The landscape of neurophysiological outcome measures in ALS interventional trials: A systematic review.

OBJECTIVE: We collated all interventional clinical trials in amyotrophic lateral sclerosis (ALS), which utilised at least one neurophysiological technique as a primary or secondary outcome measure. By identifying the strengths and limitations of these studies, we aim to guide study design in future trials. METHODS: We conducted and reported this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight databases were searched from inception. In total, 703 studies were retrieved for screening and eligibility assessment. RESULTS: Dating back to 1986, 32 eligible interventional clinical trials were identified, recruiting a median of 30 patients per completed trial. The most widely employed neurophysiological techniques were electromyography, motor unit number estimation (including motor unit number index), neurophysiological index and transcranial magnetic stimulation (including resting motor threshold and short-interval intracortical inhibition). Almost 40% of trials reported a positive outcome with respect to at least one neurophysiological measure. The interventions targeted either ion channels, immune mechanisms or neuronal metabolic pathways. CONCLUSIONS: Neurophysiology offers many promising biomarkers that can be utilised as outcome measures in interventional clinical trials in ALS. When selecting the most appropriate technique, key considerations include methodological standardisation, target engagement and logistical burden. SIGNIFICANCE: Future trial design in ALS would benefit from a standardised, updated and easily accessible repository of neurophysiological outcome measures.

Nutrigenomic effect of conjugated linoleic acid on growth and meat quality indices of growing rabbit.

Conjugated linoleic acid was detected in rabbit caecotrophs, due to the presence of microbial lipid activity in rabbit cecum. However, the effect of CLA as a functional food in growing rabbit is not well established. Therefore, this study was conducted to determine the effect of CLA on production, meat quality, and its nutrigenomic effect on edible parts of rabbit carcass including skeletal muscle, liver, and adipose tissue. Therefore, seventy five weaned V-Line male rabbits, 30 days old, were randomly allocated into three dietary treatments receiving either basal control diet, diet supplemented with 0.5% (CLAL), or 1% CLA (CLAH). Total experimental period (63 d) was segmented into 7 days adaptation and 56 days experimental period. Dietary supplementation of CLA did not alter growth performance, however, the fat percentage of longissimus lumborum muscle was decreased, with an increase in protein and polyunsaturated fatty acids (PUFA) percentage. Saturated fatty acids (SFA) and mono unsaturated fatty acids (MUFA) were not increased in CLA treated groups. There was tissue specific sensing of CLA, since subcutaneous adipose tissue gene expression of PPARA was downregulated, however, CPT1A tended to be upregulated in liver of CLAL group only (P = 0.09). In skeletal muscle, FASN and PPARG were upregulated in CLAH group only (P ≤0.01). Marked cytoplasmic vacuolation was noticed in liver of CLAH group without altering hepatocyte structure. Adipocyte size was decreased in CLA fed groups, in a dose dependent manner (P <0.01). Cell proliferation determined by PCNA was lower (P <0.01) in adipose tissue of CLA groups. Our data indicate that dietary supplementation of CLA (c9,t11-CLA and t10,c12- CLA) at a dose of 0.5% in growing rabbit diet produce rabbit meat rich in PUFA and lower fat % without altering growth performance and hepatocyte structure.

Electrodiagnostic applications of somatosensory evoked high-frequency EEG oscillations: Technical considerations.

INTRODUCTION: High frequency oscillations (HFOs) embedded within the somatosensory evoked potential (SEP) are not routinely recorded/measured as part of standard clinical SEPs. However, HFOs could provide important additional diagnostic/prognostic information in various patient groups in whom SEPs are tested routinely. One area is the management of patients with hypoxic ischaemic encephalopathy (HIE) in the intensive care unit (ICU). However, the sensitivity of standard clinical SEP recording techniques for detecting HFOs is unknown. METHODS: SEPs were recorded using routine clinical methods in 17 healthy subjects (median nerve stimulation; 0.5 ms pulse width; 5 Hz; maximum 4000 stimuli) in an unshielded laboratory. Bipolar EEG recordings were acquired (gain 50 k; bandpass 3Hz-2 kHz; sampling rate 5 kHz; non-inverting electrode 2 cm anterior to C3/C4; inverting electrode 2 cm posterior to C3/C4). Data analysis was performed in MATLAB. RESULTS: SEP-HFOs were detected in 65% of controls using standard clinical recording techniques. In 3 controls without significant HFOs, experiments were repeated using a linear electrode array with higher spatial sampling frequency. SEP-HFOs were observed in all 3 subjects. CONCLUSIONS: Currently standard clinical methods of recording SEPs are not sufficiently sensitive to permit the inclusion of SEP-HFOs in routine clinical diagnostic/prognostic assessments. Whilst an increase in the number/density of EEG electrodes should improve the sensitivity for detecting SEP-HFOs, this requires confirmation. By improving and standardising clinical SEP recording protocols to permit the acquisition/analysis of SEP-HFOs, it should be possible to gain important insights into the pathophysiology of neurological disorders and refine the management of conditions such as HIE.

Prevalence and Correlates of Smoking among Low-Income Adults Residing in New York City Public Housing Developments-2015.

To guide targeted cessation and prevention programming, this study assessed smoking prevalence and described sociodemographic, health, and healthcare use characteristics of adult smokers in public housing. Self-reported data were analyzed from a random sample of 1664 residents aged 35 and older in ten New York City public housing developments in East/Central Harlem. Smoking prevalence was 20.8%. Weighted log-binomial models identified to be having Medicaid, not having a personal doctor, and using health clinics for routine care were positively associated with smoking. Smokers without a personal doctor were less likely to receive provider quit advice. While most smokers in these public housing developments had health insurance, a personal doctor, and received provider cessation advice in the last year (72.4%), persistently high smoking rates suggest that such cessation advice may be insufficient. Efforts to eliminate differences in tobacco use should consider place-based smoking cessation interventions that extend cessation support beyond clinical settings.

Common toxidromes in movement disorder neurology.

BACKGROUND: Physicians can come across patients who are exposed to certain prescription drugs or toxins that can result in adverse effects and complications which have high rates of morbidity and mortality. OBJECTIVE: To summarise the key clinical features and management of the common movement disorder toxidromes relevant to physicians (with an interest in neurology). METHODS: We searched PUBMED from 1946 to 2016 for papers relating to movement toxidromes and their treatment. The findings from those studies were then summarised and are presented here. RESULTS: The key features of 6 of the common movement disorder toxidromes and their treatment are tabulated and highlighted. The management of toxidromes with the highest mortality like neuroleptic malignant syndrome and serotonin syndrome are discussed in detail. CONCLUSION: There are several toxidromes that have the potential to become a serious life-threatening emergency if there is a delay in recognition of key clinical features and instituting the appropriate treatment at the earliest is crucial.

Electroencephalographic markers in dementia.

Dementia is a global health problem with a huge impact on the lives of those afflicted. There are several distinct diseases that are classified under the umbrella term "dementia" ranging from neurodegenerative disorders such as Alzheimer's disease to chronic infections of the central nervous system such as subacute sclerosing panencephalitis (SSPE), a rare complication of measles virus infection in childhood. Clinical features, neuropsychological profiles and imaging characteristics of the various dementia syndromes can be sufficiently distinct to distinguish them from one another. However, in some cases, the cognitive, psychiatric and behavioural features can sufficiently overlap such that neurophysiologic testing may be of help. While it is recognized the electroencephalogram (EEG) may have a special role to play in the diagnosis of certain dementing illnesses such as SSPE and Creutzfeldt-Jakob disease (CJD) that have characteristic EEG changes, current research focusses on the potential utility of quantitative EEG as one more tool in the armamentarium of clinicians dealing with patients who suffer from a dementing illness. We searched PubMed and the Cochrane Database from 1 January 1946 up to 1 January 2016, combining the search terms "EEG," "electroencephalography," "dementia" and "status epilepticus"; identified papers from these searches were then read in detail and summarized. Here, we discuss both the qualitative and quantitative EEG findings in the various types of dementia.

Multi-system neurological disease is common in patients with OPA1 mutations.

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Non-uniform olivocerebellar conduction time in the vermis of the rat cerebellum.

It has been proposed that the conduction velocities of cerebellar climbing fibre (olivocerebellar) axons are tuned according to length, in order to precisely fix the conduction time between the inferior olive and cerebellar cortex. Some data conflict with this view. We have re-evaluated this issue using the climbing fibre reflex. The white matter of the tip of one folium in lobule VI or VII was stimulated electrically 0.5-1 mm below the surface and recordings were made from Purkinje cells in lobules VIII and IX. Reflex evoked climbing fibre (CF) responses (33 units) were recorded at different depths from Purkinje cells found in a narrow sagittal zone of cortex as complex spikes. The responses had latencies ranging from 4.3 ms to 11.3 ms. A consistent trend was that Purkinje cell responses recorded at greater depth had shorter CF reflex latencies than those recorded more superficially, both in individual experiments and in grouped data. These data show that the CF reflex latency is not constant, but is directly proportional to the distance an action potential has to travel along a CF. These data are not consistent with tuning of CF conduction velocities to normalize olivocerebellar conduction time, but are consistent with a CF conduction velocity in the cortex of approximately 0.6 m s-1. This suggests that climbing fibres projecting to different parts of the cerebellar cortex may have differences in spike conduction time of a few milliseconds, and that submillisecond precision is not an important element of the climbing fibre signal.

Treatment of stiff person syndrome with rituximab.

This case report is about the novel use of the anti-CD20 antibody, rituximab, in the treatment of a 41 year old woman with stiff person syndrome. She was admitted to hospital as an emergency with prolonged and painful extensor spasms affecting the neck and back, arms, and legs. The disease had progressed despite a favourable initial response to conventional treatment with intravenous immunoglobulin and cytotoxics. Treatment with rituximab induced a lasting clinical remission.

Structure of the voltage-gated L-type Ca2+ channel by electron cryomicroscopy.

Voltage-dependent L-type Ca(2+) channels play important functional roles in many excitable cells. We present a three-dimensional structure of an L-type Ca(2+) channel. Electron cryomicroscopy in conjunction with single-particle processing was used to determine a 30-A resolution structure of the channel protein. The asymmetrical channel structure consists of two major regions: a heart-shaped region connected at its widest end with a handle-shaped region. A molecular model is proposed for the arrangement of this skeletal muscle L-type Ca(2+) channel structure with respect to the sarcoplasmic reticulum Ca(2+)-release channel, the physical partner of the L-type channel for signal transduction during the excitation-contraction coupling in muscle.

Activation of cerebellar climbing fibres to rat cerebellar posterior lobe from motor cortical output pathways.

1. The activation of climbing fibres projecting to the posterior lobe cerebellar cortex by focal stimulation of the cerebral corticofugal pathway was investigated in anaesthetised rats. Large climbing fibre responses were evoked in parts of crus II and paramedian lobule by stimulation of corticofugal fibres. Lesions of the pyramidal tract just rostral to the inferior olive substantially reduced these responses, suggesting that they were not mediated by relays in the rostral brainstem. 2. By comparison of latencies of climbing fibre responses evoked from different locations in the corticofugal pathway, the conduction velocities of the corticofugal fibres that mediate the responses were estimated to be 1.9 +/- 0.3 m s(-1) (mean +/- S.E.M.). The fastest conducting corticofugal fibres were estimated to conduct significantly faster (18.7 +/- 2.3 m s(-1)). 3. Climbing fibre responses with similar form and cerebellar distribution were evoked from sites in the pyramidal tract rostral and caudal to the inferior olive. This suggests that at least a proportion of the fibres that activate climbing fibres are corticospinal fibres. 4. Lesions of the dorsal column nuclei did not affect the climbing fibre responses evoked in crus II, and produced a relatively small reduction of the responses in the paramedian lobule. This implies that the climbing fibre responses were not exclusively mediated via the dorsal column nuclei. 5. Corticofugal evoked climbing fibre responses were mapped across the cerebellar hemisphere. At some sites they were co-localised with responses evoked by limb afferents. On the basis of limb afferent inputs and other work, these zones were tentatively identified as being functionally equivalent to the c1, c2 and d zones described in the cat.