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issn:0148-639
1.  ARCHITECTURE OF HEALTHY AND DYSTROPHIC MUSCLES DETECTED BY OPTICAL COHERENCE TOMOGRAPHY 
Muscle & nerve  2013;47(4):588-590.
Introduction
The ability to view individual myofibers is possible with many histological techniques, but not yet with standard in vivo imaging. Optical coherence tomography (OCT) is an emerging technology that can generate high resolution 1–10 μm cross-sectional imaging of tissue in vivo and in real time.
Methods
We used OCT to determine architectural differences of tibialis anterior muscles in situ from healthy mice (wild-type [WT], n = 4) and dystrophic mice (mdx, n = 4). After diffusion tensor imaging (DTI) and OCT, muscles were harvested, snap-frozen, and sectioned for staining with wheat germ agglutinin.
Results
DTI suggested differences in pennation and OCT was used to confirm this supposition. OCT indicated a shorter intramuscular tendon (WT/mdx ratio of 1.2) and an 18% higher degree of pennation in mdx. Staining confirmed these architectural changes.
Conclusions
Architectural changes in mdx muscles, which could contribute to reduction of force, are detectable with OCT.
doi:10.1002/mus.23711
PMCID: PMC4080712  PMID: 23381871
mdx; mouse imaging; muscular dystrophy; skeletal muscle; small animal imaging
2.  GENE AND CELL-MEDIATED THERAPIES FOR MUSCULAR DYSTROPHY 
Muscle & nerve  2013;47(5):649-663.
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, the most recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and non-viral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene.
doi:10.1002/mus.23738
PMCID: PMC4077844  PMID: 23553671
Duchenne muscular dystrophy; gene therapy; cell therapy; dystrophin; stem cells
3.  The effect of recombinant human MG53 protein on tourniquet-induced ischemia reperfusion injury in rat muscle 
Muscle & nerve  2014;49(6):919-921.
Introduction
Skeletal muscle ischemia reperfusion injury (I-R) is a complex injury process that includes damage to the sarcolemmal membrane, contributing to necrosis and apoptosis. MG53, a muscle-specific TRIM family protein, has been shown to be essential for regulating membrane repair and has been shown to be protective against cardiac I-R and various forms of skeletal muscle injury. The purpose of this study was to determine if recombinant human MG53 (rhMG53) administration offered protection against I-R.
Methods
rhMG53 was administered to rats immediately before tourniquet-induced ischemia and again immediately before reperfusion. Two days later muscle damage was assessed histologically.
Results
rhMG53 offered no protective effect, as evidenced primarily by similar Evans blue dye inclusion in the muscles of rats administered rhMG53 or saline.
Discussion
Administration of rhMG53 does not offer protection against I-R in rat skeletal muscle. Additional studies are required to determine if the lack of a response is species-specific.
doi:10.1002/mus.24160
PMCID: PMC4028410  PMID: 24395153
muscle injury; ischemia reperfusion; MG53; TRIM72; tourniquet
4.  An unusual cause of thenar hypertrophy and carpal tunnel syndrome 
Muscle & nerve  2012;45(2):296-297.
doi:10.1002/mus.22164
PMCID: PMC4020621  PMID: 22246891
Neuropathy; Nerve tumor; Median nerve; Carpal tunnel; Hypertrophy
5.  Androgen receptors in muscle fibers induce rapid loss of force but not mass: Implications for spinal bulbar muscular atrophy 
Muscle & nerve  2013;47(6):823-834.
Introduction
Testosterone (T) induces motor dysfunction in transgenic (Tg) mice overexpressing wild type androgen receptor (AR) in skeletal muscles. Since many genes implicated in motor neuron disease are expressed in skeletal muscles, mutant proteins may act in muscles to instigate muscle dysfunction in motor neuron disease.
Methods
We examined contractile properties of the extensor digitorum longus (EDL) and soleus (SOL) muscles in vitro after 5 and 3 days of T treatment in motor-impaired Tg female mice.
Results
Both muscles showed deficits in tetanic force after 5 days of T treatment, without losses in muscle mass, protein content, or fiber number. By 3 days of T treatment, only SOL showed a deficit in tetanic force comparable to that at 5 days of treatment. In both treatments, EDL shows slowed twitch kinetics, whereas SOL shows deficits in the twitch/tetanus ratio.
Conclusions
These results suggest calcium handling mechanisms in muscle fibers are defective in motor-impaired mice.
doi:10.1002/mus.23813
PMCID: PMC4015727  PMID: 23629944
testosterone; skeletal muscle; Kennedy’s disease; motor dysfunction; muscle dysfunction; neuromuscular disease
6.  Impaired regeneration in LGMD2A supported by increased Pax7 positive satellite cell content and muscle specific microRNA dysregulation 
Muscle & nerve  2013;47(5):731-739.
Introduction
Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, upregulation of miR-1 and miR-206 facilitates transition from proliferating SCs to differentiating myogenic progenitors.
Methods
We examined the histopathological stages, Pax7 SC content, and muscle specific microRNA expression in biopsy specimens from well-characterized LGMD 2A patients to gain insight into disease pathogenesis.
Results
Three distinct stages of pathological changes were identified that represented the continuum of the dystrophic process from prominent inflammation with necrosis and regeneration to prominent fibrosis, which correlated with age and disease duration. Pax7-positive SCs were highest in fibrotic group and correlated with down-regulation of miR-1, miR-133a, and miR-206.
Conclusions
These observations, and other published reports, are consistent with microRNA dysregulation leading to inability of Pax7-positive SCs to transit from proliferation to differentiation. This results in impaired regeneration and fibrosis.
doi:10.1002/mus.23669
PMCID: PMC3634894  PMID: 23553538
LGMD2A; Fibrosis; microRNA; Pax; muscle regeneration
7.  Lack of caspase-3 attenuates immobilization-induced muscle atrophy and loss of tension generation along with mitigation of apoptosis and inflammation 
Muscle & nerve  2013;47(5):711-721.
Introduction
Immobilization by casting induces disuse muscle atrophy (DMA).
Methods
Using wild type (WT) and caspase-3 knockout (KO) mice, we evaluated the effect of caspase-3 on muscle mass, apoptosis and inflammation during DMA.
Results
Caspase-3 deficiency significantly attenuated muscle mass decrease [gastrocnemius: 28 ± 1% in KO vs. 41 ± 3% in WT; soleus: 47 ± 2% in KO vs. 56 ± 2% in WT; (P < 0.05)] and gastrocnemius twitch tension decrease (23 ± 4% in KO vs. 36 ± 3% in WT, P < 0.05) at day 14 in immobilized versus contralateral hindlimb. Lack of caspase-3 decreased immobilization-induced increased apoptotic myonuclei (3.2-fold) and macrophage infiltration (2.2-fold) in soleus muscle and attenuated increased monocyte chemoattractant protein-1 mRNA expression (2-fold in KO vs. 18-fold in WT) in gastrocnemius.
Conclusion
Caspase-3 plays a key role in DMA and associated decreased tension, presumably by acting on the apoptosis and inflammation pathways.
doi:10.1002/mus.23642
PMCID: PMC3634903  PMID: 23401051
skeletal muscle; inflammation; caspase-3; immobilization; apoptosis
8.  A Novel Means of Clinical Assessment of Laryngeal Nerve Conduction 
Muscle & nerve  2013;47(3):432-436.
Introduction
We describe a novel, clinically applicable conduction study of the laryngeal nerves.
Methods
17 normal volunteer subjects were included. Activation of the sensory territory of the superior laryngeal nerve was performed by administration of low level, brief electrical stimulus. The laryngeal closure reflex (LCR) evoked by this stimulus was recorded by needle electrodes. Mean minimal latencies were calculated for each response, and proposed values for the upper limit of normal were determined.
Results
Uniform consistent early ipsilateral responses and late bilateral responses, which exhibit greater variation in latency and morphology, were recorded. Significant side-to-side difference in latencies is observed, consistent with the length discrepancy between right and left recurrent laryngeal nerves.
Discussion
This technique yields clear, quantifiable data regarding neurologic integrity of laryngeal function, heretofore unobtainable in the clinical setting. This study may yield clinically relevant information regarding severity and prognosis in patients with laryngeal neuropathic injury.
doi:10.1002/mus.23544
PMCID: PMC3996560  PMID: 23382050
Laryngeal electromyography; vagus nerve; laryngeal closure reflex; brainstem reflexes; neurolaryngology
9.  Anterior Tibialis CMAP Amplitude Correlations with Impairment in CMT1A 
Muscle & nerve  2013;47(4):493-496.
Introduction
CMT1A is a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A.
Objective
Determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A.
Methods
We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross-section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data.
Results
AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS.
Discussion
AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A.
doi:10.1002/mus.23614
PMCID: PMC3608739  PMID: 23456782
Neuropathy; Charcot-Marie-Tooth Disease (CMT); Outcome measure; Charcot-Marie-Tooth Neuropathy Score (CMTNS); Nerve Conduction Studies (NCS)
10.  FIBULAR MOTOR NERVE CONDUCTION STUDIES AND ANKLE SENSORIMOTOR CAPACITIES* 
Muscle & nerve  2012;47(4):497-503.
Introduction
Nerve conduction studies provide information regarding the status of the peripheral nerve, but relationships with sensorimotor capacities that influence mobility have not been defined.
Methods
A secondary analysis was conducted of data from 41 older subjects (20 women, age 69.1 ± 8.3 years), 25 with diabetic neuropathy of varying severity, and 16 without diabetes or neuropathy. Measurements included routine fibular motor nerve conduction studies and laboratory-based determination of ankle inversion/eversion proprioceptive thresholds and ankle inversion/eversion motor function.
Results
Independent of age, fibular amplitude correlated robustly with ankle inversion/eversion proprioceptive thresholds (R2 = .591, p < .001), moderately with ankle inversion and eversion rates of torque generation (R2 = .216; p = .004 and R2 = .200; p = .006, respectively), and more strongly when fibular motor amplitude was normalized for body mass index (R2 = .350; p < .001 and R2 = .275; p = .001).
Discussion
Fibular motor amplitude was strongly associated with ankle sensorimotor capacities that influence lateral balance and recovery from perturbations during gait. The results suggest that nerve conduction study measures have potential for an expanded clinical role in evaluating mobility function in the population studied.
doi:10.1002/mus.23618
PMCID: PMC3608755  PMID: 23225524
Age; Balance; Diabetic Neuropathy; Muscle Strength; Proprioception
11.  Soleus H-Reflex Operant Conditioning Changes The H-Reflex Recruitment Curve 
Muscle & nerve  2012;47(4):539-544.
Introduction
Operant conditioning can gradually change the human soleus H-reflex. The protocol conditions the reflex near M-wave threshold. This study examined its impact on the reflexes at other stimulus strengths.
Methods
H-reflex recruitment curves were obtained before and after a 24-session exposure to an up-conditioning (HRup) or down-conditioning (HRdown) protocol and were compared.
Results
In both HRup and HRdown subjects, conditioning affected the entire H-reflex recruitment curve. In 5 of 6 HRup and 3 of 6 HRdown subjects, conditioning elevated (HRup) or depressed (HRdown), respectively, the entire curve. In the other HRup subject or the other 3 HRdown subjects, the curve was shifted to the left or to the right, respectively.
Discussion
H-reflex conditioning does not simply change the H-reflex to a stimulus of particular strength; it also changes the H-reflexes to stimuli of different strengths. Thus, it is likely to affect many actions in which this pathway participates.
doi:10.1002/mus.23620
PMCID: PMC3608758  PMID: 23281107
plasticity; motor learning; memory; rehabilitation; spinal cord
12.  A TRIAL OF PROFICIENCY OF NERVE CONDUCTION: GREATER STANDARDIZATION STILL NEEDED 
Muscle & nerve  2013;48(3):369-374.
Introduction
The aim of this study was to test the proficiency (accuracy among evaluators) of measured attributes of nerve conduction (NC).
Methods
Expert clinical neurophysiologists, without instruction or consensus development, from 4 different medical centers, independently assessed 8 attributes of NC in 24 patients with diabetes mellitus (DM) on consecutive days.
Results
No significant intraobserver differences between days 1 and 2 were found, but significant interobserver differences were seen. Use of standard reference values did not correct for these observed differences.
Conclusions
Interobserver variability was attributed to differences in performance of NC. It was of sufficient magnitude that it is of concern for the conduct of therapeutic trials. To deal with interrater variability in therapeutic trials, the same electromyographers should perform all NC assessments of individual patients or, preferably, NC procedures should be more standardized. A further trial is needed to test whether such standardization would eliminate interobserver variability.
doi:10.1002/mus.23765
PMCID: PMC3966293  PMID: 23861198
clinical trial; diabetic sensorimotor polyneuropathy; nerve conduction; proficiency; standard reference value
13.  GLUTAMATE RECEPTORS LOCALIZE POSTSYNAPTICALLY AT NEUROMUSCULAR JUNCTIONS IN MICE 
Muscle & nerve  2009;39(3):343-349.
Dlg (Discs Large) is a multidomain protein that interacts with glutamate receptors and potassium channels at Drosophila neuromuscular junctions (NMJs) and at mammalian central nervous system synapses. Dlg also localizes postsynaptically at cholinergic mammalian NMJs. We show here that α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor subunits, together with glutamate, are present at the mammalian NMJ. Both AMPA and NMDA (N-methyl-D-aspartate) glutamate receptor subunits display overlapping postsynaptic localization patterns with Dlg at all NMJs examined in normal mice. Kir2 potassium channels also localize with Dlg and glutamate receptors at this synapse. Localization of the components of a glutamatergic system suggests novel mechanisms at mammalian neuromuscular synapses.
doi:10.1002/mus.21099
PMCID: PMC3959828  PMID: 19208409
Dlg/SAP97; AMPA; NMDA; Kir2; neuromuscular junction
14.  FATIGUE AND RECOVERY FROM DYNAMIC CONTRACTIONS IN MEN AND WOMEN DIFFER FOR ARM AND LEG MUSCLES 
Muscle & nerve  2013;48(3):436-439.
Introduction
Whether there is a gender difference in fatigue and recovery from maximal velocity fatiguing contractions and across muscles is not understood.
Methods
Sixteen men and 19 women performed 90 isotonic contractions at maximal voluntary shortening velocity (maximal velocity concentric contractions, MVCC) with the elbow flexor and knee extensor muscles (separate days) at a load equivalent to 20% maximal voluntary isometric contraction (MVIC).
Results
Power (from MVCCs) decreased similarly for men and women for both muscles (P > 0.05). Men and women had similar declines in MVIC of elbow flexors, but men had greater reductions in knee extensor MVIC force and MVIC electromyogram activity than women (P < 0.05). The decline in MVIC and power was greater, and force recovery was slower for the elbow flexors compared with knee extensors.
Conclusions
The gender difference in muscle fatigue often observed during isometric tasks was diminished during fast dynamic contractions for upper and lower limb muscles.
doi:10.1002/mus.23836
PMCID: PMC3951745  PMID: 23494882
elbow flexors; gender; knee extensors; sex differences; women
15.  Neuromuscular Ultrasound for Evaluation of the Diaphragm 
Muscle & nerve  2013;47(3):319-329.
Neuromuscular clinicians are often asked to evaluate the diaphragm for diagnostic and prognostic purposes. Traditionally, this evaluation is accomplished through history, physical exam, fluoroscopic sniff test, nerve conduction studies, and electromyography (EMG). Nerve conduction studies and EMG in this setting are challenging, uncomfortable, and can cause serious complications such as pneumothorax. Neuromuscular ultrasound has emerged as a non-invasive technique that can be used in the structural and functional assessment of the diaphragm. This article reviews different techniques for assessing the diaphragm using neuromuscular ultrasound and the application of these techniques to enhance diagnosis and prognosis by neuromuscular clinicians.
doi:10.1002/mus.23671
PMCID: PMC3581727  PMID: 23382111
diaphragm; ultrasound; electromyography; nerve conduction studies; phrenic nerve injury; respiratory failure
16.  POLYSIALIC ACID EXPRESSION IS NOT NECESSARY FOR MOTOR NEURON TARGET SELECTIVITY 
Muscle & nerve  2012;47(3):364-371.
Introduction
Recovery after peripheral nerve lesions depends on guiding axons back to their targets. Polysialic acid upregulation by regrowing axons has been proposed recently as necessary for this target selectivity.
Methods
We reexamined this proposition using a cross-reinnervation model whereby axons from obturator motor neurons that do not upregulate polysialic acid regenerated into the distal femoral nerve. Our aim was to assess their target selectivity between pathways to muscle and skin.
Results
After simple cross-repair, obturator motor neurons showed no pathway preference, but the same repair with a shortened skin pathway resulted in selective targeting of these motor neurons to muscle by a polysialic acid–independent mechanism.
Conclusion
The intrinsic molecular differences between motor neuron pools can be overcome by manipulation of their access to different peripheral nerve pathways such that obturator motor neurons preferentially project to a terminal nerve branch to muscle despite not upregulating the expression of polysialic acid.
doi:10.1002/mus.23526
PMCID: PMC3740786  PMID: 23169481
femoral nerve; obturator nerve; pathway choice; PSA-NCAM; regeneration
17.  SMA VALIANT TRIAL: A PROSPECTIVE, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF VALPROIC ACID IN AMBULATORY ADULTS WITH SPINAL MUSCULAR ATROPHY 
Muscle & nerve  2014;49(2):187-192.
Introduction
An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults.
Methods
There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes.
Results
Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months.
Conclusions
VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.
doi:10.1002/mus.23904
PMCID: PMC3888833  PMID: 23681940
18.  Coexistent Autoimmune Autonomic Ganglionopathy and Myasthenia Gravis Associated with Non-Small Cell Lung Cancer 
Muscle & nerve  2010;41(3):416-419.
We report a case of a 55 year old man with non-small cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal two years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 supine, 66/47 mmHg standing after 10 minutes without a compensatory heart rate increase (57 to 59 bpm), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04, The plasma norepinephrine level was low (79 pg/ml supine to 330 pg/ml standing). Single fiber EMG of the right extensor digitorum communis revealed normal mean MCD (jitter) but several pairs exceeded a jitter of 100 µs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02] and ganglionic AChR (0.34 nmol/L, normal <0.02) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mmHg standing, 66 to 79 bpm), to Valsalva (normal blood pressure overshoot, HR ratio 1.47), norepinephrine (194 pg/ml supine, 763 standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that is improved with non-supine rest.
doi:10.1002/mus.21528
PMCID: PMC3925506  PMID: 19882640
autoimmune autonomic ganglionopathy; myasthenia gravis; paraneoplastic syndrome
19.  Tongue muscle plasticity following hypoglossal nerve stimulation in aged rats 
Muscle & nerve  2012;47(2):230-240.
Introduction
Age-related decreases in tongue muscle mass and strength have been reported. It may be possible to prevent age-related tongue muscle changes using neuromuscular electrical stimulation (NMES). Our hypothesis was that alterations in muscle contractile properties and myosin heavy chain composition would be found following NMES.
Methods
Fifty-four young, middle-aged and old Fischer 344/Brown Norway rats were included. Twenty-four rats underwent bilateral electrical stimulation of the hypoglossal nerves for 8 weeks and were compared with control or sham rats. Muscle contractile properties and myosin heavy chain (MHC) in the genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscles were examined.
Results
In comparison with unstimulated control rats, we found reduced muscle fatigue, increased contraction and half decay times and increased twitch and tetanic tension. Increased Type I MHC was found, except for GG in old and middle-aged rats.
Discussion
Transitions in tongue muscle contractile properties and phenotype were found following NMES.
doi:10.1002/mus.23499
PMCID: PMC3556192  PMID: 23169566
muscle contraction; tongue; electrical stimulation; aging; swallowing
20.  Nerve Allografts Supplemented with Schwann Cells Overexpressing GDNF 
Muscle & nerve  2012;47(2):213-223.
Introduction
We sought to determine if supplementation of acellular nerve allografts (ANAs) with Schwann Cells overexpressing GDNF (G-SCs) would enhance functional recovery following peripheral nerve injury.
Methods
SCs expanded in vitro were infected with a lentiviral vector to induce GDNF overexpression. Wild type-SCs (WT-SCs) and G-SCs were seeded into ANAs used to repair a 14mm nerve gap defect. Animals were harvested after 6 and 12 weeks for histomorphometric and muscle force analysis.
Results
At 6 weeks, histomorphometry revealed that ANAs supplemented with G-SCs promoted similar regeneration compared to the isograft at midgraft. However, G-SCs failed to promote regeneration into the distal stump. At 12 weeks, ANAs with G-SCs had lower maximum and specific force production compared to controls.
Discussion
The combined results suggest that consistent overexpression of GDNF by G-SCs trapped axons in the graft and prevented functional regeneration.
doi:10.1002/mus.23490
PMCID: PMC3556217  PMID: 23169341
Peripheral nerve injury; Neurotrophic factor; Schwann cells; GDNF; Lentiviral vector; Nerve regeneration
21.  A Progressive Translational Mouse Model of Human VCP Disease: The VCP R155H/+ Mouse 
Muscle & nerve  2012;47(2):260-270.
Introduction
Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion Body Myopathy (hIBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently they have been linked to 2% of familial ALS cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis.
Methods
The VCPR155H/+ knock-in mouse model was assessed for muscle strength, immunohistochemical, Western, apoptosis, autophagy and MicroPET/CT imaging analyses.
Results
VCPR155H/+ mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons.
Discussion
VCPR155H/+ knock-in mice represent an excellent pre-clinical model for understanding VCP-associated disease mechanisms and future treatments.
doi:10.1002/mus.23522
PMCID: PMC3556223  PMID: 23169451
Amyotrophic Lateral Sclerosis (ALS); Inclusion Body Myopathy; Paget Disease of Bone; Frontotemporal Dementia (IBMPFD); Valosin Containing Protein (VCP); molecular genetics, pathology
22.  ULTRASOUND FOR CARPAL TUNNEL SYNDROME SCREENING IN MANUAL LABORERS 
Muscle & nerve  2013;48(1):10.1002/mus.23735.
Introduction
Manual laborers are at increased risk for carpal tunnel syndrome (CTS), and a combination of history, physical examination, and nerve conduction studies is often used to screen for CTS in this population. Neuromuscular ultrasound may be a better screening tool, because it is painless. In this study we compare the accuracy of nerve conduction studies and ultrasound for CTS screening.
Methods
Five hundred thirteen manual laborers were screened prospectively for CTS using nerve conduction studies and neuromuscular ultrasound, and the accuracy of the 2 techniques was compared using the Katz hand diagram as the diagnostic standard.
Results
The ROC curves for the 2 techniques were not significantly different (P = 0.542), indicating that the approaches had similar diagnostic accuracy.
Conclusions
Neuromuscular ultrasound is a painless technique that has diagnostic accuracy similar to nerve conduction studies and can be used to screen large populations at risk for CTS.
doi:10.1002/mus.23735
PMCID: PMC3878605  PMID: 23649357
accuracy; carpal tunnel syndrome; clinical neurophysiology; screening test; ultrasound
23.  Surgical and postpartum hereditary brachial plexus attacks and prophylactic immunotherapy 
Muscle & nerve  2012;47(1):23-27.
Introduction
Surgery and childbirth can trigger attacks of hereditary brachial plexus neuropathy (HBPN), and inflammation was suggested as a component of the pathogenesis.
Methods
HBPN patients who underwent surgery or parturition from Jan.1,1996 to Dec.31,2009 were studied.
Results
Twenty-five HBPN patients underwent 48 surgeries or parturitions. Seventeen patients (68%) had attacks, including 13 periprocedural and 7 postpartum by varied anesthesia types. Three patients who had 8 earlier combined attacks (after thyroidectomy, laminectomy, and Caesarean section) were given prophylactic immunosuppressive therapy (corticosteroids ± immunoglobulin). None suffered postoperative attacks, which is uncharacteristic of their prior experience. Five had perioperative attacks as their first HBPN manifestation. Median follow-up was 11(3-48) months. Attacks occurred in the operated limb (n=6) or distant (n=7) to surgical sites. All attacks interfered with daily living, with frequent incomplete recovery. Five patients had a SEPT9 mutation.
Conclusions
Corticosteroid may prevent parturition and surgical HBPN attacks in some patients. Diverse surgeries, anesthesia and childbirth frequently trigger HBPN attacks.
doi:10.1002/mus.23462
PMCID: PMC3528817  PMID: 23042485
24.  Clinical Evolution of Pure Upper Motor Neuron Disease/Dysfunction (PUMND) 
Muscle & nerve  2012;47(1):28-32.
Introduction
PLS is defined as pure upper motor neuron disease/dysfunction (PUMND) beyond 48 months after symptom onset. We know little about its early stages, but such knowledge would help to identify the mechanisms underlying PLS and ALS and determine why PLS patients seem to be protected against lower MND (LMND).
Methods
We reviewed 622 MND cases during a 4-year period and identified 34 patients with PUMND (5.4%).
Results
Among 23 cases with follow-up data/EMGs (2 had only 1 EMG), 13 (57%) remained classified as PUMND, and 8 (35%) developed LMND (mean, 51.4 months after onset). Of these 8, LMND developed in 3 after 48 months from symptom onset. Patients with PUMND and LMND were more functionally impaired (P =.02). Separately, we identified 5 patients with PUMND who developed LMND long after 48 months (range, 50–127 months).
Conclusion
PLS belongs to the ALS spectrum, and perhaps all cases eventually develop LMND.
doi:10.1002/mus.23496
PMCID: PMC3528840  PMID: 23169452
amyotrophic lateral sclerosis; lower motor neuron; upper motor neuron; pure upper motor neuron disease/dysfunction; motor neuron disease
25.  Evaluating dermal myelinated nerve fibers in skin biopsy 
Muscle & nerve  2012;47(1):1-11.
Although there has been extensive research on small, unmyelinated fibers in the skin, little research has investigated dermal myelinated fibers in comparison. Glabrous, non-hairy skin contains mechanoreceptors that afford a vantage point for observation of myelinated fibers that have previously been seen only with invasively obtained nerve biopsies. This review discusses current morphometric and molecular expression data of normative and pathogenic glabrous skin obtained by various processing and analysis methods for cutaneous myelinated fibers. Recent publications have shed light on the role of glabrous skin biopsy in identifying signs of peripheral neuropathy and as a potential biomarker of distal myelin and mechanoreceptor integrity. The clinical relevance of a better understanding of the role of dermal myelinated nerve terminations in peripheral neuropathy will be addressed in light of recent publications in the growing field of skin biopsy.
doi:10.1002/mus.23510
PMCID: PMC3528842  PMID: 23192899
glabrous skin biopsy; myelinated nerve fibers; molecular architecture; Meissner corpuscles; peripheral neuropathy

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