Objective: To obtain normative cross sectional area (CSA) values for median nerve by ultrasound at predetermined sites and correlate them with electrophysiological variables in healthy Asian subjects.

Materials and methods: The median nerve was examined ultrasonographically in 100 healthy volunteers, mean age 39 years (range, 18–75 years). CSA of the median nerve was measured at wrist, mid-forearm, mid-arm and axilla. All subjects underwent simultaneous standardized nerve conduction studies.

Results: The mean median nerve CSAs ± standard deviation at the distal wrist crease was 7.2±1 mm2; mid-forearm 4.8±0.9 mm2; mid-arm 6.1±1mm2; axilla 5.9±0.9 mm2. The CSA at the wrist was the largest compared to other levels (p<0.001) and it increased with advancing age (p<0.002).

Conclusions: The normative data obtained from this study show that median nerve CSA is not uniform along its length. There are differences between gender, and values increase with advancing age. © 2013 Wiley Periodicals, Inc.

Introduction: Dystrophinopathies are X-linked recessive neuromuscular diseases caused by mutations in the dystrophin gene. This study aimed to detect mutations within the dystrophin gene in DMD patients, to determine the carrier status of women, and to perform a prenatal diagnosis.

Methods: We analyzed 17 individuals from 2 unrelated families with a history of DMD. We used multiplex PCR, Multiplex Ligation-dependent Probe Amplification (MLPA), and Short Tandem-Repeat (STR) segregation analysis to accurately detect and characterize the mutations and to identify the at-risk haplotype.

Results: The selected methodology allowed for the characterization of 2 single-exon out-of-frame deletions in the affected patients. 9/13 women and a fetus were excluded from being carriers. Three recombination events were found and suggested that germline mosaicism had occurred in both families.

Discussion: This methodology proved to be efficient for characterizing the disease-causing mutation in affected individuals and for assessing the carrier status in healthy relatives. These findings helped inform precise genetic counseling and contributed to characterization of the disease in the Argentine population. © 2013 Wiley Periodicals, Inc.

Neuromuscular ultrasound involves the use of high-resolution ultrasound to image the peripheral nervous system of patients with suspected neuromuscular diseases. It complements electrodiagnostic studies well by providing anatomic information regarding nerves, muscles, vessels, tendons, ligaments, bones, and other structures that cannot be obtained with nerve conduction studies and electromyography. Neuromuscular ultrasound has been studied closely over the past 10 years and has been used most often in the assessment of entrapment neuropathies. This review focuses on the use of neuromuscular ultrasound in 4 of the most common entrapment neuropathies: carpal tunnel syndrome, ulnar neuropathy at the elbow and wrist, and fibular neuropathy at the knee. © 2013 Wiley Periodicals, Inc.

Introduction: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is characterized by early selective involvement of small nerve fibers. Initial clinical diagnosis is complicated by psychosocial factors.

Objective: To evaluate diagnostic accuracy of sural sensory nerve action potentials, plantar sympathetic skin response (SSR), and cortical laser-evoked potentials (LEP) to dorsal foot stimulation in early diagnosis of TTR-FAP.

Methods: Sixty-three subjects with TTR-FAP (Val30Met) mutation were split into 2 groups (asymptomatic carriers and early-symptomatic patients) and compared with 33 healthy controls.

Results: The diagnostic accuracy of plantar SSR amplitude and LEP N2 latency was similar; all had very high specificity (94 to 97%) but low sensitivity (22 to 32%) in distinguishing controls from carriers and early-symptomatic patients. No control had abnormal results on both tests.

Conclusions: Plantar SSR and LEPs have similar diagnostic performance in detecting small-fiber dysfunction in early TTR-FAP; we propose that both tests should be used to investigate this population. © 2013 Wiley Periodicals, Inc.

Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N=57) provide insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6 minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Results: Baseline age (≥7 years), 6MWD, and selected TFT performance, are strong predictors of decline in ambulation (Δ 6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1/42 (2.3%) subjects able to stand from supine lost ambulation. Discussion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. © 2013 Wiley Periodicals, Inc.

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, crossover study of VPA in ambulatory SMA adults.

Methods: There were 33 subjects aged 20-55 years. After baseline assessments subjects were randomized to receive VPA (10-20 mg/kg/daily) 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, electrophysiologic, 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. © 2013 Wiley Periodicals, Inc.

INTRODUCTION. While deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women. METHODS. Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model. RESULTS. Young women produced more torque at baseline and during the protocol than older women (P<0.001). While fatigue did not differ between groups (P=0.53), torque variability differed by group (P=0.022) and was greater in older impaired compared with young women (P=0.010). CONCLUSIONS. These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments. © 2013 Wiley Periodicals, Inc.

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pre-treatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCID) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL^TM, heart rate determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Discussion: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. © 2013 Wiley Periodicals, Inc.

Introduction: Sporadic inclusion body myositis (sIBM) is a progressive disease that leads to extensive muscle weakness. The aim of this study was to determine whether the number and distribution of fibroblasts differ in sIBM when compared with polymyositis.

Methods: Immunofluorescence double labelling was performed on 35 biopsies with antibodies directed against perlecan and CD90, procollagen I, CD34, and CD105. In addition, non-serial ultrathin sections were studied from 3 biopsies of each condition.

Results: Fibroblasts expressing CD90 and CD34 accumulated in the endomysial compartment in polymyositis and sIBM. In addition, cells expressing CD90 were found beneath the basal lamina in both conditions. At the ultrastructural level in polymyositis, fibroblasts invaded the myofiber, with focal destruction of the basement membrane. In sIBM, by contrast, invasive fibroblasts were ensheathed by the intact myofiber basement membrane.

Discussion: The impact of intruding fibroblasts on satellite cells remains to be established. © 2013 Wiley Periodicals, Inc.

Introduction: We describe a simple and quickly applied electrodiagnostic method for confirming the diagnosis of interdigital neuropathy (IDN) caused by Morton neuroma (MN).

Methods: Interdigital nerves II-III and III-IV were stimulated with surface electrodes simultaneously touching the lateral side of 1 toe and the medial side of the other. Recording was also made with surface electrodes. The results of 20 normal controls and 14 patients with MN were evaluated.

Results: The amplitude and peak latency values elicited in the patients as well as the interside differences revealed an acceptable abnormality rate between 57.1% and 71.4%.

Conclusion: Although the most popular and effective method of MN diagnosis is clinical evaluation supported by imaging, electrophysiological studies can, in selected patients, provide valuable information © 2013 Wiley Periodicals, Inc.

Introduction: An 80 year old man had a 40 year history of chronic sensory ataxic neuropathy and 11 years of relapsing/remitting episodes of rapid deterioration with perioral paresthesiae and weakness of bulbar, respiratory, and limb muscles. Case report: An IgM paraprotein was detected 12 years before death, and Waldenstrom's macroglobulinaemia was diagnosed on bone marrow biopsy 3 years before death. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-disialyl antibodies (CANOMAD) was diagnosed. Comprehensive autopsy showed severe dorsal column atrophy and dorsal root ganglionopathy. A different pathology was identified in cranial and peripheral nerves, dorsal roots, and cauda equina, comprising infiltration of clonal B-lymphocytes within the endoneurium, perineurium, and leptomeninges. Conclusion: The autopsy provides evidence of the pathogenesis of the relapsing remitting component of CANOMAD, and we postulate that this may relate to the presence of clonal IgM anti-disiayl gangliosides secreting B-lymphocytes within nerves. © 2013 Wiley Periodicals, Inc.

INTRODUCTION: We examined the mechanomyographic amplitude (MMG_RMS)-force relationships with log-transform and polynomial regression models for the vastus lateralis (VL), rectus femoris (RF), and first dorsal interosseous (FDI) muscles. METHODS: Twelve healthy (age = 23 ± 3 yrs;) men performed isometric ramp contractions of the leg extensors and index finger from 10% to 80% of their maximal voluntary contraction (MVC) with MMG sensors positioned on the VL, RF, and FDI. Log-transform and polynomial regression models were fitted to the relationships. RESULTS: There were differences for the a terms (intercepts) and b terms (slopes) from the log-transform model between the FDI, VL, and RF, however, there were no consistent differences identified with the polynomial regression models. DISCUSSION: The log-transform model quantified differences in the patterns of responses between the FDI and the leg extensors, however, polynomial regression could not distinguish such differences. © 2013 Wiley Periodicals, Inc.

Introduction We evaluated incorporation of quantitative sudomotor axon reflex test (QSART) into diagnostic criteria for small fiber neuropathy (SFN) as an addition to quantitative sensory testing (QST) and intraepidermal nerve fiber density (IENFD).

Methods 101 patients with clinically suspected SFN underwent QSART, QST, and skin biopsy. The diagnostic yield of existing SFN criteria in these patients was compared to criteria incorporating QSART. The new combined diagnostic criteria were evaluated.

Results SFN was diagnosed in 38/101 patients (38%) using current criteria. Addition of QSART to existing SFN criteria resulted in an increased diagnostic yield of 67/101(66%). Applying new SFN criteria requiring abnormality in at least 2 assessments among QSART, QST, and IENFD resulted in a diagnosis of SFN in 57/101 (56%).

Discussion Assessment of both somatic and peripheral autonomic small nerve fibers enhances diagnostic criteria for SFN. © 2013 Wiley Periodicals, Inc.

BACKGROUND: Cachexia is a wasting condition that manifests in several types of cáncer. The main characteristic is a profound loss of muscle mass. METHODS: By using a micro-array system, the expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the Yoshida AH-130 ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals suffering from cachexia and control animals. CONCLUSIONS: The differences concern genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. The stated differences may represent a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome. © 2013 Wiley Periodicals, Inc.

INTRODUCTION: Both voluntary and evoked conditioning contractions will potentiate muscle twitch contractile properties. The response of a voluntary contraction to each condition type is not well understood and may be a more functional model than evoked twitch potentiation. METHODS: Baseline measurements from tibialis anterior were: maximal isometric twitch torque and rate of torque development (RTD), maximal evoked 50Hz torque, and maximal voluntary ballistic RTD. Potentiation was induced by a 10s voluntary, or tetanic contraction (~78% MVC), followed by 2 twitches and 2 ballistic contractions. RESULTS: Twitch properties (torque, RTD) were potentiated equally following each conditioning contraction. Ballistic RTD was greater post-tetanus (390.2 Nm/s ± 59.3) than post-voluntary (356.4 Nm/s ± 69.1), but both were reduced from baseline (422.0 Nm/s ± 88.9). CONCLUSIONS: Twitch potentiation was similar between conditioning contraction types, however ballistic RTD was lower following post-tetanus than post-voluntary. These results indicate central inhibition or fatigue concurrent to peripheral potentiation. © 2013 Wiley Periodicals, Inc.

Introduction: Acetylcholine receptor (AChR) and striated muscle antibodies (StrAbs) are frequently found in myasthenia gravis (MG) patients with thymoma. This study aimed to determine the positive (PPV) and negative predictive value (NPV) of these antibodies for thymoma in patients with MG.

Methods: Antibody findings, thymic histology, and onset age were reviewed for 1141 patients with MG. PPV and NPV of these antibodies for thymoma were determined.

Results: The PPV of AChR binding antibodies plus StrAbs was highest (50.0%) with onset before age 40. The PPV of all antibodies was low (<9%) after age 40. Higher StrAb levels did not increase the PPV. The NPV of AChR binding antibodies was high (99.7%) for all ages.

Conclusion: Patients without AChR binding antibody are unlikely to have a thymoma. StrAbs and AChR binding antibodies are not diagnostic for thymoma, but in early onset MG, their presence should raise the clinical suspicion for thymoma. © 2013 Wiley Periodicals, Inc.

Natura non facit saltus (Latin for “nature does not make jumps"). This maxim expresses the idea that natural things and properties change gradually, in a continuum, rather than suddenly. In biomedical sciences, for taxonomic purposes, we make jumps that emphasize differences more than similarities. In dysimmune neuropathies 2 disorders characterized by the presence of antibodies to gangliosides GM1 and GD1a and a peculiar exclusive motor involvement: acute motor axonal neuropathy (AMAN) and multifocal motor neuropathy (MMN) have been identified. However anti-GM1 or -GD1a antibodies are also associated with acute motor and sensory axonal motor neuropathy (AMSAN). We review the results of recent clinical and experimental studies which indicating that AMAN and MMN are not exclusively motor. We discuss the possible explanations of the greater resistance of sensory fibers to antibody attack to finally suggest that AMAN, AMSAN, and MMN belong to a continuous spectrum with a common pathophysiological mechanism. © 2013 Wiley Periodicals, Inc.

Introduction: Neuromuscular electrical stimulation (NMES) is used to improve quadriceps mass after anterior cruciate ligament (ACL) injury. We studied the effect of NMES on mRNA levels of atrophy genes in the quadriceps muscle of rats after ACL transection. Methods: mRNA levels of atrogin-1, MuRF-1, myostatin were assessed by quantitative PCR and the polyubiquitinated proteins by Western Blot at 1, 2, 3, 7, and 15 days post-injury. Results: NMES minimized the accumulation of atrogenes and myostatin according to time period. NMES prevented a reduction in muscle mass in all muscles of the ACLES group at 3 days. Conclusion: NMES decreased the accumulation of atrogenes and myostatin mRNA in the quadriceps muscles, inhibiting the early atrophy at 3 days, although it did not prevent atrophy at 7 and 15 days after ACL transection. This study indicates the importance of therapeutic NMES interventions in the acute phase after ACL transection. © 2013 Wiley Periodicals, Inc.

Introduction: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. Methods: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL-0-50^o knee flexion; n=10) or lengthened (LL- 40-90^o; n=11) position, followed by 4 weeks detraining. Controls (CON; n=10) were untrained. Quadriceps strength, Vastus Lateralis architecture, anatomical cross-sectional area (aCSA), and serum IGF-I (insulin-like growth factor 1) were measured at weeks 0, 8, 10, and 12. Results: Increases in fascicle length (29±4% vs. 14±4%), distal aCSA (53±12% vs. 18±8%), strength (26±6% vs. 7±3%), and IGF-I (31±6% vs. 7±6%) were greater in LL compared to SL (P<0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL (P<0.05). Discussion: Enhanced muscle in vivo (and somewhat IGF-I) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. © 2013 Wiley Periodicals, Inc.

Introduction: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared to nerve isografts.

Methods: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regeneration, and functional recovery were evaluated in a14 mm rat sciatic injury model and compared to isografts.

Results: At 14 days, motor or sensory-derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, histomorphometric analysis found CP-ANGs with SCs and isografts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation.

Discussion: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect. © 2013 Wiley Periodicals, Inc.

Introduction: We quantified sub-maximal torque regulation during low to moderate intensity isometric hip flexion contractions in individuals with stroke and the associations with leg function. Methods: 10 participants with chronic stroke and 10 controls performed isometric hip flexion contractions at 5%, 10%, 15%, 20%, and 40% of maximal voluntary contraction (MVC) in paretic, non-paretic, and control legs. Results: Participants with stroke had larger torque fluctuations (coefficient of variation, CV), for both the paretic and non-paretic legs, than controls (P<0.05) with the largest CV at 5% MVC in the paretic leg (P<0.05). The paretic CV correlated with walking speed (r² =0.45) and Berg Balance Score (r²=0.38). At 5% MVC, there were larger torque fluctuations in the contralateral leg during paretic contractions compared with the control leg. Conclusions: Impaired low-force regulation of paretic leg hip flexion can be functionally relevant and related to control versus strength deficits post stroke. © 2013 Wiley Periodicals, Inc.

Introduction: Stretch therapy is commonly utilized to prevent shortening maladaptation of skeletal muscle. Stretch in combination with isometric contraction prevents shortening, but the signaling mechanisms are not understood.

Methods: Using a soleus tenotomy+stretch rat model, the phosphorylation-activation of mechanosensitive kinases (Akt, p70^S6K, p38 MAPK, and ERK1/2) were measured for various stretch magnitudes, set relative to optimal soleus length (Lo).

Results: The kinases were not activated by passive stretch until it exceeded the normal physiological range. Stretch+isometric contraction resulted in relatively strong phosphorylation, even at short lengths.

Discussion: While passive stretch results in kinase phosphorylation only during extreme lengthening, isometric contraction generated pronounced phosphorylation of kinases at Lo and Lo+25%, indicating stimulation of pathways that lead to the preservation or increase of muscle length.

Relevance: Understanding the effects of passive and active stretch with respect to Lo and contraction is essential for predicting therapeutic outcomes and influencing optimal muscle length. © 2013 Wiley Periodicals, Inc.

Purpose: In Duchenne muscular dystrophy (DMD), fat replacement of muscle may be a useful endpoint in trials of therapy, though progression in different muscle groups is uneven. This study assesses the progression in fat replacement by T₁-weighted imaging over 2 9-month periods.

Methods: 8 ambulant, corticosteroid-treated boys with DMD were imaged at 3 Tesla at 3 time points (baseline, 9 and 18 months) with T₁ weighted imaging to measure fat replacement.

Results: The greatest increase in fat content was measured in the biceps femoris long head, vastus lateralis, and rectus femoris, while the biceps femoris short head, and gluteus maximus progressed more slowly. None of the lower leg muscles studied changed significantly.

Conclusion: MRI can measure specific changes in fat replacement of muscle over time, demonstrating the variability in rates of natural progression between muscle groups and identifying those muscles suitable for use as biomarkers in clinical trials. © 2013 Wiley Periodicals, Inc.

Introduction— The Reg genes play an important role in the regeneration of various tissues, however no reports have been published regarding the expression of the Reg3G gene in skeletal muscle. We have investigated the expression of Reg3G gene in regeneration of rat skeletal muscle and injured nerves.

Methods— We used three experimental models of muscle and nerve injury. RT-PCR and Western blot analysis was performed for the detection of Reg3G in regenerating muscle and nerve.

Results— We found transcriptional activation of the Reg3G gene in the soleus and extensor digitorum longus muscles and in their corresponding nerves after both muscle and nerve injury in different time periods, respectively.

Conclusions— These results suggest that the Reg3G gene plays an important role in communication between injured axons and muscle and may play a significant role in skeletal muscle and peripheral nerve regeneration. © 2013 Wiley Periodicals, Inc.

Introduction: The trigeminal nerve (CN V) supplies mostly sensory innervation to the face, and the facial nerve (CN VII) conveys primarily motor fibers. The aim of this study was to elucidate their distributions and anastomoses.

Methods: Fourteen specimens of hemisectioned faces were gathered from human cadavers and stained with Sihler staining.

Results: The temporal (Tbr), zygomatic (Zbr), and buccal (Bbr) branches of CN VII formed trigeminofacial anastomoses in the ocular area. Communications were observed between the supraorbital nerve and the Tbr (85.7%), the infraorbital nerve and the Bbr (100%) and Zbr (28.6%), and the zygomaticofacial nerve and the Zbr (41.7%). Anastomoses were formed between the supratrochlear nerve and the Tbr (57.1%) and Bbr (50%), and the infratrochlear nerve and the Bbr (85.7%).

Discussion: Motor and sensory axons to the face contribute to trigeminofacial anastomoses, which may play key roles in subtle movements of muscles of facial expression. © 2013 Wiley Periodicals, Inc.

Introduction: We investigated the clinical utility of single fiber conduction velocity (SF-CV) testing in the evaluation of motor nerve function in diabetic patients with signs and symptoms of symmetrical distal sensory polyneuropathy (DSP). SF-CV findings were compared with conventional nerve conduction studies (NCS).

Methods: Twenty eight consecutive type-2 diabetic patients with clinically diagnosed DSP were studied.

Results: SF-CV testing of the tibial nerve was abnormal in 16 (57.1%) patients. Twelve patients with normal conventional motor NCS had abnormal findings by tibial SF-CV. SF-CV testing of the tibial nerve was significantly superior to all other motor NCS.

Conclusions: SF-CV testing of the tibial nerve often demonstrates motor nerve impairment in diabetic patients with sensory DSP when conventional NCS are normal. © 2013 Wiley Periodicals, Inc.

Introduction: Recent optical recordings of transmembrane potentials in the axons of pyramidal neurons show that the internodal action potentials (APs) predicted in our previous studies do exist. These novel processes are not well understood. We aim to clarify electrical phenomena in peripheral myelinated axons (MAs). Methods: We used a multi-cable Hodgkin-Huxley-type model to simulate MAs with potassium channels that were either normal or inhibited along a short region of the internodal membrane. A brief stimulus was applied to the first node. Results: We demonstrated peculiarities in the internodal APs induced by a saltatory AP: They existed across internodal membranes, were detectable in periaxonal space but not in intracellular space, propagated continuously and then collided near the mid-internodes, and produced internodal sources of afterdischarges. Conclusion: Our results highlight the importance of the MA internodal regions as new therapeutic targets for avoiding afterdischarges provoked by reduced axonal fast potassium channel expression. © 2013 Wiley Periodicals, Inc.

Introduction: Fluoxetine is an open channel blocker of fetal muscle acetylcholine (ACh) receptor (AChR) and slow-channel mutant AChRs. It is used commonly to treat patients with slow-channel congenital myasthenic syndromes. Fluoxetine effects on adult wild-type endplate AChR are less characterized, although muscle AChR isoforms are differentially modulated by some drugs.

Methods: Excitotoxicity assays and patch clamp recordings were performed in HEK cells expressing wild-type or slow-channel mutant human AChRs.

Results: Fluoxetine (2–10 μM) abolished ACh-induced death and decreased ACh-activated whole-cell currents in cells expressing all AChR types. In outside-out patches, fluoxetine rapidly curtailed ACh-evoked unitary activity and macroscopic currents. The effect was increased if fluoxetine was applied before ACh.

Conclusions: Fluoxetine is an open channel blocker, but it also affects AChR in the closed state. AChR blockade likely underlies the rescue of HEK cells from ACh-induced death. © 2013 Wiley Periodicals, Inc.

Introduction: Viruses are commonly cited as triggers for autoimmune disease. It is unclear if West Nile virus (WNV) initiates autoimmunity.

Methods: We describe 6 cases of myasthenia gravis (MG) that developed several months after WNV infection. All patients had serologically confirmed WNV neuroinvasive disease. None had evidence of MG prior to WNV.

Results: All patients had stable neurological deficits when they developed new symptoms of MG 3-to-7 months after WNV infection. However, residual deficits from WNV confounded or delayed MG diagnosis. All patients had elevated acetylcholine receptor (Ach-R) antibodies, and 1 had thymoma. Treatment varied, but 4 patients required acetylcholinesterase inhibitors, multiple immunosuppressive drugs, and intravenous immune globulin (IVIG) or plasmapheresis for recurrent MG crises.

Discussion: The pathogenic mechanism of MG following WNV remains uncertain. We hypothesize that WNV-triggered autoimmunity breaks immunological self-tolerance to initiate MG, possibly through molecular mimicry between virus antigens and Ach-R subunits or other autoimmune mechanisms. © 2013 Wiley Periodicals, Inc.

Introduction. Muscle weakness is present in the paretic limbs of individuals with cerebral palsy (CP). We aimed to determine what neuromuscular factors contribute to weakness in adults with CP during isometric maximal voluntary contractions (iMVC).

Method. Gastrocnemius anatomical cross sectional area (ACSA) and agonist and antagonist activation were measured in 11 CP and 11 control adult men during plantarflexion iMVC.

Results. Plantarflexion iMVC torque of the paretic leg was 42% and 52% less than the non-paretic and control limbs, respectively. The paretic gastrocnemius ACSA was smaller than the control group only. Paretic agonist activation was less than the non-paretic and control groups, whereas antagonist coactivation was higher. Multiple regression analysis revealed muscle activation accounted for 57% of variation in paretic plantarflexion iMVC torque.

Discussion. This demonstrates that in individuals with CP, muscle weakness in the paretic limb is attributed primarily to impaired neural activation and, to a lesser degree, ACSA. © 2013 Wiley Periodicals, Inc.

Introduction: In progressive conditions such as Duchenne and Becker muscular dystrophy (DBMD), the need for care may outpace care use. We examined correlates that contribute to utilization of needed care. Sample: Structured interviews were conducted on use of care among 34 young men with DBMD born before 1982. Results: Disease severity, per capita income, and presence of other relatives with DBMD predicted greater use of services. Race/ethnicity, acculturation, and level of caregiver education did not significantly predict service utilization. Conclusions: We identified disparities in receipt of healthcare and related services in adult men with DBMD that can affect quality of life. Despite the high disease severity identified in this population, these men utilized only half of the services available to individuals with significant progressive conditions. Providers should be aware of low service utilization and focus on awareness and assistance to ensure access to available care. © 2013 Wiley Periodicals, Inc.

Introduction: We aimed to elucidate the linear makeup of each major nerve of the upper limb by the C7 root through sensory stimulation and functional MRI in a rat model. Methods: The C7 nerve root and major nerves of the right forelimb were stimulated electrically. Blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) was performed concurrently. Voxel overlap within the primary sensory cortex was calculated. Results: C7 comprises sensation in less than 1% in the musculocutaneous nerve, 6% in the ulnar nerve, 16% in the radial nerve, and 19% in the median nerve (P<0.005 for each). Conclusions: The overlap is always under 25% for each major nerve. Clinical relevance: This study helps explain why C7 is a suitable donor for brachial plexus injury treatment and why there is only a transient sensory deficit after transfer. © 2013 Wiley Periodicals, Inc.

Introduction: We evaluated the effect of platelet-rich plasma (PRP) injection in a rabbit model of dextrose-induced median nerve injury.

Methods: New Zealand white rabbits (n = 15) were randomly divided into 3 groups. Three different regimens (Group 1: 0.1 mL saline; Group 2: 10% dextrose with PRP; Group 3: 10% dextrose with saline) were injected within the carpal tunnel. Electrophysiological and histological findings were evaluated at 12 weeks after the injection.

Results: The mean median motor latency in group 3 was significantly longer than that in groups 1 and 2. The cross sectional area of the median nerve and subsynovial connective tissue thickness in group 3 were significantly larger than those in groups 1 and 2.

Conclusion: PRP injection may be effective in controlling median nerve injury, as demonstrated by improvement in electrophysiological and histological findings at 12 weeks after the dextrose injection. © 2013 Wiley Periodicals, Inc.

Introduction: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) and Z-band alternatively spliced PDZ motif-containing protein (ZASP) genes. Methods: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequencing of 6 candidate genes. Results: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient presented with distal weakness sparing the quadriceps muscles and had atypical results for Z-band-associated protein immunostaining. This indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. Conclusions: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations. © 2013 Wiley Periodicals, Inc.

Introduction: We examined the relationship between passive stiffness of the posterior hip and thigh muscles and muscle power output prior to and following normalization of passive stiffness to muscle cross-sectional area (CSA). Methods: Pearson correlation coefficients (r) were used to assess the relationships between the normalized and non-normalized slopes of the initial (phase 1) and final (phase 2) portions of the angle-torque curve and peak power output (Pmax). Results: A significant positive relationship was observed between the non-normalized slope of phase 1 and Pmax (r=0.723; P≤0.001); however, no correlations were observed between the normalized slope of phase 1 and Pmax (r=0.244; P=0.299) nor between Pmax and the normalized and non-normalized slopes of phase 2 (r=-0.159-0.418; P=0.067-0.504). Conclusions: These findings suggested that muscle size, rather than stiffness, accounted for a significant portion of the variance in muscle power output. © 2013 Wiley Periodicals, Inc.

Introduction: We examined if epinephrine in the local anesthetic to help control incision-related bleeding interferes with molecular measurements obtained with the Duchenne-Bergström percutaneous needle biopsy technique for sampling human skeletal muscle. Methods: Three groups received 2.5-3.0ml of 1%-lidocaine in 2 injections: 1) 0.5-1.0ml superficially that varied among the groups: i) -Epi: intra- and subcutaneous without epinephrine; ii) +Epi-Fascia: intra- and subcutaneous with epinephrine, avoiding the fascia; iii) +Epi+Fascia: intra- and subcutaneous with epinephrine, directing a small amount (~0.2ml) into the fascia area; and 2) ~2.0ml without epinephrine into the fascia area for all subjects. A muscle biopsy was obtained 5-10min later for IL-6 and MuRF-1 mRNA levels. Results: IL-6 mRNA levels were low in -Epi and +Epi-Fascia, but ~300 fold higher in +Epi+Fascia. MuRF-1 mRNA levels were similar among groups. Conclusion: Lidocaine with epinephrine can confound intramuscular measurements from needle biopsies, but this can be avoided with a careful injection approach. © 2013 Wiley Periodicals, Inc.

Introduction: We examined the role of skin biopsy in the evaluation and management of patients with suspected small fiber neuropathy (SFN).

Methods: A retrospective chart review was performed among all patients who underwent skin biopsy for evaluation of SFN at our institution between March, 2008 and March, 2011. Change in management was defined as a new diagnosis or change in treatment in response to both positive and negative skin biopsies.

Results: Among 69 patients who underwent skin biopsy, 25 had pathological evidence of an SFN, and 9 had evidence of a borderline SFN. Change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients.

Conclusions: Skin biopsy changed management or diagnosis in 52% of patients evaluated for a possible SFN and appears to play a valuable role in the workup of these patients. © 2013 Wiley Periodicals, Inc.

Introduction: To evaluate the effects of suramin, an antifibrotic agent, on the cardiac function and remodeling in the mdx mice.

Methods: mdx mice (8 months old) received intraperitoneal injections of suramin twice a week for 3 months. Control mdx mice (8 months old) were injected with saline.

Results: Suramin improved the electrocardiography profile with main corrections seen in S/R wave ratio, PR interval, Q amplitude with a significant decrease in the cardiomyopathy index. Suramin decreased myocardial fibrosis, inflammation, and myonecrosis.

Discussion - These findings suggest that the antifibrotic drug suramin may be a potential new adjunctive therapy to help improve cardiomyopathy in DMD. © 2013 Wiley Periodicals, Inc.

Introduction: To investigate differences in twitch and M-wave potentiation in the quadriceps femoris when electrical stimulation is applied over the quadriceps muscle belly versus the femoral nerve trunk.

Methods: M-waves and mechanical twitches were evoked using direct quadriceps muscle and femoral nerve stimulation between 48 successive isometric maximal voluntary contractions (MVC) from 10 young, healthy subjects. Potentiation was investigated by analyzing the changes in M-wave amplitude recorded from the vastus medialis (VM) and vastus lateralis (VL) muscles and in quadriceps peak twitch force.

Results: Potentiation of twitch, VM M-wave, and VL M-wave were greater for femoral nerve than for direct quadriceps stimulation (P<0.05). Despite a 50% decrease in MVC force, the amplitude of the M-waves increased significantly during exercise.

Conclusions: In addition to enhanced electrogenic Na⁺-K⁺ pumping, other factors (such as synchronization in activation of muscle fibers and muscle architectural properties) might significantly influence the magnitude of M-wave enlargement. © 2013 Wiley Periodicals, Inc.

Introduction: Several studies have reported high diagnostic sensitivity and specificity for the ice test in myasthenia gravis. All of the studies employed a case–control design, in which the diagnosis was already known at the time of the test for both patients and controls, leading to case selection bias. This suggests that the available literature substantially overestimates the diagnostic utility of these tests.

Methods: A retrospective cohort study without selection bias was performed to examine the sensitivity and specificity of the ice test. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the ice test were determined by means of a 2x2 table.

Results: The ice test has a sensitivity of 0.92 (95% CI, 0.62-1.00), specificity of 0.79 (95%CI, 0.56-1.00), PPV of 0.73 ( 95%CI, 0.48-0.90) and a NPV of 0.94 (95%CI, 0.70-1.00).

Discussion: Due to its high negative predictive value the ice test still is a reliable and useful bed-side test. © 2013 Wiley Periodicals, Inc.

Objectives: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy.

Methods: Twenty-one individuals with (n=11) and without (n=10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and six months after the initial DTI scan.

Results: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared to controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan.

Conclusions: DTI-derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments might be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies. © 2013 Wiley Periodicals, Inc.

Statins are among the most commonly prescribed medications that significantly reduce cardiovascular risk in selected individuals. However, these drugs can also be associated with muscle symptoms ranging from mild myalgias to severe rhabdomyolysis. While statin myotoxicity is usually self-limited, in some instances statin-exposed subjects can develop an autoimmune myopathy typically characterized by progressive weakness, muscle enzyme elevations, a necrotizing myopathy on muscle biopsy, and autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacologic target of statins. These antibodies are also found in some autoimmune myopathy patients without statin exposure. Importantly, anti-HMGCR antibodies are not found in the vast majority of statin-exposed subjects without autoimmune myopathy, including those with self-limited statin intolerance. Thus, testing for these antibodies may help differentiate those with self-limited statin myopathy who recover after statin discontinuation from those with a progressive statin-associated autoimmune myopathy who typically require immunosuppressive therapy. © 2013 Wiley Periodicals, Inc.

Introduction: Quantitative descriptions of fiber type organization in hindlimb muscles are incomplete or rare. Methods: Fiber morphometrics for both rat tibialis anterior (TA) muscles were measured in 3 dimensions. Results: Slow oxidative fiber area and perimeter varied in all zones. Fast oxidative glycolytic fibers (FOG) were predominant in the mediolateral and posterior zones, and fast glycolytic fibers (FG) predominated in the anterior zone. The mean area of FOG and succinate dehydrogenase intermediate fibers was lowest in the anterior zone. Mean area of FG was highest in the proximal and distal parts of the muscle. The area and perimeter of fast fibers differed significantly between the right and left limbs in the medial zone. In the middle and lateral zones, they differed at the proximal and distal parts. Discussion: Our detailed analysis in a high resolution, 3-dimensional map provides an essential tool for understanding the structure and function of TA muscles. © 2013 Wiley Periodicals, Inc.

Introduction: We investigated a novel application of phrenic nerve stimulation (PNS) in diaphragm dysfunction induced by mechanical ventilation (MV). Methods: Twenty-one Sprague-Dawley rats were randomly assigned to 3 groups: spontaneous breathing, 18-h controlled MV, and 18-h controlled MV with PNS. Upon completion of the experimental protocol, diaphragm contractility, gene expression of insulin-like growth factor-1 (IGF-1) and ubiquitin ligases, and serum IGF-1 levels were analyzed. Results: Compared with the spontaneously breathing rats, impaired diaphragm contractile function, including force-related properties and force-frequency responses, were pronounced with MV. Furthermore, MV suppressed IGF-1 and induced muscle ring finger 1 mRNA expression in the diaphragm. In contrast, PNS counteracted MV-induced gene expression changes in the diaphragm and restored diaphragm function. Conclusion: PNS exerted a protective effect against MV-induced diaphragm dysfunction by counteracting altered expression of IGF-1 and ubiquitin ligase in the diaphragm. © 2013 Wiley Periodicals, Inc.

Introduction: Tirasemtiv is a novel small molecule activator of the fast skeletal muscle troponin complex that produces sensitization of the sarcomere to calcium. Tirasemtiv is currently in Phase II clinical trials for neuromuscular diseases.

Methods: We conducted a blinded, randomized, placebo-controlled preclinical study of the effect of tirasemtiv on forearm grip strength, endurance, respiratory physiology, and muscle pathology in adequate sample sizes of the Lama2^dy-2J mouse model of congenital muscular dystrophy.

Results: Mice receiving a high dose of tirasemtiv had significantly higher muscle fiber cross sectional area and respiratory response to CO₂ stimulation at 16 weeks than mice on low dose or placebo. There were no changes in muscle pathology, serum creatine kinase, strength, endurance, or respiration following long-term treatment.

Discussion: We conclude that tirasemtiv influences the structure of the skeletal muscle fiber in this model of muscular dystrophy but does not impact muscle function, as evaluated in this study. © 2013 Wiley Periodicals, Inc.

Introduction: Nerve entrapment due to osseous callus formation is a rare complication after bone fractures. Electrodiagnostic studies and routine radiographic imaging often fail to demonstrate the pathology. The diagnosis is difficult and is often made incidentally upon surgical exploration. Nerve ultrasonography has not been used routinely used to assess such lesions.

Case report: We report 5 cases of nerve entrapment in osseous callus following fractures which were seen in 2011 and 2012. The diagnosis was made by ultrasound (US). We then performed a review of the relevant literature.

Conclusions: US is becoming an invaluable tool for diagnosing peripheral nerve entrapments. The current cases suggest that nerve US should be strongly considered as an adjunctive diagnostic tool for nerve palsies developing after trauma. © 2013 Wiley Periodicals, Inc.

BACKGROUND: The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in CIDP patients. METHODS: Response to therapy was defined as an improvement of at least 1 point on the Modified Rankin Score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder. RESULTS: 86 patients were included; 60.5% responded at short term and 54.6% at mid term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up. CONCLUSIONS: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment. © 2013 Wiley Periodicals, Inc.

Introduction: We sought to determine the contribution of oxidative stress-dependent activation of TRPM2 and L-type voltage-gated Ca²⁺ channels (VGCC) in dorsal root ganglion (DRG) neurons of rats following spinal cord injury (SCI).

Methods: The rats were divided into 4 groups: control, sham control, SCI, and SCI+nimodipine groups. The neurons of the SCI groups were also incubated with non-specific TRPM2 channel blockers, 2-aminoethoxydiphenyl borate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA) before H₂O₂ stimulation.

Results: The [Ca²⁺]_i concentrations were higher in the SCI group than in the control groups, although their concentrations were decreased by nimodipine and 2-APB. The H₂O₂-induced TRPM2 current densities in patch-clamp experiments were decreased by ACA and 2-APB incubation. In the nimodipine group, the TRPM2 channels of neurons were not activated by H₂O₂ or cumene hydroperoxide.

Conclusions: Increased Ca²⁺ influx and currents in DRG neurons following spinal injury indicated TRPM2 and voltage-gated Ca²⁺ channel activation. © 2013 Wiley Periodicals, Inc.

Objective: To determine correlations between ultrasonographic findings of thenar muscle and flexor retinaculum, and nerve conduction studies (NCS) in carpal tunnel syndrome (CTS).

Methods: Ultrasound and NCS were performed on 92 wrists with CTS and on 40 wrists from healthy individuals. Ultrasound of thenar and hypothenar muscles, flexor retinaculum, and median nerve were assessed. The ultrasonographic findings were compared between the 2 groups, and correlation analysis between median latency and ultrasonographic findings was performed.

Results: Motor latency correlated positively with flexor retinaculum thickness (FRT) and correlated negatively with the ratio of thenar to hypothenar muscle. FRT and motor latency were found to be significantly increased in CTS. The ratio of thenar to hypothenar muscle was found to be significantly decreased in CTS when compared with controls.

Conclusions: The ultrasonographic findings of FRT and thenar muscle reflect the severity of disease in patients with CTS and are valuable for the diagnosis of CTS. © 2013 Wiley Periodicals, Inc.

Introduction: We examined the individual patterns of responses for EMG amplitude and mean power frequency (MPF) during incremental treadmill running.

Methods: Nine physically active men performed incremental treadmill running at a constant grade of 1%. The EMG signal was recorded from the 3 superficial quadriceps femoris muscles during the workbout.

Results: The results of the polynomial regression indicated that the linear model best fit the data for the composite data for all 3 muscles and the majority (7 of 9) of subjects. There were no consistent patterns of responses for the EMG MPF responses. Also, there were no significant (P > 0.05) muscle × running velocity interactions for EMG amplitude and MPF.

Discussion: These results indicate consistent patterns of responses for EMG amplitude during incremental treadmill running regardless of which muscle was studied. © 2013 Wiley Periodicals, Inc.

INTRODUCTION: One important reason why functional electrical stimulation (FES) has not gained widespread clinical use is the limitation imposed by rapid muscle fatigue due to the non-physiological activation of the stimulated muscles. We aimed to show that asynchronous low pulse rate (LPR) electrical stimulation applied by multi-pad surface electrodes greatly postpones the occurrence of muscle fatigue compared to conventional stimulation (high pulse rate, HPR). METHODS: We compared the produced force vs. time of the forearm muscles responsible for finger flexion in 2 stimulation protocols, LPR (f_L= 10 Hz) and HPR (f_H= 40 Hz). RESULTS: Surface distributed low-frequency asynchronous stimulation (sDLFAS) doubles the time interval before the onset of fatigue (104 ± 80%) compared to conventional synchronous stimulation. DISCUSSION: Combining the performance of multi-pad electrodes (increased selectivity and facilitated positioning) with sDLFAS (decreased fatigue) can improve many FES applications in both the lower and upper extremities. © 2013 Wiley Periodicals, Inc.

Introduction: Neurological disorders with low tissue coenzyme Q₁₀ (CoQ₁₀) levels are important to identify, as they may be treatable.

Methods: We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ₁₀ deficiency in muscle to 31 with normal CoQ₁₀ values.

Results: Muscle from CoQ₁₀-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P < 0.0001). A type 2C fiber frequency of ≥ 5% had 89% sensitivity and 84% specificity for CoQ₁₀ deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ₁₀-deficient patients than in controls.

Conclusions: When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ₁₀ deficiency. © 2013 Wiley Periodicals, Inc.

INTRODUCTION: The mitochondrial network within cells is mediated by fission and fusion processes. We investigated the expression of the proteins responsible for these events during conditions of altered oxidative capacity. RESULTS: With chronic contractile activity, the mitochondrial reticulum increased in size, along with concomitant increases in the fusion proteins Opa1 and Mfn2 (by 36% and 53%, p<0.05). When we induced muscle disuse through denervation for 7-days, fragmented mitochondria were observed, along with significant decreases in the expression of Mfn2 and Opa1 (by 84% and 70%). To assess the effects of aging on mitochondrial morphology, young (5 month) and aged (35 month) Fisher344 Brown Norway rats were used. Aged animals also possessed smaller mitochondria and displayed increased levels of fission proteins. CONCLUSIONS: Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles. © 2013 Wiley Periodicals, Inc.

Introduction: Post-stroke muscle weakness is commonly thought to be the result of a combination of decreased voluntary activation and decreased maximum force generating ability (MFGA). We assessed the ability of muscle volumes obtained using magnetic resonance imaging (MRI) to estimate the MFGA of the plantar flexor muscle group in individuals post-stroke.

Methods: MRI was used to measure muscle volume for the plantar flexor muscle group for 17 individuals with post-stroke hemiparesis. A modified burst superimposition test was used to measure MVC and predict the MFGA of the plantar flexors.

Results: While muscle volume obtained via MRI provided information on the overall size of muscle, it overestimated the force generating ability of the paretic plantar flexors.

Discussion: Results suggest that MRI-derived muscle volume underestimates the functional impairment in individuals post-stroke. Interestingly, the central activation ratio had a strong relationship with the maximum volitional force of contraction. © 2013 Wiley Periodicals, Inc.

Introduction: Whether there is gender difference in fatigue and recovery from maximal velocity fatiguing contractions and across muscles is not understood.

Methods: 16 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 EMG activity than women (P<0.05). The decline in MVIC and power was greater, and force recovery was slower for the elbow flexors compared to knee extensors.

Discussion: The gender difference in muscle fatigue often observed during isometric tasks was diminished during fast dynamic contractions for upper and lower limb muscles. © 2013 Wiley Periodicals, Inc.

Introduction: We sought to determine whether electrical impedance myography (EIM) could serve as a diagnostic procedure for evaluation of radiculopathy.

Methods: Twenty-seven patients with clinically and radiologically diagnosed cervical or lumbosacral radiculopathy who met a gold-standard definition underwent EIM and standard needle electromyography (EMG) of multiple upper or lower extremity muscles.

Results: EIM reactance values revealed consistent reductions in the radiculopathy-affected myotomal muscles as compared to those on the unaffected side; the degree of asymmetry was associated strongly with the degree of EMG abnormality (P < 0.001). EIM had a sensitivity of 64.5% and a specificity of 77.0%; in comparison, EMG had a sensitivity of 79.7% but a specificity of 69.7%.

Discussion: These findings support the potential for EIM to serve as a new noninvasive tool to assist in diagnosis of radiculopathy; however, further refinement of the technique for this specific application is needed. © 2013 Wiley Periodicals, Inc.

Introduction: Muscle growth and regeneration are processes closely associated with the proliferation, differentiation, and apoptosis of muscle cells. Death-associated protein 1 (DAP1) has been identified as a negative regulator of autophagy. Little is known about the function of DAP1 in the regulation of myogenesis and satellite cells. Methods: Chicken satellite cells were transfected with DAP1 cloned into the pCMS-Enhanced Green Fluorescent Protein vector or pcDNA3.1 vector, or a small interference RNA against the endogenous DAP1 gene. They were assayed for proliferation, differentiation, and apoptosis. Results: The over-expression of DAP1 increased proliferation, differentiation, and myotube diameter but it had no effect on satellite cell apoptosis. In contrast, knockdown of DAP1 significantly decreased proliferation, differentiation, and number of nuclei per myotube, and it increased apoptosis of the cells. Conclusion: DAP1 is required for regulating myogenesis and apoptosis of satellite cells, which may affect muscle mass accretion and regeneration, and ameliorate muscle sarcopenia. © 2013 Wiley Periodicals, Inc.

Alterations of the lamin A/C (LMNA) gene are associated with different clinical entities, including disorders that affect skeletal and cardiac muscle, peripheral nerves, metabolism, bones, and disorders that cause premature aging. This article reviews the clinical and genetic characteristics of cardiac and skeletal muscle diseases related to alterations in the LMNA gene. There is not a univocal explanation of how LMNA gene alterations may cause these disorders; however, important goals have been achieved in understanding the pathogenic effects of LMNA gene mutations on cardiac and skeletal muscle. © 2013 Wiley Periodicals, Inc.

Introduction: Chemokines and their receptors are important mediators of inflammation. Guillain-Barré syndrome (GBS) is the most common cause of acute paralysis worldwide. Despite current treatments, outcomes are suboptimal. Specific chemokine receptor antagonists have the potential to be efficacious against pathogenic leukocyte trafficking in GBS.

Methods: A 36-year literature review was performed to summarize available data on chemokine expression in GBS and its representative animal model, experimental autoimmune neuritis (EAN).

Results: Although there were a few observational human and animal studies demonstrating chemokine ligand/ receptor expression in GBS and EAN, in vitro and in vivo functional studies using gene knockouts, neutralizing antibodies, or small molecular antagonists were limited. CCL2-CCR2, CCL5-CCR5, and CXCL10-CXCR3 have been most strongly implicated in EAN and GBS pathogenesis, providing targets for molecular blockade.

Discussion: Preclinical human in vitro and in vivo EAN studies are needed to evaluate the potential efficacy of chemokine signaling inhibition in GBS. © 2013 Wiley Periodicals, Inc.

Introduction: Ipilimumab, a monoclonal anti-CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. Methods: Retrospective review of records. Results: After 3 doses of ipilimumab a 31-year old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749. Nerve pathology showed inflammation around endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. Discussion: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood-nerve barrier due to a microvasculopathy. © 2013 Wiley Periodicals, Inc.

Introduction We investigated the motor unit (MU) firing pattern in type 2 diabetes mellitus (T2DM) patients by means of multi-channel surface electromyography (SEMG). Methods Eight T2DM patients and 8 age-matched healthy men performed a ramp-up contraction up to 20% of maximal voluntary contraction (MVC). They also performed a sustained contraction at 10% of MVC during isometric knee extension. Multi-channel SEMG signals recorded from the vastus lateralis muscle were decomposed with the Convolution Kernel Compensation technique to extract individual MU firing patterns. Results During the ramp contraction, the extent of MU firing modulation was significantly attenuated in T2DM. Variability of MU firing rate was significantly higher in T2DM at later periods during the sustained contraction. Discussion Our findings suggest that T2DM patients manifest characteristic MU activity patterns due possibly to some degree of neuromuscular impairment affecting the integrity of MU firing modulation. © 2013 Wiley Periodicals, Inc.

Carpal tunnel syndrome (CTS) is not difficult to confirm by electrodiagnosis (EDX), but the challenge lies in whether to grade the severity and the method for doing so. The arguments about grading are discussed, with an emphasis in favor, using a method that relies on the EDX data, but qualifies that it is the median neuropathy being graded and not the syndrome of CTS. Although use of latencies can be arbitrary and misleading, it is possible to apply other criteria, such as low amplitudes or conduction block and denervation, to develop a grading scale that could be applied widely. Several previously published grading schemes are reviewed, and a new method is described that combines the prior ranking criteria into 3 basic categories. Application of a grading system identifies the degree of nerve injury and thus allows the referring physician to optimally utilize the EDX report to manage the patient. © 2013 Wiley Periodicals, Inc.

Introduction: The expression of secreted protein acidic and rich in cysteine (SPARC) in skeletal muscle decreases with age. Here, we examined the role of SPARC in skeletal muscle by reducing its expression.

Methods: SPARC expression was suppressed by introducing short interfering RNA (siRNA) into mouse tibialis anterior muscle. Myofiber diameter, atrogin1 and muscle RING-finger protein 1 (MuRF1) expression, and tumor necrosis factor-α (TNFα) and tumor growth factor-β (TGFβ) signaling were then analyzed.

Results: Reduced SPARC expression caused decreases in the diameter of myofibers, especially fast-type ones, accompanied by upregulation of atrogin1, but not MuRF1, at 10 days after siRNA transfection. The expression of TNFα and TGFβ and the phosphorylation status of p38 were not affected by SPARC knockdown, whereas Smad3 phosphorylation was increased at 2 days after siRNA transfection.

Discussion: The loss of SPARC not only upregulates atrogin1 expression but also enhances TGFβ signaling, which may in turn cause muscle atrophy. © 2013 Wiley Periodicals, Inc.

Introduction: Sensory chronic inflammatory demyelinating polyneuropathy (CIDP) can be difficult to diagnose.

Method: We report 22 patients with chronic sensory polyneuropathy with ≥1 clinical sign atypical for chronic idiopathic axonal polyneuropathy (CIAP) but no electrodiagnostic criteria for CIDP.

Results: Clinical signs atypical for CIAP were: sensory ataxia (59%), generalized areflexia (36%), cranial nerve involvement (32%), rapid upper limb involvement (40%), and age at onset ≤55 years (50%). Additional features were: normal sensory nerve action potentials (36%), abnormal radial/normal sural pattern (23%), abnormal somatosensory evoked potentials (SSEPs) (100%), elevated CSF protein (73%), and demyelinating features in 5/7 nerve biopsies. Over 90% of patients responded to immunotherapy. We conclude that all patients had sensory CIDP.

Discussion: Sensory CIDP patients can be misdiagnosed as having CIAP. If atypical clinical/electrophysiologic features are present, we recommend performing SSEPs and CSF examination. Nerve biopsy should be restricted to disabled patients if other examinations are inconclusive. © 2013 Wiley Periodicals, Inc.

Introduction: We examined whether lifestyle factors differ between patients with ulnar neuropathy confirmed by electroneurography (ENG) and those with ulnar neuropathy-like symptoms with normal ulnar nerve ENG.

Methods: Among patients examined by ENG for suspected ulnar neuropathy, we identified 546 patients with ulnar neuropathy and 633 patients with ulnar neuropathy-like symptoms. These groups were compared to 2 separate groups of matched community referents and to each other. Questionnaire information on lifestyle was obtained. The electrophysiological severity of neuropathy was also graded. We used conditional and unconditional logistic regression.

Results: The responses were obtained from 59%. Ulnar neuropathy was related to smoking, adjusted OR 4.31 (95% CI 2.43-7.64) for >24 pack-years. Ulnar neuropathy-like symptoms were related to body mass index ≥30 kg/m², OR 1.99 (95% CI 1.25-3.19). Smoking was associated with increased severity of ulnar neuropathy.

Discussion: Findings suggest that smoking specifically affects the ulnar nerve. © 2013 Wiley Periodicals, Inc.

Introduction: The reliability of estimated motor unit parameters using spike triggered averaging (STA) of the surface electromyogram (sEMG) has not been tested thoroughly. We investigated factors that may induce amplitude bias in estimated motor unit action potentials (MUAPs) and shape variations.

Methods: An sEMG record was simulated. MUAPs were then estimated from the STA of the simulated EMG.

Results: Variations in MUAP duration led to under-estimation of real MUAP amplitude, while synchronized firing led to over estimation of amplitude. Spurious firing resulted in over estimation of the amplitude of small motor units but under estimation of the amplitude of large ones. Variability in amplitude and high firing rates had minimal influence on amplitude estimation. High firing rates and variation in MUAP duration led to large variations in MUAP shape. Estimation errors also correlated with shape variations.

Conclusions: Recommendations to enhance the accuracy of the STA estimates have been proposed. © 2013 Wiley Periodicals, Inc.

Introduction: Excitotoxicity plays an important role in the pathogenesis of the preferential motor neuron death observed in ALS. Continuous Theta Burst Stimulation (cTBS) by transcranial magnetic stimulation has an inhibitory effect on corticospinal excitability (CSE). We characterized the neurophysiological changes induced by cTBS in ALS. Methods: The patients received 5 daily sessions of cTBS. CSE was assessed at baseline and after each session of cTBS. Results: The amplitude of a single pulse motor evoked potential was significantly decreased (34%) over the days. The amplitude returned to baseline a week after the last session. The resting motor threshold increased significantly, whereas intracortical inhibition and facilitation did not change over the sessions. Discussion: Daily cTBS has a cumulative depressing effect on CSE in patients with ALS. Our results suggest that modulation of CSE in ALS is possible, but repetitive sessions are needed to maintain the effect. © 2013 Wiley Periodicals, Inc.

Patients with neuromuscular diseases pose many anesthetic challenges and are at a greater risk of perioperative complications, including respiratory or cardiovascular dysfunction and pulmonary aspiration. Therefore, these patients require special precautions, including interdisciplinary communication between primary care physician, neurologists, physiatrists, surgeons, and anesthesiologists. Preoperative evaluation and optimization of comorbid conditions is critical. These patients may have adverse response to neuromuscular blocking drugs and the reversal drugs (e.g., neostigmine). They should be used with caution and titrated based on objective neuromuscular monitoring. Drugs that potentiate neuromuscular blocking drugs should also be avoided or their doses limited if possible. The risk of malignant hyperthermia in certain neuromuscular diseases mandates avoidance of triggering agents such as succinylcholine and inhaled anesthetics. Patients with neuromuscular disease may also be sensitive to sedative-hypnotics and opioids, which should be used judiciously. Finally, the postoperative period requires close monitoring due to increased risk of postoperative cardiorespiratory dysfunction. © 2013 Wiley Periodicals, Inc.

Introduction: Hypertrophy of the nerve roots of the cauda equina may occur with both acquired and inherited neuropathies. Although selective nerve root involvement of the sensory roots has been described and termed chronic inflammatory sensory polyradiculoneuropathy (CISP), selective involvement of the proximal motor roots has not been described.

Methods: Clinical, electrophysiological, MRI and pathological findings are reported.

Results: Here we report a patient with cauda equina hypertrophy presenting with a pure lower motor neuron syndrome without clinical or electrophysiological evidence of sensory fiber involvement. Bowel and bladder functions were spared. Nerve root biopsy demonstrated abundant onion bulb formations. The patient experienced improvement in motor function with immunomodulatory treatment.

Conclusions: We suggest the term chronic immune demyelinating motor polyradiculopathy (CIMP) to describe this particular form of CIDP, thereby expanding the clinical spectrum of CIDP. © 2013 Wiley Periodicals, Inc.

Introduction: Psoriasis is a T-cell mediated skin disorder with uncommon extracutaneous manifestations. Rare patients with psoriasis and myopathy have been reported. Methods: We conducted a retrospective review of medical records of psoriasis patients seen at the Mayo Clinic January 1, 1996 - May 31, 2011. Patients who had pathologically-confirmed myopathy or lymphocytic infiltrates in muscle were included. Results: Among 11,370 psoriasis patients, 13 had pathologically-confirmed myopathies. Seventy percent were inflammatory myopathies, and 2 had focal inflammation in muscle. Psoriasis preceded myopathy onset in two-thirds (median, 14.7 years). Half had psoriatic arthritis; 60% had other autoimmune disorders. Patients who received anti-TNF-α therapy had a higher risk for developing myopathy or inflammation in muscle (odds ratio: 4.45). Conclusions: Myopathy or inflammation in muscle affects 1.32 in 1,000 psoriasis patients. Concomitant autoimmune disorders, psoriatic arthritis, and exposure to anti-TNF-α therapy may be associated with increased risk of developing myopathy in psoriasis patients. © 2013 Wiley Periodicals, Inc.

BACKGROUND: Nerve deformation affects physiological function. Bands of Fontana are an optical manifestation of axonal undulations and may provide a structural indicator of nerve strain.

METHODS: We developed an automated Fourier-based image processing method to quantify the periodicity of bands of Fontana both in bright field images and in axonal undulations in immuno-labeled longitudinal sections.

RESULTS: We found a strong linear relationship between applied strain and the frequency of bands of Fontana in rat sciatic nerves (-0.0056 μm^-1.%^-1, r² = 0.829; P < 0.05). This relationship agreed with the observed trend between strain and axonal waviness, calculated from longitudinal sections of sciatic nerves immuno-labeled against myelin basic protein.

CONCLUSIONS: This accurate and objective approach has potential to increase our understanding of structure-function relationships in the nervous system and to guide preservation and enhancement of neural function. © 2013 Wiley Periodicals, Inc.

This report summarizes the progress made in newborn screening for Duchenne muscular dystrophy (DMD). This subject was discussed fully at a symposium held on September 11-12, 2012, in Bethesda, MD, by a group of experts from multiple disciplines. The meeting was triggered by the simultaneous combination of improvements in methods for newborn screening for DMD and greater potential for treatment. On the screening side, a two-tier system of newborn screening was introduced that enabled creatine kinase levels and DMD gene analysis to be done on the same dried blood spots obtained at birth. Treatment improvements included promising results from exon skipping as well as multiple studies showing long-term benefits of glucocorticoids and data indicating that early intervention of both forms of therapy was the most beneficial. Conclusions from this symposium with supportive data could have a significant impact on propelling efforts for approval of newborn screening for DMD. © 2013 Wiley Periodicals, Inc.

Introduction: Sepsis often causes diaphragm contractile dysfunction. Dihydropyridine receptors (DHPRα1s and DHPRα1c) and ryanodine receptors (RyR1, RyR2, and RyR3) are essential for excitation-contraction coupling in striated muscles. However, their expressions in diaphragm during sepsis have not been explored. Methods: Eight rats received endotoxin while eight more rats received a placebo. After 24 hours, diaphragmatic isometric contractile force was measured. The mRNA and protein levels of DHPRs and RyRs in diaphragm muscles were determined. Results: Sepsis weakened the diaphragm contractile function. The expression levels of DHPRα1s and RyR1 were significantly lower in septic rats than in control rats. The expression levels of DHPRα1c and RyR3 were unaffected by sepsis. RyR2 was undetectable at both mRNA and protein levels in control and sepsis groups. Conclusions: Weakened diaphragm contraction observed in the septic rats was associated with the reduced mRNA and protein expressions of DHPRα1s and RyR1, the isoforms of skeletal muscles. © 2013 Wiley Periodicals, Inc.

Introduction: We investigated neural mechanisms of finger force control. Methods: Ten right-handed subjects performed isometric finger flexion and extension force productions at 10 ~ 60% of maximum voluntary contraction (MVC) using 4 fingers of the dominant hand. Transcranial magnetic stimulation (TMS) was applied over the contralateral hand motor area. We measured fluctuation of the background force and TMS responses from finger flexor and extensor muscles. Results: Force fluctuation was greater during finger extension than during finger flexion. The motor evoked potentials (MEPs) increased with force levels in the flexor digitorum superfialis (FDS) during finger flexion and the extensor digitorum communis (EDC) during finger extension. The TMS-induced forces increased up to 40% MVC and then decreased during finger flexion, whereas they continuously decreased through the tested force levels during finger extension. Conclusions: These results suggest that FDS and EDC are controlled by different neural mechanisms, most likely attributable to their different functional roles in daily activities. © 2013 Wiley Periodicals, Inc.

Introduction: A protocol for quantitative ultrasound of facial muscles (procerus, zygomaticus major, levator labii superior, depressor anguli oris, mentalis, orbicularis oris pars labialis, orbicularis oris pars marginalis) was developed.

Methods: Muscle thickness (MT) and echo intensity (EI) were measured in 12 healthy subjects and a myotonic dystrophy type 1 patient.

Results: MT ranged between 0.15 - 0.30 mm, except for the procerus muscle (0.06 mm). EIs ranged from 1 to 34, except for the procerus muscle. Reproducibility for MT was fair for the orbicularis oris pars labialis, excellent for the procerus and levator labii, and good for the other muscles. The myotonic dystrophy type 1 patient showed high EIs, outside the range in healthy subjects in 6 of the 7 muscles. MT was lower than the range in healthy subjects in 4 muscles.

Discussion: Quantitative muscle ultrasound of the facial muscles is feasible and shows moderate to excellent reproducibility. © 2012 Wiley Periodicals, Inc.

Introduction: Triple A syndrome is an autosomal recessive disease, characterized by esophageal achalasia, alacrima, adrenal insufficiency, and involvement of central, peripheral, and autonomic nervous systems. This disease mimics amyotrophic lateral sclerosis in some patients. The causative gene encodes ALADIN, a nuclear pore complex (NPC) component. Only 5 patients have been reported in Japan.

Methods: We conducted the first nationwide survey of Triple A syndrome. Identified mutants were expressed as GFP-fusion proteins in cultured cells.

Results: Two new patients were identified, and 1 had a novel mutation (p.Ser182fsX19). All mutant proteins tested were mislocalized from NPC to cytoplasm.

Conclusions: The most consistent neurologic manifestation of Triple A syndrome in Japanese patients was progressive bulbospinal muscular atrophy with both upper and lower motor neuron involvement, which mimicked motor neuron disease, similar to patients reported in Western countries. The identification of the new patients suggests that more cases are undiagnosed in Japan. © 2012 Wiley Periodicals, Inc.

Introduction: Severe lesions in the facial nerve may have extensive neural tissue loss and leave isolated stumps that impose technical difficulties for nerve grafting.

Methods: We evaluated bone marrow stem cells (BMSC) in a silicone conduit for rat facial nerve regeneration from isolated stumps. Group A utilized empty silicone tubes; in groups B-D the tube was filled with acellular gel; and in groups C and D undifferentiated BMSC (uBMSC) or Schwann-like cells differentiated from BMSC (dBMSC) were added, respectively. Compound muscle action potentials (CMAP) were measured, and histology was evaluated.

Results: Groups C and D had the highest CMAP amplitudes. Group C had shorter CMAP durations than groups A, B, and D. Distal axonal number and density were increased in group C compared to groups A and B.

Conclusions: Regeneration of the facial nerve was improved by both uBMSC and dBMSC in rats, yet uBMSC was associated with superior functional results. © 2012 Wiley Periodicals, Inc.

Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches still remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnosis, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests. © 2013 Wiley Periodicals, Inc.

Introduction: CMT2A2 is associated with mutations in the mitofusin 2 gene, which encodes a protein involved in mitochondrial fusion. Ethambutol is an antimycobacterial agent associated with toxic optic neuropathies. Ethambutol-induced optic neuropathy occurs in patients with mutations in a related fusion gene, OPA1, which is responsible for Autosomal Dominant Optic Atrophy.

Case: We describe a patient with CMT2A2 (MFN2 mutation: T669G, F223L) who developed accelerated weakness, vocal cord paralysis and optic atrophy after receiving ethambutol. Deterioration began within months of initiating ethambutol therapy. With discontinuation of ethambutol, neurologic deterioration stabilized with subsequent improvement in visual fields.

Discussion: CMT2A2 is part of a group of genetic disorders which share an association with the process of mitochondrial fusion. This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely susceptible to ethambutol-induced neurotoxicity. This has implications regarding the underlying pathophysiology of mitochondrial fusion defects. © 2012 Wiley Periodicals, Inc.

INTRODUCTION

Peripheral neuropathy is the most common neurological complication of HIV but is widely under-diagnosed in resource-limited settings. We investigated the utility of screening tools administered by non-physician health care workers (HCW) and quantitative sensory testing (QST) administered by trained individuals for identification of moderate/severe neuropathy.

METHODS

We enrolled 240 HIV-infected outpatients using two-stage cluster randomized sampling. HCWs administered the several screening tools. Trained study staff performed QST. Tools were validated against a clinical diagnosis of neuropathy.

RESULTS

Participants were 65% women, mean age 36.4 years, median CD4 324 cells/μL. 65% were taking antiretrovirals, and 18% had moderate/severe neuropathy. The screening tests were 76% sensitive in diagnosing moderate/severe neuropathy with negative predictive values of 84-92%. QST was less sensitive but more specific.

DISCUSSION

Screening tests administered by HCW have excellent negative predictive values and are promising tools for scale-up in resource-limited settings. QST shows promise for research use. © 2013 Wiley Periodicals, Inc.

Introduction: Duchenne muscular dystrophy (DMD) is caused by a genetic defect resulting in absent dystrophin, yet children are able to walk when small and young but lose this ability as they grow. The mdx mouse has absent dystrophin yet does not exhibit significant disability.

Methods: Allometric modeling of linearly increasing load per muscle fiber and stress on the sarcolemma with growth and exponential decline associated with loss of muscle fibers correlated with case studies and animal models of DMD.

Results: Smaller species or breeds are predictably less affected than large as follows: mdx mice < small Golden Retriever muscular dystrophy (GRMD) dogs < large GRMD dogs < humans. Case reports of combined growth hormone and dystrophin deficiency show a relatively benign course of disease.

Conclusions: Future therapeutic trials in DMD might include specific growth inhibitors in combination with standard of care treatments to the delay the clinical onset and reduce severity of disease and disability. © 2013 Wiley Periodicals, Inc.

Purpose: We examined the influence of maximum range of motion (MROM) and passive stiffness on the viscoelastic stretch response. Methods: Four 30-s constant-angle passive stretches of the plantar flexors at a pre-determined torque were performed to determine the rate and relative change in stress relaxation (decline in torque during each 30-s stretch) and creep (increase in ankle joint angle across all 4 stretches). Stress relaxation and creep responses were examined between participants after they were ranked into high and low groups based on MROM and passive stiffness values. Results: Stress relaxation responses were unaffected by MROM and passive stiffness, however creep was influenced by differences in passive stiffness but not MROM. Conclusion: Passive stiffness but not MROM influences the acute viscoelastic responses to passive stretching. Participants with less stiff plantar flexors experience greater increases in range of motion when they are stretched at a constant torque. © 2013 Wiley Periodicals, Inc.

Introduction: Reliability and reference values are not well established for most dynamic sonographic measurements of the median nerve (MN) and flexor tendons that may be used for diagnosing carpal tunnel syndrome (CTS).

Methods: Wrists of 20 healthy participants were imaged using ultrasound. Cines of the carpal tunnel inlet were acquired during hand motion. Based on shape and displacement measurements, intrarater and interrater reliability and reference values were calculated.

Results: Intraclass correlation coefficients (ICC) for measurements of the MN and most flexor tendons were ≥0.51 for shape parameters and ≥0.71 for displacement parameters. During motion the MN flattened with ulnar movement, tendons became more circular, and flexor tendons of corresponding fingers moved towards each other.

Discussion: Shape and displacement measurements of the MN and most flexor tendons had reliability results ranging from moderate to excellent. The reference values may be useful for the diagnosis of CTS. © 2013 Wiley Periodicals, Inc.

Introduction: Motor unit action potential (MUAP) reference values are usually given per muscle and age group.

Objectives: To evaluate the change in MUAP size at different contraction levels using the Concentric Macro (ConMac) EMG technique.

Methods: ConMac needles were used to record the electrode cannula MUAP and measure its amplitude and area during weak, moderate, and strong muscle contractions.

Results: MUAP area and amplitude gradually increased from weak to strong contraction levels in all muscles studied. MUAP amplitudes were larger in distal than proximal muscles, likely because of a higher fiber density distally.

Discussion: MUAP normal values in the literature per muscle do not take into account the contraction level at which they were recorded and can misrepresent the interpretation of normal. Concentric Macro EMG is a simple and useful compliment to routine EMG studies and yields additional information on MUAP neurophysiology. © 2013 Wiley Periodicals, Inc.

Introduction: Changes in muscle architecture induced by eccentric knee extensor training remain unclear, as well as the adaptive responses of synergistic knee extensor muscles with different geometrical designs. Methods: Ultrasonographic images were taken from rectus femoris (RF) and vastus lateralis (VL) of 20 male volunteers before and after a non-training control period of 4 weeks, and additional evaluations were performed after 4, 8, and 12 weeks of isokinetic eccentric training. Results: RF and VL had significant changes in muscle architecture within the first 4 training weeks, and the adaptive response throughout the intervention was similar. Muscle thickness increased around 7-10%; fascicle length increased 17-19%; and pennation angle was unchanged. Discussion: Increased muscle thickness due to eccentric training was related to increased fascicle length and not to pennation angle changes. Even though RF and VL have different fascicular geometry, these muscles had similar morphological adaptations to eccentric training. © 2013 Wiley Periodicals, Inc.

Introduction: Quadriceps muscle dysfunction is common in COPD. Determining, and, if possible, predicting quadriceps phenotype in COPD is important for patient stratification for therapeutic trials.

Methods: In biopsies from 114 COPD patients and 30 controls, we measured fiber size and proportion and assessed the relationship with quadriceps function (strength and endurance), clinical phenotype (lung function, physical activity, fat-free mass) and exercise performance. In a subset (n=40) we measured muscle mid-thigh cross-sectional area by computed tomography.

Results: Normal ranges for fiber proportions and fiber cross-sectional area were defined from controls; we found isolated fiber shift in 31% of patients, isolated fiber (predominantly type II) atrophy in 20%, both shift and atrophy in 25%, and a normal fiber appearance in 24%. Clinical parameters related poorly to muscle biopsy appearances.

Discussion: Quadriceps morphology is heterogeneous in COPD and cannot be predicted without biopsy, underlining the need for biomarkers. © 2013 Wiley Periodicals, Inc.

Introduction: The aim of this study was to determine whether the manner in which a target force is approached can influence the EMG and mechanical parameters evoked by transcranial magnetic stimulation (TMS) during brief muscle contractions.

Methods: The amplitude of motor-evoked potentials (MEP) and superimposed twitch and the duration of the silent period were recorded in 8 healthy participants in response to TMS delivered during brief isometric voluntary contractions of the quadriceps maintaining a target force (10 and 50% of maximal voluntary force) or gradually increasing or decreasing to it. Results: MEP and superimposed twitch, unlike the silent period, are influenced by the manner of reaching a low force.

Discussion: This study demonstrates that clear instructions must be provided to research participants and patients. Rapidly increasing to a target force without exceeding it and maintaining the force before the delivery of TMS results in stable and representative MEP amplitudes. © 2013 Wiley Periodicals, Inc.

Methods: Spontaneous activity in the tongue and sternocleidomastoid (SCM) muscles was reviewed retrospectively in 17 ALS patients.

Results: Needle EMG showed spontaneous activity in the tongue in 14 out of 17 patients (82%) and in 6 patients of 17 (35%) in SCM. Spontaneous EMG activity in the tongue was found in patients with and without bulbar symptoms.

Conclusions: Needle EMG is a valuable method for assessing clinical and subclinical involvement of the tongue in patients with bulbar and limb onset ALS. Adequate relaxation of the tongue is a prerequisite for proper spontaneous activity recording. © 2013 Wiley Periodicals, Inc.

Introduction: Fatty infiltration of muscles may be seen in many neuromuscular disorders, including glycogen storage diseases (GSD), muscular dystrophies, and amyotrophic lateral sclerosis. Recording pathologic involvement of musculature in these patients is cumbersome, given marked disease heterogeneity within each individual. We describe a novel method for simplifying this process and present its application in a patient with GSD type IIIa. Methods: A color-coded visual mapping tool was developed based on a commonly used spreadsheet platform. Results: This tool depicts individual muscle groups as shapes linked to data cells corresponding to quantitative MRI-based measures of fatty infiltration and weakness assessed by physical examination. It allows for rapid evaluation and chronological comparison of all mapped muscle groups on a single graphical sheet, as well as assessment of response to therapy. Discussion: This can be applied in any neuromuscular disorder where muscle function is assessed by clinical or imaging scores. © 2013 Wiley Periodicals, Inc.

Introduction: We investigated muscle activation strategy and performance of knee extensor and flexor muscles of children and adults with Generalized Joint Hypermobility (GJH) compared with controls. Methods: Muscle activation, torque steadiness, electromechanical delay, and muscle strength were evaluated in 39 children and 36 adults during isometric knee extension and flexion. Subjects performed isometric maximum contractions, submaximal contractions at 25%MVC, and explosive contractions. Results: Agonist activation was reduced, and co-activation ratio was greater in GJH during knee flexions compared to controls. Torque steadiness was impaired in adults with GJH during knee flexion. No effect of GJH was found on muscle strength or electromechanical delay. Correlation analysis revealed association between GJH severity and function in adults. Conclusions: The results indicate that muscle activation strategy and quality of force control were significantly affected in adults with GJH during knee flexion, while only muscle activation strategy was affected in children with GJH. © 2013 Wiley Periodicals, Inc.

Introduction: We examined generalized versus joint-specific influences on muscle co-activation.

Methods: Muscle co-activation was assessed during maximal isometric and isokinetic knee and elbow joint extension moments in 48 healthy subjects (27 men). Local (joint-specific) and generalized (person-specific) contributions were examined using a combination of statistical tests: regression using generalized estimating equations (GEEs), exploratory factor analysis, and cluster analysis.

Results: GEEs produced similar significant coefficients for gender and joint; contraction type and test condition (angle or velocity) were not significant. Factor analysis indicated 2 joint-based factors, and cluster analysis indicated 2 groups of individuals, those with or without elevated co-activation at the knee and elbow. Women exhibited greater co-activation at both joints, however, no consistent influences of angle or velocity were observed at either joint.

Discussion: We conclude that muscle co-activation is a neuromuscular control response determined by local, joint-specific, and generalized, individual-specific influences. © 2013 Wiley Periodicals, Inc.

Background: Little data is available to quantify the risks and benefits of microvascular decompression (MVD) in elderly patients with hemifacial spasm.

Methods: Twenty-seven patients above the age of 65 years and 104 younger patients who underwent MVD for HFS over a three-year period were analyzed retrospectively and compared.

Results: Twenty-six (96.3%) elderly patients and 93 of 104 (89.4%) young patients reported a spasm-free status at a mean follow-up of 26.5 months after MVD. No significant difference in spasm-free status was noted. Cranial nerve complications and other major complications were compared, and no significant differences were noted.

Discussion: Although this study does not offer definitive inclusion or exclusion criteria or clearly establish the safety of MVD for HFS in the elderly, our experience suggests that many elderly patients with HFS can undergo MVD safely, with outcomes and risk profiles similar to younger patients. © 2013 Wiley Periodicals, Inc.

Introduction: Cachexia increases morbidity and mortality of cancer patients. The progressive loss of muscle mass negatively affects physical function and quality of life. We previously showed reduced muscle IGF-1 expression and enhanced myostatin signaling in tumor-bearing animals. This study was aimed at investigating whether similar perturbations occur in gastric cancer patients.

Methods: Early perturbations of myostatin and IGF-1 signaling (including the expression of muscle-specific ubiquitin-ligases) were investigated in 16 gastric cancer patients and in 6 controls by analyzing muscle mRNA expression with semi-quantitative Reverse Transcriptase-PCR and real-time PCR.

Results: In gastric cancer patients, muscle mRNA levels for IGF-1, myostatin, and atrogin-1 were reduced irrespective of weight loss (≤ 5% or > 5%) while MuRF1 expression was unchanged.

Discussion: IGF-1 and myostatin mRNA levels are down-regulated in gastric cancer patients who have minimal or no weight loss. These early alterations are particularly relevant in order to devise preventative and therapeutic strategies for cancer cachexia. © 2013 Wiley Periodicals, Inc.

Introduction: The prevalence of bifid median nerves and persistent median arteries, their co-occurrence, and their relationship to carpal tunnel syndrome (CTS) are only partially understood.

Methods: We screened 1026 wrists in 513 Latino manual laborers in North Carolina for bifid median nerves and persistent median arteries with electrodiagnosis and ultrasound.

Results: 8.6% of wrists had a bifid median nerve, and 3.7% of wrists had a persistent median artery independent of sub-group ethnicity, age, gender, or type of work. An association with definite carpal tunnel syndrome was not found. The presence of either anatomic variant was associated with a high likelihood of co-occurrence of another variant in the same or the contralateral wrist.

Conclusions: The occurrence of median anatomic variants can be determined in field studies using ultrasound. Persistent median arteries and bifid median nerves tend to co-occur but do not put manual laborers at additional risk of developing CTS. © 2013 Wiley Periodicals, Inc.

Specific Aim: To test 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 of 24 patients with diabetes (DM) on consecutive days. Results: No significant intra-observer differencesbetween days 1 and 2 were found, but significant inter-observer differences were found. Use of standard reference values did not correctfor these observed differences. Discussion: The inter-observer 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 inter-rater variability in therapeutic trials, the same electromyographers might 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 will eliminate inter-observer variability. © 2012 Wiley Periodicals, Inc.

Purpose: To examine and compare the effects of 3 days of dynamic constant external resistance (DCER) and isokinetic (ISOK) training and subsequent detraining on the electromechanical delay (EMD). Methods: Thirty-one men (mean ± SD age = 22.2 ± 4.2 yrs; body mass = 77.9 ± 12.9 kg; height = 173.9 ± 5.4 cm) were randomly assigned to a DCER training group, ISOK training group, or control (CONT) group. Results: No significant changes were found for EMD from pre- to post-training assessments 1, 2, and 3 (mean SE = 4.5 ± 0.2 ms, 4.7 ± 0.2, 4.5 ± 0.1, 4.5 ± 0.2, respectively) (P> 0.05). Discussion: It can be hypothesized that increases in strength observed following a short-term resistance training program may not be attributed to stiffness changes in the series elastic component. © 2012 Wiley Periodicals, Inc.

Introduction: Hindlimb unloading-induced muscle atrophy is often assessed after a homeostatic state is established, thus overlooking theearly adaptations that are critical to developing this pattern of atrophy. Methods: Muscle function and physiology werecharacterizedat 0, 1, 3, 7, and 14 days of hindlimb suspension (HS). Results: Reductions in muscle mass were maximal by Day 14 of HS. Functional strength and isolated muscle strength were reduced. MyHC-I and –IIa expressing fibers were reduced in sizeby Day 7 in the soleus and by Day 14 in the gastrocnemius (MyHC-I fibers only). Atrogin-1 and MuRF1expression was increased by Day 1 in both the calf and tibialis anteriorwhile IGF-1 expression was significantly reduced on Day 3. Phosphorylation of Akt was reduced on Day 14. Conclusions: Insight into these early changes in response to HS improves understanding of the molecular and functional changes that lead to muscle atrophy. © 2012 Wiley Periodicals, Inc.

Introduction Anatomical properties between proximal and other regions within the human rectus femoris (RF) muscle are non-uniform. We aimed to clarify the possible region-specific myoelectric manifestations of fatigue within the RF muscle by using an advanced surface electromyography (SEMG) technique. Methods Nine healthy men performed sustained contractions at 50% of maximal voluntary contraction until exhaustion during isometric knee extension and hip flexion. During these contractions, multi-channel SEMG was recorded from the RF muscle by using 46 electrode pairs which cover most of the superficial area of the muscle. Results Fatigue-induced SEMG, i.e. an increase in root mean square and a decrease in median frequency, was not uniform within the muscle during both tasks and was greater in proximal regions. Discussion Our findings suggest that myoelectric manifestations of fatigue within the human RF muscle are localized, and proximal regions are more fatigable than other regions within this muscle. © 2012 Wiley Periodicals, Inc.

Cervical spondylosis (CS) is a common disease in adults and may coexist with amyotrophic lateral sclerosis (ALS). It is important to detect ALS coexisting with CS (ALS-cs) at an early stage, especially when surgical treatment of CS is planned.

In this review, we present an overview of the role of exercise in neuromuscular disease (NMD). We demonstrate that despite the different pathologies in NMDs, exercise is beneficial, whether aerobic/endurance or strength/resistive training, and we explore whether this benefit has a similar mechanism to that of healthy subjects. We discuss further areas for study, incorporating imaginative and novel approaches to training and its assessment in NMD. We conclude by suggesting ways to improve future trials by avoiding previous methodological flaws and drawbacks in this field. Muscle Nerve, 2013

In patients with obstructive sleep apnea (OSA), intermittent apnea and hypopnea might cause different adaptations in inspiratory and peripheral muscles. In this study we aimed to determine the changes that occur in muscle activation characteristics during incremental exercise testing in patients with severe OSA. Surface electromyography of inspiratory muscles and knee extensors was performed.

Introduction: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). Results: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3-point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo (P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo (P < 0.0001). Eculizumab was well tolerated. Conclusion: The data suggest that eculizumab may have a role in treating severe, refractory MG. Muscle Nerve 000:000–000, 2013

Introduction: In 2004, a Cochrane Review and AAN practice parameter concluded that prednisone 0.75 mg/kg/day is of short-term efficacy in Duchenne muscular dystrophy (DMD). Subsequent efforts to standardize care for DMD indicated wide variation in corticosteroid use. Methods: We surveyed physicians who follow patients with DMD, including: (1) clinics in the TREAT-NMD (Translational Research in Europe—Assessment and Treatment of Neuromuscular Diseases) network (predominantly Europe) and (2) U.S. MDA clinic directors. We also documented the co-administered corticosteroids in a trial of a putative treatment (ataluren) for DMD. Results: Of 105 Treat-NMD clinicians, corticosteroids were not used in 10 clinics, and 29 different regimens were used—the most frequent 0.75 mg/kg/day prednisone (61 centers); 10 days on/10 days off (36 centers); 0.9 mg/kg/day deflazacort (32 centers); and 5 mg/kg/day on weekends (10 centers). Similar diversity was identified in MDA clinics and in the ataluren trial. Conclusions: Variability in corticosteroid use suggests uncertainty about risks/benefits of corticosteroid regimens for DMD. Muscle Nerve 000:000–000, 2013

Introduction: Far-field potentials (FFPs) from muscles other than the abductor digiti minimi (ADM) may interfere with motor unit number estimation (MUNE) from that muscle. Methods: We identified the origin of each surface motor unit potential (SMUP) during hypothenar MUNE using the multiple point stimulation method in 20 control subjects by recording from individual ulnar-innervated muscles with a common proximal reference (pref). Results: ADM SMUPs comprised 39.0% of the accepted SMUPs, followed by those from the fourth dorsal interosseous muscle (14.0%), the fourth lumbrical muscle (9.2%), and the second and third palmar interosseous muscles (8.8% each). The percentage of ADM SMUPs varied from 18% to 73% of accepted SMUPs among individual subjects. Accepted non-ADM SMUPs were usually much smaller than ADM SMUPs, and many more non-ADM SMUPs were excluded due to their small size. Conclusions: A large contribution from non-ADM or non-hypothenar SMUPs obscures the meaning of the MUNE value. Muscle Nerve, 2013

Introduction: Contamination by far-field potentials (FFPs) may interfere with motor unit number estimation (MUNE) in the ulnar nerve. Methods: Surface motor unit potentials (SMUPs) from 29 spinal and bulbar muscular atrophy (SBMA) patients and 27 control subjects were classified into SMUPs from the abductor digiti minimi muscle (ADM SMUPs) or non-ADM SMUPs, based on the waveform patterns from 3-channel recordings. Results: The mean areas of the ADM SMUPs and non-ADM SMUPs in control subjects were 219.0 ± 131.3 and 63.7 ± 48.5 μVms, respectively. In SBMA patients they were 1988.9 ± 999.4 and 222.7 ± 125.7 μVms, respectively. The percentages of non-ADM SMUPs were 68 ± 22% in controls and 84 ± 15% in SBMA patients. Conclusions: Non-ADM SMUPs generated mainly by FFPs often had a negative onset in the routine lead and were indistinguishable from ADM SMUPs. More frequent exclusion of smaller non-ADM SMUPs in controls by size criteria would reduce the diagnostic yield of MUNE. Muscle Nerve, 2013

Interferons (IFNs) are potent extracellular protein mediators of host defense and homeostasis. Type I IFNs have well-established direct antiviral, antiproliferative, and immunomodulatory properties. The worldwide, increasing and long-term use of INFα, particularly for the treatment of chronic hepatitis C virus infection, has drawn attention to the development or exacerbation of numerous autoimmune phenomena, including a spectrum of myopathies. Management entailed withdrawal of INFα with supportive, immunomodulatory, and symptomatic treatment as deemed clinically indicated. However, IFNβ therapy for relapsing-remitting multiple sclerosis rarely triggered clinically manifest autoimmunity. The mechanisms through which type I IFNs induce autoimmunity are incompletely understood, and they likely vary depending on the inherent differences in the pathogenesis of the immune disorder on a background of patient genetic susceptibility. INFα therapy had unpredictable effects on hepatitis C-associated myopathies. The immunomodulating effects of IFNβ therapy showed no clinically significant benefit during prospective controlled treatment trials of inclusion body myositis. Type I IFNs have the theoretical potential to either cause or treat autoimmune muscular disorders by altering the complicated and delicate balances within immune system networks. Muscle Nerve, 2009

Current standards for diagnosing polyneuropathies (PN) and motor neuron disease (MND) sometimes lack early sensitivity and result in delayed diagnosis and treatment. Neuromuscular ultrasound (NMUS), already established in the diagnosis of entrapment neuropathies, may offer another means of diagnosis and monitoring response to therapy. This review of current evidence discusses diffuse nerve hypertrophy in hereditary demyelinating neuropathies, multifocal nerve enlargement in acquired demyelinating PN and the lack of readily apparent structural change in axonal neuropathies. NMUS detection of fasciculations and muscular change in MND is also reviewed, along with the need for further research to better define the role of nerve imaging in patients with PN. Muscle Nerve 47: 790–804, 2013

Neuromuscular clinicians are frequently asked to evaluate patients referred for asymptomatic elevations in creatine kinase (CK), a catalytic enzyme that combines creatine and ATP to form phosphocreatine and ADP. This reaction is crucial for cellular energy generation and metabolism. This laboratory finding, often referred to in simplified lexicon as asymptomatic hyperCKemia, continues to generate controversy at several levels, including definition, the extent of evaluation, and the yield of diagnostic testing. In this review, we summarize the literature based on series of patients with asymptomatic hyperCKemia and provide a rational clinical approach to reveal identifiable underlying causes. Muscle Nerve 47: 805–815, 2013

No longitudinal data on the normal development of muscle thickness (MT), quantitative muscle ultrasound echo intensity (EI), and muscle force (MF) in healthy children are yet available.

The aims of this study were to identify factors affecting the measurement of nerve cross-sectional area (CSA) and to establish normal reference values for nerve ultrasonography of the upper extremity.

We investigated whether intrinsic muscle contractile properties in force summation and postactivation potentiation (PAP) can be used as indices of maximal muscle strength and muscle fatigue.

Characterization of muscle elasticity will improve the diagnosis and treatment of muscle disorders. The purpose is to compare the use of magnetic resonance elastography (MRE) and ultrasound elastography (USE) techniques to elucidate the MRE cartography of thigh muscles.

Introduction: There is no therapeutic approach that provides precise and rapidly reversible inhibition of motor nerve and muscle activity for treatment of spastic hypertonia. Methods: We used optogenetics to demonstrate precise and rapidly reversible light-mediated inhibition of motor nerve and muscle activity in vivo in transgenic Thy1::eNpHR2.0 mice. Results: We found optical inhibition of motor nerve and muscle activity to be effective at all muscle force amplitudes and determined that muscle activity can be modulated by changing light pulse duration and light power density. Conclusions: This demonstration of optical inhibition of motor nerves is an important advancement toward novel optogenetics-based therapies for spastic hypertonia. Muscle Nerve 47: 916–921, 2013

Introduction: The influence of cold temperatures on neuropathies has been reported previously, but its impact on carpal tunnel syndrome (CTS) is not well analyzed. Methods: We analyzed the frequency of CTS among neurophysiological evaluations according to seasonal variation in 9574 consecutive patients (4260 with CTS). Results: A higher frequency of CTS was found in the winter (50.8%), and the lowest number for CTS diagnosis was found in the summer (38.9%). In both autumn and spring the prevalence remained stable at an intermediate level between summer and winter at 42.8% and 43.5%, respectively. Conclusion: CTS frequency was much higher in winter in this center. Muscle Nerve 47: 925–927, 2013