Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy.

Objective: We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy.

Methods: Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR.

Results: All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation.

Investigating sodium valproate as a treatment for McArdle disease in sheep.

McArdle disease is due to an absence of the enzyme muscle glycogen phosphorylase and results in significant physical impairment in humans. We hypothesised that sodium valproate, an HDAC inhibitor, might have the ability to up-regulate the enzyme. We treated McArdle sheep with sodium valproate given enterically at 20-60 mg/kg body wt.

Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans.

Antisense oligonucleotide induction of progerin in human myogenic cells.

We sought to use splice-switching antisense oligonucleotides to produce a model of accelerated ageing by enhancing expression of progerin, translated from a mis-spliced lamin A gene (LMNA) transcript in human myogenic cells. The progerin transcript (LMNA Δ150) lacks the last 150 bases of exon 11, and is translated into a truncated protein associated with the severe premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS). HGPS arises from de novo mutations that activate a cryptic splice site in exon 11 of LMNA and result in progerin accumulation in tissues of mesodermal origin.

Normal and aberrant splicing of LMNA.

The LMNA gene gives rise to at least three isoforms (lamin A, C, lamin AΔ10) as a result of normal alternative splicing, regulated by cis- and trans-acting regulatory factors, as well as the 5' and 3' untranslated regions of the gene. The two main isoforms, lamin A and C, are constitutive components of the fibrous nuclear lamina and have diverse physiological roles, ranging from mechanical nuclear membrane maintenance to gene regulation. The clinical spectrum of diseases (called 'laminopathies') caused by LMNA mutations is broad, including at least eight well-characterised phenotypes, some of which are confined to the skeletal muscles or skin, while others are multisystemic.

Evidence that the LRRK2 ROC domain Parkinson's disease-associated mutants A1442P and R1441C exhibit increased intracellular degradation.

Mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are the leading genetic cause of Parkinson's disease (PD). In characterizing the novel ROC domain mutant A1442P, we compared its steady-state protein levels, propensity to aggregate, and toxicity with the pathogenic R1441C mutant and wild-type (WT) LRRK2. Mutant (R1441C and A1442P) and WT LRRK2 fused to green fluorescent protein (GFP) and FLAG were transiently expressed in HEK293 cells using plasmid constructs.

Phosphorylase re-expression, increase in the force of contraction and decreased fatigue following notexin-induced muscle damage and regeneration in the ovine model of McArdle disease.

McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease.

Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles.

Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of healthy people and its implication in 'natural' ageing has been proposed.

Is cholesterol and amyloid-β stress induced CD147 expression a protective response? Evidence that extracellular cyclophilin a mediated neuroprotection is reliant on CD147.

The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-β (Aβ), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aβ can alter CD147 expression in rat cortical neuronal cultures.

Primary over-expression of AβPP in muscle does not lead to the development of inclusion body myositis in a new lineage of the MCK-AβPP transgenic mouse.

The aim of this study is to determine whether primary over-expression of AβPP in skeletal muscle results in the development of features of inclusion body myositis (IBM) in a new lineage of the MCK-AβPP transgenic mouse. Quantitative histological, immunohistochemical and western blotting studies were performed on muscles from 3 to 18 month old transgenic and wild-type C57BL6/SJL mice. Electron microscopy was also performed on muscle sections from selected animals.

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.

A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in Parkinson's disease and is reversed by levodopa.

Objectives: In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinson's disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion-extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa.

Methods: In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min.

Complement-mediated muscle cell lysis: a possible mechanism of myonecrosis in anti-SRP associated necrotizing myopathy (ASANM).

The mechanism of necrotizing myopathy associated with antibodies to signal recognition particle (SRP) remains unclear. We investigated the effect of anti-SRP+serum and complement on cell viability in myoblast cultures. Cell viability was only slightly reduced by incubation with anti-SRP+serum compared with control serum.

Investigation of splicing changes and post-translational processing of LMNA in sporadic inclusion body myositis.

Some features of sporadic inclusion body myositis (s-IBM) suggest that there is acceleration of the normal ageing process in muscle tissue. LMNA encodes the nuclear lamina proteins lamin A/C through alternative splicing, and aberrant splicing of exon 11 leads to the premature ageing disease, Hutchinson-Gilford progeria syndrome. Progerin, the pathogenic isoform expressed in HGPS tissues, has also been detected at low levels in tissues of normal individuals with aging.

Preserved corticospinal conduction without voluntary movement after spinal cord injury.

Study Design: Case report.

Objectives: To identify preserved corticomotor connection in chronic spinal cord injury (SCI) in the absence of clinically observable movement.

Setting: Rehabilitation Hospital and Medical Research Institute, NY, USA.

FAST-Mag protocol with or without mild hypothermia (35°C) does not improve outcome after permanent MCAO in rats.

The current study assessed the neuroprotective efficacy of magnesium using a FAST-Mag trial treatment protocol alone, and in combination with mild hypothermia, in Sprague Dawley rats subjected to permanent, middle cerebral artery occlusion (MCAO). Treatment with magnesium (MgSO4.7H2O) consisted of an intravenous loading dose (LD: 360 μmol/kg) and a 24 hour infusion (120 μmol/kg/h), while mild hypothermia at 35°C was maintained for 24 hours.

Inverse correlation between resting motor threshold and corticomotor excitability after static magnetic stimulation of human motor cortex.

Background: High-strength static magnetic field stimulation (SMS) results in a period of reduced corticomotor excitability that may be mediated through a decrease in membrane excitability.

Objective: As resting motor threshold (RMT) is thought to reflect membrane excitability, we hypothesized that SMS may increase RMT and that there would be an inverse relationship between RMT and motor-evoked potential (MEP) amplitude.

Methods: Ten healthy subjects (aged 20-29; 4 females) participated in a double-blinded crossover design comparing MEP amplitude and RMT before and after a 15-min period of SMS or sham stimulation over primary motor cortex (M1).

The relationship between muscle pain and fatigue.

Pain and fatigue may occur together during sustained exhausting muscle contractions, particularly as the limit of endurance is approached, and both can restrict muscle performance. Patients with neuromuscular disorders may have chronic myofascial pain (e.g.

Conditioning the cortical silent period with paired transcranial magnetic stimulation.

Background: A single supra-threshold pulse of transcranial magnetic stimulation (TMS) over human motor cortex elicits multiple descending volleys (I-waves) that generate a motor evoked potential (MEP) followed by a period of electromyographic silence in the tonically contracted target muscle (silent period; SP). A sub-threshold conditioning stimulus (CS) delivered at inter-pulse intervals (IPIs) of 1-5 ms after a supra-threshold test stimulus (TS) conditions I-waves elicited by TS and can increase MEP amplitude (short-interval intracortical facilitation; SICF), however its effect on the SP remains unknown.

Objective: We investigated whether it is possible to modulate the SP resulting from a TS by delivering a sub-threshold CS 1-5 ms later.

A comparison of relative-frequency and threshold-hunting methods to determine stimulus intensity in transcranial magnetic stimulation.

Objective: Stimulation intensity (SI) in transcranial magnetic stimulation is commonly set in relation to motor threshold (MT), or to achieve a motor-evoked potential (MEP) of predefined amplitude (usually 1 mV). Recently, IFCN recommended adaptive threshold-hunting over the previously endorsed relative-frequency method. We compared the Rossini-Rothwell (R-R) relative-frequency method to an adaptive threshold-hunting method based on parameter estimation by sequential testing (PEST) for determining MT and the SI to target a MEP amplitude of 1 mV (I(1) mV).

Evidence for high-fidelity timing-dependent synaptic plasticity of human motor cortex.

A single transcranial magnetic stimulation (TMS) pulse typically evokes a short series of spikes in corticospinal neurons [known as indirect (I)-waves] which are thought to arise from transynaptic input. Delivering a second pulse at inter-pulse intervals (IPIs) corresponding to the timing of these I-waves leads to a facilitation of the response, and if stimulus pairs are delivered repeatedly, a persistent LTP-like increase in excitability can occur. This has been demonstrated at an IPI of 1.

Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis.

We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01.

Breakdown in central motor control can be attenuated by motor practice and neuro-modulation of the primary motor cortex.

The performance of a repetitive index finger flexion-extension task at maximal voluntary rate (MVR) begins to decline just a few seconds into the task and we have previously postulated that this breakdown has a central origin. To test this hypothesis, we have combined two objectives; to determine whether motor practice can lessen the performance deterioration in an MVR task, and whether further gains can be achieved with a transcranial magnetic stimulation (TMS) protocol that increases corticomotor excitability (CME). Eleven right-handed subjects participated in a randomized crossover study design that consisted of a 15-min interventional TMS at I-wave periodicity (ITMS) and single-pulsed Sham intervention prior to six 10-s practice sets of a repetitive finger flexion-extension task at MVR.

High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: an analysis of disease-associated alleles and diplotypes.

We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective.