis in 613 Chinese patients with dystrophinopathy.

PubMed

Guo, Ruolan; Zhu, Guosheng; Zhu, Huimin; Ma, Ruiyu; Peng, Ying; Liang, Desheng; Wu, Lingqian

2015-08-01

Dystrophinopathy is a group of inherited diseases caused by mutations in the DMD gene. Within the dystrophinopathy spectrum, Duchenne and Becker muscular dystrophies are common X-linked recessive disorders that mainly feature striated muscle necrosis. We combined multiplex ligation-dependent probe amplification with Sanger sequencing to detect large deletions/duplications and point mutations in the DMD gene in 613 Chinese patients. A total of 571 (93.1%) patients were diagnosed, including 428 (69.8%) with large deletions/duplications and 143 (23.3%) with point mutations. Deletion/duplication breakpoints gathered mostly in introns 44-55. Reading frame rules could explain 88.6% of deletion mutations. We identified seventy novel point mutations that had not been previously reported. Spectrum expansion and genotype-phenotype analysis of DMD mutations on such a large sample size in Han Chinese population would provide new insights into the pathogenic mechanism underlying dystrophinopathies.

Dimensional and material characteristics of direct deposited tool steel by CO II laser

NASA Astrophysics Data System (ADS)

Choi, J.

2006-01-01

Laser aided direct metalimaterial deposition (DMD) process builds metallic parts layer-by-layer directly from the CAD representation. In general, the process uses powdered metaUmaterials fed into a melt pool, creating fully dense parts. Success of this technology in the die and tool industry depends on the parts quality to be achieved. To obtain designed geometric dimensions and material properties, delicate control of the parameters such as laser power, spot diameter, traverse speed and powder mass flow rate is critical. In this paper, the dimensional and material characteristics of directed deposited H13 tool steel by CO II laser are investigated for the DMD process with a feedback height control system. The relationships between DMD process variables and the product characteristics are analyzed using statistical techniques. The performance of the DMD process is examined with the material characteristics of hardness, porosity, microstructure, and composition.

Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy

PubMed Central

HINTON, VERONICA J.; DE VIVO, DARRYL C.; NEREO, NANCY E.; GOLDSTEIN, EDWARD; STERN, YAAKOV

2007-01-01

Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal, visuospatial, attention/memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the DMD group did significantly more poorly than their siblings on specific measures of story recall, digit span, and auditory comprehension, as well as in all areas of academic achievement (reading, writing, and math). This profile indicates that verbal working memory skills are selectively impaired in DMD, and that that likely contributes to limited academic achievement. The association between the known impact of the genetic mutation on the development of the central nervous system and boys’ cognitive profile is discussed. PMID:11253841

Full complex spatial filtering with a phase mostly DMD. [Deformable Mirror Device

NASA Technical Reports Server (NTRS)

Florence, James M.; Juday, Richard D.

1991-01-01

A new technique for implementing fully complex spatial filters with a phase mostly deformable mirror device (DMD) light modulator is described. The technique combines two or more phase-modulating flexure-beam mirror elements into a single macro-pixel. By manipulating the relative phases of the individual sub-pixels within the macro-pixel, the amplitude and the phase can be independently set for this filtering element. The combination of DMD sub-pixels into a macro-pixel is accomplished by adjusting the optical system resolution, thereby trading off system space bandwidth product for increased filtering flexibility. Volume in the larger dimensioned space, space bandwidth-complex axes count, is conserved. Experimental results are presented mapping out the coupled amplitude and phase characteristics of the individual flexure-beam DMD elements and demonstrating the independent control of amplitude and phase in a combined macro-pixel. This technique is generally applicable for implementation with any type of phase modulating light modulator.

SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy.

PubMed

Sarathy, Apurva; Wuebbles, Ryan D; Fontelonga, Tatiana M; Tarchione, Ashley R; Mathews Griner, Lesley A; Heredia, Dante J; Nunes, Andreia M; Duan, Suzann; Brewer, Paul D; Van Ry, Tyler; Hennig, Grant W; Gould, Thomas W; Dulcey, Andrés E; Wang, Amy; Xu, Xin; Chen, Catherine Z; Hu, Xin; Zheng, Wei; Southall, Noel; Ferrer, Marc; Marugan, Juan; Burkin, Dean J

2017-06-07

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by mutations in the dystrophin gene, resulting in a complete loss of the dystrophin protein. Dystrophin is a critical component of the dystrophin glycoprotein complex (DGC), which links laminin in the extracellular matrix to the actin cytoskeleton within myofibers and provides resistance to shear stresses during muscle activity. Loss of dystrophin in DMD patients results in a fragile sarcolemma prone to contraction-induced muscle damage. The α7β1 integrin is a laminin receptor protein complex in skeletal and cardiac muscle and a major modifier of disease progression in DMD. In a muscle cell-based screen for α7 integrin transcriptional enhancers, we identified a small molecule, SU9516, that promoted increased α7β1 integrin expression. Here we show that SU9516 leads to increased α7B integrin in murine C2C12 and human DMD patient myogenic cell lines. Oral administration of SU9516 in the mdx mouse model of DMD increased α7β1 integrin in skeletal muscle, ameliorated pathology, and improved muscle function. We show that these improvements are mediated through SU9516 inhibitory actions on the p65-NF-κB pro-inflammatory and Ste20-related proline alanine rich kinase (SPAK)/OSR1 signaling pathways. This study identifies a first in-class α7 integrin-enhancing small-molecule compound with potential for the treatment of DMD. Copyright © 2017 The American Society of Gene and Cell Therapy. All rights reserved.

Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy.

PubMed

Vieira, Natassia M; Spinazzola, Janelle M; Alexander, Matthew S; Moreira, Yuri B; Kawahara, Genri; Gibbs, Devin E; Mead, Lillian C; Verjovski-Almeida, Sergio; Zatz, Mayana; Kunkel, Louis M

2017-06-06

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN ( DMD ) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these "escaper" dogs revealed reduced expression of phosphatidylinositol transfer protein-α ( PITPNA ) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.

Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

PubMed Central

Vieira, Natassia M.; Spinazzola, Janelle M.; Alexander, Matthew S.; Moreira, Yuri B.; Kawahara, Genri; Gibbs, Devin E.; Mead, Lillian C.; Zatz, Mayana; Kunkel, Louis M.

2017-01-01

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these “escaper” dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases. PMID:28533404

The influence of visual and tactile perception on hand control in children with Duchenne muscular dystrophy.

PubMed

Troise, Denise; Yoneyama, Simone; Resende, Maria Bernadette; Reed, Umbertina; Xavier, Gilberto Fernando; Hasue, Renata

2014-09-01

To investigate tactile perception and manual dexterity, with or without visual feedback, in males with Duchenne muscular dystrophy (DMD). Forty males with DMD (mean age 9 y 8 mo, SD 2 y 3 mo; range 5-14 y), recruited from the teaching hospital of the School of Medicine of the University of São Paulo, with disease severity graded as '1' to '6' on the Vignos Scale and '1' on Brooke's Scale, and 49 healthy males (mean age 8 y 2 mo; range 5-11 y; SD 1 y 11 mo), recruited from a local education center, participated in the study. We assessed tactile perception using two-point discrimination and stereognosis tests, and manual dexterity using the Pick-Up test with the eyes either open or closed. Analysis of variance was used to compare groups; a p value of less than 0.05 was considered statistically significant. Males with DMD exhibited no impairment in tactile perception, as measured by the two-point discrimination test and the number of objects correctly named in the stereognosis test. Manipulation during stereognosis was statistically slower with both hands (p<0.001), and manual dexterity was much worse in males with DMD when there was no visual feedback (p<0.001). Males with DMD exhibited disturbances in manipulation during stereognosis and dexterity tests. Hand control was highly dependent on visual information rather than on tactile perception. Motor dysfunction in males with DMD, therefore, might be related to altered neural control. © 2014 Mac Keith Press.

Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients.

PubMed

Zanotti, Simona; Bragato, Cinzia; Zucchella, Andrea; Maggi, Lorenzo; Mantegazza, Renato; Morandi, Lucia; Mora, Marina

2016-01-15

Tissue fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the end point of diseases affecting the kidney, bladder, liver, lung, gut, skin, heart and muscle. In Duchenne muscular dystrophy (DMD), connective fibrotic tissue progressively substitutes muscle fibers. So far no specific pharmacological treatment is available for muscle fibrosis. Among promising anti-fibrotic molecules, pirfenidone has shown anti-fibrotic and anti-inflammatory activity in animal and cell models, and has already been employed in clinical trials. Therefore we tested pirfenidone anti-fibrotic properties in an in vitro model of muscle fibrosis. We evaluated effect of pirfenidone on fibroblasts isolated from DMD muscle biopsies. These cells have been previously characterized as having a pro-fibrotic phenotype. We tested cell proliferation and migration, secretion of soluble collagens, intracellular levels of collagen type I and fibronectin, and diameter of 3D fibrotic nodules. We found that pirfenidone significantly reduced proliferation and cell migration of control and DMD muscle-derived fibroblasts, decreased extracellular secretion of soluble collagens by control and DMD fibroblasts, as well as levels of collagen type I and fibronectin, and, in DMD fibroblasts only, reduced synthesis and deposition of intracellular collagen. Furthermore, pirfenidone was able to reduce the diameter of fibrotic-nodules in our 3D model of in vitro fibrosis. These pre-clinical results indicate that pirfenidone has potential anti-fibrotic effects also in skeletal muscle fibrosis, urging further studies in in vivo animal models of muscular dystrophy in order to translate the drug into the treatment of muscle fibrosis in DMD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Basis-neutral Hilbert-space analyzers

PubMed Central

Martin, Lane; Mardani, Davood; Kondakci, H. Esat; Larson, Walker D.; Shabahang, Soroush; Jahromi, Ali K.; Malhotra, Tanya; Vamivakas, A. Nick; Atia, George K.; Abouraddy, Ayman F.

2017-01-01

Interferometry is one of the central organizing principles of optics. Key to interferometry is the concept of optical delay, which facilitates spectral analysis in terms of time-harmonics. In contrast, when analyzing a beam in a Hilbert space spanned by spatial modes – a critical task for spatial-mode multiplexing and quantum communication – basis-specific principles are invoked that are altogether distinct from that of ‘delay’. Here, we extend the traditional concept of temporal delay to the spatial domain, thereby enabling the analysis of a beam in an arbitrary spatial-mode basis – exemplified using Hermite-Gaussian and radial Laguerre-Gaussian modes. Such generalized delays correspond to optical implementations of fractional transforms; for example, the fractional Hankel transform is the generalized delay associated with the space of Laguerre-Gaussian modes, and an interferometer incorporating such a ‘delay’ obtains modal weights in the associated Hilbert space. By implementing an inherently stable, reconfigurable spatial-light-modulator-based polarization-interferometer, we have constructed a ‘Hilbert-space analyzer’ capable of projecting optical beams onto any modal basis. PMID:28344331

Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications.

PubMed Central

Den Dunnen, J T; Grootscholten, P M; Bakker, E; Blonden, L A; Ginjaar, H B; Wapenaar, M C; van Paassen, H M; van Broeckhoven, C; Pearson, P L; van Ommen, G J

1989-01-01

We have studied 34 Becker and 160 Duchenne muscular dystrophy (DMD) patients with the dystrophin cDNA, using conventional blots and FIGE analysis. One hundred twenty-eight mutations (65%) were found, 115 deletions and 13 duplications, of which 106 deletions and 11 duplications could be precisely mapped in relation to both the mRNA and the major and minor mutation hot spots. Junction fragments, ideal markers for carrier detection, were found in 23 (17%) of the 128 cases. We identified eight new cDNA RFLPs within the DMD gene. With the use of cDNA probes we have completed the long-range map of the DMD gene, by the identification of a 680-kb SfiI fragment containing the gene's 3' end. The size of the DMD gene is now determined to be about 2.3 million basepairs. The combination of cDNA hybridizations with long-range analysis of deletion and duplication patients yields a global picture of the exon spacing within the dystrophin gene. The gene shows a large variability of intron size, ranging from only a few kilobases to 160-180 kb for the P20 intron. Images Figure 1 Figure 4 PMID:2573997

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

PubMed Central

Spinazzola, Janelle M.; Kunkel, Louis M.

2016-01-01

Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation. PMID:28670506

Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne muscular dystrophy.

PubMed

Galindo, Cristi L; Soslow, Jonathan H; Brinkmeyer-Langford, Candice L; Gupte, Manisha; Smith, Holly M; Sengsayadeth, Seng; Sawyer, Douglas B; Benson, D Woodrow; Kornegay, Joe N; Markham, Larry W

2016-04-01

In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.

Heme oxygenase and carbon monoxide protect from muscle dystrophy.

PubMed

Chan, Mun Chun; Ziegler, Olivia; Liu, Laura; Rowe, Glenn C; Das, Saumya; Otterbein, Leo E; Arany, Zoltan

2016-11-28

Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children worldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high side-effect profile. New therapeutic approaches are urgently needed. Here, we leverage PGC-1α, a powerful transcriptional coactivator known to protect against dystrophy in the mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy. We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of HO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic haploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects against muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron and carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in mdx mice, as does pharmacological treatment with CO-releasing molecules. These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety profiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these observations.

Molecular hydrogen alleviates motor deficits and muscle degeneration in mdx mice.

PubMed

Hasegawa, Satoru; Ito, Mikako; Fukami, Mayu; Hashimoto, Miki; Hirayama, Masaaki; Ohno, Kinji

2017-01-01

Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by a mutation in DMD encoding dystrophin. Oxidative stress accounts for dystrophic muscle pathologies in DMD. We examined the effects of molecular hydrogen in mdx mice, a model animal for DMD. The pregnant mother started to take supersaturated hydrogen water (>5 ppm) ad libitum from E15.5 up to weaning of the offspring. The mdx mice took supersaturated hydrogen water from weaning until age 10 or 24 weeks when they were sacrificed. Hydrogen water prevented abnormal body mass gain that is commonly observed in mdx mice. Hydrogen improved the spontaneous running distance that was estimated by a counter-equipped running-wheel, and extended the duration on the rota-rod. Plasma creatine kinase activities were decreased by hydrogen at ages 10 and 24 weeks. Hydrogen also decreased the number of central nuclei of muscle fibers at ages 10 and 24 weeks, and immunostaining for nitrotyrosine in gastrocnemius muscle at age 24 weeks. Additionally, hydrogen tended to increase protein expressions of antioxidant glutathione peroxidase 1, as well as anti-apoptotic Bcl-2, in skeletal muscle at age 10 weeks. Although molecular mechanisms of the diverse effects of hydrogen remain to be elucidated, hydrogen potentially improves muscular dystrophy in DMD patients.

Functional correction of dystrophin actin binding domain mutations by genome editing

PubMed Central

Kyrychenko, Viktoriia; Kyrychenko, Sergii; Tiburcy, Malte; Shelton, John M.; Long, Chengzu; Schneider, Jay W.; Zimmermann, Wolfram-Hubertus; Bassel-Duby, Rhonda

2017-01-01

Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD) that result in progressive, debilitating muscle weakness, cardiomyopathy, and a shortened lifespan. Mutations of dystrophin that disrupt the amino-terminal actin-binding domain 1 (ABD-1), encoded by exons 2–8, represent the second-most common cause of DMD. In the present study, we compared three different strategies for CRISPR/Cas9 genome editing to correct mutations in the ABD-1 region of the DMD gene by deleting exons 3–9, 6–9, or 7–11 in human induced pluripotent stem cells (iPSCs) and by assessing the function of iPSC-derived cardiomyocytes. All three exon deletion strategies enabled the expression of truncated dystrophin protein and restoration of cardiomyocyte contractility and calcium transients to varying degrees. We show that deletion of exons 3–9 by genomic editing provides an especially effective means of correcting disease-causing ABD-1 mutations. These findings represent an important step toward eventual correction of common DMD mutations and provide a means of rapidly assessing the expression and function of internally truncated forms of dystrophin-lacking portions of ABD-1. PMID:28931764

Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.

PubMed

Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

2014-11-01

Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. © 2014 Wiley Periodicals, Inc.

Developing standardized corticosteroid treatment for Duchenne muscular dystrophy.

PubMed

Guglieri, Michela; Bushby, Kate; McDermott, Michael P; Hart, Kimberly A; Tawil, Rabi; Martens, William B; Herr, Barbara E; McColl, Elaine; Wilkinson, Jennifer; Kirschner, Janbernd; King, Wendy M; Eagle, Michele; Brown, Mary W; Willis, Tracey; Hirtz, Deborah; Shieh, Perry B; Straub, Volker; Childs, Anne-Marie; Ciafaloni, Emma; Butterfield, Russell J; Horrocks, Iain; Spinty, Stefan; Flanigan, Kevin M; Kuntz, Nancy L; Baranello, Giovanni; Roper, Helen; Morrison, Leslie; Mah, Jean K; Manzur, Adnan Y; McDonald, Craig M; Schara, Ulrike; von der Hagen, Maja; Barohn, Richard J; Campbell, Craig; Darras, Basil T; Finkel, Richard S; Vita, Giuseppe; Hughes, Imelda; Mongini, Tiziana; Pegoraro, Elena; Wicklund, Matthew; Wilichowski, Ekkehard; Bryan Burnette, W; Howard, James F; McMillan, Hugh J; Thangarajh, Mathula; Griggs, Robert C

2017-07-01

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments. Copyright © 2017. Published by Elsevier Inc.

[Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

PubMed

Magot, A; Mercier, S; Péréon, Y

2015-12-01

Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Comparative Analysis of Vertebrate Dystrophin Loci Indicate Intron Gigantism as a Common Feature

PubMed Central

Pozzoli, Uberto; Elgar, Greg; Cagliani, Rachele; Riva, Laura; Comi, Giacomo P.; Bresolin, Nereo; Bardoni, Alessandra; Sironi, Manuela

2003-01-01

The human DMD gene is the largest known to date, spanning > 2000 kb on the X chromosome. The gene size is mainly accounted for by huge intronic regions. We sequenced 190 kb of Fugu rubripes (pufferfish) genomic DNA corresponding to the complete dystrophin gene (FrDMD) and provide the first report of gene structure and sequence comparison among dystrophin genomic sequences from different vertebrate organisms. Almost all intron positions and phases are conserved between FrDMD and its mammalian counterparts, and the predicted protein product of the Fugu gene displays 55% identity and 71% similarity to human dystrophin. In analogy to the human gene, FrDMD presents several-fold longer than average intronic regions. Analysis of intron sequences of the human and murine genes revealed that they are extremely conserved in size and that a similar fraction of total intron length is represented by repetitive elements; moreover, our data indicate that intron expansion through repeat accumulation in the two orthologs is the result of independent insertional events. The hypothesis that intron length might be functionally relevant to the DMD gene regulation is proposed and substantiated by the finding that dystrophin intron gigantism is common to the three vertebrate genes. [Supplemental material is available online at www.genome.org.] PMID:12727896

Synchronized brain activity during rehearsal and short-term memory disruption by irrelevant speech is affected by recall mode.

PubMed

Kopp, Franziska; Schröger, Erich; Lipka, Sigrid

2006-08-01

EEG coherence as a measure of synchronization of brain activity was used to investigate effects of irrelevant speech. In a delayed serial recall paradigm 21 healthy participants retained verbal items over a 10-s delay with and without interfering irrelevant speech. Recall after the delay was varied in two modes (spoken vs. written). Behavioral data showed the classic irrelevant speech effect and a superiority of written over spoken recall mode. Coherence, however, was more sensitive to processing characteristics and showed interactions between the irrelevant speech effect and recall mode during the rehearsal delay in theta (4-7.5 Hz), alpha (8-12 Hz), beta (13-20 Hz), and gamma (35-47 Hz) frequency bands. For gamma, a rehearsal-related decrease of the duration of high coherence due to presentation of irrelevant speech was found in a left-lateralized fronto-central and centro-temporal network only in spoken but not in written recall. In theta, coherence at predominantly fronto-parietal electrode combinations was indicative for memory demands and varied with individual working memory capacity assessed by digit span. Alpha coherence revealed similar results and patterns as theta coherence. In beta, a left-hemispheric network showed longer high synchronizations due to irrelevant speech only in written recall mode. EEG results suggest that mode of recall is critical for processing already during the retention period of a delayed serial recall task. Moreover, the finding that different networks are engaged with different recall modes shows that the disrupting effect of irrelevant speech is not a unitary mechanism.

Mode Selection Rules for a Two-Delay System with Positive and Negative Feedback Loops

NASA Astrophysics Data System (ADS)

Takahashi, Kin'ya; Kobayashi, Taizo

2018-04-01

The mode selection rules for a two-delay system, which has negative feedback with a short delay time t1 and positive feedback with a long delay time t2, are studied numerically and theoretically. We find two types of mode selection rules depending on the strength of the negative feedback. When the strength of the negative feedback |α1| (α1 < 0) is sufficiently small compared with that of the positive feedback α2 (> 0), 2m + 1-th harmonic oscillation is well sustained in a neighborhood of t1/t2 = even/odd, i.e., relevant condition. In a neighborhood of the irrelevant condition given by t1/t2 = odd/even or t1/t2 = odd/odd, higher harmonic oscillations are observed. However, if |α1| is slightly less than α2, a different mode selection rule works, where the condition t1/t2 = odd/even is relevant and the conditions t1/t2 = odd/odd and t1/t2 = even/odd are irrelevant. These mode selection rules are different from the mode selection rule of the normal two-delay system with two positive feedback loops, where t1/t2 = odd/odd is relevant and the others are irrelevant. The two types of mode selection rules are induced by individually different mechanisms controlling the Hopf bifurcation, i.e., the Hopf bifurcation controlled by the "boosted bifurcation process" and by the "anomalous bifurcation process", which occur for |α1| below and above the threshold value αth, respectively.

Manifold-Based Image Understanding

DTIC Science & Technology

2010-06-30

3] employs a Texas Instruments digital micromirror device (DMD), which consists of an array of N electrostatically actuated micromirrors . The camera...image x) is reflected off a digital micromirror device (DMD) array whose mirror orientations are modulated in the pseudorandom pattern φm supplied by a

Dominant modal decomposition method

NASA Astrophysics Data System (ADS)

Dombovari, Zoltan

2017-03-01

The paper deals with the automatic decomposition of experimental frequency response functions (FRF's) of mechanical structures. The decomposition of FRF's is based on the Green function representation of free vibratory systems. After the determination of the impulse dynamic subspace, the system matrix is formulated and the poles are calculated directly. By means of the corresponding eigenvectors, the contribution of each element of the impulse dynamic subspace is determined and the sufficient decomposition of the corresponding FRF is carried out. With the presented dominant modal decomposition (DMD) method, the mode shapes, the modal participation vectors and the modal scaling factors are identified using the decomposed FRF's. Analytical example is presented along with experimental case studies taken from machine tool industry.

Comparison of preferences of healthcare professionals and MS patients for attributes of disease-modifying drugs: A best-worst scaling.

PubMed

Kremer, Ingrid E H; Evers, Silvia M A A; Jongen, Peter J; Hiligsmann, Mickaël

2018-02-01

The choice between disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS) becomes more often a shared decision between the patient and the neurologist and MS nurse. This study aimed to assess which DMD attributes are most important for the healthcare professionals in selecting a DMD for a patient. Subsequently, within this perspective, the neurologists' and nurses' perspectives were compared. Lastly, the healthcare professionals' perspective was compared with the patients' perspective to detect any differences that may need attention in the communication about DMDs. A best-worst scaling (BWS) was conducted among 27 neurologists and 33 MS nurses treating patients with MS to determine the importance of 27 DMD attributes. These attributes were identified through three focus groups with MS patients in a previous study (N=19). Relative importance scores (RISs) were estimated for each attribute. Multivariable linear regression analyses were used to compare the different perspectives. According to the neurologists and nurses, safety of the DMD was the most important DMD attribute in the treatment decision, closely followed by effect on disability progression, quality of life and relapse rate. Patients with MS agreed with the importance of the last three attributes, but valued safety significantly lower (b=-2.59, P<.001). This study suggests that, overall, neurologists and nurses regard the same DMD attributes as important as MS patients with the notable exception of safety. This study provides valuable information for the development of interventions to support shared decision making and highlights which attributes of DMDs may need additional attention. © 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

PubMed

Posner, Andrew D; Soslow, Jonathan H; Burnette, W Bryan; Bian, Aihua; Shintani, Ayumi; Sawyer, Douglas B; Markham, Larry W

2016-01-01

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.

Evolving therapeutic strategies for Duchenne muscular dystrophy: targeting downstream events.

PubMed

Tidball, James G; Wehling-Henricks, Michelle

2004-12-01

Duchenne muscular dystrophy (DMD) is a progressive, lethal, muscle wasting disease that affects 1 of 3500 boys born worldwide. The disease results from mutation of the dystrophin gene that encodes a cytoskeletal protein associated with the muscle cell membrane. Although gene therapy will likely provide the cure for DMD, it remains on the distant horizon, emphasizing the need for more rapid development of palliative treatments that build on improved understanding of the complex pathology of dystrophin deficiency. In this review, we have focused on therapeutic strategies that target downstream events in the pathologic progression of DMD. Much of this work has been developed initially using the dystrophin-deficient mdx mouse to explore basic features of the pathophysiology of dystrophin deficiency and to test potential therapeutic interventions to slow, reverse, or compensate for functional losses that occur in muscular dystrophy. In some cases, the initial findings in the mdx model have led to clinical treatments for DMD boys that have produced improvements in muscle function and quality of life. Many of these investigations have concerned interventions that can affect protein balance in muscle, by inhibiting specific proteases implicated in the DMD pathology, or by providing anabolic factors or depleting catabolic factors that can contribute to muscle wasting. Other investigations have exploited the use of anti-inflammatory agents that can reduce the contribution of leukocytes to promoting secondary damage to dystrophic muscle. A third general strategy is designed to increase the regenerative capacity of dystrophic muscle and thereby help retain functional muscle mass. Each of these general approaches to slowing the pathology of dystrophin deficiency has yielded encouragement and suggests that targeting downstream events in dystrophinopathy can yield worthwhile, functional improvements in DMD.

Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans

PubMed Central

Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna

2011-01-01

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research PMID:21509823

3D head mount display with single panel

NASA Astrophysics Data System (ADS)

Wang, Yuchang; Huang, Junejei

2014-09-01

The head mount display for entertainment usually requires light weight. But in the professional application has more requirements. The image quality, field of view (FOV), color gamut, response and life time are considered items, too. A head mount display based on 1-chip TI DMD spatial light modulator is proposed. The multiple light sources and splitting images relay system are the major design tasks. The relay system images the object (DMD) into two image planes to crate binocular vision. The 0.65 inch 1080P DMD is adopted. The relay has a good performance which includes the doublet to reduce the chromatic aberration. Some spaces are reserved for placing the mirror and adjustable mechanism. The mirror splits the rays to the left and right image plane. These planes correspond to the eyepieces objects and image to eyes. A changeable mechanism provides the variable interpupillary distance (IPD). The folding optical path makes sure that the HMD center of gravity is close to the head and prevents the uncomfortable downward force being applied to head or orbit. Two RGB LED assemblies illuminate to the DMD in different angle. The light is highly collimated. The divergence angle is small enough such that one LED ray would only enters to the correct eyepiece. This switching is electronic controlled. There is no moving part to produce vibration and fast switch would be possible. Two LED synchronize with 3D video sync by a driving board which also controls the DMD. When the left eye image is displayed on DMD, the LED for left optical path turns on. Vice versa for right image and 3D scene is accomplished.

Long-term functional adeno-associated virus-microdystrophin expression in the dystrophic CXMDj dog.

PubMed

Koo, Taeyoung; Okada, Takashi; Athanasopoulos, Takis; Foster, Helen; Takeda, Shin'ichi; Dickson, George

2011-09-01

Duchenne muscular dystrophy (DMD) is a severe, inherited, muscle-wasting disorder caused by mutations in the dystrophin gene. Preclinical studies of adeno-associated virus gene therapy for DMD have been described in mouse and dog models of this disease. However, low and transient expression of microdystrophin in dystrophic dogs and a lack of long-term microdystrophin expression associated with a CD8(+)  T-cell response in DMD patients suggests that the development of improved microdystrophin genes and delivery strategies is essential for successful clinical trials in DMD patients. We have previously shown the efficiency of mRNA sequence optimization of mouse microdystrophin in ameliorating the pathology of dystrophic mdx mice. In the present study, we generated adeno-associated virus (AAV)2/8 vectors expressing an mRNA sequence-optimized canine microdystrophin under the control of a muscle-specific promoter and injected intramuscularly into a single canine X-linked muscular dystrophy (CXMDj) dog. Expression of stable and high levels of microdystrophin was observed along with an association of the dystrophin-associated protein complex in intramuscularly injected muscles of a CXMDj dog for at least 8 weeks without immune responses. Treated muscles were highly protected from dystrophic damage, with reduced levels of myofiber permeability and central nucleation. The data obtained in the present study suggest that the use of canine-specific and mRNA sequence-optimized microdystrophin genes in conjunction with a muscle-specific promoter results in high and stable levels of microdystrophin expression in a canine model of DMD. This approach will potentially allow the reduction of dosage and contribute towards the development of a safe and effective AAV gene therapy clinical trial protocol for DMD. Copyright © 2011 John Wiley & Sons, Ltd.

Early myocardial damage assessment in dystrophinopathies using (99)Tc(m)-MIBI gated myocardial perfusion imaging.

PubMed

Zhang, Li; Liu, Zhe; Hu, Ke-You; Tian, Qing-Bao; Wei, Ling-Ge; Zhao, Zhe; Shen, Hong-Rui; Hu, Jing

2015-01-01

Early detection of muscular dystrophy (MD)-associated cardiomyopathy is important because early medical treatment may slow cardiac remodeling and attenuate symptoms of cardiac dysfunction; however, no sensitive and standard diagnostic method for MD at an earlier stage has been well-recognized. Thus, the aim of this study was to test the early diagnostic value of technetium 99m-methoxyisobutylisonitrile ((99)Tc(m)-MIBI) gated myocardial perfusion imaging (G-MPI) for MD. Ninety-one patients underwent (99)Tc(m)-MIBI G-MPI examinations when they were diagnosed with Duchenne muscular dystrophy (DMD) (n=77) or Becker muscular dystrophy (BMD; n=14). (99)Tc(m)-MIBI G-MPI examinations were repeated in 43 DMD patients who received steroid treatments for 2 years as a follow-up examination. Myocardial defects were observed in nearly every segment of the left ventricular wall in both DMD and BMD patients compared with controls, especially in the inferior walls and the apices by using (99)Tc(m)-MIBI G-MPI. Cardiac wall movement impairment significantly correlated with age in the DMD and BMD groups (r s=0.534 [P<0.05] and r s=0.784 [P<0.05], respectively). Intermittent intravenous doses of glucocorticoids and continuation with oral steroid treatments significantly improved myocardial function in DMD patients (P<0.05), but not in BMD patients. (99)Tc(m)-MIBI G-MPI is a sensitive and safe approach for early evaluation of cardiomyopathy in patients with DMD or BMD, and can serve as a candidate method for the evaluation of progression, prognosis, and assessment of the effect of glucocorticoid treatment in these patients.

Potential of direct metal deposition technology for manufacturing thick functionally graded coatings and parts for reactors components

NASA Astrophysics Data System (ADS)

Thivillon, L.; Bertrand, Ph.; Laget, B.; Smurov, I.

2009-03-01

Direct metal deposition (DMD) is an automated 3D deposition process arising from laser cladding technology with co-axial powder injection to refine or refurbish parts. Recently DMD has been extended to manufacture large-size near-net-shape components. When applied for manufacturing new parts (or their refinement), DMD can provide tailored thermal properties, high corrosion resistance, tailored tribology, multifunctional performance and cost savings due to smart material combinations. In repair (refurbishment) operations, DMD can be applied for parts with a wide variety of geometries and sizes. In contrast to the current tool repair techniques such as tungsten inert gas (TIG), metal inert gas (MIG) and plasma welding, laser cladding technology by DMD offers a well-controlled heat-treated zone due to the high energy density of the laser beam. In addition, this technology may be used for preventative maintenance and design changes/up-grading. One of the advantages of DMD is the possibility to build functionally graded coatings (from 1 mm thickness and higher) and 3D multi-material objects (for example, 100 mm-sized monolithic rectangular) in a single-step manufacturing cycle by using up to 4-channel powder feeder. Approved materials are: Fe (including stainless steel), Ni and Co alloys, (Cu,Ni 10%), WC compounds, TiC compounds. The developed coatings/parts are characterized by low porosity (<1%), fine microstructure, and their microhardness is close to the benchmark value of wrought alloys after thermal treatment (Co-based alloy Stellite, Inox 316L, stainless steel 17-4PH). The intended applications concern cooling elements with complex geometry, friction joints under high temperature and load, light-weight mechanical support structures, hermetic joints, tubes with complex geometry, and tailored inside and outside surface properties, etc.

Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy.

PubMed

Beekman, Chantal; Janson, Anneke A; Baghat, Aabed; van Deutekom, Judith C; Datson, Nicole A

2018-01-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by progressive weakness of the skeletal and cardiac muscles. This X-linked disorder is caused by open reading frame disrupting mutations in the DMD gene, resulting in strong reduction or complete absence of dystrophin protein. In order to use dystrophin as a supportive or even surrogate biomarker in clinical studies on investigational drugs aiming at correcting the primary cause of the disease, the ability to reliably quantify dystrophin expression in muscle biopsies of DMD patients pre- and post-treatment is essential. Here we demonstrate the application of the ProteinSimple capillary immunoassay (Wes) method, a gel- and blot-free method requiring less sample, antibody and time to run than conventional Western blot assay. We optimized dystrophin quantification by Wes using 2 different antibodies and found it to be highly sensitive, reproducible and quantitative over a large dynamic range. Using a healthy control muscle sample as a reference and α-actinin as a protein loading/muscle content control, a panel of skeletal muscle samples consisting of 31 healthy controls, 25 Becker Muscle dystrophy (BMD) and 17 DMD samples was subjected to Wes analysis. In healthy controls dystrophin levels varied 3 to 5-fold between the highest and lowest muscle samples, with the reference sample representing the average of all 31 samples. In BMD muscle samples dystrophin levels ranged from 10% to 90%, with an average of 33% of the healthy muscle average, while for the DMD samples the average dystrophin level was 1.3%, ranging from 0.7% to 7% of the healthy muscle average. In conclusion, Wes is a suitable, efficient and reliable method for quantification of dystrophin expression as a biomarker in DMD clinical drug development.

Sliding Mode Control of Fractional-Order Delayed Memristive Chaotic System with Uncertainty and Disturbance

NASA Astrophysics Data System (ADS)

Ding, Da-Wei; Liu, Fang-Fang; Chen, Hui; Wang, Nian; Liang, Dong

2017-12-01

In this paper, a simplest fractional-order delayed memristive chaotic system is proposed in order to control the chaos behaviors via sliding mode control strategy. Firstly, we design a sliding mode control strategy for the fractional-order system with time delay to make the states of the system asymptotically stable. Then, we obtain theoretical analysis results of the control method using Lyapunov stability theorem which guarantees the asymptotic stability of the non-commensurate order and commensurate order system with and without uncertainty and an external disturbance. Finally, numerical simulations are given to verify that the proposed sliding mode control method can eliminate chaos and stabilize the fractional-order delayed memristive system in a finite time. Supported by the National Nature Science Foundation of China under Grant No. 61201227, Funding of China Scholarship Council, the Natural Science Foundation of Anhui Province under Grant No. 1208085M F93, 211 Innovation Team of Anhui University under Grant Nos. KJTD007A and KJTD001B

The macrophage as a Trojan horse for antisense oligonucleotide delivery.

PubMed

Novak, James S; Jaiswal, Jyoti K; Partridge, Terence A

2018-06-04

The gateway to the promised land of gene therapy has been obstructed by the problem of accurate and efficient delivery of therapeutic agents to their target sites. This is true both of constructs designed to directly express proteins of interest, and of constructs or agents aimed at modifying the expression of endogenous genes. It is recognized as a major impediment to the effective application of genetic therapies currently or incipiently in clinical trial. Our recent study has examined the mechanism underlying delivery of therapeutic antisense oligonucleotides (ASO) for treating the devastating muscle disease Duchenne muscular dystrophy [1]. Working to understand the mode of ASO delivery in DMD, we discovered that inflammatory cells act as a depot that locally stores the intravenously administered ASO. This local depot of ASO then becomes available to the muscle fibres by way of satellite cells that deliver their cargo by fusion with damaged fibres during muscle repair. This finding points to a potentially novel strategy for systemic ASO delivery, involving the use of the inflammatory cell as a Trojan horse. Such an approach would have the benefit not only of enhancing tissue-specific delivery of ASO, but also of reducing the impact of their rapid clearance from the circulation. Here, we discuss the issues surrounding ASO-mediated exon skipping efficacy for DMD, and outline research aimed at improving targeted ASO delivery.

Quantitative electromyography in ambulatory boys with Duchenne muscular dystrophy.

PubMed

Verma, Sumit; Lin, Jenny; Travers, Curtis; McCracken, Courtney; Shah, Durga

2017-12-01

This study's objective was to evaluate quantitative electromyography (QEMG) using multiple-motor-unit (multi-MUP) analysis in Duchenne muscular dystrophy (DMD). Ambulatory DMD boys, aged 5-15 years, were evaluated with QEMG at 6-month intervals over 14 months. EMG was performed in the right biceps brachii (BB) and tibialis anterior (TA) muscles. Normative QEMG data were obtained from age-matched healthy boys. Wilcoxon signed-rank tests were performed. Eighteen DMD subjects were enrolled, with a median age of 7 (interquartile range 7-10) years. Six-month evaluations were performed on 14 subjects. QEMG showed significantly abnormal mean MUP duration in BB and TA muscles, with no significant change over 6 months. QEMG is a sensitive electrophysiological marker of myopathy in DMD. Preliminary data do not reflect a significant change in MUP parameters over a 6-month interval; long-term follow-up QEMG studies are needed to understand its role as a biomarker for disease progression. Muscle Nerve 56: 1361-1364, 2017. © 2017 Wiley Periodicals, Inc.

Progress toward Gene Therapy for Duchenne Muscular Dystrophy.

PubMed

Chamberlain, Joel R; Chamberlain, Jeffrey S

2017-05-03

Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.

PubMed

Blanchet, Emilie; Annicotte, Jean-Sébastien; Pradelli, Ludivine A; Hugon, Gérald; Matecki, Stéfan; Mornet, Dominique; Rivier, François; Fajas, Lluis

2012-09-01

E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.

Cardioprotective effect of vitamin D2 on isoproterenol-induced myocardial infarction in diabetic rats.

PubMed

El Agaty, Sahar M

2018-03-08

To assess the effect of vitamin D 2 and to elucidate the underlying mechanisms on acute myocardial injury induced by isoproterenol (ISO) in diabetic rats. Rats were divided into control rats, diabetic rats (DM), diabetic rats received ISO (DM-ISO), and diabetic rats pretreated with vitamin D 2 and received ISO (DM-D 2 -ISO). Vitamin D 2 pretreatment significantly decreased fasting glucose and myocardial malondialdehyde, associated with increased insulin, myocardial glutathione and superoxide dismutase in DM-D 2 -ISO versus DM-ISO. The serum triglycerides, total cholesterol, and LDL were significantly decreased, along with increased HDL and adiponectin. Poly-ADP ribose polymerase, cyclooxygenase-2, tumour necrosis factor alpha, interleukin-6, caspase-3, BAX, and p53 were significantly downregulated in myocardium of DM-D 2 -ISO versus DM-ISO. Histological studies showed diminished inflammatory cells infiltration in myocardium of DM-D 2 -ISO versus DM-ISO. Vitamin D 2 ameliorates hyperglycaemia, dyslipidaemia, redox imbalance, inflammatory and apoptotic processes, protecting the myocardium of diabetic rats against acute myocardial infarction.

Identification of de novo mutations of Duchénnè/Becker muscular dystrophies in southern Spain.

PubMed

Garcia, Susana; de Haro, Tomás; Zafra-Ceres, Mercedes; Poyatos, Antonio; Gomez-Capilla, Jose A; Gomez-Llorente, Carolina

2014-01-01

Duchénnè/Becker muscular dystrophies (DMD/BMD) are X-linked diseases, which are caused by a de novo gene mutation in one-third of affected males. The study objectives were to determine the incidence of DMD/BMD in Andalusia (Spain) and to establish the percentage of affected males in whom a de novo gene mutation was responsible. Multiplex ligation-dependent probe amplification (MLPA) technology was applied to determine the incidence of DMD/BMD in 84 males with suspicion of the disease and 106 female relatives. Dystrophin gene exon deletion (89.5%) or duplication (10.5%) was detected in 38 of the 84 males by MLPA technology; de novo mutations account for 4 (16.7%) of the 24 mother-son pairs studied. MLPA technology is adequate for the molecular diagnosis of DMD/BMD and establishes whether the mother carries the molecular alteration responsible for the disease, a highly relevant issue for genetic counseling.

Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan

PubMed Central

Birnkrant, David J; Bushby, Katharine; Bann, Carla M; Apkon, Susan D; Blackwell, Angela; Colvin, Mary K; Cripe, Linda; Herron, Adrienne R; Kennedy, Annie; Kinnett, Kathi; Naprawa, James; Noritz, Garey; Poysky, James; Street, Natalie; Trout, Christina J; Weber, David R; Ward, Leanne M

2018-01-01

Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy. PMID:29398641

Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.

PubMed

Nance, Michael E; Duan, Dongsheng

2015-12-01

Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.

Optical system design of dynamic infrared scene projector based on DMD

NASA Astrophysics Data System (ADS)

Lu, Jing; Fu, Yuegang; Liu, Zhiying; Li, Yandong

2014-09-01

Infrared scene simulator is now widely used to simulate infrared scene practicality in the laboratory, which can greatly reduce the research cost of the optical electrical system and offer economical experiment environment. With the advantage of large dynamic range and high spatial resolution, dynamic infrared projection technology, which is the key part of the infrared scene simulator, based on digital micro-mirror device (DMD) has been rapidly developed and widely applied in recent years. In this paper, the principle of the digital micro-mirror device is briefly introduced and the characteristics of the DLP (Digital Light Procession) system based on digital micromirror device (DMD) are analyzed. The projection system worked at 8~12μm with 1024×768 pixel DMD is designed by ZEMAX. The MTF curve is close to the diffraction limited curve and the radius of the spot diagram is smaller than that of the airy disk. The result indicates that the system meets the design requirements.

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy.

PubMed

Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang-Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S; Le Rumeur, Elisabeth; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

2015-05-28

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

PubMed Central

Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang-Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S.; Le Rumeur, Elisabeth; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

2015-01-01

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1. PMID:26018658

Partial least squares based identification of Duchenne muscular dystrophy specific genes.

PubMed

An, Hui-bo; Zheng, Hua-cheng; Zhang, Li; Ma, Lin; Liu, Zheng-yan

2013-11-01

Large-scale parallel gene expression analysis has provided a greater ease for investigating the underlying mechanisms of Duchenne muscular dystrophy (DMD). Previous studies typically implemented variance/regression analysis, which would be fundamentally flawed when unaccounted sources of variability in the arrays existed. Here we aim to identify genes that contribute to the pathology of DMD using partial least squares (PLS) based analysis. We carried out PLS-based analysis with two datasets downloaded from the Gene Expression Omnibus (GEO) database to identify genes contributing to the pathology of DMD. Except for the genes related to inflammation, muscle regeneration and extracellular matrix (ECM) modeling, we found some genes with high fold change, which have not been identified by previous studies, such as SRPX, GPNMB, SAT1, and LYZ. In addition, downregulation of the fatty acid metabolism pathway was found, which may be related to the progressive muscle wasting process. Our results provide a better understanding for the downstream mechanisms of DMD.

Optimal micro-mirror tilt angle and sync mark design for digital micro-mirror device based collinear holographic data storage system.

PubMed

Liu, Jinpeng; Horimai, Hideyoshi; Lin, Xiao; Liu, Jinyan; Huang, Yong; Tan, Xiaodi

2017-06-01

The collinear holographic data storage system (CHDSS) is a very promising storage system due to its large storage capacities and high transfer rates in the era of big data. The digital micro-mirror device (DMD) as a spatial light modulator is the key device of the CHDSS due to its high speed, high precision, and broadband working range. To improve the system stability and performance, an optimal micro-mirror tilt angle was theoretically calculated and experimentally confirmed by analyzing the relationship between the tilt angle of the micro-mirror on the DMD and the power profiles of diffraction patterns of the DMD at the Fourier plane. In addition, we proposed a novel chess board sync mark design in the data page to reduce the system bit error rate in circumstances of reduced aperture required to decrease noise and median exposure amount. It will provide practical guidance for future DMD based CHDSS development.

Cardiac considerations in the operative management of the patient with Duchenne or Becker muscular dystrophy.

PubMed

Cripe, Linda H; Tobias, Joseph D

2013-09-01

Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) is a progressive multisystem neuromuscular disorder. In addition to the skeletal muscle, the myocardium in the DMD/BMD patient is dystrophin deficient which results in a progressive cardiomyopathy. The myopathic myocardium poses significant risk of increased morbidity and mortality at the time of major surgical procedures. Careful attention must be given to the DMD/BMD patient during the intraoperative and postoperative period. Anesthesia selection is critical and anesthetics should be avoided which have been shown to be harmful in this patient population. Preanesthesia assessment should include cardiac consultation and detailed preoperative evaluation. Intraoperative management needs to insure that the weakened myocardium is not compromised by physiologic changes such as hypotension or major fluid shifts. Finally, attention to the cardiac status of the patient must continue into the postoperative period. The surgical care of the DMD/BMD patient requires a multispecialty approach to insure operative success. © 2013 John Wiley & Sons Ltd.

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

PubMed

Spurney, Christopher F; Rocha, Carolina Tesi; Henricson, Erik; Florence, Julaine; Mayhew, Jill; Gorni, Ksenija; Pasquali, Livia; Pestronk, Alan; Martin, Gerard R; Hu, Fengming; Nie, Lei; Connolly, Anne M; Escolar, Diana M

2011-08-01

Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. Copyright © 2011 Wiley Periodicals, Inc.

Impact of medication adherence to disease-modifying drugs on severe relapse, and direct and indirect costs among employees with multiple sclerosis in the US.

PubMed

Ivanova, J I; Bergman, R E; Birnbaum, H G; Phillips, A L; Stewart, M; Meletiche, D M

2012-01-01

To compare rates of severe relapse and total direct and indirect costs over a 2-year period between US-based employees with multiple sclerosis (MS) who were adherent and non-adherent to disease-modifying drugs (DMDs). Employees with ≥1 MS diagnosis (ICD-9-CM: 340.x) and ≥1 DMD pharmacy claim between 1/1/2002-12/31/2007 were identified from a large US administrative claims database. Patients had continuous coverage ≥6 months before (baseline) and ≥24 months after (study period) their index date (first DMD claim). Adherence was measured using medication possession ratio (MPR) over the study period. Patients with MPR ≥80% were considered adherent (n = 448) and those with MPR <80% as non-adherent (n = 200). Multivariate analyses were used to compare rates of severe relapse (inpatient or Emergency Department visit with MS diagnosis) and costs in 2007 dollars between DMD adherent and non-adherent patients. Direct costs were calculated as reimbursements to providers for medical services and prescription drugs excluding DMDs. Indirect costs included disability and medically-related absenteeism costs. DMD adherent patients were on average older (43.5 vs 41.8 years, p = 0.015) and more likely to be male (38.6% vs 26.0%, p = 0.002) compared with non-adherent patients. Adherent patients had lower rates of depression, higher rates of previous DMD use, and higher baseline MS-related costs. After adjusting for differences in baseline characteristics, DMD adherent patients had a lower rate of severe relapse (12.4% vs 19.9%, p = 0.013) and lower total (direct and indirect) costs ($14,095 vs $16,638, p = 0.048) over the 2-year study period. In this study, DMD adherence was associated with a significantly lower rate of severe relapse and lower total costs over 2 years. Causality cannot be inferred because adherence and outcomes were measured over the same period. The study was subject to limitations associated with use of claims data and the absence of clinical measures.

Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Milad, Nadia; White, Zoe; Tehrani, Arash Y; Sellers, Stephanie; Rossi, Fabio M V; Bernatchez, Pascal

2017-09-12

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin expression and leads to severe ambulatory and cardiac function decline. However, the dystrophin-deficient mdx murine model of DMD only develops a very mild form of the disease. Our group and others have shown vascular abnormalities in animal models of MD, a likely consequence of the fact that blood vessels express the same dystrophin-associated glycoprotein complex (DGC) proteins as skeletal muscles. To test the blood vessel contribution to muscle damage in DMD, mdx 4cv mice were given elevated lipid levels via apolipoprotein E (ApoE) gene knockout combined with normal chow or lipid-rich Western diets. Ambulatory function and heart function (via echocardiogram) were assessed at 4 and 7 months of age. After sacrifice, muscle histology and aortic staining were used to assess muscle pathology and atherosclerosis development, respectively. Plasma levels of total cholesterol, high-density lipoprotein (HDL), triglycerides, and creatine kinase (CK) were also measured. Although there was an increase in left ventricular heart volume in mdx-ApoE mice compared to that in mdx mice, parameters of heart function were not affected. Compared with wild-type and ApoE-null, only mdx-ApoE KO mice showed significant ambulatory dysfunction. Despite no significant difference in plasma CK, histological analyses revealed that elevated plasma lipids in chow- and Western diet-fed mdx-ApoE mice was associated with severe exacerbation of muscle pathology compared to mdx mice: significant increase in myofiber damage and fibrofatty replacement in the gastrocnemius and triceps brachii muscles, more reminiscent of human DMD pathology. Finally, although both ApoE and mdx-ApoE groups displayed increased plasma lipids, mdx-ApoE exhibited atherosclerotic plaque deposition equal to or less than that of ApoE mice. Since others have shown that lipid abnormalities correlate with DMD severity, our data suggest that plasma lipids could be primary contributors to human DMD severity and that the notoriously mild phenotype of mdx mice might be attributable in part to their endogenously low plasma lipid profiles. Hence, DMD patients may benefit from lipid-lowering and vascular-targeted therapies.

T2 mapping provides multiple approaches to characterize muscle involvement in neuromuscular diseases: a cross-sectional study of lower leg muscles in 5–15 year old boys with Duchenne Muscular Dystrophy

PubMed Central

Arpan, Ishu; Forbes, Sean C; Lott, Donovan J; Senesac, Claudia R; Daniels, Michael J; Triplett, William T; Deol, Jasjit K; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

2012-01-01

Purpose Skeletal muscles of children with Duchenne muscular dystrophy (DMD) have enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in magnetic resonance proton transverse relaxation time (T2). Therefore, examining T2 changes in individual muscles may be useful for monitoring disease progression in DMD. In this study we utilized mean T2, percent elevated pixels, and T2 heterogeneity to assess changes in composition of dystrophic muscles. In addition, we used fat saturation (fatsat) to distinguish T2 changes due to edema and inflammation from fat infiltration in muscles. Methods Thirty subjects with DMD and 15 age-matched controls underwent T2-weighted imaging of their lower leg using 3-T MR system. T2 maps were developed and four lower leg muscles were manually traced (soleus, medial gastrocnemius, peroneal and tibialis anterior). Mean T2 of the traced regions of interest (ROI), width of T2 histograms, and percent-elevated pixels were calculated. Results We found that even in young children with DMD, muscles had elevated mean T2, were more heterogeneous, and had a greater percent-elevated pixels in the lower leg muscles than controls. T2 measures decreased with fat saturation, but were still higher (p<0.05) in dystrophic muscles than controls. Further, T2 measures showed positive correlations with timed functional tests (r=0.23–0.79). Conclusion The elevated T2 measures with and without fat saturation in all ages of DMD examined (5–15 years) compared to unaffected controls indicate that the dystrophic muscles have increased regions of damage, edema, and fat infiltration. This study shows that T2 mapping provides multiple approaches that can be effectively utilized to characterize muscle tissue in children with DMD even in the early stages of the disease. Therefore, T2 mapping may prove clinically useful in monitoring muscle changes due to disease process or therapeutic interventions in DMD. PMID:23044995

T₂ mapping provides multiple approaches for the characterization of muscle involvement in neuromuscular diseases: a cross-sectional study of lower leg muscles in 5-15-year-old boys with Duchenne muscular dystrophy.

PubMed

Arpan, Ishu; Forbes, Sean C; Lott, Donovan J; Senesac, Claudia R; Daniels, Michael J; Triplett, William T; Deol, Jasjit K; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

2013-03-01

Skeletal muscles of children with Duchenne muscular dystrophy (DMD) show enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in the MR proton transverse relaxation time (T₂). Therefore, the examination of T₂ changes in individual muscles may be useful for the monitoring of disease progression in DMD. In this study, we used the mean T₂, percentage of elevated pixels and T₂ heterogeneity to assess changes in the composition of dystrophic muscles. In addition, we used fat saturation to distinguish T₂ changes caused by edema and inflammation from fat infiltration in muscles. Thirty subjects with DMD and 15 age-matched controls underwent T₂ -weighted imaging of their lower leg using a 3-T MR system. T₂ maps were developed and four lower leg muscles were manually traced (soleus, medial gastrocnemius, peroneal and tibialis anterior). The mean T₂ of the traced regions of interest, width of the T₂ histograms and percentage of elevated pixels were calculated. We found that, even in young children with DMD, lower leg muscles showed elevated mean T₂, were more heterogeneous and had a greater percentage of elevated pixels than in controls. T₂ measures decreased with fat saturation, but were still higher (P < 0.05) in dystrophic muscles than in controls. Further, T₂ measures showed positive correlations with timed functional tests (r = 0.23-0.79). The elevated T₂ measures with and without fat saturation at all ages of DMD examined (5-15 years) compared with unaffected controls indicate that the dystrophic muscles have increased regions of damage, edema and fat infiltration. This study shows that T₂ mapping provides multiple approaches that can be used effectively to characterize muscle tissue in children with DMD, even in the early stages of the disease. Therefore, T₂ mapping may prove to be clinically useful in the monitoring of muscle changes caused by the disease process or by therapeutic interventions in DMD. Copyright © 2012 John Wiley & Sons, Ltd.

Designed materials: what and how

NASA Astrophysics Data System (ADS)

Mazumder, Jyotirmoy; Dutta, Debasish; Ghosh, Amit K.; Kikuchi, Noboru

2003-03-01

Quest for a material to suit the service performance is almost as old as human civilization. So far materials engineers have developed a series of alloys, polymers, ceramics, and composites to serve many of the performance requirements in a modern society. However, challenges appear when one needs to satisfy more than one boundary condition. For example, a component with negative Coefficient of Thermal Expansion (CTE) using a ductile metal was almost impossible until recently. Synthesis of various technologies such as Direct Metal Deposition (DMD) Homogenization Design Method (HDM) and mutli material Computer Aided Design (CAD) was necessary to achieve this goal. Rapid fabrication of three-dimensional shapes of engineering materials such as H13 tool steel and nickel super alloys are now possible using Direct Materials Deposition (DMD) technique as well as similar techniques such as Light Engineered New Shaping (LENS) or Directed Light Fabrication (DLF). However, DMD has closed loop capability that enables better dimension and thermal cycle control. This enables one to deposit different material at different pixels with a given height directly from a CAD drawing. The feedback loop also controls the thermal cycle. H13 tool steel is one of the difficult alloys for deposition due to residual stress accumulation from martensitic transformation. However, it is the material of choice for the die and tool industry. DMD has demonstrated successful fabrication of complicated shapes and dies and tools, even with H13 alloys. This process also offers copper chill blocks and water-cooling channels as the integral part of the tool. On the other hand ZrO2 was co-deposited with nickel super alloys using DMD. Flexibility of the process is enormous and essentially it is an enabling technology to marterialize many a design. Using DMD in conjunction with HDM and multi-material CAD, one can produce components with predetermined performance such as negative co-efficient of expansion, by synthesis of designed microstructure. This paper briefly reviews the state of the art of DMD and describes the synthesis of three core technologies to produce designed materials with desired performance.

Spatially modulated laser pulses for printing electronics.

PubMed

Auyeung, Raymond C Y; Kim, Heungsoo; Mathews, Scott; Piqué, Alberto

2015-11-01

The use of a digital micromirror device (DMD) in laser-induced forward transfer (LIFT) is reviewed. Combining this technique with high-viscosity donor ink (silver nanopaste) results in laser-printed features that are highly congruent in shape and size to the incident laser beam spatial profile. The DMD empowers LIFT to become a highly parallel, rapidly reconfigurable direct-write technology. By adapting half-toning techniques to the DMD bitmap image, the laser transfer threshold fluence for 10 μm features can be reduced using an edge-enhanced beam profile. The integration of LIFT with this beam-shaping technique allows the printing of complex large-area patterns with a single laser pulse.

Virtual reality 3D headset based on DMD light modulators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernacki, Bruce E.; Evans, Allan; Tang, Edward

We present the design of an immersion-type 3D headset suitable for virtual reality applications based upon digital micro-mirror devices (DMD). Our approach leverages silicon micro mirrors offering 720p resolution displays in a small form-factor. Supporting chip sets allow rapid integration of these devices into wearable displays with high resolution and low power consumption. Applications include night driving, piloting of UAVs, fusion of multiple sensors for pilots, training, vision diagnostics and consumer gaming. Our design is described in which light from the DMD is imaged to infinity and the user’s own eye lens forms a real image on the user’s retina.

Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

ERIC Educational Resources Information Center

Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

2013-01-01

Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of…

Muscle ultrasound elastography and MRI in preschool children with Duchenne muscular dystrophy.

PubMed

Pichiecchio, Anna; Alessandrino, Francesco; Bortolotto, Chandra; Cerica, Alessandra; Rosti, Cristina; Raciti, Maria Vittoria; Rossi, Marta; Berardinelli, Angela; Baranello, Giovanni; Bastianello, Stefano; Calliada, Fabrizio

2018-06-01

The aim of this study was to determine muscle tissue elasticity, measured with shear-wave elastography, in selected lower limb muscles of patients affected by Duchenne muscular dystrophy (DMD) and to correlate the values obtained with those recorded in healthy children and with muscle magnetic resonance imaging (MRI) data from the same DMD children, specifically the pattern on T1-weighted (w) and short-tau inversion recovery (STIR) sequences. Five preschool DMD children and five age-matched healthy children were studied with shear-wave elastography. In the DMD children, muscle stiffness was moderately higher compared with the muscle stiffness in HC, in the rectus femoris, vastus lateralis, adductor magnus and gluteus maximus muscles. On muscle MRI T1-w images showed fatty replacement in 3/5 patients at the level of the GM, while thigh and leg muscles were affected in 2/5; hyperintensity on STIR images was identified in 4/5 patients. No significant correlation was observed between stiffness values and MRI scoring. Our study demonstrated that lower limb muscles of preschool DMD patients show fatty replacement and patchy edema on muscle MRI and increased stiffness on shear-wave elastography. In conclusion, although further studies in larger cohorts are needed, shear-wave elastography could be considered a useful non-invasive tool to easily monitor muscle changes in early stages of the disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Orthodontic soft-tissue parameters: a comparison of cone-beam computed tomography and the 3dMD imaging system.

PubMed

Metzger, Tasha E; Kula, Katherine S; Eckert, George J; Ghoneima, Ahmed A

2013-11-01

Orthodontists rely heavily on soft-tissue analysis to determine facial esthetics and treatment stability. The aim of this retrospective study was to determine the equivalence of soft-tissue measurements between the 3dMD imaging system (3dMD, Atlanta, Ga) and the segmented skin surface images derived from cone-beam computed tomography. Seventy preexisting 3dMD facial photographs and cone-beam computed tomography scans taken within minutes of each other for the same subjects were registered in 3 dimensions and superimposed using Vultus (3dMD) software. After reliability studies, 28 soft-tissue measurements were recorded with both imaging modalities and compared to analyze their equivalence. Intraclass correlation coefficients and Bland-Altman plots were used to assess interexaminer and intraexaminer repeatability and agreement. Summary statistics were calculated for all measurements. To demonstrate equivalence of the 2 methods, the difference needed a 95% confidence interval contained entirely within the equivalence limits defined by the repeatability results. Statistically significant differences were reported for the vermilion height, mouth width, total facial width, mouth symmetry, soft-tissue lip thickness, and eye symmetry. There are areas of nonequivalence between the 2 imaging methods; however, the differences are clinically acceptable from the orthodontic point of view. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Memory-Based Structured Application Specific Integrated Circuit (ASIC) Study

DTIC Science & Technology

2008-10-01

memory interface, arbiter/ schedulers for rescheduling the memory requests according to some schedule policy, and memory channels for communicating...between the power-savings and the wakeup overhead with respect to both wakeup power and wakeup delay. For example, dream mode can save 50% more static...power than sleep mode, but at the expense of twice the wake delay and three times the wakeup energy. The user can specify power-gating modes for various components.

Mode Decomposition Methods for Soil Moisture Prediction

NASA Astrophysics Data System (ADS)

Jana, R. B.; Efendiev, Y. R.; Mohanty, B.

2014-12-01

Lack of reliable, well-distributed, long-term datasets for model validation is a bottle-neck for most exercises in soil moisture analysis and prediction. Understanding what factors drive soil hydrological processes at different scales and their variability is very critical to further our ability to model the various components of the hydrologic cycle more accurately. For this, a comprehensive dataset with measurements across scales is very necessary. Intensive fine-resolution sampling of soil moisture over extended periods of time is financially and logistically prohibitive. Installation of a few long term monitoring stations is also expensive, and needs to be situated at critical locations. The concept of Time Stable Locations has been in use for some time now to find locations that reflect the mean values for the soil moisture across the watershed under all wetness conditions. However, the soil moisture variability across the watershed is lost when measuring at only time stable locations. We present here a study using techniques such as Dynamic Mode Decomposition (DMD) and Discrete Empirical Interpolation Method (DEIM) that extends the concept of time stable locations to arrive at locations that provide not simply the average soil moisture values for the watershed, but also those that can help re-capture the dynamics across all locations in the watershed. As with the time stability, the initial analysis is dependent on an intensive sampling history. The DMD/DEIM method is an application of model reduction techniques for non-linearly related measurements. Using this technique, we are able to determine the number of sampling points that would be required for a given accuracy of prediction across the watershed, and the location of those points. Locations with higher energetics in the basis domain are chosen first. We present case studies across watersheds in the US and India. The technique can be applied to other hydro-climates easily.

Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

ERIC Educational Resources Information Center

De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

2010-01-01

Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

Multi-beam and single-chip LIDAR with discrete beam steering by digital micromirror device

NASA Astrophysics Data System (ADS)

Rodriguez, Joshua; Smith, Braden; Hellman, Brandon; Gin, Adley; Espinoza, Alonzo; Takashima, Yuzuru

2018-02-01

A novel Digital Micromirror Device (DMD) based beam steering enables a single chip Light Detection and Ranging (LIDAR) system for discrete scanning points. We present increasing number of scanning point by using multiple laser diodes for Multi-beam and Single-chip DMD-based LIDAR.

Compressed Sensing (CS) Imaging with Wide FOV and Dynamic Magnification

DTIC Science & Technology

2011-03-14

Digital Micromirror Device (DMD) to implement the CS measurement patterns. The core component of the DMD is a 768(V)?1024(H) aluminum micromirror array...image has different curves and textures, thus has different statistical model parameters. The sampling 19 Table 2: Reconstruction of images in

Hydrogen jet combustion in a scramjet combustor with the rearwall-expansion cavity

NASA Astrophysics Data System (ADS)

Zhang, Yan-Xiang; Wang, Zhen-Guo; Sun, Ming-Bo; Yang, Yi-Xin; Wang, Hong-Bo

2018-03-01

This study is carried out to experimentally investigate the combustion characteristics of the hydrogen jet flame stabilized by the rearwall-expansion cavity in a model scramjet combustor. The flame distributions are characterized by the OH* spontaneous emission images, and the dynamic features of the flames are studied through the high speed framing of the flame luminosity. The combustion modes are further analyzed based on the visual flame structure and wall pressure distributions. Under the present conditions, the combustion based on the rearwall-expansion cavity appears in two distinguished modes - the typical cavity shear-layer stabilized combustion mode and the lifted-shear-layer stabilized combustion mode. In contrast with the shear-layer stabilized mode, the latter holds stronger flame. The transition from shear-layer stabilized combustion mode to lifted-shear-layer stabilized mode usually occurs when the equivalence ratio is high enough. While the increases of the offset ratio and upstream injection distance both lead to weaker jet-cavity interactions, cause longer ignition delay, and thus delay the mode transition. The results reveal that the rearwall-expansion cavity with an appropriate offset ratio should be helpful in delaying mode transition and preventing thermal choke, and meanwhile just brings minor negative impact on the combustion stability and efficiency.

Measuring a Fiber-Optic Delay Line Using a Mode-Locked Laser

NASA Technical Reports Server (NTRS)

Tu, Meirong; McKee, Michael R.; Pak, Kyung S.; Yu, Nan

2010-01-01

The figure schematically depicts a laboratory setup for determining the optical length of a fiber-optic delay line at a precision greater than that obtainable by use of optical time-domain reflectometry or of mechanical measurement of length during the delay-line-winding process. In this setup, the delay line becomes part of the resonant optical cavity that governs the frequency of oscillation of a mode-locked laser. The length can then be determined from frequency-domain measurements, as described below. The laboratory setup is basically an all-fiber ring laser in which the delay line constitutes part of the ring. Another part of the ring - the laser gain medium - is an erbium-doped fiber amplifier pumped by a diode laser at a wavelength of 980 nm. The loop also includes an optical isolator, two polarization controllers, and a polarizing beam splitter. The optical isolator enforces unidirectional lasing. The polarization beam splitter allows light in only one polarization mode to pass through the ring; light in the orthogonal polarization mode is rejected from the ring and utilized as a diagnostic output, which is fed to an optical spectrum analyzer and a photodetector. The photodetector output is fed to a radio-frequency spectrum analyzer and an oscilloscope. The fiber ring laser can generate continuous-wave radiation in non-mode-locked operation or ultrashort optical pulses in mode-locked operation. The mode-locked operation exhibited by this ring is said to be passive in the sense that no electro-optical modulator or other active optical component is used to achieve it. Passive mode locking is achieved by exploiting optical nonlinearity of passive components in such a manner as to obtain ultra-short optical pulses. In this setup, the particular nonlinear optical property exploited to achieve passive mode locking is nonlinear polarization rotation. This or any ring laser can support oscillation in multiple modes as long as sufficient gain is present to overcome losses in the ring. When mode locking is achieved, oscillation occurs in all the modes having the same phase and same polarization. The frequency interval between modes, often denoted the free spectral range (FSR), is given by c/nL, where c is the speed of light in vacuum, n is the effective index of refraction of the fiber, and L is the total length of optical path around the ring. Therefore, the length of the fiber-optic delay line, as part of the length around the ring, can be calculated from the FSRs measured with and without the delay line incorporated into the ring. For this purpose, the FSR measurements are made by use of the optical and radio-frequency spectrum analyzers. In experimentation on a 10-km-long fiber-optic delay line, it was found that this setup made it possible to measure the length to within a fractional error of about 3 10(exp -6), corresponding to a length error of 3 cm. In contrast, measurements by optical time-domain reflectometry and mechanical measurement were found to be much less precise: For optical time-domain reflectometry, the fractional error was found no less than 10(exp -4) (corresponding to a length error of 1 m) and for mechanical measurement, the fractional error was found to be about 10(exp -2) (corresponding to a length error of 100 m).

Cardiac consequences to skeletal muscle-centric therapeutics for Duchenne muscular dystrophy.

PubMed

Townsend, DeWayne; Yasuda, Soichiro; Chamberlain, Jeffrey; Metzger, Joseph M

2009-02-01

Duchenne muscular dystrophy (DMD) is a fatal disease of muscle deterioration. Duchenne muscular dystrophy affects all striated muscles in the body, including the heart. Recent advances in palliative care, largely directed at improving respiratory function, have extended life but paradoxically further unmasked emergent heart disease in DMD patients. New experimental strategies have shown promise in restoring dystrophin in the skeletal muscles of dystrophin- deficient animals. These strategies often have little or no capacity for restitution of dystrophin in the hearts of these animals. This article draws on both clinical data and recent experimental data to posit that effective skeletal muscle restricted therapies for DMD will paradoxically heighten cardiomyopathy and heart failure in these patients.

Gene Therapy for Hemophilia and Duchenne Muscular Dystrophy in China.

PubMed

Liu, Xionghao; Liu, Mujun; Wu, Lingqian; Liang, Desheng

2018-02-01

Gene therapy is a new technology that provides potential for curing monogenic diseases caused by mutations in a single gene. Hemophilia and Duchenne muscular dystrophy (DMD) are ideal target diseases of gene therapy. Important advances have been made in clinical trials, including studies of adeno-associated virus vectors in hemophilia and antisense in DMD. However, issues regarding the high doses of viral vectors required and limited delivery efficiency of antisense oligonucleotides have not yet been fully addressed. As an alternative strategy to classic gene addition, genome editing based on programmable nucleases has also shown promise to correct mutations in situ. This review describes the recent progress made by Chinese researchers in gene therapy for hemophilia and DMD.

Optical investigation of effective permeability of dilute magnetic dielectrics with magnetic field

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee, Ananya, E-mail: banerjee.ananya2008@gmail.com; Sarkar, A.

The prime objective of this paper is to investigate the magnetic nature of dilute magnetic dielectrics (DMD) under variation of external magnetic field. The said variation is studied over developed nano-sized Gadolinium Oxide as a DMD system. The observed experimental field variation of the effective magnetic permeability is analyzed results of optical experiment. The experiment records the variation of Brewster angle of incident polarized LASER beam from the surface of developed DMD specimen with applied out of plane external magnetic field. The effective refractive index and hence relative magnetic permeability were estimated following electro-magnetic theory. The overall results obtained andmore » agreement between theory and experiment are good.« less

An Efficient Power Saving Mechanism for Delay-Guaranteed Services in IEEE 802.16e

NASA Astrophysics Data System (ADS)

Park, Yunju; Hwang, Gang Uk

As the IEEE 802.16e Wireless Metropolitan Access Network (WMAN) supports the mobility of a mobile station (MS), increasing MS power efficiency has become an important issue. In this paper, we analyze the sleep-mode operation for an efficient power saving mechanism for delay-guaranteed services in the IEEE 802.16e WMAN and observe the effects of the operating parameters related to this operation. For the analysis we use the M/GI/1/K queueing system with multiple vacations, exhaustive services and setup times. In the analysis, we consider the power consumption during the wake-mode period as well as the sleep-mode period. As a performance measure for the power consumption, we propose the power consumption per unit time per effective arrival which considers the power consumption and the packet blocking probability simultaneously. In addition, since we consider delay-guaranteed services, the average packet response delay is also considered as a performance measure. Based on the performance measures, we obtain the optimal sleep-mode operation which minimizes the power consumption per unit time per effective arrival with a given delay requirement. Numerical studies are also provided to investigate the system performance and to show how to achieve our objective.

Preliminary Validation of a New Instrument to Measure Life Satisfaction in Adolescents with Neuromuscular Disorders.

ERIC Educational Resources Information Center

Reid, Denise T.; Renwick, Rebecca M.

1994-01-01

A new questionnaire instrument, the Life Satisfaction Index for Adolescents (LSIA), has been developed for adolescents with Duchenne muscular dystrophy (DMD). This article reviews the conceptual basis of the LSIA, its development, and its reliability and validity (established with 15 male adolescents with DMD). (DB)

Delay-dependent stability and added damping of SDOF real-time dynamic hybrid testing

NASA Astrophysics Data System (ADS)

Chi, Fudong; Wang, Jinting; Jin, Feng

2010-09-01

It is well-recognized that a transfer system response delay that reduces the test stability inevitably exists in real-time dynamic hybrid testing (RTDHT). This paper focuses on the delay-dependent stability and added damping of SDOF systems in RTDHT. The exponential delay term is transferred into a rational fraction by the Padé approximation, and the delay-dependent stability conditions and instability mechanism of SDOF RTDHT systems are investigated by the root locus technique. First, the stability conditions are discussed separately for the cases of stiffness, mass, and damping experimental substructure. The use of root locus plots shows that the added damping effect and instability mechanism for mass are different from those for stiffness. For the stiffness experimental substructure case, the instability results from the inherent mode because of an obvious negative damping effect of the delay. For the mass case, the delay introduces an equivalent positive damping into the inherent mode, and instability occurs at an added high frequency mode. Then, the compound stability condition is investigated for a general case and the results show that the mass ratio may have both upper and lower limits to remain stable. Finally, a high-emulational virtual shaking table model is built to validate the stability conclusions.

Patients with Duchenne and Becker muscular dystrophies are not more asymmetrical than healthy controls on timed performance of upper limb tasks

PubMed Central

Artilheiro, M.C.; Sá, C.S.C.; Fávero, F.M.; Caromano, F.A.; Voos, M.C.

2017-01-01

This study aimed to investigate possible asymmetries and relationships between performance of dominant and non-dominant upper limbs (UL) in patients with Duchenne and Becker muscular dystrophies (DMD/BMD), to compare UL performance of patients and healthy subjects and to investigate the relationship between timed performance of UL and age, motor function and muscle strength in DMD/BMD patients. Sixteen patients with DMD and 3 with BMD were evaluated with Jebsen-Taylor Test (timed performance), Vignos scale and Dimension 3 of Motor Function Measure (motor function), and Medical Research Council scale (muscle strength) on a single session. ANOVA showed no asymmetry between dominant and non-dominant UL, except in the writing subtest, in patients and in healthy controls. There were relationships between dominant and non-dominant UL performances. Correlations between timed performance, motor function and muscle strength were found, but age was not correlated with these variables. These findings may reduce the assessment time, prevent fatigue and provide more accurate clinical reasoning involving UL in DMD/BMD treatment. PMID:28746422

Optimizing Bone Health in Duchenne Muscular Dystrophy.

PubMed

Buckner, Jason L; Bowden, Sasigarn A; Mahan, John D

2015-01-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA.

Preimplantation genetic diagnosis for Duchenne muscular dystrophy by multiple displacement amplification.

PubMed

Ren, Zi; Zeng, Hai-tao; Xu, Yan-wen; Zhuang, Guang-lun; Deng, Jie; Zhang, Cheng; Zhou, Can-quan

2009-02-01

To evaluate the use of multiple displacement amplification (MDA) in preimplantation genetic diagnosis (PGD) for female carriers with Duchenne muscular dystrophy (DMD). MDA was used to amplify a whole genome of single cells. Following the setup on single cells, the test was applied in two clinical cases of PGD. One mutant exon, six short tandem repeats (STR) markers within the dystrophin gene, and amelogenin were incorporated into singleplex polymerase chain reaction (PCR) assays on MDA products of single blastomeres. Center for reproductive medicine in First Affiliated Hospital, Sun Yat-sen University, China. Two female carriers with a duplication of exons 3-11 and a deletion of exons 47-50, respectively. The MDA of single cells and fluorescent PCR assays for PGD. The ability to analyze single blastomeres for DMD using MDA. The protocol setup previously allowed for the accurate diagnosis of each embryo. Two clinical cases resulted in a healthy girl, which was the first successful clinical application of MDA in PGD for DMD. We suggest that this protocol is reliable to increase the accuracy of the PGD for DMD.

Digital micromirror device-based ultrafast pulse shaping for femtosecond laser.

PubMed

Gu, Chenglin; Zhang, Dapeng; Chang, Yina; Chen, Shih-Chi

2015-06-15

In this Letter, we present a new digital micromirror device (DMD)-based ultrafast pulse shaper, i.e., DUPS. To the best of our knowledge, the DUPS is the first binary pulse shaper that can modulate high repetition rate laser sources at up to a 32 kHz rate (limited by the DMD pattern rate). Since pulse modulation occurs in the frequency domain through reflective two-dimensional micromirror arrays, i.e., DMD, the DUPS is not only compact and low in cost, but also possesses a high damage threshold that is critical for high pulse energy laser applications. In this work, a grating pair was introduced in the DUPS to compensate the DMD induced dispersion. Double pulses were generated to validate the effectiveness of the DUPS and calibrate the system. Subsequently, we demonstrated arbitrary phase shaping capability by continuous tuning of group velocity dispersion (GVD) and modulation of half-spectrum shifted by π. The overall efficiency was measured to be 1.7%, while an efficiency of up to 5% can be expected when high efficiency gratings and properly coated DMDs are used.

Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy.

PubMed

Nakamura, Akinori; Fueki, Noboru; Shiba, Naoko; Motoki, Hirohiko; Miyazaki, Daigo; Nishizawa, Hitomi; Echigoya, Yusuke; Yokota, Toshifumi; Aoki, Yoshitsugu; Takeda, Shin'ichi

2016-07-01

Few cases of dystrophinopathy show an asymptomatic phenotype with mutations in the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene. Our patient showed increased serum creatine kinase levels at 12 years of age. A muscle biopsy at 15 years of age led to a diagnosis of Becker muscular dystrophy. The patient showed a slight decrease in cardiac function at the age of 21 years and was administered a β-blocker, but there was no muscle involvement even at the age of 27 years. A deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene was detected, and dystrophin protein expression was ∼15% that of control level. We propose that in-frame deletion of exons 3-9 may produce a functional protein, and that multiexon skipping therapy targeting these exons may be feasible for severe dystrophic patients with a mutation in the 5' hot spot of the DMD gene.

Genetic ablation of P65 subunit of NF-κB in mdx mice to improve muscle physiological function.

PubMed

Yin, Xi; Tang, Ying; Li, Jian; Dzuricky, Anna T; Pu, Chuanqiang; Fu, Freddie; Wang, Bing

2017-10-01

Duchenne muscular dystrophy (DMD) is a genetic muscle disease characterized by dystrophin deficiency. Beyond gene replacement, the question of whether ablation of the p65 gene of nuclear factor-kappa B (NF-κB) in DMD can improve muscle physiology function is unknown. In this study, we investigated muscle physiological improvement in mdx mice (DMD model) with a genetic reduction of NF-κB. Muscle physiological function and histology were studied in 2-month-old mdx/p65 +/- , wild-type, mdx, and human minidystrophin gene transgenic mdx (TghΔDys/mdx) mice. Improved muscle physiological function was found in mdx/p65 +/- mice when compared with mdx mice; however, it was similar to TghΔDys/mdx mice. The results indicate that genetic reduction of p65 levels diminished chronic inflammation in dystrophic muscle, thus leading to amelioration of muscle pathology and improved muscle physiological function. The results show that inhibition of NF-κB may be a promising therapy when combined with gene therapy for DMD. Muscle Nerve 56: 759-767, 2017. © 2016 Wiley Periodicals, Inc.

DMD-based multi-object spectrograph on Galileo telescope

NASA Astrophysics Data System (ADS)

Zamkotsian, Frederic; Spano, Paolo; Lanzoni, Patrick; Bon, William; Riva, Marco; Nicastro, Luciano; Molinari, Emilio; Di Marcantonio, Paolo; Zerbi, Filippo; Valenziano, Luca

2013-03-01

Next-generation infrared astronomical instrumentation for ground-based and space telescopes could be based on MOEMS programmable slit masks for multi-object spectroscopy (MOS). This astronomical technique is used extensively to investigate the formation and evolution of galaxies. We propose to develop a 2048x1080 DMD-based MOS instrument to be mounted on the Galileo telescope and called BATMAN. A two-arm instrument has been designed for providing in parallel imaging and spectroscopic capabilities. The two arms with F/4 on the DMD are mounted on a common bench, and an upper bench supports the detectors thanks to two independent hexapods. Very good optical quality on the DMD and the detectors will be reached. ROBIN, a BATMAN demonstrator, has been designed, realized and integrated. It permits to determine the instrument integration procedure, including optics and mechanics integration, alignment procedure and optical quality. First images have been obtained and measured. A DMD pattern manager has been developed in order to generate any slit mask according to the list of objects to be observed; spectra have been generated and measured. Observation strategies will be studied and demonstrated for the scientific optimization strategy over the whole FOV. BATMAN on the sky is of prime importance for characterizing the actual performance of this new family of MOS instruments, as well as investigating the operational procedures on astronomical objects. This instrument will be placed on the Telescopio Nazionale Galileo at the beginning of next year, in 2014.

The 6 minute walk test and performance of upper limb in ambulant duchenne muscular dystrophy boys.

PubMed

Pane, Marika; Mazzone, Elena Stacy; Sivo, Serena; Fanelli, Lavinia; De Sanctis, Roberto; D'Amico, Adele; Messina, Sonia; Battini, Roberta; Bianco, Flaviana; Scutifero, Marianna; Petillo, Roberta; Frosini, Silvia; Scalise, Roberta; Vita, Gian Luca; Bruno, Claudio; Pedemonte, Marina; Mongini, Tiziana; Pegoraro, Elena; Brustia, Francesca; Gardani, Alice; Berardinelli, Angela; Lanzillotta, Valentina; Viggiano, Emanuela; Cavallaro, Filippo; Sframeli, Maria; Bello, Luca; Barp, Andrea; Busato, Fabio; Bonfiglio, Serena; Rolle, Enrica; Colia, Giulia; Bonetti, Annamaria; Palermo, Concetta; Graziano, Alessandra; D'Angelo, Grazia; Pini, Antonella; Corlatti, Alice; Gorni, Ksenija; Baranello, Giovanni; Antonaci, Laura; Bertini, Enrico; Politano, Luisa; Mercuri, Eugenio

2014-10-07

The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.

High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD

PubMed Central

Gibbs, Elizabeth M.; Marshall, Jamie L.; Ma, Eva; Nguyen, Thien M.; Hong, Grace; Lam, Jessica S.; Spencer, Melissa J.

2016-01-01

Abstract Duchenne muscular dystrophy (DMD) is a genetic disorder that causes progressive muscle weakness, ultimately leading to early mortality in affected teenagers and young adults. Previous work from our lab has shown that a small transmembrane protein called sarcospan (SSPN) can enhance the recruitment of adhesion complex proteins to the cell surface. When human SSPN is expressed at three-fold levels in mdx mice, this increase in adhesion complex abundance improves muscle membrane stability, preventing many of the histopathological changes associated with DMD. However, expressing higher levels of human SSPN (ten-fold transgenic expression) causes a severe degenerative muscle phenotype in wild-type mice. Since SSPN-mediated stabilization of the sarcolemma represents a promising therapeutic strategy in DMD, it is important to determine whether SSPN can be introduced at high levels without toxicity. Here, we show that mouse SSPN (mSSPN) can be overexpressed at 30-fold levels in wild-type mice with no deleterious effects. In mdx mice, mSSPN overexpression improves dystrophic pathology and sarcolemmal stability. We show that these mice exhibit increased resistance to eccentric contraction-induced damage and reduced fatigue following exercise. mSSPN overexpression improved pulmonary function and reduced dystrophic histopathology in the diaphragm. Together, these results demonstrate that SSPN overexpression is well tolerated in mdx mice and improves sarcolemma defects that underlie skeletal muscle and pulmonary dysfunction in DMD. PMID:27798107

A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice.

PubMed

Porter, John D; Khanna, Sangeeta; Kaminski, Henry J; Rao, J Sunil; Merriam, Anita P; Richmonds, Chelliah R; Leahy, Patrick; Li, Jingjin; Guo, Wei; Andrade, Francisco H

2002-02-01

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.

Oral muscles are progressively affected in Duchenne muscular dystrophy: implications for dysphagia treatment.

PubMed

van den Engel-Hoek, Lenie; Erasmus, Corrie E; Hendriks, Jan C M; Geurts, Alexander C H; Klein, Willemijn M; Pillen, Sigrid; Sie, Lilian T; de Swart, Bert J M; de Groot, Imelda J M

2013-05-01

Dysphagia is reported in advanced stages of Duchenne muscular dystrophy (DMD). The population of DMD is changing due to an increasing survival. We aimed to describe the dysphagia in consecutive stages and to assess the underlying mechanisms of dysphagia in DMD, in order to develop mechanism based recommendations for safe swallowing. In this cross-sectional study, participants were divided into: early and late ambulatory stage (AS, n = 6), early non-ambulatory stage (ENAS, n = 7), and late non-ambulatory stage (LNAS, n = 11). Quantitative oral muscle ultrasound was performed to quantify echo intensity. Swallowing was assessed with a video fluoroscopic swallow study, surface electromyography (sEMG) of the submental muscle group and tongue pressure. Differences in outcome parameters among the three DMD stages were tested with analysis of variance. Oral muscles related to swallowing were progressively affected, starting in the AS with the geniohyoid muscle. Tongue (pseudo) hypertrophy was found in 70 % of patients in the ENAS and LNAS. Oral phase problems and post-swallow residue were observed, mostly in the LNAS with solid food. sEMG and tongue pressure data of swallowing solid food revealed the lowest sEMG amplitude, the longest duration and lowest tongue pressure in the LNAS. In case of swallowing problems in DMD, based on the disturbed mechanisms of swallowing, it is suggested to (1) adjust meals in terms of less solid food, and (2) drink water after meals to clear the oropharyngeal area.

Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements.

PubMed

Vohra, Ravneet S; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

2015-01-01

The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD.

Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements

PubMed Central

Vohra, Ravneet S.; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C.; Sweeney, H. Lee; Walter, Glenn A.; Vandenborne, Krista

2015-01-01

Introduction The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Methods Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Results Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Discussion Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD. PMID:26103164

Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism.

PubMed

Al-Khalidi, Rasha; Panicucci, Chiara; Cox, Paul; Chira, Natalia; Róg, Justyna; Young, Christopher N J; McGeehan, Rhiannon E; Ambati, Kameshwari; Ambati, Jayakrishna; Zabłocki, Krzysztof; Gazzerro, Elisabetta; Arkle, Stephen; Bruno, Claudio; Górecki, Dariusz C

2018-04-11

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMD mdx mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMD mdx mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and may be effective in alleviating both muscle and non-muscle abnormalities.

Quality of life of patients with Duchenne muscular dystrophy: from adolescence to young men.

PubMed

Lue, Yi-Jing; Chen, Shun-Sheng; Lu, Yen-Mou

2017-07-01

This study investigated quality of life (QOL) in adolescent and young men with Duchenne muscular dystrophy (DMD). Health-related QOL and global QOL were assessed with the Short Form 36 (SF-36) and World Health Organization Quality of Life-BREF (WHOQOL-BREF). Associations between functional status and QOL were assessed. All domains of the SF-36 were below Taiwan norms (effect size: -14.2 to -0.5), especially Physical Function, Role Physical, and Social Function. Three of the four domains of the WHOQOL-BREF were below Taiwan norms (effect size: -2.0 to -0.7). The Physical Function of the SF-36 was moderately correlated with functional status (mobility, basic activities of daily living, and arm function). The Social Function of the SF-36 and Social Relationships of the WHOQOL-BREF were also moderately correlated with functional status (impairment, basic activities of daily living, and arm function). The adolescent and young men with DMD had poor health-related and global QOL. Poor QOL was related to both physical condition and social health. We suggest that rehabilitation programs focus on using assistive devices to facilitate arm function and encouraging participation in social activities to improve the QOL of patients with DMD. Implications for rehabilitation Duchenne muscular dystrophy (DMD) is a progressive muscle weakness disease that not only impacts physical health but also leads to poor quality of life in many domains. A valuable rehabilitation goal for patients with DMD is to encourage participation in social activities. Medical care and educational programs should plan a formal transition processes for patients with DMD from pediatric to adult care to maximum their quality of life. Arm function is associated with many domains of global quality of life, so a key element in improving quality of life may be to improve arm function.

Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy From 2000 to 2011.

PubMed

Andrews, Jennifer G; Soim, Aida; Pandya, Shree; Westfield, Christina P; Ciafaloni, Emma; Fox, Deborah J; Birnkrant, David J; Cunniff, Christopher M; Sheehan, Daniel W

2016-10-01

Duchenne muscular dystrophy (DMD) causes progressive respiratory muscle weakness and decline in function, which can go undetected without monitoring. DMD respiratory care guidelines recommend scheduled respiratory assessments and use of respiratory assist devices. To determine the extent of adherence to these guidelines, we evaluated respiratory assessments and interventions among males with DMD in the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from 2000 to 2011. MD STARnet is a population-based surveillance system that identifies all individuals born during or after 1982 residing in Arizona, Colorado, Georgia, Hawaii, Iowa, and western New York with Duchenne or Becker muscular dystrophy. We analyzed MD STARnet respiratory care data for non-ambulatory adolescent males (12-17 y old) and men (≥18 y old) with DMD, assessing whether: (1) pulmonary function was measured twice yearly; (2) awake and asleep hypoventilation testing was performed at least yearly; (3) home mechanical insufflation-exsufflation, noninvasive ventilation, and tracheostomy/ventilators were prescribed; and (4) pulmonologists provided evaluations. During 2000-2010, no more than 50% of both adolescents and men had their pulmonary function monitored twice yearly in any of the years; 67% or fewer were assessed for awake and sleep hypoventilation yearly. Although the use of mechanical insufflation-exsufflation and noninvasive ventilation is probably increasing, prior use of these devices did not prevent all tracheostomies, and at least 18 of 29 tracheostomies were performed due to acute respiratory illnesses. Fewer than 32% of adolescents and men had pulmonologist evaluations in 2010-2011. Since the 2004 publication of American Thoracic Society guidelines, there have been few changes in pulmonary clinical practice. Frequencies of respiratory assessments and assist device use among males with DMD were lower than recommended in clinical guidelines. Collaboration of respiratory therapists and pulmonologists with clinicians caring for individuals with DMD should be encouraged to ensure access to the full spectrum of in-patient and out-patient pulmonary interventions. Copyright © 2016 by Daedalus Enterprises.

Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

PubMed Central

2012-01-01

Background Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. Methods Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. Results The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. Conclusions This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype. PMID:22894145

Non-neural Muscle Weakness Has Limited Influence on Complexity of Motor Control during Gait

PubMed Central

Goudriaan, Marije; Shuman, Benjamin R.; Steele, Katherine M.; Van den Hauwe, Marleen; Goemans, Nathalie; Molenaers, Guy; Desloovere, Kaat

2018-01-01

Cerebral palsy (CP) and Duchenne muscular dystrophy (DMD) are neuromuscular disorders characterized by muscle weakness. Weakness in CP has neural and non-neural components, whereas in DMD, weakness can be considered as a predominantly non-neural problem. Despite the different underlying causes, weakness is a constraint for the central nervous system when controlling gait. CP demonstrates decreased complexity of motor control during gait from muscle synergy analysis, which is reflected by a higher total variance accounted for by one synergy (tVAF1). However, it remains unclear if weakness directly contributes to higher tVAF1 in CP, or whether altered tVAF1 reflects mainly neural impairments. If muscle weakness directly contributes to higher tVAF1, then tVAF1 should also be increased in DMD. To examine the etiology of increased tVAF1, muscle activity data of gluteus medius, rectus femoris, medial hamstrings, medial gastrocnemius, and tibialis anterior were measured at self-selected walking speed, and strength data from knee extensors, knee flexors, dorsiflexors and plantar flexors, were analyzed in 15 children with CP [median (IQR) age: 8.9 (2.2)], 15 boys with DMD [8.7 (3.1)], and 15 typical developing (TD) children [8.6 (2.7)]. We computed tVAF1 from 10 concatenated steps with non-negative matrix factorization, and compared tVAF1 between the three groups with a Mann-Whiney U-test. Spearman's rank correlation coefficients were used to determine if weakness in specific muscle groups contributed to altered tVAF1. No significant differences in tVAF1 were found between DMD [tVAF1: 0.60 (0.07)] and TD children [0.65 (0.07)], while tVAF1 was significantly higher in CP [(0.74 (0.09)] than in the other groups (both p < 0.005). In CP, weakness in the plantar flexors was related to higher tVAF1 (r = −0.72). In DMD, knee extensor weakness related to increased tVAF1 (r = −0.50). These results suggest that the non-neural weakness in DMD had limited influence on complexity of motor control during gait and that the higher tVAF1 in children with CP is mainly related to neural impairments caused by the brain lesion. PMID:29445330

Validation of ultrasonography for non-invasive assessment of diaphragm function in muscular dystrophy.

PubMed

Whitehead, Nicholas P; Bible, Kenneth L; Kim, Min Jeong; Odom, Guy L; Adams, Marvin E; Froehner, Stanley C

2016-12-15

Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease that is commonly studied using the mdx mouse. The mdx diaphragm muscle closely mimics the pathophysiological changes in DMD muscles. mdx diaphragm force is commonly assessed ex vivo, precluding time course studies. Here we used ultrasonography to evaluate time-dependent changes in diaphragm function in vivo, by measuring diaphragm movement amplitude. In mdx mice, diaphragm amplitude decreased with age and values were much lower than for wild-type mice. Importantly, diaphragm amplitude strongly correlated with ex vivo specific force values. Micro-dystrophin administration increased mdx diaphragm amplitude by 26% after 4 weeks. Diaphragm amplitude correlated positively with ex vivo force values and negatively with diaphragm fibrosis, a major cause of DMD muscle weakness. These studies validate diaphragm ultrasonography as a reliable technique for assessing time-dependent changes in mdx diaphragm function in vivo. This technique will be valuable for testing potential therapies for DMD. Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease caused by dystrophin mutations. The mdx mouse is a widely used animal model of DMD. The mdx diaphragm muscle most closely recapitulates key features of DMD muscles, including progressive fibrosis and considerable force loss. Diaphragm function in mdx mice is commonly evaluated by specific force measurements ex vivo. While useful, this method only measures force from a small muscle sample at one time point. Therefore, accurate assessment of diaphragm function in vivo would provide an important advance to study the time course of functional decline and treatment benefits. Here, we evaluated an ultrasonography technique for measuring time-dependent changes of diaphragm function in mdx mice. Diaphragm movement amplitude values for mdx mice were considerably lower than those for wild-type, decreased from 8 to 18 months of age, and correlated strongly with ex vivo specific force. We then investigated the time course of diaphragm amplitude changes following administration of an adeno-associated viral vector expressing Flag-micro-dystrophin (AAV-μDys) to young adult mdx mice. Diaphragm amplitude peaked 4 weeks after AAV-μDys administration, and was 26% greater than control mdx mice at this time. This value decreased slightly to 21% above mdx controls after 12 weeks of treatment. Importantly, diaphragm amplitude again correlated strongly with ex vivo specific force. Also, diaphragm amplitude and specific force negatively correlated with fibrosis levels in the muscle. Together, our results validate diaphragm ultrasonography as a reliable technique for assessing time-dependent changes in dystrophic diaphragm function in vivo, and for evaluating potential therapies for DMD. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Validation of ultrasonography for non‐invasive assessment of diaphragm function in muscular dystrophy

PubMed Central

Bible, Kenneth L.; Kim, Min Jeong; Odom, Guy L.; Adams, Marvin E.; Froehner, Stanley C.

2016-01-01

Key points Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease that is commonly studied using the mdx mouse. The mdx diaphragm muscle closely mimics the pathophysiological changes in DMD muscles. mdx diaphragm force is commonly assessed ex vivo, precluding time course studies. Here we used ultrasonography to evaluate time‐dependent changes in diaphragm function in vivo, by measuring diaphragm movement amplitude.In mdx mice, diaphragm amplitude decreased with age and values were much lower than for wild‐type mice. Importantly, diaphragm amplitude strongly correlated with ex vivo specific force values.Micro‐dystrophin administration increased mdx diaphragm amplitude by 26% after 4 weeks. Diaphragm amplitude correlated positively with ex vivo force values and negatively with diaphragm fibrosis, a major cause of DMD muscle weakness.These studies validate diaphragm ultrasonography as a reliable technique for assessing time‐dependent changes in mdx diaphragm function in vivo. This technique will be valuable for testing potential therapies for DMD. Abstract Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease caused by dystrophin mutations. The mdx mouse is a widely used animal model of DMD. The mdx diaphragm muscle most closely recapitulates key features of DMD muscles, including progressive fibrosis and considerable force loss. Diaphragm function in mdx mice is commonly evaluated by specific force measurements ex vivo. While useful, this method only measures force from a small muscle sample at one time point. Therefore, accurate assessment of diaphragm function in vivo would provide an important advance to study the time course of functional decline and treatment benefits. Here, we evaluated an ultrasonography technique for measuring time‐dependent changes of diaphragm function in mdx mice. Diaphragm movement amplitude values for mdx mice were considerably lower than those for wild‐type, decreased from 8 to 18 months of age, and correlated strongly with ex vivo specific force. We then investigated the time course of diaphragm amplitude changes following administration of an adeno‐associated viral vector expressing Flag‐micro‐dystrophin (AAV‐μDys) to young adult mdx mice. Diaphragm amplitude peaked 4 weeks after AAV‐μDys administration, and was 26% greater than control mdx mice at this time. This value decreased slightly to 21% above mdx controls after 12 weeks of treatment. Importantly, diaphragm amplitude again correlated strongly with ex vivo specific force. Also, diaphragm amplitude and specific force negatively correlated with fibrosis levels in the muscle. Together, our results validate diaphragm ultrasonography as a reliable technique for assessing time‐dependent changes in dystrophic diaphragm function in vivo, and for evaluating potential therapies for DMD. PMID:27570057

Reduced-order modeling of fluids systems, with applications in unsteady aerodynamics

NASA Astrophysics Data System (ADS)

Dawson, Scott T. M.

This thesis focuses on two major themes: modeling and understanding the dynamics of rapidly pitching airfoils, and developing methods that can be used to extract models and pertinent features from datasets obtained in the study of these and other systems in fluid mechanics and aerodynamics. Much of the work utilizes in some capacity dynamic mode decomposition (DMD), a recently developed method to extract dynamical features and models from data. The investigation of pitching airfoils includes both wind tunnel experiments and direct numerical simulations. Experiments are performed on a NACA 0012 airfoil undergoing rapid pitching motion, with the focus on developing a switched linear modeling framework that can accurately predict unsteady aerodynamic forces and pressure distributions throughout arbitrary pitching motions. Numerical simulations are used to study the behavior of sinusoidally pitching airfoils. By systematically varying the amplitude, frequency, mean angle and axis of pitching, a comprehensive database of results is acquired, from which interesting regions in parameter space are identified and studied. Attention is given to pitching at "preferred" frequencies, where vortex shedding in the wake is excited or amplified, leading to larger lift forces. More generally, the ability to extract nonlinear models that describe the behavior of complex fluids systems can assist in not only understanding the dominant features of such systems, but also to achieve accurate prediction and control. One potential avenue to achieve this objective is through numerical approximation of the Koopman operator, an infinite-dimensional linear operator capable of describing finite-dimensional nonlinear systems, such as those that might describe the dominant dynamics of fluids systems. This idea is explored by showing that algorithms designed to approximate the Koopman operator can indeed be utilized to accurately model nonlinear fluids systems, even when the data available is limited or noisy. Data-driven algorithms can be adversely affected by noisy data. Focusing on DMD, it is shown analytically that the algorithm is biased to sensor noise, which explains a previously observed sensitivity to noisy data. Using this finding, a number of modifications to DMD are proposed, which all give better approximations of the true dynamics using noise-corrupted data.

Timing the Mode Switch in a Sequential Mixed-Mode Survey: An Experimental Evaluation of the Impact on Final Response Rates, Key Estimates, and Costs

PubMed Central

Wagner, James; Schroeder, Heather M.; Piskorowski, Andrew; Ursano, Robert J.; Stein, Murray B.; Heeringa, Steven G.; Colpe, Lisa J.

2017-01-01

Mixed-mode surveys need to determine a number of design parameters that may have a strong influence on costs and errors. In a sequential mixed-mode design with web followed by telephone, one of these decisions is when to switch modes. The web mode is relatively inexpensive but produces lower response rates. The telephone mode complements the web mode in that it is relatively expensive but produces higher response rates. Among the potential negative consequences, delaying the switch from web to telephone may lead to lower response rates if the effectiveness of the prenotification contact materials is reduced by longer time lags, or if the additional e-mail reminders to complete the web survey annoy the sampled person. On the positive side, delaying the switch may decrease the costs of the survey. We evaluate these costs and errors by experimentally testing four different timings (1, 2, 3, or 4 weeks) for the mode switch in a web–telephone survey. This experiment was conducted on the fourth wave of a longitudinal study of the mental health of soldiers in the U.S. Army. We find that the different timings of the switch in the range of 1–4 weeks do not produce differences in final response rates or key estimates but longer delays before switching do lead to lower costs. PMID:28943717

Responding Logistically to Future Natural and Man-Made Disasters and Catastrophes

DTIC Science & Technology

2008-03-15

Logistics Operations, Plans and Exercises, Distribution Management and Property Management. Each competency has associated roles, missions and...professional development. LMD’s Distribution Management Division (DMD) Within the LMD, FEMA also created the Distribution Management Division (DMD...to stock in anticipation of future disasters. A Distribution Management Strategy Working Group was formed with Federal, private and nongovernmental

Distributed Compressive Sensing vs. Dynamic Compressive Sensing: Improving the Compressive Line Sensing Imaging System through Their Integration

DTIC Science & Technology

2015-01-01

streak tube imaging Lidar [15]. Nevertheless, instead of one- dimensional (1D) fan beam, a laser source modulates the digital micromirror device DMD and...Trans. Inform. Theory, vol. 52, pp. 1289-1306, 2006. [10] D. Dudley, W. Duncan and J. Slaughter, "Emerging Digital Micromirror Device (DMD) Applications

Temporal focusing-based multiphoton excitation microscopy via digital micromirror device.

PubMed

Yih, Jenq-Nan; Hu, Yvonne Yuling; Sie, Yong Da; Cheng, Li-Chung; Lien, Chi-Hsiang; Chen, Shean-Jen

2014-06-01

This Letter presents an enhanced temporal focusing-based multiphoton excitation (MPE) microscope in which the conventional diffraction grating is replaced by a digital micromirror device (DMD). Experimental results from imaging a thin fluorescence film show that the 4.0 μm axial resolution of the microscope is comparable with that of a setup incorporating a 600  lines/mm grating; hence, the optical sectioning ability of the proposed setup is demonstrated. Similar to a grating, the DMD diffracts illuminating light frequencies for temporal focusing; additionally, it generates arbitrary patterns. Since the DMD is placed on the image-conjugate plane of the objective lens' focal plane, the MPE pattern can be projected on the focal plane precisely.

Phase-conjugate holographic lithography based on micromirror array recording.

PubMed

Lim, Yongjun; Hahn, Joonku; Lee, Byoungho

2011-12-01

We present phase-conjugate holographic lithography with a hologram recorded by a digital micromirror device (DMD) and a telecentric lens. In our lithography system, a phase-conjugate hologram is applied instead of conventional masks or reticles to form patterns. This method has the advantage of increasing focus range, and it is applicable to the formation of patterns on fairly uneven surfaces. The hologram pattern is dynamically generated by the DMD, and its resolution is mainly determined by the demagnification of the telecentric lens. We experimentally demonstrate that our holographic lithographic system has a large focus range, and it is feasible to make a large-area hologram by stitching each pattern generated by the DMD without a falling off in resolution. © 2011 Optical Society of America

Implementing transmission eigenchannels of disordered media by a binary-control digital micromirror device

NASA Astrophysics Data System (ADS)

Kim, Donggyu; Choi, Wonjun; Kim, Moonseok; Moon, Jungho; Seo, Keumyoung; Ju, Sanghyun; Choi, Wonshik

2014-11-01

We report a method for measuring the transmission matrix of a disordered medium using a binary-control of a digital micromirror device (DMD). With knowledge of the measured transmission matrix, we identified the transmission eigenchannels of the medium. We then used binary control of the DMD to shape the wavefront of incident waves and to experimentally couple light to individual eigenchannels. When the wave was coupled to the eigenchannel with the largest eigenvalue, in particular, we were able to achieve about two times more energy transmission than the mean transmittance of the medium. Our study provides an elaborated use of the DMD as a high-speed wavefront shaping device for controlling the multiple scattering of waves in highly scattering media.

A Novel Energy Saving Algorithm with Frame Response Delay Constraint in IEEE 802.16e

NASA Astrophysics Data System (ADS)

Nga, Dinh Thi Thuy; Kim, Mingon; Kang, Minho

Sleep-mode operation of a Mobile Subscriber Station (MSS) in IEEE 802.16e effectively saves energy consumption; however, it induces frame response delay. In this letter, we propose an algorithm to quickly find the optimal value of the final sleep interval in sleep-mode in order to minimize energy consumption with respect to a given frame response delay constraint. The validations of our proposed algorithm through analytical results and simulation results suggest that our algorithm provide a potential guidance to energy saving.

Improvement of time-delayed feedback control by periodic modulation: analytical theory of Floquet mode control scheme.

PubMed

Just, Wolfram; Popovich, Svitlana; Amann, Andreas; Baba, Nilüfer; Schöll, Eckehard

2003-02-01

We investigate time-delayed feedback control schemes which are based on the unstable modes of the target state, to stabilize unstable periodic orbits. The periodic time dependence of these modes introduces an external time scale in the control process. Phase shifts that develop between these modes and the controlled periodic orbit may lead to a huge increase of the control performance. We illustrate such a feature on a nonlinear reaction diffusion system with global coupling and give a detailed investigation for the Rössler model. In addition we provide the analytical explanation for the observed control features.

Synchronization of discrete-time neural networks with delays and Markov jump topologies based on tracker information.

PubMed

Yang, Xinsong; Feng, Zhiguo; Feng, Jianwen; Cao, Jinde

2017-01-01

In this paper, synchronization in an array of discrete-time neural networks (DTNNs) with time-varying delays coupled by Markov jump topologies is considered. It is assumed that the switching information can be collected by a tracker with a certain probability and transmitted from the tracker to controller precisely. Then the controller selects suitable control gains based on the received switching information to synchronize the network. This new control scheme makes full use of received information and overcomes the shortcomings of mode-dependent and mode-independent control schemes. Moreover, the proposed control method includes both the mode-dependent and mode-independent control techniques as special cases. By using linear matrix inequality (LMI) method and designing new Lyapunov functionals, delay-dependent conditions are derived to guarantee that the DTNNs with Markov jump topologies to be asymptotically synchronized. Compared with existing results on Markov systems which are obtained by separately using mode-dependent and mode-independent methods, our result has great flexibility in practical applications. Numerical simulations are finally given to demonstrate the effectiveness of the theoretical results. Copyright © 2016 Elsevier Ltd. All rights reserved.

FREQUENCY DEPENDENCE OF POLARIZATION OF ZEBRA PATTERN IN TYPE-IV SOLAR RADIO BURSTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaneda, Kazutaka; Misawa, H.; Tsuchiya, F.

2015-08-01

We investigated the polarization characteristics of a zebra pattern (ZP) in a type-IV solar radio burst observed with AMATERAS on 2011 June 21 for the purpose of evaluating the generation processes of ZPs. Analyzing highly resolved spectral and polarization data revealed the frequency dependence of the degree of circular polarization and the delay between two polarized components for the first time. The degree of circular polarization was 50%–70% right-handed and it varied little as a function of frequency. Cross-correlation analysis determined that the left-handed circularly polarized component was delayed by 50–70 ms relative to the right-handed component over the entiremore » frequency range of the ZP and this delay increased with the frequency. We examined the obtained polarization characteristics by using pre-existing ZP models and concluded that the ZP was generated by the double-plasma-resonance process. Our results suggest that the ZP emission was originally generated in a completely polarized state in the O-mode and was partly converted into the X-mode near the source. Subsequently, the difference between the group velocities of the O-mode and X-mode caused the temporal delay.« less

Whole-body vibration training in children with Duchenne muscular dystrophy and spinal muscular atrophy.

PubMed

Vry, Julia; Schubert, Isabel J; Semler, Oliver; Haug, Verena; Schönau, Eckhard; Kirschner, Janbernd

2014-03-01

Whole-body-vibration training is used to improve muscle strength and function and might therefore constitute a potential supportive therapy for neuromuscular diseases. To evaluate safety of whole-body vibration training in ambulatory children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). 14 children with DMD and 8 with SMA underwent an 8-week vibration training programme on a Galileo MedM at home (3 × 3 min twice a day, 5 days a week). Primary outcome was safety of the training, assessed clinically and by measuring serum creatine kinase levels. Secondary outcome was efficacy as measured by changes in time function tests, muscle strength and angular degree of dorsiflexion of the ankles. All children showed good clinical tolerance. In boys with DMD, creatine kinase increased by 56% after the first day of training and returned to baseline after 8 weeks of continuous whole-body vibration training. No changes in laboratory parameters were observed in children with SMA. Secondary outcomes showed mild, but not significant, improvements with the exception of the distance walked in the 6-min walking test in children with SMA, which rose from 371.3 m to 402.8 m (p < 0.01). Whole-body vibration training is clinically well tolerated in children with DMD and SMA. The relevance of the temporary increase in creatine kinase in DMD during the first days of training is unclear, but it is not related to clinical symptoms or deterioration. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy.

PubMed

Rancourt, Ann; Dufresne, Sébastien S; St-Pierre, Guillaume; Lévesque, Julie-Christine; Nakamura, Haruka; Kikuchi, Yodai; Satoh, Masahiko S; Frenette, Jérôme; Sato, Sachiko

2018-06-12

The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), in which mutations in the dystrophin gene disrupts the firm adhesion. In patients with DMD, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in patients with DMD, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina and increases the efficiency of the myogenesis. Galectin-3 is an oligosaccharide-binding protein and is known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle, although its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the synthesis of binding partners (oligosaccharides) of galectin-3, promote myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N-acetylglucosamine increased muscle-force production. The results suggest that treatment with N-acetylglucosamine might mitigate the burden of DMD.-Rancourt, A., Dufresne, S. S., St-Pierre, G., Lévesque, J.-C., Nakamura, H., Kikuchi, Y., Satoh, M. S., Frenette, J., Sato, S. Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy.

Multi-slice MRI reveals heterogeneity in disease distribution along the length of muscle in Duchenne muscular dystrophy.

PubMed

Chrzanowski, Stephen M; Baligand, Celine; Willcocks, Rebecca J; Deol, Jasjit; Schmalfuss, Ilona; Lott, Donovan J; Daniels, Michael J; Senesac, Claudia; Walter, Glenn A; Vandenborne, Krista

2017-09-01

Duchenne muscular dystrophy (DMD) causes progressive pathologic changes to muscle secondary to a cascade of inflammation, lipid deposition, and fibrosis. Clinically, this manifests as progressive weakness, functional loss, and premature mortality. Though insult to whole muscle groups is well established, less is known about the relationship between intramuscular pathology and function. Differences of intramuscular heterogeneity across muscle length were assessed using an ordinal MRI grading scale in lower leg muscles of boys with DMD and correlated to patient's functional status. Cross sectional T 1 weighted MRI images with fat suppression were obtained from ambulatory boys with DMD. Six muscles (tibialis anterior, extensor digitorum longus, peroneus, soleus, medial and lateral gastrocnemii) were graded using an ordinal grading scale over 5 slice sections along the lower leg length. The scores from each slice were combined and results were compared to global motor function and age. Statistically greater differences of involvement were observed at the proximal ends of muscle compared to the midbellies. Multi-slice assessment correlated significantly to age and the Vignos functional scale, whereas single-slice assessment correlated to the Vignos functional scale only. Lastly, differential disease involvement of whole muscle groups and intramuscular heterogeneity were observed amongst similar age subjects. A multi-slice ordinal MRI grading scale revealed that muscles are not uniformly affected, with more advanced disease visible near the tendons in a primarily ambulatory population with DMD. A geographically comprehensive evaluation of the heterogeneously affected muscle in boys with DMD may more accurately assess disease involvement.

Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and α7 integrin

PubMed Central

Marshall, Jamie L.; Oh, Jennifer; Chou, Eric; Lee, Joy A.; Holmberg, Johan; Burkin, Dean J.; Crosbie-Watson, Rachelle H.

2015-01-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin–glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of α7β1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of α7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan ‘rescue’ of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or α7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and α7β1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and α7β1 integrin. PMID:25504048

Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice.

PubMed

Bish, Lawrence T; Yarchoan, Mark; Sleeper, Meg M; Gazzara, Jeffrey A; Morine, Kevin J; Acosta, Pedro; Barton, Elisabeth R; Sweeney, H Lee

2011-01-01

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6-9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease.

Reduced mandibular range of motion in Duchenne Muscular Dystrophy: predictive factors.

PubMed

van Bruggen, H W; Van Den Engel-Hoek, L; Steenks, M H; Bronkhorst, E M; Creugers, N H J; de Groot, I J M; Kalaykova, S I

2015-06-01

Patients with Duchenne muscular dystrophy (DMD) experience negative effects upon feeding and oral health. We aimed to determine whether the mandibular range of motion in DMD is impaired and to explore predictive factors for the active maximum mouth opening (aMMO). 23 patients with DMD (mean age 16.7 ± 7.7 years) and 23 controls were assessed using a questionnaire about mandibular function and impairments. All participants underwent a clinical examination of the masticatory system, including measurement of mandibular range of motion and variables related to mandibular movements. In all patients, quantitative ultrasound of the digastric muscle and the geniohyoid muscle and the motor function measure (MFM) scale were performed. The patients were divided into early and late ambulatory stage (AS), early non-ambulatory stage (ENAS) and late non-ambulatory stage (LNAS). All mandibular movements were reduced in the patient group (P < 0.001) compared to the controls. Reduction in the aMMO (<40 mm) was found in 26% of the total patient group. LNAS patients had significantly smaller mandibular movements compared to AS and ENAS (P < 0.05). Multiple linear regression analysis for aMMO revealed a positive correlation with the body height and disease progression, with MFM total score as the strongest independent risk factor (R(2) = 0.71). Mandibular movements in DMD are significantly reduced and become more hampered with loss of motor function, including the sitting position, arm function, and neck and head control. We suggest that measurement of the aMMO becomes a part of routine care of patients with DMD. © 2015 John Wiley & Sons Ltd.

Pharmacologic Management of Duchenne Muscular Dystrophy: Target Identification and Preclinical Trials

PubMed Central

Kornegay, Joe N.; Spurney, Christopher F.; Nghiem, Peter P.; Brinkmeyer-Langford, Candice L.; Hoffman, Eric P.; Nagaraju, Kanneboyina

2014-01-01

Duchenne muscular dystrophy (DMD) is an X-linked human disorder in which absence of the protein dystrophin causes degeneration of skeletal and cardiac muscle. For the sake of treatment development, over and above definitive genetic and cell-based therapies, there is considerable interest in drugs that target downstream disease mechanisms. Drug candidates have typically been chosen based on the nature of pathologic lesions and presumed underlying mechanisms and then tested in animal models. Mammalian dystrophinopathies have been characterized in mice (mdx mouse) and dogs (golden retriever muscular dystrophy [GRMD]). Despite promising results in the mdx mouse, some therapies have not shown efficacy in DMD. Although the GRMD model offers a higher hurdle for translation, dogs have primarily been used to test genetic and cellular therapies where there is greater risk. Failed translation of animal studies to DMD raises questions about the propriety of methods and models used to identify drug targets and test efficacy of pharmacologic intervention. The mdx mouse and GRMD dog are genetically homologous to DMD but not necessarily analogous. Subcellular species differences are undoubtedly magnified at the whole-body level in clinical trials. This problem is compounded by disparate cultures in clinical trials and preclinical studies, pointing to a need for greater rigor and transparency in animal experiments. Molecular assays such as mRNA arrays and genome-wide association studies allow identification of genetic drug targets more closely tied to disease pathogenesis. Genes in which polymorphisms have been directly linked to DMD disease progression, as with osteopontin, are particularly attractive targets. PMID:24936034

Long-term systemic myostatin inhibition via liver-targeted gene transfer in golden retriever muscular dystrophy.

PubMed

Bish, Lawrence T; Sleeper, Meg M; Forbes, Sean C; Morine, Kevin J; Reynolds, Caryn; Singletary, Gretchen E; Trafny, Dennis; Pham, Jennifer; Bogan, Janet; Kornegay, Joe N; Vandenborne, Krista; Walter, Glenn A; Sweeney, H Lee

2011-12-01

Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients.

Nonbulk motion system for simultaneously measuring the refractive index and thickness of a sample using tunable optics and spatial signal processing-based Gaussian beam imaging.

PubMed

Reza, Syed Azer; Qasim, Muhammad

2016-01-10

This paper presents a novel approach to simultaneously measuring the thickness and refractive index of a sample. The design uses an electronically controlled tunable lens (ECTL) and a microelectromechanical-system-based digital micromirror device (DMD). The method achieves the desired results by using the DMD to characterize the spatial profile of a Gaussian laser beam at different focal length settings of the ECTL. The ECTL achieves tunable lensing through minimal motion of liquid inside a transparent casing, whereas the DMD contains an array of movable micromirrors, which make it a reflective spatial light modulator. As the proposed system uses an ECTL, a DMD, and other fixed optical components, it measures the thickness and refractive index without requiring any motion of bulk components such as translational and rotational stages. A motion-free system improves measurement repeatability and reliability. Moreover, the measurement of sample thickness and refractive index can be completely automated because the ECTL and DMD are controlled through digital signals. We develop and discuss the theory in detail to explain the measurement methodology of the proposed system and present results from experiments performed to verify the working principle of the method. Refractive index measurement accuracies of 0.22% and 0.2% were achieved for two BK-7 glass samples used, and the thicknesses of the two samples were measured with a 0.1 mm accuracy for each sample, corresponding to a 0.39% and 0.78% measurement error, respectively, for the aforementioned samples.

Improving the Reading Skills of Young People with Duchenne Muscular Dystrophy in Preparation for Adulthood

ERIC Educational Resources Information Center

Hoskin, Janet; Fawcett, Angela

2014-01-01

Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34…

More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1995-11-06

This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

Context-Aided Tracking with Adaptive Hyperspectral Imagery

DTIC Science & Technology

2011-06-01

narrow spectral bands (e). . . . . . . . . . . . . . . . . . . . . 14 ix Figure Page 2.2. An illustration of a small portion of a digital micromirror ...incorporates two light paths: imaging and spectroscopy. Each pixel is steered towards a light path indepen- dently via the digital micromirror device (DMD...With the advent of digital micromirror device (DMD) arrays (DMA), the Rochester Institute of Technology Multi-Object Spectrometer (RITMOS) [36

A new type of density-management diagram for slash pine plantations

Treesearch

Curtis L. VanderSchaaf

2006-01-01

Many Density-Management Diagrams (DMD) have been developed for conifer species throughout the world based on stand density index (SDI). The diagrams often plot the logarithm of average tree size (volume, weight, or quadratic mean diameter) over the logarithm of trees per unit area. A new type of DMD is presented for slash pine (Pinus elliottii var elliottii)...

Loss of miR-29 in Myoblasts Contributes to Dystrophic Muscle Pathogenesis

PubMed Central

Wang, Lijun; Zhou, Liang; Jiang, Peiyong; Lu, Leina; Chen, Xiaona; Lan, Huiyao; Guttridge, Denis C; Sun, Hao; Wang, Huating

2012-01-01

microRNAs (miRNAs) are noncoding RNAs that regulate gene expression in post-transcriptional fashion, and emerging studies support their importance in a multitude of physiological and pathological processes. Here, we describe the regulation and function of miR-29 in Duchenne muscular dystrophy (DMD) and its potential use as therapeutic target. Our results demonstrate that miR-29 expression is downregulated in dystrophic muscles of mdx mice, a model of DMD. Restoration of its expression by intramuscular and intravenous injection improved dystrophy pathology by both promoting regeneration and inhibiting fibrogenesis. Mechanistic studies revealed that loss of miR-29 in muscle precursor cells (myoblasts) promotes their transdifferentiation into myofibroblasts through targeting extracellular molecules including collagens and microfibrillar-associated protein 5 (Mfap5). We further demonstrated that miR-29 is under negative regulation by transforming growth factor-β (TGF-β) signaling. Together, these results not only identify TGF-β–miR-29 as a novel regulatory axis during myoblasts conversion into myofibroblasts which constitutes a novel contributing route to muscle fibrogenesis of DMD but also implicate miR-29 replacement therapy as a promising treatment approach for DMD. PMID:22434133

Exon skipping and gene transfer restore dystrophin expression in human induced pluripotent stem cells-cardiomyocytes harboring DMD mutations.

PubMed

Dick, Emily; Kalra, Spandan; Anderson, David; George, Vinoj; Ritso, Morten; Laval, Steven H; Barresi, Rita; Aartsma-Rus, Annemieke; Lochmüller, Hanns; Denning, Chris

2013-10-15

With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47-50 or 48-50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart.

COUP-TFII regulates satellite cell function and muscular dystrophy.

PubMed

Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer

2016-10-03

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease's pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII-overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

1.5% root-mean-square flat-intensity laser beam formed using a binary-amplitude spatial light modulator.

PubMed

Liang, Jinyang; Kohn, Rudolph N; Becker, Michael F; Heinzen, Daniel J

2009-04-01

We demonstrate a digital micromirror device (DMD)-based optical system that converts a spatially noisy quasi-Gaussian to an eighth-order super-Lorentzian flat-top beam. We use an error-diffusion algorithm to design the binary pattern for the Texas Instruments DLP device. Following the DMD, a telescope with a pinhole low-pass filters the beam and scales it to the desired sized image. Experimental measurements show a 1% root-mean-square (RMS) flatness over a diameter of 0.28 mm in the center of the flat-top beam and better than 1.5% RMS flatness over its entire 1.43 mm diameter. The power conversion efficiency is 37%. We develop an alignment technique to ensure that the DMD pattern is correctly positioned on the incident beam. An interferometric measurement of the DMD surface flatness shows that phase uniformity is maintained in the output beam. Our approach is highly flexible and is able to produce not only flat-top beams with different parameters, but also any slowly varying target beam shape. It can be used to generate the homogeneous optical lattice required for Bose-Einstein condensate cold atom experiments.

Exon Skipping and Gene Transfer Restore Dystrophin Expression in Human Induced Pluripotent Stem Cells-Cardiomyocytes Harboring DMD Mutations

PubMed Central

Dick, Emily; Kalra, Spandan; Anderson, David; George, Vinoj; Ritso, Morten; Laval, Steven H.; Barresi, Rita; Aartsma-Rus, Annemieke; Lochmüller, Hanns

2013-01-01

With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47–50 or 48–50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart. PMID:23829870

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Chao; Lignell, David O.; Hawkes, Evatt R.

Here, the effect of differential molecular diffusion (DMD) in turbulent non-premixed flames is studied by examining two previously reported DNS of temporally evolving planar jet flames, one with CO/H 2 as the fuel and the other with C 2H 4 as the fuel. The effect of DMD in the CO/H 2 DNS flames in which H 2 is part of fuel is found to behave similar to laminar flamelet, while in the C 2H 4 DNS flames in which H 2 is not present in the fuel it is similar to laminar flamelet in early stages but becomes different frommore » laminar flamelet later. The scaling of the effect of DMD with respect to the Reynolds number Re is investigated in the CO/H 2 DNS flames, and an evident power law scaling (~Re –a with a a positive constant) is observed. The scaling of the effect of DMD with respect to the Damkohler number Da is explored in both laminar counter-flow jet C 2H 4 diffusion flames and the C 2H 4 DNS flames. A power law scaling (~ Daa with a a positive constant) is clearly demonstrated for C 2H 4 nonpremixed flames.« less

Dynamic spatial filtering using a digital micromirror device for high-speed optical diffraction tomography.

PubMed

Jin, Di; Zhou, Renjie; Yaqoob, Zahid; So, Peter T C

2018-01-08

Optical diffraction tomography (ODT) is an emerging microscopy technique for three-dimensional (3D) refractive index (RI) mapping of transparent specimens. Recently, the digital micromirror device (DMD) based scheme for angle-controlled plane wave illumination has been proposed to improve the imaging speed and stability of ODT. However, undesired diffraction noise always exists in the reported DMD-based illumination scheme, which leads to a limited contrast ratio of the measurement fringe and hence inaccurate RI mapping. Here we present a novel spatial filtering method, based on a second DMD, to dynamically remove the diffraction noise. The reported results illustrate significantly enhanced image quality of the obtained interferograms and the subsequently derived phase maps. And moreover, with this method, we demonstrate mapping of 3D RI distribution of polystyrene beads as well as biological cells with high accuracy. Importantly, with the proper hardware configuration, our method does not compromise the 3D imaging speed advantage promised by the DMD-based illumination scheme. Specifically, we have been able to successfully obtain interferograms at over 1 kHz speed, which is critical for potential high-throughput label-free 3D image cytometry applications.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management

PubMed Central

Birnkrant, David J; Bushby, Katharine; Bann, Carla M; Apkon, Susan D; Blackwell, Angela; Brumbaugh, David; Case, Laura E; Clemens, Paula R; Hadjiyannakis, Stasia; Pandya, Shree; Street, Natalie; Tomezsko, Jean; Wagner, Kathryn R; Ward, Leanne M; Weber, David R

2018-01-01

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management. PMID:29395989

Assessing delay and lag in sagittal trunk control using a tracking task.

PubMed

Reeves, N Peter; Luis, Abraham; Chan, Elizabeth C; Sal Y Rosas, Victor G; Tanaka, Martin L

2018-05-17

Slower trunk muscle responses are linked to back pain and injury. Unfortunately, clinical assessments of spine function do not objectively evaluate this important attribute, which reflects speed of trunk control. Speed of trunk control can be parsed into two components: (1) delay, the time it takes to initiate a movement, and (2) lag, the time it takes to execute a movement once initiated. The goal of this study is to demonstrate a new approach to assess delay and lag in trunk control using a simple tracking task. Ten healthy subjects performed four blocks of six trials of trunk tracking in the sagittal plane. Delay and lag were estimated by modeling trunk control for predictable and unpredictable (control mode) trunk movements in flexion and extension (control direction) at movement amplitudes of 2°, 4°, and 6° (control amplitude). The main effect of control mode, direction, and amplitude of movement were compared between trial blocks to assess secondary influencers (e.g., fatigue). Only control mode was consistent across trial blocks with predictable movements being faster than unpredictable for both delay and lag. Control direction and amplitude effects on delay and lag were consistent across the first two trial blocks and less consistent in later blocks. Given the heterogeneity in the presentation of back pain, clinical assessment of trunk control should include different control modes, directions, and amplitudes. To reduce testing time and the influence of fatigue, we recommend six trials to assess trunk control. Copyright © 2018 Elsevier Ltd. All rights reserved.

NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.

PubMed

Zhang, Hongbo; Ryu, Dongryeol; Wu, Yibo; Gariani, Karim; Wang, Xu; Luan, Peiling; D'Amico, Davide; Ropelle, Eduardo R; Lutolf, Matthias P; Aebersold, Ruedi; Schoonjans, Kristina; Menzies, Keir J; Auwerx, Johan

2016-06-17

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals. Copyright © 2016, American Association for the Advancement of Science.

Comparison of acid-detergent lignin, alkaline-peroxide lignin, and acid-detergent insoluble ash as internal markers for predicting fecal output and digestibility by cattle offered bermudagrass hays of varying nutrient composition.

PubMed

Kanani, Juvenal; Philipp, Dirk; Coffey, Kenneth P; Kegley, Elizabeth B; West, Charles P; Gadberry, Shane; Jennings, John; Young, Ashley N; Rhein, Robert T

2014-01-13

The potential for acid-detergent insoluble ash (ADIA), alkaline-peroxide lignin (APL), and acid-detergent lignin (ADL) to predict fecal output (FO) and dry matter digestibility (DMD) by cattle offered bermudagrass [Cynodon dactylon (L.) Pers.] hays of different qualities was evaluated. Eight ruminally cannulated cows (594 ± 35.5 kg) were allocated randomly to 4 hay diets: low (L), medium low (ML), medium high (MH), and high (H) crude protein (CP) concentration (79, 111, 131, and 164 g CP/kg on a DM basis, respectively). Diets were offered in 3 periods with 2 diet replicates per period and were rotated across cows between periods. Cows were individually fed 20 g DM/kg of body weight in equal feedings at 08:00 and 16:00 h for a 10-d adaptation followed by a 5-d total fecal collection. Actual DM intake (DMI), DMD, and FO were determined based on hay offered, ort, and feces excreted. These components were then analyzed for ADL, APL, and ADIA concentration to determine marker recovery and marker-based estimates of FO and DMD. Forage DMI was affected by diet (P = 0.02), and DMI from MH and H was greater (P < 0.05) than from L. Apparent DMD tended (P = 0.08) to differ among diets while FO (P = 0.20) was not affected by diet treatments. Average ADL recovery (1.16) was greater (P < 0.05) than that of ADIA (1.03) and APL (1.06), but ADIA and APL did not differ (P = 0.42). Estimates of FO and DMD derived using APL and ADIA were not different (P ≥ 0.05) from total fecal collection while those using ADL differed (P < 0.05). There was no diet by marker interaction (P ≥ 0.22) for either FO or DMD. Acid-detergent insoluble ash and APL accurately predicted FO and DMD of cattle fed bermudagrass hay of varying nutrient composition. These internal markers may facilitate studies involving large numbers of animals and forages. Results from such studies may be used to develop improved equations to predict energy values of forages based on the relationship of dietary components to digestibility across a wide range of forages.

Evaluation of in vitro models for predicting acidosis risk of barley grain in finishing beef cattle.

PubMed

Anele, U Y; Swift, M-L; McAllister, T A; Galyean, M L; Yang, W Z

2015-10-01

Our objective was to develop a model to predict the acidosis potential of barley based on the in vitro batch culture incubation of 50 samples varying in bulk density, starch content, processing method, growing location, and agronomic practices. The model was an adaptation of the acidosis index (calculated from a combination of in situ and in vitro analyses and from several components of grain chemical composition) developed in Australia for use in the feed industry to estimate the potential for grains to increase the risk of ruminal acidosis. Of the independent variables considered, DM disappearance at 6 h of incubation (DMD6) using reduced-strength (20%) buffer in the batch culture accounted for 90.5% of the variation in the acidosis index with a root mean square error (RMSE) of 4.46%. To evaluate our model using independent datasets (derived from previous batch culture studies using full-strength [100%] buffer), we performed another batch culture study using full-strength buffer. The full-strength buffer model using in vitro DMD6 (DMD6-FS) accounted for 66.5% of the variation in the acidosis index with an RMSE of 8.30%. When the new full-strength buffer model was applied to 3 independent datasets to predict acidosis, it accounted for 20.1, 28.5, and 30.2% of the variation in the calculated acidosis index. Significant ( < 0.001) mean bias was evident in 2 of the datasets, for which the DMD6 model underpredicted the acidosis index by 46.9 and 5.73%. Ranking of samples from the most diverse independent dataset using the DMD6-FS model and the Black (2008) model (calculated using in situ starch degradation) indicated the relationship between the rankings using Spearman's rank correlation was negative (ρ = -0.30; = 0.059). When the reduced-strength buffer model was used, however, there were similarities in the acidosis index ranking of barley samples by the models as shown by the result of a correlation analysis between calculated (using the Australian model) and predicted (using the reduced-strength buffer DMD6 model) acidosis index (ρ = 0.67; < 0.001). Results suggest that our model, which is based on a reduced-strength buffer in vitro DMD6, has the potential to predict acidosis risk and can rank barley samples based on their acidotic risk. Nonetheless, the model would benefit from further refinement by expanding the database.

Group delay spread analysis of coupled-multicore fibers: A comparison between weak and tight bending conditions

NASA Astrophysics Data System (ADS)

Fujisawa, Takeshi; Saitoh, Kunimasa

2017-06-01

Group delay spread of coupled three-core fiber is investigated based on coupled-wave theory. The differences between supermode and discrete core mode models are thoroughly investigated to reveal applicability of both models for specific fiber bending condition. A macrobending with random twisting is taken into account for random modal mixing in the fiber. It is found that for weakly bent condition, both supermode and discrete core mode models are applicable. On the other hand, for strongly bent condition, the discrete core mode model should be used to account for increased differential modal group delay for the fiber without twisting and short correlation length, which were experimentally observed recently. Results presented in this paper indicate the discrete core mode model is superior to the supermode model for the analysis of coupled-multicore fibers for various bent condition. Also, for estimating GDS of coupled-multicore fiber, it is critically important to take into account the fiber bending condition.

Performance analysis of TCP traffic and its influence on ONU's energy saving in energy efficient TDM-PON

NASA Astrophysics Data System (ADS)

Alaelddin, Fuad Yousif Mohammed; Newaz, S. H. Shah; Lee, Joohyung; Uddin, Mohammad Rakib; Lee, Gyu Myoung; Choi, Jun Kyun

2015-12-01

The majority of the traffic over the Internet is TCP based, which is very sensitive to packet loss and delay. Existing research efforts in TDM-Passive Optical Networks (TDM-PONs) mostly evaluate energy saving and traffic delay performances under different energy saving solutions. However, to the best of our knowledge, how energy saving mechanisms could affect TCP traffic performance in TDM-PONs has hardly been studied. In this paper, by means of our state-of-art OPNET Modular based TDM-PON simulator, we evaluate TCP traffic delay, throughput, and Optical Network Unit (ONU) energy consumption performances in a TDM-PON where energy saving mechanisms are employed in ONUs. Here, we study the performances under commonly used energy saving mechanisms defined in standards for TDM-PONs: cyclic sleep and doze mode. In cyclic sleep mode, we evaluate the performances under two well-known sleep interval length deciding algorithms (i.e. fixed sleep interval (FSI) and exponential sleep interval deciding (ESID)) that an OLT uses to decide sleep interval lengths for an ONU. Findings in this paper put forward the strong relationship among TCP traffic delay, throughput and ONU energy consumption under different sleep interval lengths. Moreover, we reveal that under high TCP traffic, both FSI and ESID will end up showing similar delay, energy and throughput performance. Our findings also show that doze mode can offer better TCP throughput and delay performance at the price of consuming more energy than cyclic sleep mode. In addition, our results provide a glimpse on understanding at what point doze mode becomes futile in improving energy saving of an ONU under TCP traffic. Furthermore, in this paper, we highlight important research issues that should be studied in future research to maximize energy saving in TDM-PONs while meeting traffic Quality of Service requirements.

A density management diagram for Scots pine (Pinus sylvestris L.): A tool for assessing the forest's protective effect

Treesearch

Giorgio Vacchiano; Renzo Motta; James N. Long; John D. Shaw

2008-01-01

Density management diagrams (DMD) are graphical tools used in the design of silvicultural regimes in even-aged forests. They depict the relationship between stand density, average tree size, stand yield and dominant height, based upon relevant ecological and allometric relationships such as the self-thinning rule, the yield-density effect, and site index curves. DMD...

Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy

DTIC Science & Technology

2015-12-01

Amelioration of hyperbilirubinemia in Gunn rats after transplantation of human induced pluripotent stem cell -derived hepatocytes. Stem Cell Reports 2015...use of differentiated pluripotent stem cells as replacement therapy in treating disease. Science 2014; 345:1247391. 12. Nishikawa T, Bell A, Brooks...Award Number: W81XWH-11-1-0803 TITLE: Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy PRINCIPAL INVESTIGATOR

Modulating Calcium Signals to Boost AON Exon Skipping for DMD

DTIC Science & Technology

2016-10-01

RNA Seq analysis to identify mechanisms of activity and specificity in order to guide discovery of second-generation skipping drugs or combinations...with greater activity. 15. SUBJECT TERMS Exon skipping, Dantrolene, Calcium, Duchenne, Dytrophy, Dystrophin, anti-sense-oligonucleatide, DMD, RNA ...for a subset of very rare mutations. Finally, we hypothesize that by combining chemical genomics with RNA Seq analysis we can begin to identify

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

PubMed

Hooijmans, M T; Doorenweerd, N; Baligand, C; Verschuuren, J J G M; Ronen, I; Niks, E H; Webb, A G; Kan, H E

2017-01-01

To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24–month follow-up

PubMed Central

Doorenweerd, N.; Baligand, C.; Verschuuren, J. J. G. M.; Ronen, I.; Niks, E. H.; Webb, A. G.; Kan, H. E.

2017-01-01

Objectives To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Methods Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5–15.4 years) and 12 age-matched healthy controls (range: 5–14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. Results PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. Discussion and conclusion The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients. PMID:28763477

Surface EMG signals in very late-stage of Duchenne muscular dystrophy: a case study.

PubMed

Lobo-Prat, Joan; Janssen, Mariska M H P; Koopman, Bart F J M; Stienen, Arno H A; de Groot, Imelda J M

2017-08-29

Robotic arm supports aim at improving the quality of life for adults with Duchenne muscular dystrophy (DMD) by augmenting their residual functional abilities. A critical component of robotic arm supports is the control interface, as is it responsible for the human-machine interaction. Our previous studies showed the feasibility of using surface electromyography (sEMG) as a control interface to operate robotic arm supports in adults with DMD (22-24 years-old). However, in the biomedical engineering community there is an often raised skepticism on whether adults with DMD at the last stage of their disease have sEMG signals that can be measured and used for control. In this study sEMG signals from Biceps and Triceps Brachii muscles were measured for the first time in a 37 year-old man with DMD (Brooke 6) that lost his arm function 15 years ago. The sEMG signals were measured during maximal and sub-maximal voluntary isometric contractions and evaluated in terms of signal-to-noise ratio and co-activation ratio. Beyond the profound deterioration of the muscles, we found that sEMG signals from both Biceps and Triceps muscles were measurable in this individual, although with a maximum signal amplitude 100 times lower compared to sEMG from healthy subjects. The participant was able to voluntarily modulate the required level of muscle activation during the sub-maximal voluntary isometric contractions. Despite the low sEMG amplitude and a considerable level of muscle co-activation, simulations of an elbow orthosis using the measured sEMG as driving signal indicated that the sEMG signals of the participant had the potential to provide control of elbow movements. To the best of our knowledge this is the first time that sEMG signals from a man with DMD at the last-stage of the disease were measured, analyzed and reported. These findings offer promising perspectives to the use of sEMG as an intuitive and natural control interface for robotic arm supports in adults with DMD until the last stage of the disease.

SU-F-T-263: Dosimetric Characteristics of the Cine Acquisition Mode of An A-Si EPID

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bawazeer, O; Deb, P; Sarasanandarajah, S

2016-06-15

Purpose: To investigate the dosimetric characteristics of Varian a-Si-500 electronic portal imaging device (EPID) operated in cine mode particularly considering linearity with delivered dose, dose rate, field size, phantom thickness, MLC speed and common IMRT fields. Methods: The EPID that attached to a Varian Clinac 21iX linear accelerator, was irradiated with 6 and 18 MV using 600 MU/min. Image acquisition is controlled by the IAS3 software, Trigger delay was 6 ms, BeamOnDelay and FrameStartDelay were zero. Different frame rates were utilized. Cine mode response was calculated using MATLAB as summation of mean pixel values in a region of interest ofmore » the acquired images. The performance of cine mode was compared to integrated mode and dose measurements in water using CC13 ionization chamber. Results: Figure1 illustrates that cine mode has nonlinear response for small MU, when delivering 10 MU was about 0.5 and 0.64 for 6 and 18 MV respectively. This is because the missing acquired images that were calculated around four images missing in each delivery. With the increase MU the response became linear and comparable with integrated mode and ionization chamber within 2%. Figure 2 shows that cine mode has comparable response with integrated mode and ionization chamber within 2% with changing dose rate for 10 MU delivered. This indicates that the dose rate change has no effect on nonlinearity of cine mode response. Except nonlinearity, cine mode is well matched to integrated mode response within 2% for field size, phantom thickness, MLC speed dependences. Conclusion: Cine mode has similar dosimetric characteristics to integrated mode with open and IMRT fields, and the main limitation with cine mode is missing images. Therefore, the calibration of EPID images with this mode should be run with large MU, and when IMRT verification field has low MU, the correction for missing images are required.« less

Energy-saving EPON Bandwidth Allocation Algorithm Supporting ONU's Sleep Mode

NASA Astrophysics Data System (ADS)

Zhang, Yinfa; Ren, Shuai; Liao, Xiaomin; Fang, Yuanyuan

2014-09-01

A new bandwidth allocation algorithm was presented by combining merits of the IPACT algorithm and the cyclic DBA algorithm based on the DBA algorithm for ONU's sleep mode. Simulation results indicate that compared with the normal mode ONU, the ONU's sleep mode can save about 74% of energy. The new algorithm has a smaller average packet delay and queue length in the upstream direction. While in the downstream direction, the average packet delay of the new algorithm is less than polling cycle Tcycle and the average queue length is less than the product of Tcycle and the maximum link rate. The new algorithm achieves a better compromise between energy-saving and ensuring quality of service.

Longitudinal mode selection in a delay-line homogeneously broadened oscillator with a fast saturable amplifier.

PubMed

Fleyer, Michael; Horowitz, Moshe

2017-05-01

Homogeneously broadened delay-line oscillators such as lasers or optoelectronic oscillators (OEOs) can potentially oscillate in a large number of cavity modes that are supported by their amplifier bandwidth. In a continuous wave operating mode, the oscillating mode is selected between one or few cavity modes that experience the highest small-signal gain. In this manuscript, we show that the oscillation mode of a homogeneously broadened oscillator can be selected from a large number of modes in a frequency region that can be broader than the full width at half maximum of the effective cavity filter. The mode is selected by a short-time injection of an external signal into the oscillator. After the external signal is turned off, the oscillation is maintained in the selected mode even if this mode has a significantly lower small-signal gain than that of other cavity modes. The stability of the oscillation is obtained due to nonlinear saturation effect in the oscillator amplifier. We demonstrate, experimentally and theoretically, mode selection in a long cavity OEO. We could select any desired mode between 400 cavity modes while maintaining ultra-low phase noise in the selected mode and in the non-oscillating modes. No mode-hopping was observed during our maximum measurement duration of about 24 hours.

A new pro-migratory activity on human myogenic precursor cells for a synthetic peptide within the E domain of the mechano growth factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mills, Philippe; Lafreniere, Jean-Francois; Benabdallah, Basma Fattouma

2007-02-01

Duchenne muscular dystrophy (DMD) is an inherited disease that leads to progressive muscle wasting. Myogenic precursor cell transplantation is an approach that can introduce the normal dystrophin gene in the muscle fibers of the patients. Unfortunately, these myogenic precursor cells do not migrate well in the muscle and thus many injections have to be done to enable a good graft success. Recent reports have shown that there is extensive splicing of the IGF-1 gene in muscles. The MGF isoform contains a C-terminal 24 amino acids peptide in the E domain (MGF-Ct24E) that has intrinsic properties. It can promote the proliferationmore » while delaying the differentiation of C{sub 2}C{sub 12} cells. Here, we demonstrated that this synthetic peptide is a motogenic factor for human precursor myogenic cells in vitro and in vivo. Indeed, MGF-Ct24E peptide can modulate members of the fibrinolytic and metalloproteinase systems, which are implicated in the migration of myogenic cells. MGF-Ct24E peptide enhances the expression of u-PA, u-PAR and MMP-7 while reducing PAI-1 activity. Moreover, it has no effect on the gelatinases MMP-2 and -9. Those combined effects can favour cell migration. Finally, we present some results suggesting that the MGF-Ct24E peptide induces these cell responses through a mechanism that does not involve the IGF-1 receptor. Thus, this MGF-Ct24E peptide has a new pro-migratory activity on human myogenic precursor cells that may be helpful in the treatment of DMD. Those results reinforce the possibility that the IGF-1Ec isoform may produce an E domain peptide that can act as a cytokine.« less

Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients.

PubMed

Leborgne, Christian; Latournerie, Virginie; Boutin, Sylvie; Desgue, Diana; Quéré, Aliénor; Pignot, Elodie; Collaud, Fanny; Charles, Séverine; Simon Sola, Marcelo; Masat, Elisa; Jouen, Fabienne; Boyer, Olivier; Masurier, Carole; Mingozzi, Federico; Veron, Philippe

2018-03-16

Adeno-associated virus (AAV) vectors are promising candidates for gene therapy and have been explored as gene delivery vehicles in the treatment of Duchenne Muscular Dystrophy (DMD). Recent studies showed compelling evidence of therapeutic efficacy in large animal models following the intravenous delivery of AAV vectors expressing truncated forms of dystrophin. However, to translate these results to humans, careful assessment of the prevalence of anti-AAV neutralizing antibodies (NAbs) is needed, as presence of preexisting NABs to AAV in serum have been associated with a drastic diminution of vector transduction. Here we measured binding and neutralizing antibodies against AAV serotype 1, 2, and 8 in serum from children and young adults with DMD (n = 130). Results were compared with to age-matched healthy donors (HD, n = 113). Overall, approximately 54% of all subjects included in the study presented IgG to AAV2, 49% to AAV1, and 41% to AAV8. A mean of around 80% of IgG positive sera showed neutralizing activity with no statistical difference between DMD and HD. NAb titers for AAV2 were higher than AAV1, and AAV8 in both populations studied. Older DMD patients (13-24 years old) presented significantly lower anti-AAV8 IgG4 subclass. Anti-AAV antibodies were found to be decreased in DMD patients subjected to a 6-month course of corticosteroids and in subjects receiving a variety of immunosuppressive drugs including B cell targeting drugs. Longitudinal follow up of humoral responses to AAV over up to 6 years showed no change in antibody titers, suggesting that in this patient population, seroconversion is a rare event in humans. Copyright © 2018. Published by Elsevier Inc.

Diffusion-Tensor Imaging of Thigh Muscles in Duchenne Muscular Dystrophy: Correlation of Apparent Diffusion Coefficient and Fractional Anisotropy Values With Fatty Infiltration.

PubMed

Li, Gui Dian; Liang, Ying Yin; Xu, Ping; Ling, Jian; Chen, Ying Ming

2016-04-01

The purpose of this study is to investigate the correlation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values with fatty infiltration in the thigh muscles of patients with Duchenne muscular dystrophy (DMD) using diffusion-tensor imaging (DTI). Twenty-one boys with DMD were recruited. The grade of fatty infiltration and the ADC and FA values of four thigh muscles (rectus femoris, semitendinosus, sartorius, and gracilis) were measured, and the FA and ADC values were compared with the grade of fatty infiltration. Twenty age-matched healthy boys were enrolled as the control group. The differences in the ADC and FA values of the thigh muscles between patients with DMD and the control group were compared. The patients with DMD showed lower FA values and higher ADC values in all measured muscles when compared with the control group. The FA and ADC values were correlated with the grade of fatty infiltration. For the rectus femoris muscle, r = -0.753 and p = 0.007 for FA, and r = 0.685 and p = 0.001 for ADC. For the semitendinosus muscle, r = -0.621 and p = 0.041 for FA, and r = 0.705 and p = 0.021 for ADC. For the sartorius muscle, r = -0.662 and p = 0.027 for FA, and r = 0.701 and p = 0.017 for ADC. For the gracilis muscle, r = -0.618 and p = 0.043 for FA, and r = 0.695 and p = 0.022 for ADC. Damage to the thigh muscles in patients with DMD can be detected by ADC and FA values using DTI. DTI can be used to assess the severity of the disease.

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin.

PubMed

Lecompte, S; Abou-Samra, M; Boursereau, R; Noel, L; Brichard, S M

2017-07-01

Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN. Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes. ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog). ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.

The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy.

PubMed

Assereto, Stefania; Piccirillo, Rosanna; Baratto, Serena; Scudieri, Paolo; Fiorillo, Chiara; Massacesi, Manuela; Traverso, Monica; Galietta, Luis J; Bruno, Claudio; Minetti, Carlo; Zara, Federico; Gazzerro, Elisabetta

2016-08-01

Activation of the proteasome pathway is one of the secondary processes of cell damage, which ultimately lead to muscle degeneration and necrosis in Duchenne muscular dystrophy (DMD). In mdx mice, the proteasome inhibitor bortezomib up-regulates the membrane expression of members of the dystrophin complex and reduces the inflammatory reaction. However, chronic inhibition of the 26S proteasome may be toxic, as indicated by the systemic side-effects caused by this drug. Therefore, we sought to determine the components of the ubiquitin-proteasome pathway that are specifically activated in human dystrophin-deficient muscles. The analysis of a cohort of patients with genetically determined DMD or Becker muscular dystrophy (BMD) unveiled a selective up-regulation of the ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). The induction of TRIM32 was due to a transcriptional effect and it correlated with disease severity in BMD patients. In contrast, atrogin1 and muscle RING-finger protein-1 (MuRF-1), which are strongly increased in distinct types of muscular atrophy, were not affected by the DMD dystrophic process. Knock-out models showed that TRIM32 is involved in ubiquitination of muscle cytoskeletal proteins as well as of protein inhibitor of activated STAT protein gamma (Piasγ) and N-myc downstream-regulated gene, two inhibitors of satellite cell proliferation and differentiation. Accordingly, we showed that in DMD/BMD muscle tissue, TRIM32 induction was more pronounced in regenerating myofibers rather than in necrotic muscle cells, thus pointing out a role of this protein in the regulation of human myoblast cell fate. This finding highlights TRIM32 as a possible therapeutic target to favor skeletal muscle regeneration in DMD patients.

Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy.

PubMed

Terrill, Jessica R; Duong, Marisa N; Turner, Rufus; Le Guiner, Caroline; Boyatzis, Amber; Kettle, Anthony J; Grounds, Miranda D; Arthur, Peter G

2016-10-01

Duchenne Muscular Dystrophy (DMD) is a fatal skeletal muscle wasting disease presenting with excessive myofibre necrosis and increased inflammation and oxidative stress. In the mdx mouse model of DMD, homeostasis of the amino acid taurine is altered, and taurine administration drastically decreases muscle necrosis, dystropathology, inflammation and protein thiol oxidation. Since the severe pathology of the Golden Retriever Muscular Dystrophy (GRMD) dog model more closely resembles the human DMD condition, we aimed to assess the generation of oxidants by inflammatory cells and taurine metabolism in this species. In muscles of 8 month GRMD dogs there was an increase in the content of neutrophils and macrophages, and an associated increase in elevated myeloperoxidase, a protein secreted by neutrophils that catalyses production of the highly reactive hypochlorous acid (HOCl). There was also increased chlorination of tyrosines, a marker of HOCl generation, increased thiol oxidation of many proteins and irreversible oxidative protein damage. Taurine, which functions as an antioxidant by trapping HOCl, was reduced in GRMD plasma; however taurine was increased in GRMD muscle tissue, potentially due to increased muscle taurine transport and synthesis. These data indicate a role for HOCl generated by neutrophils in the severe dystropathology of GRMD dogs, which may be exacerbated by decreased availability of taurine in the blood. These novel data support continued research into the precise roles of oxidative stress and taurine in DMD and emphasise the value of the GRMD dogs as a suitable pre-clinical model for testing taurine as a therapeutic intervention for DMD boys. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.

PubMed

Pillers, D A; Fitzgerald, K M; Duncan, N M; Rash, S M; White, R A; Dwinnell, S J; Powell, B R; Schnur, R E; Ray, P N; Cibis, G W; Weleber, R G

1999-01-01

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.

Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice.

PubMed

Pietraszek-Gremplewicz, Katarzyna; Kozakowska, Magdalena; Bronisz-Budzynska, Iwona; Ciesla, Maciej; Mucha, Olga; Podkalicka, Paulina; Madej, Magdalena; Glowniak, Urszula; Szade, Krzysztof; Stepniewski, Jacek; Jez, Mateusz; Andrysiak, Kalina; Bukowska-Strakova, Karolina; Kaminska, Anna; Kostera-Pruszczyk, Anna; Jozkowicz, Alicja; Loboda, Agnieszka; Dulak, Jozef

2018-07-10

Muscle damage in Duchenne muscular dystrophy (DMD) caused by the lack of dystrophin is strongly linked to inflammation. Heme oxygenase-1 (HO-1; Hmox1) is an anti-inflammatory and cytoprotective enzyme affecting myoblast differentiation by inhibiting myomiRs. The role of HO-1 has not been so far well addressed in DMD. In dystrophin-deficient mdx mice, expression of Hmox1 in limb skeletal muscles and diaphragm is higher than in wild-type animals, being consistently elevated from 8 up to 52 weeks, both in myofibers and inflammatory leukocytes. Accordingly, HO-1 expression is induced in muscles of DMD patients. Pharmacological inhibition of HO-1 activity or genetic ablation of Hmox1 aggravates muscle damage and inflammation in mdx mice. Double knockout animals (Hmox1 -/- mdx) demonstrate impaired exercise capacity in comparison with mdx mice. Interestingly, in contrast to the effect observed in muscle fibers, in dystrophin-deficient muscle satellite cells (SCs) expression of Hmox1 is decreased, while MyoD, myogenin, and miR-206 are upregulated compared with wild-type counterparts. Mdx SCs demonstrate disturbed and enhanced differentiation, which is further intensified by Hmox1 deficiency. RNA sequencing revealed downregulation of Atf3, MafK, Foxo1, and Klf2 transcription factors, known to activate Hmox1 expression, as well as attenuation of nitric oxide-mediated cGMP-dependent signaling in mdx SCs. Accordingly, treatment with NO-donor induces Hmox1 expression and inhibits differentiation. Finally, differentiation of mdx SCs was normalized by CO, a product of HO-1 activity. Innovation and Conclusions: HO-1 is induced in DMD, and HO-1 inhibition aggravates DMD pathology. Therefore, HO-1 can be considered a therapeutic target to alleviate this disease. Antioxid. Redox Signal. 00, 000-000.

Why are some patients with Duchenne muscular dystrophy dying young: An analysis of causes of death in North East England.

PubMed

Van Ruiten, H J A; Marini Bettolo, C; Cheetham, T; Eagle, M; Lochmuller, H; Straub, V; Bushby, K; Guglieri, M

2016-11-01

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). Detailed information was available on 21 patients. Mean age of death in group 1 (17 patients) was 23.9 (14.4-39.5) years, in group 2 (4 patients) 14 (12.7-14.9) years. Causes of death in group 2 were acute pneumonia, cardiac arrest, acute respiratory distress and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy.

PubMed

Mercuri, Eugenio; Signorovitch, James Edward; Swallow, Elyse; Song, Jinlin; Ward, Susan J

2016-09-01

High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n = 25), moderate decline (n = 19), stable function (n = 37), and improving function (n = 15) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

[Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

PubMed

Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

2016-08-16

Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions. To describe the development of a scale to evaluate upper limb function (UL) in patients with DMD and SMA, and describe its validation process, which includes self-training for evaluators. The development of the scale included a review of published scales, an exploratory application of a pilot scale in healthy children and those with DMD, self-training of evaluators in applying the scale using a handbook and video tutorial, and assessment of a group of children with DMD and SMA using the final scale. Reliability was assessed using Cronbach and Kendall concordance and with intra and inter-rater test-retest, and validity with concordance and factorial analysis. A high level of reliability was observed, with high internal consistency (Cronbach α=0.97), and inter-rater (Kendall W=0.96) and intra-rater concordance (r=0.97 to 0.99). The validity was demonstrated by the absence of significant differences between results by different evaluators with an expert evaluator (F=0.023, P>.5), and by the factor analysis that showed that four factors account for 85.44% of total variance. This scale is a reliable and valid tool for assessing UL functionality in children with DMD and SMA. It is also easily implementable due to the possibility of self-training and the use of simple and inexpensive materials. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort.

PubMed

Vengalil, Seena; Preethish-Kumar, Veeramani; Polavarapu, Kiran; Mahadevappa, Manjunath; Sekar, Deepha; Purushottam, Meera; Thomas, Priya Treesa; Nashi, Saraswathi; Nalini, Atchayaram

2017-01-01

Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

Abundance and Distribution of Dimethylsulfoniopropionate Degradation Genes and the Corresponding Bacterial Community Structure at Dimethyl Sulfide Hot Spots in the Tropical and Subtropical Pacific Ocean

PubMed Central

Suzuki, Shotaro; Omori, Yuko; Wong, Shu-Kuan; Ijichi, Minoru; Kaneko, Ryo; Kameyama, Sohiko; Tanimoto, Hiroshi; Hamasaki, Koji

2015-01-01

Dimethylsulfoniopropionate (DMSP) is mainly produced by marine phytoplankton but is released into the microbial food web and degraded by marine bacteria to dimethyl sulfide (DMS) and other products. To reveal the abundance and distribution of bacterial DMSP degradation genes and the corresponding bacterial communities in relation to DMS and DMSP concentrations in seawater, we collected surface seawater samples from DMS hot spot sites during a cruise across the Pacific Ocean. We analyzed the genes encoding DMSP lyase (dddP) and DMSP demethylase (dmdA), which are responsible for the transformation of DMSP to DMS and DMSP assimilation, respectively. The averaged abundance (±standard deviation) of these DMSP degradation genes relative to that of the 16S rRNA genes was 33% ± 12%. The abundances of these genes showed large spatial variations. dddP genes showed more variation in abundances than dmdA genes. Multidimensional analysis based on the abundances of DMSP degradation genes and environmental factors revealed that the distribution pattern of these genes was influenced by chlorophyll a concentrations and temperatures. dddP genes, dmdA subclade C/2 genes, and dmdA subclade D genes exhibited significant correlations with the marine Roseobacter clade, SAR11 subgroup Ib, and SAR11 subgroup Ia, respectively. SAR11 subgroups Ia and Ib, which possessed dmdA genes, were suggested to be the main potential DMSP consumers. The Roseobacter clade members possessing dddP genes in oligotrophic subtropical regions were possible DMS producers. These results suggest that DMSP degradation genes are abundant and widely distributed in the surface seawater and that the marine bacteria possessing these genes influence the degradation of DMSP and regulate the emissions of DMS in subtropical gyres of the Pacific Ocean. PMID:25862229

Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy.

PubMed

Ponnusamy, Suriyan; Sullivan, Ryan D; You, Dahui; Zafar, Nadeem; He Yang, Chuan; Thiyagarajan, Thirumagal; Johnson, Daniel L; Barrett, Maron L; Koehler, Nikki J; Star, Mayra; Stephenson, Erin J; Bridges, Dave; Cormier, Stephania A; Pfeffer, Lawrence M; Narayanan, Ramesh

2017-07-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival. While castration of dystrophin and utrophin double mutant (mdx-dm) mice to mimic pre-pubertal nadir androgen condition resulted in premature death, maintenance of androgen levels extended the survival. Non-steroidal selective-AR modulator, GTx-026, which selectively builds muscle and bone was tested in X-linked muscular dystrophy mice (mdx). GTx-026 significantly increased body weight, lean mass and grip strength by 60-80% over vehicle-treated mdx mice. While vehicle-treated castrated mdx mice exhibited cardiopulmonary impairment and fibrosis of heart and lungs, GTx-026 returned cardiopulmonary function and intensity of fibrosis to healthy control levels. GTx-026 elicits its musculoskeletal effects through pathways that are distinct from dystrophin-regulated pathways, making AR agonists ideal candidates for combination approaches. While castration of mdx-dm mice resulted in weaker muscle and shorter survival, GTx-026 treatment increased the muscle mass, function and survival, indicating that androgens are important for extended survival. These preclinical results support the importance of androgens and the need for intervention with AR agonists to treat DMD-affected boys. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mean, covariance, and effective dimension of stochastic distributed delay dynamics

NASA Astrophysics Data System (ADS)

René, Alexandre; Longtin, André

2017-11-01

Dynamical models are often required to incorporate both delays and noise. However, the inherently infinite-dimensional nature of delay equations makes formal solutions to stochastic delay differential equations (SDDEs) challenging. Here, we present an approach, similar in spirit to the analysis of functional differential equations, but based on finite-dimensional matrix operators. This results in a method for obtaining both transient and stationary solutions that is directly amenable to computation, and applicable to first order differential systems with either discrete or distributed delays. With fewer assumptions on the system's parameters than other current solution methods and no need to be near a bifurcation, we decompose the solution to a linear SDDE with arbitrary distributed delays into natural modes, in effect the eigenfunctions of the differential operator, and show that relatively few modes can suffice to approximate the probability density of solutions. Thus, we are led to conclude that noise makes these SDDEs effectively low dimensional, which opens the possibility of practical definitions of probability densities over their solution space.

Influence of additive laser manufacturing parameters on surface using density of partially melted particles

NASA Astrophysics Data System (ADS)

Rosa, Benoit; Brient, Antoine; Samper, Serge; Hascoët, Jean-Yves

2016-12-01

Mastering the additive laser manufacturing surface is a real challenge and would allow functional surfaces to be obtained without finishing. Direct Metal Deposition (DMD) surfaces are composed by directional and chaotic textures that are directly linked to the process principles. The aim of this work is to obtain surface topographies by mastering the operating process parameters. Based on experimental investigation, the influence of operating parameters on the surface finish has been modeled. Topography parameters and multi-scale analysis have been used in order to characterize the DMD obtained surfaces. This study also proposes a methodology to characterize DMD chaotic texture through topography filtering and 3D image treatment. In parallel, a new parameter is proposed: density of particles (D p). Finally, this study proposes a regression modeling between process parameters and density of particles parameter.

DMD: a digital light processing application to projection displays

NASA Astrophysics Data System (ADS)

Feather, Gary A.

1989-01-01

Summary Revolutionary technologies achieve rapid product and subsequent business diffusion only when the in- ventors focus on technology application, maturation, and proliferation. A revolutionary technology is emerg- ing with micro-electromechanical systems (MEMS). MEMS are being developed by leveraging mature semi- conductor processing coupled with mechanical systems into complete, integrated, useful systems. The digital micromirror device (DMD), a Texas Instruments invented MEMS, has focused on its application to projec- tion displays. The DMD has demonstrated its application as a digital light processor, processing and produc- ing compelling computer and video projection displays. This tutorial discusses requirements in the projection display market and the potential solutions offered by this digital light processing system. The seminar in- cludes an evaluation of the market, system needs, design, fabrication, application, and performance results of a system using digital light processing solutions.

Systemic Delivery of Morpholinos to Skip Multiple Exons in a Dog Model of Duchenne Muscular Dystrophy.

PubMed

Maruyama, Rika; Echigoya, Yusuke; Caluseriu, Oana; Aoki, Yoshitsugu; Takeda, Shin'ichi; Yokota, Toshifumi

2017-01-01

Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (AONs) to splice out frame-disrupting parts of mRNA, restore the reading frame, and produce truncated yet functional proteins. Multiple exon skipping utilizing a cocktail of AONs can theoretically treat 80-90% of patients with Duchenne muscular dystrophy (DMD). The success of multiple exon skipping by the systemic delivery of a cocktail of AONs called phosphorodiamidate morpholino oligomers (PMOs) in a DMD dog model has made a significant impact on the development of therapeutics for DMD, leading to clinical trials of PMO-based drugs. Here, we describe the systemic delivery of a cocktail of PMOs to skip multiple exons in dystrophic dogs and the evaluation of the efficacies and toxicity in vivo.

Optical Evaluation of DMDs with UV-Grade FS, Sapphire, MgF2 Windows and Reflectance of Bare Devices

NASA Technical Reports Server (NTRS)

Quijada, Manuel A.; Heap, Sara; Travinsky, Anton; Vorobiev, Dmitry; Ninkov, Zoran; Raisanen, Alan; Roberto, Massimo

2016-01-01

Digital Micro-mirror Devices (DMDs) have been identified as an alternative to microshutter arrays for space-based multi-object spectrometers (MOS). Specifically, the MOS at the heart of a proposed Galactic Evolution Spectroscopic Explorer (GESE) that uses the DMD as a reprogrammable slit mask. Unfortunately, the protective borosilicate windows limit the use of DMDs in the UV and IR regimes, where the glass has insufficient throughput. In this work, we present our efforts to replace standard DMD windows with custom windows made from UV-grade fused silica, Low Absorption Optical Sapphire (LAOS) and magnesium fluoride. We present reflectance measurements of the antireflection coated windows and a reflectance study of the DMDs active area (window removed). Furthermore, we investigated the long-term stability of the DMD reflectance and recoating device with fresh Al coatings.

Ultra-fast quantitative imaging using ptychographic iterative engine based digital micro-mirror device

NASA Astrophysics Data System (ADS)

Sun, Aihui; Tian, Xiaolin; Kong, Yan; Jiang, Zhilong; Liu, Fei; Xue, Liang; Wang, Shouyu; Liu, Cheng

2018-01-01

As a lensfree imaging technique, ptychographic iterative engine (PIE) method can provide both quantitative sample amplitude and phase distributions avoiding aberration. However, it requires field of view (FoV) scanning often relying on mechanical translation, which not only slows down measuring speed, but also introduces mechanical errors decreasing both resolution and accuracy in retrieved information. In order to achieve high-accurate quantitative imaging with fast speed, digital micromirror device (DMD) is adopted in PIE for large FoV scanning controlled by on/off state coding by DMD. Measurements were implemented using biological samples as well as USAF resolution target, proving high resolution in quantitative imaging using the proposed system. Considering its fast and accurate imaging capability, it is believed the DMD based PIE technique provides a potential solution for medical observation and measurements.

DMD-based quantitative phase microscopy and optical diffraction tomography

NASA Astrophysics Data System (ADS)

Zhou, Renjie

2018-02-01

Digital micromirror devices (DMDs), which offer high speed and high degree of freedoms in steering light illuminations, have been increasingly applied to optical microscopy systems in recent years. Lately, we introduced DMDs into digital holography to enable new imaging modalities and break existing imaging limitations. In this paper, we will first present our progress in using DMDs for demonstrating laser-illumination Fourier ptychographic microscopy (FPM) with shotnoise limited detection. After that, we will present a novel common-path quantitative phase microscopy (QPM) system based on using a DMD. Building on those early developments, a DMD-based high speed optical diffraction tomography (ODT) system has been recently demonstrated, and the results will also be presented. This ODT system is able to achieve video-rate 3D refractive-index imaging, which can potentially enable observations of high-speed 3D sample structural changes.

Finite Element Analysis of Lamb Waves Acting within a Thin Aluminum Plate

DTIC Science & Technology

2007-09-01

signal to avoid time aliasing % LambWaveMode % lamb wave mode to simulate; use proper phase velocity curve % thickness % thickness of...analysis of the simulated signal response data demonstrated that elevated temperatures delay wave propagation, although the delays are minimal at the...Echo Techniques Ultrasonic NDE techniques are based on the propagation and reflection of elastic waves , with the assumption that damage in the

The reliability and validity of the Greenspan Social Emotional Growth Chart (GSEGC) in Israeli children with developmental delay and autism-A pilot study.

PubMed

Tede, Zoma; Ophir Cohen, Michal; Riskin, Arieh; Tirosh, Emanuel

2016-08-01

Healthy social-emotional development in early childhood is important as an indicator of general well-being and for positive outcome in later childhood. Therefore, screening for potential social emotional problems is valuable. Accurate, usable, and affordable screening tools have been especially difficult to develop. The cross cultural validity of a screening instrument should be assessed. The aim of the current study was to investigate the reliability and validity of the Greenspan social-emotional growth chart (GSEGC) in Israeli children of three diagnostic groups: (1) Autistic spectrum disorder (ASD) (2) Developmental language disorder (DLD) and (3) Developmental motor delay (DMD). An internal reliability of alpha of 0.95 for the GSEGC standardized for age score and of 0.78 for the sensory processing sub scores was found. A confirmatory factor analysis (CFA) using a 5-factor model confirmed an acceptable fit. Positive (62.86%) and negative (94.73%) predictive values also support the clinical usefulness of the GSEGC in identifying children at low risk for ASD. The GSEGC appears to be a promising tool for the screening of social emotional problems in early childhood. Further studies in different cultures are warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

Numerical modeling of deflagration mode in coaxial plasma guns

NASA Astrophysics Data System (ADS)

Sitaraman, Hariswaran; Raja, Laxminarayan

2012-10-01

Pulsed coaxial plasma guns have been used in several applications in the field of space propulsion, nuclear fusion and materials processing. These devices operate in two modes based on the delay between gas injection and breakdown initiation. Larger delay led to the plasma detonation mode where a compression wave in the form of a luminous front propagates from the breech to the muzzle. Shorter delay led to the more efficient deflagration mode characterized by a relatively diffuse plasma with higher resistivity. The overall physics of the discharge in the two modes of operation and in particular the latter remain relatively unexplored. Here we perform a computational modeling study by solving the non-ideal Magneto-hydrodynamics equations for the quasi-neutral plasma in the coaxial plasma gun. A finite volume formulation on an unstructured mesh framework with an implicit scheme is used to do stable computations. The final work will present details of important species in the plasma, particle energies and Mach number at the muzzle. A comparison of the plasma parameters will be made with the experiments reported in ref. [1]. [4pt] [1] F. R. Poehlmann et al., Phys. Plasmas 17, 123508 (2010)

High Information Capacity Quantum Imaging

DTIC Science & Technology

2014-09-19

single-pixel camera [41, 75]. An object is imaged onto a Digital Micromirror device ( DMD ), a 2D binary array of individually-addressable mirrors that...reflect light either to a single detector or a dump. Rows of the sensing matrix A consist of random, binary patterns placed sequentially on the DMD ...The single-pixel camera concept naturally adapts to imaging correlations by adding a second detector. Consider placing separate DMDs in the near-field

Feasibility Study of Compressive Sensing Underwater Imaging Lidar

DTIC Science & Technology

2014-03-28

Texas Instruments Digital Micromirror Devices development system. In addition, through these studies, the deficiencies and/or areas of lack...device, such as the Digital Micromirror Device (DMD), to spatially modulate the laser source that illuminates the target plane. The same binary patterns...Digital Micromirror Device (DMD) Applications," Proc. of SPIE, 2003, 4985, 14-25. [8] T. E. Giddings and J. J. Shirron, "Numerical Simulation of the

Review of Defense Display Research Programs

DTIC Science & Technology

2001-01-01

micromirror device (DMD) projection displays, or some future contender, such as organic light emitting diode displays (OLED)—will be installed via...Instruments (TI) digital micromirror device (DMD) technology, developed in an $11.3M research effort managed by the Air Force Research Laboratory from 1991...systems for simulator/trainer systems in the near-mid term and advanced cockpits in the far term. Such large area, curved display systems will require the

Optical transmission properties of an anisotropic defect cavity in one-dimensional photonic crystal

NASA Astrophysics Data System (ADS)

Ouchani, Noama; El Moussaouy, Abdelaziz; Aynaou, Hassan; El Hassouani, Youssef; El Boudouti, El Houssaine; Djafari-Rouhani, Bahram

2018-01-01

We investigate theoretically the possibility to control the optical transmission in the visible and infrared regions by a defective one dimensional photonic crystal formed by a combination of a finite isotropic superlattice and an anisotropic defect layer. The Green's function approach has been used to derive the reflection and the transmission coefficients, as well as the densities of states of the optical modes. We evaluate the delay times of the localized modes and we compare their behavior with the total densities of states. We show that the birefringence of an anisotropic defect layer has a significant impact on the behavior of the optical modes in the electromagnetic forbidden bands of the structure. The amplitudes of the defect modes in the transmission and the delay time spectrum, depend strongly on the position of the cavity layer within the photonic crystal. The anisotropic defect layer induces transmission zeros in one of the two components of the transmission as a consequence of a destructive interference of the two polarized waves within this layer, giving rise to negative delay times for some wavelengths in the visible and infrared light ranges. This property is a typical characteristic of the anisotropic photonic layer and is without analogue in their counterpart isotropic defect layers. This structure offers several possibilities for controlling the frequencies, transmitted intensities and the delay times of the optical modes in the visible and infrared regions. It can be a good candidate for realizing high-precision optical filters.

Tongue pressure during swallowing is decreased in patients with Duchenne muscular dystrophy.

PubMed

Hamanaka-Kondoh, Sato; Kondoh, Jugo; Tamine, Ken-Ichi; Hori, Kazuhiro; Fujiwara, Shigehiro; Maeda, Yoshinobu; Matsumura, Tsuyoshi; Yasui, Kumiko; Fujimura, Harutoshi; Sakoda, Saburo; Ono, Takahiro

2014-06-01

Although dysphagia is a life-threatening problem in patients with Duchenne muscular dystrophy (DMD), the pathophysiology of oral stage dysphagia is yet to be understood. The present study investigated the tongue motor deficit during swallowing in patients with DMD and its relationship with disease-specific palatal morphology. Tongue pressure during swallowing water was recorded in 11 male patients with DMD and 11 age- and sex-matched healthy subjects using an intra-oral sensor with five measuring points, and the state of tongue pressure production was compared between the groups. Palatal morphology was assessed by a non-contact three-dimensional scanner on maxillary plaster models. In patients with DMD, the normal sequential order of tongue-palate contact was lost and the maximal magnitude and integrated value of tongue pressure on the mid-anterior part of palate were smaller than those in healthy subjects. The width of the palate in patients was greater than that in healthy subjects and the depth of the palate in patients had a negative correlation with tongue pressure magnitude on the median palate. Our results suggested that the deteriorated tongue motor kinetics prevented tongue movement during swallowing that was appropriate for the depth of the palate and affects the state of tongue pressure production during swallowing. Copyright © 2014 Elsevier B.V. All rights reserved.

Histological effects of givinostat in boys with Duchenne muscular dystrophy.

PubMed

Bettica, Paolo; Petrini, Stefania; D'Oria, Valentina; D'Amico, Adele; Catteruccia, Michela; Pane, Marika; Sivo, Serena; Magri, Francesca; Brajkovic, Simona; Messina, Sonia; Vita, Gian Luca; Gatti, Barbara; Moggio, Maurizio; Puri, Pier Lorenzo; Rocchetti, Maurizio; De Nicolao, Giuseppe; Vita, Giuseppe; Comi, Giacomo P; Bertini, Enrico; Mercuri, Eugenio

2016-10-01

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

PubMed

Larcher, Thibaut; Lafoux, Aude; Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

2014-01-01

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Electrical impedance myography for the assessment of children with muscular dystrophy: a preliminary study

NASA Astrophysics Data System (ADS)

Rutkove, S. B.; Darras, B. T.

2013-04-01

Electrical impedance myography (EIM) provides a non-invasive approach for quantifying the severity of neuromuscular disease. Here we determine how well EIM data correlates to functional and ultrasound (US) measures of disease in children with Duchenne muscular dystrophy (DMD) and healthy subjects. Thirteen healthy boys, aged 2-12 years and 14 boys with DMD aged 4-12 years underwent both EIM and US measurements of deltoid, biceps, wrist flexors, quadriceps, tibialis anterior, and medial gastrocnemius. EIM measurements were performed with a custom-designed probe using a commercial multifrequency bioimpedance device. US luminosity data were quantified using a gray-scale analysis approach. Children also underwent the 6-minute walk test, timed tests and strength measurements. EIM and US data were combined across muscles. EIM 50 kHz phase was able to discriminate DMD children from healthy subjects with 98% accuracy. In the DMD patients, average EIM phase measurements also correlated well with standard functional measures. For example the 50 kHz phase correlated with the Northstar Ambulatory Assessment test (R = 0.83, p = 0.02). EIM 50 kHz phase and US correlated as well, with R = -0.79 (p < 0.001). These results show that EIM provides valuable objective measures Duchenne muscular dystrophy severity.

Polyplanar optical display electronics

NASA Astrophysics Data System (ADS)

DeSanto, Leonard; Biscardi, Cyrus

1997-07-01

The polyplanar optical display (POD) is a unique display screen which can be used with any projection source. The prototype ten inch display is two inches thick and has a matte black face which allows for high contrast images. The prototype being developed is a form, fit and functional replacement display for the B-52 aircraft which uses a monochrome ten-inch display. In order to achieve a long lifetime, the new display uses a 100 milliwatt green solid- state laser at 532 nm as its light source. To produce real- time video, the laser light is being modulated by a digital light processing (DLP) chip manufactured by Texas Instruments. In order to use the solid-state laser as the light source and also fit within the constraints of the B-52 display, the digital micromirror device (DMD) circuit board is removed from the Texas Instruments DLP light engine assembly. Due to the compact architecture of the projection system within the display chassis, the DMD chip is operated remotely from the Texas Instruments circuit board. We discuss the operation of the DMD divorced from the light engine and the interfacing of the DMD board with various video formats including the format specific to the B-52 aircraft. A brief discussion of the electronics required to drive the laser is also presented.

Examination of the effect of differential molecular diffusion in DNS of turbulent non-premixed flames

DOE PAGES

Han, Chao; Lignell, David O.; Hawkes, Evatt R.; ...

2017-02-09

Here, the effect of differential molecular diffusion (DMD) in turbulent non-premixed flames is studied by examining two previously reported DNS of temporally evolving planar jet flames, one with CO/H 2 as the fuel and the other with C 2H 4 as the fuel. The effect of DMD in the CO/H 2 DNS flames in which H 2 is part of fuel is found to behave similar to laminar flamelet, while in the C 2H 4 DNS flames in which H 2 is not present in the fuel it is similar to laminar flamelet in early stages but becomes different frommore » laminar flamelet later. The scaling of the effect of DMD with respect to the Reynolds number Re is investigated in the CO/H 2 DNS flames, and an evident power law scaling (~Re –a with a a positive constant) is observed. The scaling of the effect of DMD with respect to the Damkohler number Da is explored in both laminar counter-flow jet C 2H 4 diffusion flames and the C 2H 4 DNS flames. A power law scaling (~ Daa with a a positive constant) is clearly demonstrated for C 2H 4 nonpremixed flames.« less

A Streamlined Protocol for Molecular Testing of the DMD Gene within a Diagnostic Laboratory: A Combination of Array Comparative Genomic Hybridization and Bidirectional Sequence Analysis

PubMed Central

Marquis-Nicholson, Renate; Lai, Daniel; Love, Jennifer M.; Love, Donald R.

2013-01-01

Purpose. The aim of this study was to develop a streamlined mutation screening protocol for the DMD gene in order to confirm a clinical diagnosis of Duchenne or Becker muscular dystrophy in affected males and to clarify the carrier status of female family members. Methods. Sequence analysis and array comparative genomic hybridization (aCGH) were used to identify mutations in the dystrophin DMD gene. We analysed genomic DNA from six individuals with a range of previously characterised mutations and from eight individuals who had not previously undergone any form of molecular analysis. Results. We successfully identified the known mutations in all six patients. A molecular diagnosis was also made in three of the four patients with a clinical diagnosis who had not undergone prior genetic screening, and testing for familial mutations was successfully completed for the remaining four patients. Conclusion. The mutation screening protocol described here meets best practice guidelines for molecular testing of the DMD gene in a diagnostic laboratory. The aCGH method is a superior alternative to more conventional assays such as multiplex ligation-dependent probe amplification (MLPA). The combination of aCGH and sequence analysis will detect mutations in 98% of patients with the Duchenne or Becker muscular dystrophy. PMID:23476807

Provision and financing of assistive technology devices in Germany: a bureaucratic odyssey? The case of amyotrophic lateral sclerosis and Duchenne muscular dystrophy.

PubMed

Henschke, Cornelia

2012-05-01

The regulations for financing assistive technology devices (ATDs) are complex and fragmented and, thus, might influence adequate provision of these devices to people who need multiple ATDs. This study aims to explore and analyze patients' problems with the provision and financing of ATDs for the following two rare diseases: amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). A survey was conducted by means of semi-standardized questionnaires addressing the issues of coverage decisions for ATDs and problems with provision of ATDs. Information was retrieved from ALS (n=19) and DMD (n=14) patients. Conducted interviews were transcribed verbatim and analyzed using qualitative content analysis. Respondents experienced difficulties with the provision and financing of ATDs. They underlined problems such as long approval processes and a serious bureaucratic burden, which induced inadequate provision of ATDs. Experiences of ALS and DMD respondents frequently were similar, especially regarding financing decisions and the process of decision making by sickness funds. The results suggest that difficulties in receiving and financing ATDs are common problems among ALS and DMD patients. There is a need for an interdisciplinary approach in the provision of ATDs and their financing, which should be coordinated by case managers. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A two-dimensional location method based on digital micromirror device used in interactive projection systems

NASA Astrophysics Data System (ADS)

Chen, Liangjun; Ni, Kai; Zhou, Qian; Cheng, Xuemin; Ma, Jianshe; Gao, Yuan; Sun, Peng; Li, Yi; Liu, Minxia

2010-11-01

Interactive projection systems based on CCD/CMOS have been greatly developed in recent years. They can locate and trace the movement of a pen equipped with an infrared LED, and displays the user's handwriting or react to the user's operation in real time. However, a major shortcoming is that the location device and the projector are independent with each other, including both the optical system and the control system. This requires construction of two optical systems, calibration of the differences between the projector view and the camera view, and also synchronization between two control systems, etc. In this paper, we introduced a two-dimensional location method based on digital micro-mirror device (DMD). The DMD is used as the display device and the position detector in turn. By serially flipping the micro-mirrors on the DMD according to a specially designed scheme and monitoring the reflected light energy, the image spot of the infrared LED can be quickly located. By using this method, the same optical system as well as the DMD can be multiplexed for projection and location, which will reduce the complexity and cost of the whole system. Furthermore, this method can also achieve high positioning accuracy and sampling rates. The results of location experiments are given.

Optical Evaluation of Digital Micromirror Devices (DMDs) with UV-Grade Fused Silica, Sapphire, and Magnesium Fluoride Windows and Longterm Reflectance of Bare Devices

NASA Technical Reports Server (NTRS)

Quijada, Manuel A.; Travinsky, Anton; Vorobiev, Dmitry; Ninkov, Zoran; Raisanen, Alan; Robberto, Massimo; Heap, Sara

2016-01-01

Digital micromirror devices (DMDs) are commercial micro-electromechanical systems, consisting of millions of mirrors which can be individually addressed and tilted into one of two states (+/-12deg). These devices were developed to create binary patterns in video projectors, in the visible range. Commercially available DMDs are hermetically sealed and extremely reliable. Recently, DMDs have been identified as an alternative to microshutter arrays for space-based multi-object spectrometers (MOS). Specifically, the MOS at the heart of the proposed Galactic Evolution Spectroscopic Explorer (GESE) uses the DMD as a reprogrammable slit mask. Unfortunately, the protective borosilicate windows limit the use of DMDs in the UV and IR regimes, where the glass has insufficient throughput. In this work, we present our efforts to replace standard DMD windows with custom windows made from UV-grade fused silica, low-absorption optical sapphire (LAOS) and magnesium fluoride (MgF2). We present transmission measurements of the antireflection coated windows and the reflectance of bare (window removed) DMDs. Furthermore, we investigated the long-term stability of the DMD reflectance and experiments for coating DMD active area with a layer of pure aluminum (Al) to boost reflectance performance in the UV spectral range (200-400 nm).

Genetic correction of dystrophin deficiency and skeletal muscle remodeling in adult MDX mouse via transplantation of retroviral producer cells.

PubMed Central

Fassati, A; Wells, D J; Sgro Serpente, P A; Walsh, F S; Brown, S C; Strong, P N; Dickson, G

1997-01-01

Duchenne muscular dystrophy (DMD) is an X-linked, lethal disease caused by mutations of the dystrophin gene. No effective therapy is available, but dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. We have developed a strategy for efficient in vivo gene transfer of dystrophin cDNA into regenerating skeletal muscle. Retroviral producer cells, which release a vector carrying the therapeutically active dystrophin minigene, were mitotically inactivated and transplanted in adult nude/mdx mice. Transplantation of 3 x 10(6) producer cells in a single site of the tibialis anterior muscle resulted in the transduction of between 5.5 and 18% total muscle fibers. The same procedure proved also feasible in immunocompetent mdx mice under short-term pharmacological immunosuppression. Minidystrophin expression was stable for up to 6 mo and led to alpha-sarcoglycan reexpression. Muscle stem cells could be transduced in vivo using this procedure. Transduced dystrophic skeletal muscle showed evidence of active remodeling reminiscent of the genetic normalization process which takes place in female DMD carriers. Overall, these results demonstrate that retroviral-mediated dystrophin gene transfer via transplantation of producer cells is a valid approach towards the long-term goal of gene therapy of DMD. PMID:9239410

Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice.

PubMed

Lu-Nguyen, Ngoc B; Jarmin, Susan A; Saleh, Amer F; Popplewell, Linda; Gait, Michael J; Dickson, George

2015-08-01

The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD.

Optical evaluation of digital micromirror devices (DMDs) with UV-grade fused silica, sapphire, and magnesium fluoride windows and long-term reflectance of bare devices

NASA Astrophysics Data System (ADS)

Quijada, Manuel A.; Travinsky, Anton; Vorobiev, Dmitry; Ninkov, Zoran; Raisanen, Alan; Robberto, Massimo; Heap, Sara

2016-07-01

Digital micromirror devices (DMDs) are commercial micro-electromechanical systems, consisting of millions of mirrors which can be individually addressed and tilted into one of two states (+/-12°). These devices were developed to create binary patterns in video projectors, in the visible range. Commercially available DMDs are hermetically sealed and extremely reliable. Recently, DMDs have been identified as an alternative to microshutter arrays for space-based multi-object spectrometers (MOS). Specifically, the MOS at the heart of the proposed Galactic Evolution Spectroscopic Explorer (GESE) uses the DMD as a reprogrammable slit mask. Unfortunately, the protective borosilicate windows limit the use of DMDs in the UV and IR regimes, where the glass has insufficient throughput. In this work, we present our efforts to replace standard DMD windows with custom windows made from UV-grade fused silica, low-absorption optical sapphire (LAOS) and magnesium fluoride (MgF2). We present transmission measurements of the antireflection coated windows and the reflectance of bare (window removed) DMDs. Furthermore, we investigated the long-term stability of the DMD reflectance and experiments for coating DMD active area with a layer of pure aluminum (Al) to boost reflectance performance in the UV spectral range (200-400 nm).

Service system finance: implications for children with depression and manic depression.

PubMed

Glied, S; Neufeld, A

2001-06-15

An estimated 6.2% of children in the United States satisfy the criteria for a depression diagnosis, but approximately half of this group do not receive necessary treatment. Thus it is important to consider potential barriers to use through service system finance. This article reviews three major types of changes affecting access: parity legislation, managed care, and public contracting. How these developments will affect children with depression and manic depression (DMD) is unclear. To better understand the potential effects on children with DMD, this review uses new data from the Medical Expenditure Panel Survey to describe the service use patterns of this population. These children have higher levels of expenditures, higher rates of inpatient use, and higher rates of Medicaid payment than do other children with mental health diagnoses; they also are overrepresented among the costliest cases of mental illness in children. Children with DMD pay a relatively low out-of-pocket share, suggesting that parity efforts focusing only on copayments and deductibles will have little effect on the absolute out-of-pocket burden for these children. Because children with DMD are overrepresented among high utilizers of health services, health care rationing arrangements or techniques, such as utilization review and capitation, may place this population at particular risk.

Functional rescue of dystrophin-deficient mdx mice by a chimeric peptide-PMO.

PubMed

Yin, Haifang; Moulton, Hong M; Betts, Corinne; Merritt, Thomas; Seow, Yiqi; Ashraf, Shirin; Wang, Qingsong; Boutilier, Jordan; Wood, Matthew Ja

2010-10-01

Splice modulation using antisense oligonucleotides (AOs) has been shown to yield targeted exon exclusion to restore the open reading frame and generate truncated but partially functional dystrophin protein. This has been successfully demonstrated in dystrophin-deficient mdx mice and in Duchenne muscular dystrophy (DMD) patients. However, DMD is a systemic disease; successful therapeutic exploitation of this approach will therefore depend on effective systemic delivery of AOs to all affected tissues. We have previously shown the potential of a muscle-specific/arginine-rich chimeric peptide-phosphorodiamidate morpholino (PMO) conjugate, but its long-term activity, optimized dosing regimen, capacity for functional correction and safety profile remain to be established. Here, we report the results of this chimeric peptide-PMO conjugate in the mdx mouse using low doses (3 and 6 mg/kg) administered via a 6 biweekly systemic intravenous injection protocol. We show 100% dystrophin-positive fibers and near complete correction of the dystrophin transcript defect in all peripheral muscle groups, with restoration of 50% dystrophin protein over 12 weeks, leading to correction of the DMD pathological phenotype and restoration of muscle function in the absence of detectable toxicity or immune response. Chimeric muscle-specific/cell-penetrating peptides therefore represent highly promising agents for systemic delivery of splice-correcting PMO oligomers for DMD therapy.

Experimental measurement and numerical analysis of group velocity dispersion in cladding modes of an endlessly single-mode photonic crystal fiber

NASA Astrophysics Data System (ADS)

Baselt, Tobias; Taudt, Christopher; Nelsen, Bryan; Lasagni, Andrés. Fabián.; Hartmann, Peter

2017-06-01

The optical properties of the guided modes in the core of photonic crystal fibers (PCFs) can be easily manipulated by changing the air-hole structure in the cladding. Special properties can be achieved in this case such as endless singlemode operation. Endlessly single-mode fibers, which enable single-mode guidance over a wide spectral range, are indispensable in the field of fiber technology. A two-dimensional photonic crystal with a silica central core and a micrometer-spaced hexagonal array of air holes is an established method to achieve endless single-mode properties. In addition to the guidance of light in the core, different cladding modes occur. The coupling between the core and the cladding modes can affect the endlessly single-mode guides. There are two possible ways to determine the dispersion: measurement and calculation. We calculate the group velocity dispersion (GVD) of different cladding modes based on the measurement of the fiber structure parameters, the hole diameter and the pitch of a presumed homogeneous hexagonal array. Based on the scanning electron image, a calculation was made of the optical guiding properties of the microstructured cladding. We compare the calculation with a method to measure the wavelength-dependent time delay. We measure the time delay of defined cladding modes with a homemade supercontinuum light source in a white light interferometric setup. To measure the dispersion of cladding modes of optical fibers with high accuracy, a time-domain white-light interferometer based on a Mach-Zehnder interferometer is used. The experimental setup allows the determination of the wavelengthdependent differential group delay of light travelling through a thirty centimeter piece of test fiber in the wavelength range from VIS to NIR. The determination of the GVD using different methods enables the evaluation of the individual methods for characterizing the cladding modes of an endlessly single-mode fiber.

Influences of Duration of Inspiratory Effort, Respiratory Mechanics, and Ventilator Type on Asynchrony With Pressure Support and Proportional Assist Ventilation.

PubMed

Vasconcelos, Renata S; Sales, Raquel P; Melo, Luíz H de P; Marinho, Liégina S; Bastos, Vasco Pd; Nogueira, Andréa da Nc; Ferreira, Juliana C; Holanda, Marcelo A

2017-05-01

Pressure support ventilation (PSV) is often associated with patient-ventilator asynchrony. Proportional assist ventilation (PAV) offers inspiratory assistance proportional to patient effort, minimizing patient-ventilator asynchrony. The objective of this study was to evaluate the influence of respiratory mechanics and patient effort on patient-ventilator asynchrony during PSV and PAV plus (PAV+). We used a mechanical lung simulator and studied 3 respiratory mechanics profiles (normal, obstructive, and restrictive), with variations in the duration of inspiratory effort: 0.5, 1.0, 1.5, and 2.0 s. The Auto-Trak system was studied in ventilators when available. Outcome measures included inspiratory trigger delay, expiratory trigger asynchrony, and tidal volume (V T ). Inspiratory trigger delay was greater in the obstructive respiratory mechanics profile and greatest with a effort of 2.0 s (160 ms); cycling asynchrony, particularly delayed cycling, was common in the obstructive profile, whereas the restrictive profile was associated with premature cycling. In comparison with PSV, PAV+ improved patient-ventilator synchrony, with a shorter triggering delay (28 ms vs 116 ms) and no cycling asynchrony in the restrictive profile. V T was lower with PAV+ than with PSV (630 mL vs 837 mL), as it was with the single-limb circuit ventilator (570 mL vs 837 mL). PAV+ mode was associated with longer cycling delays than were the other ventilation modes, especially for the obstructive profile and higher effort values. Auto-Trak eliminated automatic triggering. Mechanical ventilation asynchrony was influenced by effort, respiratory mechanics, ventilator type, and ventilation mode. In PSV mode, delayed cycling was associated with shorter effort in obstructive respiratory mechanics profiles, whereas premature cycling was more common with longer effort and a restrictive profile. PAV+ prevented premature cycling but not delayed cycling, especially in obstructive respiratory mechanics profiles, and it was associated with a lower V T . Copyright © 2017 by Daedalus Enterprises.

Influence of feeding supplements of almond hulls and ensiled citrus pulp on the milk production, milk composition, and methane emissions of dairy cows.

PubMed

Williams, S R O; Chaves, A V; Deighton, M H; Jacobs, J L; Hannah, M C; Ribaux, B E; Morris, G L; Wales, W J; Moate, P J

2018-03-01

Almond hulls and citrus pulp have been fed to dairy cows with variable responses for milk production, but no information exists on their effect on enteric methane emissions. This experiment examined the effects of dietary supplementation with either almond hulls or ensiled citrus pulp on the milk yield, milk composition, and enteric methane emissions of dairy cows. Thirty-two Holstein dairy cows in mid lactation were offered 1 of 3 diets over a 28-d experiment. Twelve cows received a control (CON) diet, 10 cows a diet containing almond hulls (ALH), and 10 cows a diet containing ensiled citrus pulp (CIT). All cows were offered 6.0 kg of dry matter (DM)/d of crushed corn, 2.0 kg of DM/d of cold-pressed canola, and 0.2 kg of DM/d of a mineral mix. In addition, cows fed the CON diet were offered 14.5 kg of DM/d of alfalfa cubes; cows fed the ALH diet were offered 10.5 kg of DM/d of alfalfa cubes and 4.0 kg of DM/d of almond hulls; and cows on the CIT diet were offered 11.5 kg of DM/d of alfalfa cubes and 3.0 kg of DM/d of ensiled citrus pulp. Milk yield was measured daily and milk composition was measured on 4 d of each week. Individual cow methane emissions were measured by a sulfur hexafluoride tracer technique on d 24 to 28 of the experiment. The mean milk yield of cows fed the CON diet (27.4 kg/d) was greater than the mean milk yield of cows fed the ALH diet (24.6 kg/cow per day), whereas the mean milk yield of cows fed the CIT diet (26.2 kg/cow per day) was not different from the mean milk yield from cows fed the other 2 diets. Dietary treatment did not influence the concentrations of milk fat, protein, and lactose or fat yields, but the mean protein yield from cows fed the CON diet (0.87 kg/d) was greater than that from cows fed the ALH diet (0.78 kg/d) but not different to those fed the CIT diet (0.85 kg/d). In general, we found no differences in the proportion of individual fatty acids in milk. The mean pH of ruminal fluid from cows offered the CON diet was not different to the pH in the ruminal fluids of cows offered the ALH or the CIT diets. The mean methane emissions (g/d) and yields (g/kg of DM intake) were not influenced by dietary treatment. These findings indicate that, although almond hulls and ensiled citrus pulp can be used as a low-cost feed supplement, almond hulls did negatively affect milk production and neither inhibited enteric methane emissions. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A hybrid silicon membrane spatial light modulator for optical information processing

NASA Technical Reports Server (NTRS)

Pape, D. R.; Hornbeck, L. J.

1984-01-01

A new two dimensional, fast, analog, electrically addressable, silicon based membrane spatial light modulator (SLM) was developed for optical information processing applications. Coherent light reflected from the mirror elements is phase modulated producing an optical Fourier transform of an analog signal input to the device. The DMD architecture and operating parameters related to this application are presented. A model is developed that describes the optical Fourier transform properties of the DMD.

Holographic Waveguide Array Rollable Display.

DTIC Science & Technology

1997-04-01

scale lithography for fabrication. Projection systems offer large images, in the range of 40 - 60 inches diagonal, and both front-view and rear-view...Boulder, CO, and a l-D array of digital micromirrors ( DMD ) from Texas Instruments. The linear format permits simple driving electronics and high...TI’s DMD , or a CMOS-SLM. A collimated laser beaming (combine three colors) or a collimated white light beam from a high intensity halogen lamp can be

"The Things That Are inside of You Are Horrible": Children and Young Men with Duchenne Muscular Dystrophy Talk about the Impact of Living with a Long-Term Condition

ERIC Educational Resources Information Center

Abbott, David; Carpenter, John

2015-01-01

Duchenne muscular dystrophy (DMD) is an inherited, progressive and life-limiting neuromuscular disease that affects boys. During their lives, they experience a series of medical and surgical interventions. Research reported in this paper took place in England with 37 young men living with DMD and their families and explored their experiences of…

Pattern of deletions of the dystrophin gene in Mexican Duchenne/Becker muscular dystrophy patients: the use of new designed primers for the analysis of the major deletion "hot spot" region.

PubMed

Coral-Vazquez, R; Arenas, D; Cisneros, B; Peñaloza, L; Salamanca, F; Kofman, S; Mercado, R; Montañez, C

1997-06-13

We have analyzed 59 unrelated Mexican Duchenne/Becker muscular dystrophy patients (DMD/BMD) using PCR analysis of the 2 prone deletion regions in the DMD gene. Thirty one (52%) of the patients had a deletion of one or several of the exons. Most of the alterations (87%) were clustered in exons 44-52, this being the highest percentage reported until now. In order to improve the molecular diagnosis in the Mexican population, we designed a new multiplex assay to PCR amplify exons 44-52. This assay allowed for the identification of a greater number of deletions in this region compared with the 9 and 5-plex assays previously described and to determine most of the deletion end boundaries. This is a reliable alternative for the initial screening of the DMD patients in the Mexican population.

Psychological Aspects in Children Affected by Duchenne De Boulogne Muscular Dystrophy

PubMed Central

Parisi, Lucia; Roccella, Michele

2014-01-01

Impairment of intelligence in Duchenne muscular dystrophy (DMD) patients was described by Duchenne de Boulogne himself in 1868. Further studies report intelligence disorders with mayor impairment of memory. The aim of the present study was to assess the presence of affective and personality disorders in a group of children affected by DMD. Twenty six male DMD patients, mean age eleven and four months years old, were assessed for their affective and personality disorder. Only eight subjects had a total IQ below average with major difficulties in verbal and visual-spatial memory, comprehension, arithmetic and vocabulary. All the subjects presented some disorders: tendency to marginalization and isolation, self-depreciation, sense of insecurity, hypochondriac thoughts and marked state of anxiety. These disorders are often a dynamic prolongation of a psychological process which starts when the diagnosis is made and continues, in a slow and latent fashion, throughout the evolution of the disease. PMID:25478112

Psychological aspects in children affected by duchenne de boulogne muscular dystrophy.

PubMed

Filippo, Teresa Di; Parisi, Lucia; Roccella, Michele

2012-07-26

Impairment of intelligence in Duchenne muscular dystrophy (DMD) patients was described by Duchenne de Boulogne himself in 1868. Further studies report intelligence disorders with mayor impairment of memory. The aim of the present study was to assess the presence of affective and personality disorders in a group of children affected by DMD. Twenty six male DMD patients, mean age eleven and four months years old, were assessed for their affective and personality disorder. Only eight subjects had a total IQ below average with major difficulties in verbal and visual-spatial memory, comprehension, arithmetic and vocabulary. All the subjects presented some disorders: tendency to marginalization and isolation, self-depreciation, sense of insecurity, hypochondriac thoughts and marked state of anxiety. These disorders are often a dynamic prolongation of a psychological process which starts when the diagnosis is made and continues, in a slow and latent fashion, throughout the evolution of the disease.

Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shomrat, R.; Gluck, E.; Legum, C.

1994-02-15

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and themore » remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.« less

CLINICAL FOLLOW-UP FOR DUCHENNE MUSCULAR DYSTROPHY NEWBORN SCREENING: A PROPOSAL

PubMed Central

KWON, JENNIFER M.; ABDEL-HAMID, HODA Z.; AL-ZAIDY, SAMIAH A.; MENDELL, JERRY R.; KENNEDY, ANNIE; KINNETT, KATHI; CWIK, VALERIE A.; STREET, NATALIE; BOLEN, JULIE; DAY, JOHN W.; CONNOLLY, ANNE M.

2017-01-01

New developments in the rapid diagnosis and treatment of boys with Duchenne muscular dystrophy (DMD) have led to growing enthusiasm for instituting DMD newborn screening (NBS) in the United States. Our group has been interested in developing clinical guidance to be implemented consistently in specialty care clinics charged with the care of presymptomatically identified newborns referred after DMD-NBS. We reviewed the existing literature covering patient-centered clinical follow-up after NBS, educational material from public health and advocacy sites, and federal recommendations on effective NBS follow-up. We discussed the review as a group and added our own experience to develop materials suitable for initial parent and primary care provider education. These materials and a series of templates for subspecialist encounters could be used to provide consistent care across centers and serve as the basis for ongoing quality improvement. PMID:27170260

High throughput dual-wavelength temperature distribution imaging via compressive imaging

NASA Astrophysics Data System (ADS)

Yao, Xu-Ri; Lan, Ruo-Ming; Liu, Xue-Feng; Zhu, Ge; Zheng, Fu; Yu, Wen-Kai; Zhai, Guang-Jie

2018-03-01

Thermal imaging is an essential tool in a wide variety of research areas. In this work we demonstrate high-throughput double-wavelength temperature distribution imaging using a modified single-pixel camera without the requirement of a beam splitter (BS). A digital micro-mirror device (DMD) is utilized to display binary masks and split the incident radiation, which eliminates the necessity of a BS. Because the spatial resolution is dictated by the DMD, this thermal imaging system has the advantage of perfect spatial registration between the two images, which limits the need for the pixel registration and fine adjustments. Two bucket detectors, which measures the total light intensity reflected from the DMD, are employed in this system and yield an improvement in the detection efficiency of the narrow-band radiation. A compressive imaging algorithm is utilized to achieve under-sampling recovery. A proof-of-principle experiment was presented to demonstrate the feasibility of this structure.

Generation of nondiffracting Bessel beam using digital micromirror device.

PubMed

Gong, Lei; Ren, Yu-Xuan; Xue, Guo-Sheng; Wang, Qian-Chang; Zhou, Jin-Hua; Zhong, Min-Cheng; Wang, Zi-Qiang; Li, Yin-Mei

2013-07-01

We experimentally demonstrated Bessel-like beams utilizing digital micromirror device (DMD). DMD with images imitating the equivalent axicon can shape the collimated Gaussian beam into Bessel beam. We reconstructed the 3D spatial field of the generated beam through a stack of measured cross-sectional images. The output beams have the profile of Bessel function after intensity modulation, and the beams extend at least 50 mm while the lateral dimension of the spot remains nearly invariant. Furthermore, the self-healing property has also been investigated, and all the experimental results agree well with simulated results numerically calculated through beam propagation method. Our observations demonstrate that the DMD offers a simple and efficient method to generate Bessel beams with distinct nondiffracting and self-reconstruction behaviors. The generated Bessel beams will potentially expand the applications to the optical manipulation and high-resolution fluorescence imaging owing to the unique nondiffracting property.

Kilohertz binary phase modulator for pulsed laser sources using a digital micromirror device.

PubMed

Hoffmann, Maximilian; Papadopoulos, Ioannis N; Judkewitz, Benjamin

2018-01-01

The controlled modulation of an optical wavefront is required for aberration correction, digital phase conjugation, or patterned photostimulation. For most of these applications, it is desirable to control the wavefront modulation at the highest rates possible. The digital micromirror device (DMD) presents a cost-effective solution to achieve high-speed modulation and often exceeds the speed of the more conventional liquid crystal spatial light modulator but is inherently an amplitude modulator. Furthermore, spatial dispersion caused by DMD diffraction complicates its use with pulsed laser sources, such as those used in nonlinear microscopy. Here we introduce a DMD-based optical design that overcomes these limitations and achieves dispersion-free high-speed binary phase modulation. We show that this phase modulation can be used to switch through binary phase patterns at the rate of 20 kHz in two-photon excitation fluorescence applications.

Digital micromirror device camera with per-pixel coded exposure for high dynamic range imaging.

PubMed

Feng, Wei; Zhang, Fumin; Wang, Weijing; Xing, Wei; Qu, Xinghua

2017-05-01

In this paper, we overcome the limited dynamic range of the conventional digital camera, and propose a method of realizing high dynamic range imaging (HDRI) from a novel programmable imaging system called a digital micromirror device (DMD) camera. The unique feature of the proposed new method is that the spatial and temporal information of incident light in our DMD camera can be flexibly modulated, and it enables the camera pixels always to have reasonable exposure intensity by DMD pixel-level modulation. More importantly, it allows different light intensity control algorithms used in our programmable imaging system to achieve HDRI. We implement the optical system prototype, analyze the theory of per-pixel coded exposure for HDRI, and put forward an adaptive light intensity control algorithm to effectively modulate the different light intensity to recover high dynamic range images. Via experiments, we demonstrate the effectiveness of our method and implement the HDRI on different objects.

Kilohertz binary phase modulator for pulsed laser sources using a digital micromirror device

NASA Astrophysics Data System (ADS)

Hoffmann, Maximilian; Papadopoulos, Ioannis N.; Judkewitz, Benjamin

2018-01-01

The controlled modulation of an optical wavefront is required for aberration correction, digital phase conjugation or patterned photostimulation. For most of these applications it is desirable to control the wavefront modulation at the highest rates possible. The digital micromirror device (DMD) presents a cost-effective solution to achieve high-speed modulation and often exceeds the speed of the more conventional liquid crystal spatial light modulator, but is inherently an amplitude modulator. Furthermore, spatial dispersion caused by DMD diffraction complicates its use with pulsed laser sources, such as those used in nonlinear microscopy. Here we introduce a DMD-based optical design that overcomes these limitations and achieves dispersion-free high-speed binary phase modulation. We show that this phase modulation can be used to switch through binary phase patterns at the rate of 20 kHz in two-photon excitation fluorescence applications.

DLP technolgy: applications in optical networking

NASA Astrophysics Data System (ADS)

Yoder, Lars A.; Duncan, Walter M.; Koontz, Elisabeth M.; So, John; Bartlett, Terry A.; Lee, Benjamin L.; Sawyers, Bryce D.; Powell, Donald; Rancuret, Paul

2001-11-01

For the past five years, Digital Light Processing (DLP) technology from Texas Instruments has made significant inroads in the projection display market. With products encompassing the world's smallest data & video projectors, HDTVs, and digital cinema, DLP is an extremely flexible technology. At the heart of these display solutions is Texas Instruments Digital Micromirror Device (DMD), a semiconductor-based light switch array of thousands of individually addressable, tiltable, mirror-pixels. With success of the DMD as a spatial light modulator in the visible regime, the use of DLP technology under the constraints of coherent, infrared light for optical networking applications is being explored. As a coherent light modulator, the DMD device can be used in Dense Wavelength Division Multiplexed (DWDM) optical networks to dynamically manipulate and shape optical signals. This paper will present the fundamentals of using DLP with coherent wavefronts, discuss inherent advantages of the technology, and present several applications for DLP in dynamic optical networks.

Clinical Follow-Up for Duchenne Muscular Dystrophy Newborn Screening: A Proposal.

PubMed

Kwon, Jennifer M; Abdel-Hamid, Hoda Z; Al-Zaidy, Samiah A; Mendell, Jerry R; Kennedy, Annie; Kinnett, Kathi; Cwik, Valerie A; Street, Natalie; Bolen, Julie; Day, John W; Connolly, Anne M

2016-08-01

New developments in the rapid diagnosis and treatment of boys with Duchenne muscular dystrophy (DMD) have led to growing enthusiasm for instituting DMD newborn screening (NBS) in the United States. Our group has been interested in developing clinical guidance to be implemented consistently in specialty care clinics charged with the care of presymptomatically identified newborns referred after DMD-NBS. We reviewed the existing literature covering patient-centered clinical follow-up after NBS, educational material from public health and advocacy sites, and federal recommendations on effective NBS follow-up. We discussed the review as a group and added our own experience to develop materials suitable for initial parent and primary care provider education. These materials and a series of templates for subspecialist encounters could be used to provide consistent care across centers and serve as the basis for ongoing quality improvement. Muscle Nerve 54: 186-191, 2016. © 2016 Wiley Periodicals, Inc.

Insights into skeletal muscle development and applications in regenerative medicine.

PubMed

Tran, T; Andersen, R; Sherman, S P; Pyle, A D

2013-01-01

Embryonic and postnatal development of skeletal muscle entails highly regulated processes whose complexity continues to be deconstructed. One key stage of development is the satellite cell, whose niche is composed of multiple cell types that eventually contribute to terminally differentiated myotubes. Understanding these developmental processes will ultimately facilitate treatments of myopathies such as Duchenne muscular dystrophy (DMD), a disease characterized by compromised cell membrane structure, resulting in severe muscle wasting. One theoretical approach is to use pluripotent stem cells in a therapeutic setting to help replace degenerated muscle tissue. This chapter discusses key myogenic developmental stages and their regulatory pathways; artificial myogenic induction in pluripotent stem cells; advantages and disadvantages of DMD animal models; and therapeutic approaches targeting DMD. Furthermore, skeletal muscle serves as an excellent paradigm for understanding general cell fate decisions throughout development. Copyright © 2013 Elsevier Inc. All rights reserved.

Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient.

PubMed

Greer, Kane; Mizzi, Kayla; Rice, Emily; Kuster, Lukas; Barrero, Roberto A; Bellgard, Matthew I; Lynch, Bryan J; Foley, Aileen Reghan; O Rathallaigh, Eoin; Wilton, Steve D; Fletcher, Sue

2015-07-01

We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45-47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient.

Observer-based robust finite time H∞ sliding mode control for Markovian switching systems with mode-dependent time-varying delay and incomplete transition rate.

PubMed

Gao, Lijun; Jiang, Xiaoxiao; Wang, Dandan

2016-03-01

This paper investigates the problem of robust finite time H∞ sliding mode control for a class of Markovian switching systems. The system is subjected to the mode-dependent time-varying delay, partly unknown transition rate and unmeasurable state. The main difficulty is that, a sliding mode surface cannot be designed based on the unknown transition rate and unmeasurable state directly. To overcome this obstacle, the set of modes is firstly divided into two subsets standing for known transition rate subset and unknown one, based on which a state observer is established. A component robust finite-time sliding mode controller is also designed to cope with the effect of partially unknown transition rate. It is illustrated that the reachability, finite-time stability, finite-time boundedness, finite-time H∞ state feedback stabilization of sliding mode dynamics can be ensured despite the unknown transition rate. Finally, the simulation results verify the effectiveness of robust finite time control problem. Copyright © 2015 ISA. Published by Elsevier Ltd. All rights reserved.

Locked-mode avoidance and recovery without momentum input

NASA Astrophysics Data System (ADS)

Delgado-Aparicio, L.; Rice, J. E.; Wolfe, S.; Cziegler, I.; Gao, C.; Granetz, R.; Wukitch, S.; Terry, J.; Greenwald, M.; Sugiyama, L.; Hubbard, A.; Hugges, J.; Marmar, E.; Phillips, P.; Rowan, W.

2015-11-01

Error-field-induced locked-modes (LMs) have been studied in Alcator C-Mod at ITER-Bϕ, without NBI fueling and momentum input. Delay of the mode-onset and locked-mode recovery has been successfully obtained without external momentum input using Ion Cyclotron Resonance Heating (ICRH). The use of external heating in-sync with the error-field ramp-up resulted in a successful delay of the mode-onset when PICRH > 1 MW, which demonstrates the existence of a power threshold to ``unlock'' the mode; in the presence of an error field the L-mode discharge can transition into H-mode only when PICRH > 2 MW and at high densities, avoiding also the density pump-out. The effects of ion heating observed on unlocking the core plasma may be due to ICRH induced flows in the plasma boundary, or modifications of plasma profiles that changed the underlying turbulence. This work was performed under US DoE contracts including DE-FC02-99ER54512 and others at MIT, DE-FG03-96ER-54373 at University of Texas at Austin, and DE-AC02-09CH11466 at PPPL.

Spectral modification of the laser emission of a terahertz quantum cascade laser induced by broad-band double pulse injection seeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Markmann, Sergej, E-mail: sergej.markmann@ruhr-uni-bochum.de; Nong, Hanond, E-mail: nong.hanond@ruhr-uni-bochum.de; Hekmat, Negar

2015-09-14

We demonstrate by injection seeding that the spectral emission of a terahertz (THz) quantum cascade laser (QCL) can be modified with broad-band THz pulses whose bandwidths are greater than the QCL bandwidth. Two broad-band THz pulses delayed in time imprint a modulation on the single THz pulse spectrum. The resulting spectrum is used to injection seed the THz QCL. By varying the time delay between the THz pulses, the amplitude distribution of the QCL longitudinal modes is modified. By applying this approach, the QCL emission is reversibly switched from multi-mode to single mode emission.

Early signs of gait deviation in Duchenne muscular dystrophy.

PubMed

Doglio, L; Pavan, E; Pernigotti, I; Petralia, P; Frigo, C; Minetti, C

2011-12-01

Most analytical studies found in literature only focus on specific aspects of Duchenne muscular dystrophy (DMD) gait and posture (joint range of motion, standing balance, variations of gait spatial-temporal parameters). Some of them analyze single cases and do not provide a comprehensive evaluation of locomotion. There are few studies about DMD gait patterns, most of them concerning small groups of patients, sometimes not homogeneous, in which the clinical manifestations of the next stages of DMD were present. The goal of our study was to analyze the characteristics of gait patterns in early stage patients, when clinical and functional evaluation do not allow to quantify initial walking worsening or to identify the changes adopted to compensate for muscle weakness. Gait Analysis Laboratory by using a six-camera motion capture system (Vicon, Oxford Metrics, UK), set at a sampling rate of 60 Hz. Subjects were asked to walk barefoot at their usual cadence, along a 10-m walkway, where one force platform (Kistler, Switzerland), embedded in the middle portion of the pathway, measured the foot-ground reaction forces. Retroreflective markers were placed on the subjects according to the protocol described in Davis et al. A group of 15 patients aging from 5 to 6.8 years was compared with a similar age control group composed of 9 healthy children. Spatial and temporal parameters showed significant differences between the two groups: cadence was increased and step length was decreased significantly in the DMD group. We found a significant increase in the range of anterior-posterior pelvic tilt and in pelvic rotation. In the frontal plane there was a tendency for an increased pelvic obliquity. Dynamic range of motion in sagittal plane showed a significant difference at the ankle, with an increased plantarflexion in swing in the dystrophic patients. Maximum dorsiflexion was reduced in the DMD group. Kinetic analysis showed significant differences in power generation and absorption at the hip joint and at the ankle joint. At knee there was a reduced flexor moment in mid-stance. Ankle showed a reduced dorsiflexor moment in terminal stance and pre-swing with a consequent reduction in the peak-to-peak excursion. It was shown that instrumented gait analysis, being more sensitive than other clinical and functional assessment methods, allowed to quantify the very early modifications characterizing locomotion worsening in the first stage of the DMD.

Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial.

PubMed

Hafner, Patricia; Bonati, Ulrike; Rubino, Daniela; Gocheva, Vanya; Zumbrunn, Thomas; Gueven, Nuri; Fischer, Dirk

2016-08-03

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests. A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children. The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration. ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013.

1 H NMRS of carnosine combined with 31 P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy.

PubMed

Reyngoudt, Harmen; Turk, Suna; Carlier, Pierre G

2018-01-01

In recent years, quantitative nuclear magnetic resonance imaging and spectroscopy (NMRI and NMRS) have been used more systematically as outcome measures in natural history and clinical trial studies for Duchenne muscular dystrophy (DMD). Whereas most of these studies have emphasized the evaluation of the fat fraction as an assessment for disease severity, less focus has been placed on metabolic indices measured by NMRS. 31 P NMRS in DMD reveals an alkaline inorganic phosphate (P i ) pool, originating from either leaky dystrophic myocytes or an increased interstitial space. 1 H NMRS, exploiting the pH-sensitive proton resonances of carnosine, an intracellular dipeptide, was used to distinguish between these two hypotheses. NMR data were obtained in 23 patients with DMD and 14 healthy subjects on a 3-T clinical NMR system. Both 31 P and 1 H NMRS data were acquired at the level of the gastrocnemius medialis muscle. A multi-slice multi-echo imaging acquisition was performed for the determination of water T 2 and fat fraction in the same region of interest. Whereas nearly all patients with DMD showed an elevated pH compared with healthy controls when using 31 P NMRS, 1 H NMRS-determined pH was not systematically increased. As expected, the carnosine-based intracellular pH was never found to be alkaline in the absence of a concurrent P i -based pH elevation. In addition, abnormal intracellular pH, based on carnosine, was never associated with normal water T 2 values. We conclude that, in one group of patients, both 1 H and 31 P NMRS showed an alkaline pH, originating from the intracellular compartment and reflecting ionic dysregulation in dystrophic myocytes. In the other patients with DMD, intracellular pH was normal, but an alkaline P i pool was still present, suggesting an extracellular origin, probably revealing an expanded interstitial volume fraction, often associated with fibrotic changes. The data demonstrate that 1 H NMRS could serve as a biomarker to assess the normalization of intramyocytic pH and sarcolemmal permeability following therapy inducing dystrophin expression in patients with DMD. Copyright © 2017 John Wiley & Sons, Ltd.

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study.

PubMed

Florian, Anca; Rösch, Sabine; Bietenbeck, Michael; Engelen, Markus; Stypmann, Jörg; Waltenberger, Johannes; Sechtem, Udo; Yilmaz, Ali

2016-03-01

Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)--in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003). Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement demonstrate the same myocardial fibrosis pattern as their male counterparts with overt disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Neural network topology in ADHD; evidence for maturational delay and default-mode network alterations.

PubMed

Janssen, T W P; Hillebrand, A; Gouw, A; Geladé, K; Van Mourik, R; Maras, A; Oosterlaan, J

2017-11-01

Attention-deficit/hyperactivity disorder (ADHD) has been associated with widespread brain abnormalities in white and grey matter, affecting not only local, but global functional networks as well. In this study, we explored these functional networks using source-reconstructed electroencephalography in ADHD and typically developing (TD) children. We expected evidence for maturational delay, with underlying abnormalities in the default mode network. Electroencephalograms were recorded in ADHD (n=42) and TD (n=43) during rest, and functional connectivity (phase lag index) and graph (minimum spanning tree) parameters were derived. Dependent variables were global and local network metrics in theta, alpha and beta bands. We found evidence for a more centralized functional network in ADHD compared to TD children, with decreased diameter in the alpha band (η p 2 =0.06) and increased leaf fraction (η p 2 =0.11 and 0.08) in the alpha and beta bands, with underlying abnormalities in hub regions of the brain, including default mode network. The finding of a more centralized network is in line with maturational delay models of ADHD and should be replicated in longitudinal designs. This study contributes to the literature by combining high temporal and spatial resolution to construct EEG network topology, and associates maturational-delay and default-mode interference hypotheses of ADHD. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

A new design of robust H∞ sliding mode control for uncertain stochastic T-S fuzzy time-delay systems.

PubMed

Gao, Qing; Feng, Gang; Xi, Zhiyu; Wang, Yong; Qiu, Jianbin

2014-09-01

In this paper, a novel dynamic sliding mode control scheme is proposed for a class of uncertain stochastic nonlinear time-delay systems represented by Takagi-Sugeno fuzzy models. The key advantage of the proposed scheme is that two very restrictive assumptions in most existing sliding mode control approaches for stochastic fuzzy systems have been removed. It is shown that the closed-loop control system trajectories can be driven onto the sliding surface in finite time almost certainly. It is also shown that the stochastic stability of the resulting sliding motion can be guaranteed in terms of linear matrix inequalities; moreover, the sliding-mode controller can be obtained simultaneously. Simulation results illustrating the advantages and effectiveness of the proposed approaches are also provided.

Developing a Field Artillery Training System Based on Devices and Simulations: Evaluation of Training Devices and Simulations

DTIC Science & Technology

1984-12-01

best trained by instruction alone or with simple demonstration materials. Training Devices are judged best for training the routine use of specific...pieces of equipment (e.g., Howitzer, BCS, DMD/FIST DMD, GLLD, LRF, map/compass/ plotting tools). Simulations are judged best for training more complex...at all phases of engagement operations. Simulations are also judged best for conducting training of any task under extreme environments and

Analysis of fatty infiltration and inflammation of the pelvic and thigh muscles in boys with Duchenne muscular dystrophy (DMD): grading of disease involvement on MR imaging and correlation with clinical assessments.

PubMed

Kim, Hee Kyung; Merrow, Arnold C; Shiraj, Sahar; Wong, Brenda L; Horn, Paul S; Laor, Tal

2013-10-01

Prior reports focus primarily on muscle fatty infiltration in Duchenne muscular dystrophy (DMD). However, the significance of muscle edema is uncertain. To evaluate the frequency and degree of muscle fat and edema, and correlate these with clinical function. Forty-two boys (ages 5-19 years) with DMD underwent pelvic MRI. Axial T1- and fat-suppressed T2-weighted images were evaluated to grade muscle fatty infiltration (0-4) and edema (0-3), respectively. Degree and frequency of disease involvement were compared to clinical evaluations. Gluteus maximus had the greatest mean fatty infiltration score, followed by adductor magnus and gluteus medius muscles, and had the most frequent and greatest degree of fatty infiltration. Gluteus maximus also had the greatest mean edema score, followed by vastus lateralis and gluteus medius muscles. These muscles had the most frequent edema, although the greatest degree of edema was seen in other muscles. There was correlation between cumulative scores of fatty infiltration and all clinical evaluations (P < 0.05). In DMD, the muscles with the most frequent fatty infiltration had the greatest degree of fatty infiltration and correlated with patient function. However, the muscles with the most frequent edema were different from those with the greatest degree of edema. Thus, edema may not predict patient functional status.

Non-uniform muscle fat replacement along the proximodistal axis in Duchenne muscular dystrophy.

PubMed

Hooijmans, M T; Niks, E H; Burakiewicz, J; Anastasopoulos, C; van den Berg, S I; van Zwet, E; Webb, A G; Verschuuren, J J G M; Kan, H E

2017-05-01

The progressive replacement of muscle tissue by fat in Duchenne muscular dystrophy (DMD) has been studied using quantitative MRI between, but not within, individual muscles. We studied fat replacement along the proximodistal muscle axis using the Dixon technique on a 3T MR scanner in 22 DMD patients and 12 healthy controls. Mean fat fractions per muscle per slice for seven lower and upper leg muscles were compared between and within groups assuming a parabolic distribution. Average fat fraction for a small central slice stack and a large coverage slice stack were compared to the value when the stack was shifted one slice (15 mm) up or down. Higher fat fractions were observed in distal and proximal muscle segments compared to the muscle belly in all muscles of the DMD subjects (p <0.001). A shift of 15 mm resulted in a difference in mean fat fraction which was on average 1-2% ranging up to 12% (p <0.01). The muscle end regions are exposed to higher mechanical strain, which points towards mechanical disruption of the sarcolemma as one of the key factors in the pathophysiology. Overall, this non-uniformity in fat replacement needs to be taken into account to prevent sample bias when applying quantitative MRI as biomarker in clinical trials for DMD. Copyright © 2017 Elsevier B.V. All rights reserved.

Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice.

PubMed

Kim, Jong-Hee; Lawler, John M

2012-05-01

Duchenne muscular dystrophy (DMD) is a common and devastating type of childhood-onset muscular dystrophy, attributed to an X-linked defect in the gene that encodes dystrophin. Myopathy with DMD is most pronounced in the diaphragm muscle and fast-twitch limb muscles and is dependent upon susceptibility to damage, inflammatory cell infiltration, and proinflammatory signaling (nuclear factor-κB; NF-κB). Although recent papers have reawakened the notion that oxidative stress links inflammatory signaling with pathology in DMD in limb muscle, the importance of redox mechanisms had been clouded by inconsistent results from indirect scavenger approaches, including in the diaphragm muscle. Therefore, we used a novel catalytic mimetic of superoxide dismutase and catalase (EUK-134) as a direct scavenger of oxidative stress in myopathy in the diaphragm of the mdx mouse model. EUK-134 reduced 4-hydroxynonenal and total hydroperoxides, markers of oxidative stress in the mdx diaphragm. EUK-134 also attenuated positive staining of macrophages and T-cells as well as activation of NF-κB and p65 protein abundance. Moreover, EUK-134 ameliorated markers of muscle damage including internalized nuclei, variability of cross-sectional area, and type IIc fibers. Finally, impairment of contractile force was partially rescued by EUK-134 in the diaphragm of mdx mice. We conclude that oxidative stress amplifies DMD pathology in the diaphragm muscle. Copyright © 2012 Elsevier Inc. All rights reserved.

Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy.

PubMed

Meng, Jinhong; Counsell, John R; Reza, Mojgan; Laval, Steven H; Danos, Olivier; Thrasher, Adrian; Lochmüller, Hanns; Muntoni, Francesco; Morgan, Jennifer E

2016-01-27

Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation.

Single DMD time-multiplexed 64-views autostereoscopic 3D display

NASA Astrophysics Data System (ADS)

Loreti, Luigi

2013-03-01

Based on previous prototype of the Real time 3D holographic display developed last year, we developed a new concept of auto-stereoscopic multiview display (64 views), wide angle (90°) 3D full color display. The display is based on a RGB laser light source illuminating a DMD (Discovery 4100 0,7") at 24.000 fps, an image deflection system made with an AOD (Acoustic Optic Deflector) driven by a piezo-electric transducer generating a variable standing acoustic wave on the crystal that acts as a phase grating. The DMD projects in fast sequence 64 point of view of the image on the crystal cube. Depending on the frequency of the standing wave, the input picture sent by the DMD is deflected in different angle of view. An holographic screen at a proper distance diffuse the rays in vertical direction (60°) and horizontally select (1°) only the rays directed to the observer. A telescope optical system will enlarge the image to the right dimension. A VHDL firmware to render in real-time (16 ms) 64 views (16 bit 4:2:2) of a CAD model (obj, dxf or 3Ds) and depth-map encoded video images was developed into the resident Virtex5 FPGA of the Discovery 4100 SDK, thus eliminating the needs of image transfer and high speed links

The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy.

PubMed

Dorchies, Olivier M; Reutenauer-Patte, Julie; Dahmane, Elyes; Ismail, Heham M; Petermann, Olivier; Patthey- Vuadens, Ophélie; Comyn, Sophie A; Gayi, Elinam; Piacenza, Tony; Handa, Robert J; Décosterd, Laurent A; Ruegg, Urs T

2013-02-01

Duchenne muscular dystrophy (DMD) is a severe disorder characterized by progressive muscle wasting,respiratory and cardiac impairments, and premature death. No treatment exists so far, and the identification of active substances to fight DMD is urgently needed. We found that tamoxifen, a drug used to treat estrogen-dependent breast cancer, caused remarkable improvements of muscle force and of diaphragm and cardiac structure in the mdx(5Cv) mouse model of DMD. Oral tamoxifen treatment from 3 weeks of age for 15 months at a dose of 10 mg/kg/day stabilized myofiber membranes, normalized whole body force, and increased force production and resistance to repeated contractions of the triceps muscle above normal values. Tamoxifen improved the structure of leg muscles and diminished cardiac fibrosis by~ 50%. Tamoxifen also reduced fibrosis in the diaphragm, while increasing its thickness,myofiber count, and myofiber diameter, thereby augmenting by 72% the amount of contractile tissue available for respiratory function. Tamoxifen conferred a markedly slower phenotype to the muscles.Tamoxifen and its metabolites were present in nanomolar concentrations in plasma and muscles,suggesting signaling through high-affinity targets. Interestingly, the estrogen receptors ERa and ERb were several times more abundant in dystrophic than in normal muscles, and tamoxifen normalized the relative abundance of ERb isoforms. Our findings suggest that tamoxifen might be a useful therapy for DMD.

Second-generation compound for the modulation of utrophin in the therapy of DMD

PubMed Central

Guiraud, Simon; Squire, Sarah E.; Edwards, Benjamin; Chen, Huijia; Burns, David T.; Shah, Nandini; Babbs, Arran; Davies, Stephen G.; Wynne, Graham M.; Russell, Angela J.; Elsey, David; Wilson, Francis X.; Tinsley, Jon M.; Davies, Kay E.

2015-01-01

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation. PMID:25935002

Virtual reality 3D headset based on DMD light modulators

NASA Astrophysics Data System (ADS)

Bernacki, Bruce E.; Evans, Allan; Tang, Edward

2014-06-01

We present the design of an immersion-type 3D headset suitable for virtual reality applications based upon digital micromirror devices (DMD). Current methods for presenting information for virtual reality are focused on either polarizationbased modulators such as liquid crystal on silicon (LCoS) devices, or miniature LCD or LED displays often using lenses to place the image at infinity. LCoS modulators are an area of active research and development, and reduce the amount of viewing light by 50% due to the use of polarization. Viewable LCD or LED screens may suffer low resolution, cause eye fatigue, and exhibit a "screen door" or pixelation effect due to the low pixel fill factor. Our approach leverages a mature technology based on silicon micro mirrors delivering 720p resolution displays in a small form-factor with high fill factor. Supporting chip sets allow rapid integration of these devices into wearable displays with high-definition resolution and low power consumption, and many of the design methods developed for DMD projector applications can be adapted to display use. Potential applications include night driving with natural depth perception, piloting of UAVs, fusion of multiple sensors for pilots, training, vision diagnostics and consumer gaming. Our design concept is described in which light from the DMD is imaged to infinity and the user's own eye lens forms a real image on the user's retina resulting in a virtual retinal display.

Effects of functional level on balance in children with Duchenne Muscular Dystrophy.

PubMed

Alkan, Halil; Mutlu, Akmer; Fırat, Tüzün; Bulut, Numan; Karaduman, Aynur Ayşe; Yılmaz, Öznur Tunca

2017-07-01

This study was planned to compare the static and dynamic balance in children with Duchenne Muscular Dystrophy (DMD) at different functional levels with each other and with healthy peers. Sixty nine children between the ages of 6 and 11 were included in this study where 52 of them were diagnosed with DMD in Level I (18 patients), Level II (17 patients), and Level III (17 patients) according to Brooke Functional Classification Scale and 17 of them healthy peers were included. In order to assess static and dynamic balance pediatric functional reach test (PFRT) and timed up and go test (TUGT) were used. When compared in terms of the TUGT, differences were found between all groups, i.e. Level 1 and 2, Level 2 and 3, Level 1 and 3, Healthy peers and Level 1, Healthy peers and Level 2, and Healthy peers and Level 3 (p < 0.0083). When compared in terms of the PFRT in the standing positions, there was difference between level 3 and healthy peers (p < 0.0083), but not between the other groups. We found poor functional level in DMD to affect the dynamic and static balance parameters in this study. The dynamic balance of a child with DMD at Level 3 is decreased to a third of a healthy peer. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Experimental evaluation of the optical quality of DMD SLM for its application as Fourier holograms displaying device

NASA Astrophysics Data System (ADS)

Molodtsov, D. Y.; Cheremkhin, P. A.; Krasnov, V. V.; Rodin, V. G.

2016-04-01

In this paper, the optical quality of micromirror DMD spatial light modulator (SLM) is evaluated and its applicability as an output device for holographic filters in dispersive correlators is analyzed. The possibility of using of DMD SLM extracted from consumer DLP-projector was experimentally evaluated by displaying of Fourier holograms. Software for displaying of holograms was developed. Experiments on holograms reconstruction was conducted with a different number of holograms pixels (and different placement on SLM). Reduction of number of pixels of output hologram (i.e. size of minimum resolvable element) led to improvement of reconstructed image quality. The evaluation shows that not every DMD-chip has acceptable optical quality for its application as display device for Fourier holograms. It was determined that major factor of reconstructed image quality degradation is a curvature of surface of SLM or its safety glass. Ranging hologram size allowed to estimate approximate size of sufficiently flat area of SLM matrix. For tested SLM it was about 1.5 mm. Further hologram size increase led to significant reconstructed image quality degradation. Developed and applied a technique allows to quickly estimate maximum size of holograms that can be displayed with specific SLM without significant degradation of reconstructed image. Additionally it allows to identify areas on the SLM with increased curvature of the surface.

The reasons for the high power density of fuel cells fabricated with directly deposited membranes

NASA Astrophysics Data System (ADS)

Vierrath, Severin; Breitwieser, Matthias; Klingele, Matthias; Britton, Benjamin; Holdcroft, Steven; Zengerle, Roland; Thiele, Simon

2016-09-01

In a previous study, we reported that polymer electrolyte fuel cells prepared by direct membrane deposition (DMD) produced power densities in excess of 4 W/cm2. In this study, the underlying origins that give rise to these high power densities are investigated and reported. The membranes of high power, DMD-fabricated fuel cells are relatively thin (12 μm) compared to typical benchmark, commercially available membranes. Electrochemical impedance spectroscopy, at high current densities (2.2 A/cm2) reveals that mass transport resistance was half that of reference, catalyst-coated-membranes (CCM). This is attributed to an improved oxygen supply in the cathode catalyst layer by way of a reduced propensity of flooding, and which is facilitated by an enhancement in the back diffusion of water from cathode to anode through the thin directly deposited membrane. DMD-fabricated membrane-electrode-assemblies possess 50% reduction in ionic resistance (15 mΩcm2) compared to conventional CCMs, with contributions of 9 mΩcm2 for the membrane resistance and 6 mΩcm2 for the contact resistance of the membrane and catalyst layer ionomer. The improved mass transport is responsible for 90% of the increase in power density of the DMD fuel cell, while the reduced ionic resistance accounts for a 10% of the improvement.

A comparison of control modes for time-delayed remote manipulation

NASA Technical Reports Server (NTRS)

Starr, G. P.

1982-01-01

Transmission time delay in the communication channel of a manual control system is investigated. A time delay can exist in remote manipulation systems, caused by long communication distances or bandwidth limitations. Ferrell 1 conducted the first research in time-delayed manipulation using a two degree-of-freedom manipulator. His subjects, working at time delays of 1.0, 2.1, and 3.2 s, could accomplish tasks even requiring great accuracy. The subjects spontaneously adopted a pattern of moving cautiously, then waiting to see the results of their actions. In experiments with a six degree-of-freedom master-slave manipulator system and time delays of 1.0 to 6 s, Black 2 saw that subjects tried to use the move-and-wait strategy; but there were often difficulties. The subjects seemed to have a problem in holding the master arm stationary while waiting for feedback. Any undesired drifting of the master arm introduced a discrepancy between the positions of the master and slave. This discrepancy was not perceived because of the time delay. The subject would then begin his next move with an inherent error. The difficulty of effectively using the move-and-wait strategy with a master-slave manipulator suggested that rate control might be a more effective control mode with time delay.

Evaluation of skeletal muscle DTI in patients with duchenne muscular dystrophy.

PubMed

Hooijmans, M T; Damon, B M; Froeling, M; Versluis, M J; Burakiewicz, J; Verschuuren, J J G M; Niks, E H; Webb, A G; Kan, H E

2015-11-01

Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and λ3 (p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and λ3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd.