Fasciculation electromechanical latency is prolonged in amyotrophic lateral sclerosis.

OBJECTIVE: In amyotrophic lateral sclerosis (ALS), motor neurons become hyperexcitable and spontaneously discharge electrical impulses causing fasciculations. These can be detected by two noninvasive methods: high-density surface electromyography (HDSEMG) and muscle ultrasonography (MUS). We combined these methods simultaneously to explore the electromechanical properties of fasciculations, seeking a novel biomarker of disease. METHODS: Twelve ALS patients and thirteen healthy participants each provided up to 24 minutes of recordings from the right biceps brachii (BB) and gastrocnemius medialis (GM). Two automated algorithms (Surface Potential Quantification Engine and a Gaussian mixture model) were applied to HDSEMG and MUS data to identify correlated electromechanical fasciculation events. RESULTS: We identified 4,197 correlated electromechanical fasciculation events. HDSEMG reliably detected electromechanical events up to 30 mm below the skin surface with an inverse correlation between amplitude and depth in ALS muscles. Compared to Healthy-GM muscles (mean = 79.8 ms), electromechanical latency was prolonged in ALS-GM (mean = 108.8 ms; p = 0.0458) and ALS-BB (mean = 112.0 ms; p = 0.0128) muscles. Electromechanical latency did not correlate with disease duration, symptom burden, sum muscle power score or fasciculation frequency. CONCLUSIONS: Prolonged fasciculation electromechanical latency indicates impairment of the excitation-contraction coupling mechanism, warranting further exploration as a potential novel biomarker of disease in ALS. SIGNIFICANCE: This study points to an electromechanical defect within the muscles of ALS patients.

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.

Demystifying the spontaneous phenomena of motor hyperexcitability.

Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control by the central nervous system, a hierarchical network of these specialist neurons ensures muscular strength is coordinated, gradated and adaptable. However, spontaneous activation of these cells and their axons can result in abnormal muscular twitching. The muscular twitch is the common building block of several distinct clinical patterns, namely fasciculation, myokymia and neuromyotonia. When attempting to distinguish these entities electromyographically, their unique temporal and morphological profiles must be appreciated. Detection and quantification of burst duration, firing frequency, multiplet patterns and amplitude are informative. A common feature is their persistence during sleep. In this review, we explain the accepted terminology used to describe the spontaneous phenomena of motor hyperexcitability, highlighting potential pitfalls amidst a bemusing and complex collection of overlapping terms. We outline the relevance of these findings within the context of disease, principally amyotrophic lateral sclerosis, Isaacs syndrome and Morvan syndrome. In addition, we highlight the use of high-density surface electromyography, suggesting that more widespread use of this non-invasive technique is likely to provide an enhanced understanding of these motor hyperexcitability syndromes.

The evolving role of surface electromyography in amyotrophic lateral sclerosis: A systematic review.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads to inexorable motor decline and a median survival of three years from symptom onset. Surface EMG represents a major technological advance that has been harnessed in the development of novel neurophysiological biomarkers. We have systematically reviewed the current application of surface EMG techniques in ALS. METHODS: We searched PubMed to identify 42 studies focusing on surface EMG and its associated analytical methods in the diagnosis, prognosis and monitoring of ALS patients. RESULTS: A wide variety of analytical techniques were identified, involving motor unit decomposition from high-density grids, motor unit number estimation and measurements of neuronal hyperexcitability or neuromuscular architecture. Some studies have proposed specific diagnostic and prognostic criteria however clinical calibration in large ALS cohorts is currently lacking. The most validated method to monitor disease is the motor unit number index (MUNIX), which has been implemented as an outcome measure in two ALS clinical trials. CONCLUSION: Surface EMG offers significant practical and analytical flexibility compared to invasive techniques. To capitalise on this fully, emphasis must be placed upon the multi-disciplinary collaboration of clinicians, bioengineers, mathematicians and biostatisticians. SIGNIFICANCE: Surface EMG techniques can enrich effective biomarker development in ALS.

Preprocessing surface EMG data removes voluntary muscle activity and enhances SPiQE fasciculation analysis.

OBJECTIVES: Fasciculations are a clinical hallmark of amyotrophic lateral sclerosis (ALS). The Surface Potential Quantification Engine (SPiQE) is a novel analytical tool to identify fasciculation potentials from high-density surface electromyography (HDSEMG). This method was accurate on relaxed recordings amidst fluctuating noise levels. To avoid time-consuming manual exclusion of voluntary muscle activity, we developed a method capable of rapidly excluding voluntary potentials and integrating with the established SPiQE pipeline. METHODS: Six ALS patients, one patient with benign fasciculation syndrome and one patient with multifocal motor neuropathy underwent monthly thirty-minute HDSEMG from biceps and gastrocnemius. In MATLAB, we developed and compared the performance of four Active Voluntary IDentification (AVID) strategies, producing a decision aid for optimal selection. RESULTS: Assessment of 601 one-minute recordings permitted the development of sensitive, specific and screening strategies to exclude voluntary potentials. Exclusion times (0.2-13.1 minutes), processing times (10.7-49.5 seconds) and fasciculation frequencies (27.4-71.1 per minute) for 165 thirty-minute recordings were compared. The overall median fasciculation frequency was 40.5 per minute (10.6-79.4 IQR). CONCLUSION: We hereby introduce AVID as a flexible, targeted approach to exclude voluntary muscle activity from HDSEMG recordings. SIGNIFICANCE: Longitudinal quantification of fasciculations in ALS could provide unique insight into motor neuron health.

SPiQE: An automated analytical tool for detecting and characterising fasciculations in amyotrophic lateral sclerosis.

OBJECTIVES: Fasciculations are a clinical hallmark of amyotrophic lateral sclerosis (ALS). Compared to concentric needle EMG, high-density surface EMG (HDSEMG) is non-invasive and records fasciculation potentials (FPs) from greater muscle volumes over longer durations. To detect and characterise FPs from vast data sets generated by serial HDSEMG, we developed an automated analytical tool. METHODS: Six ALS patients and two control patients (one with benign fasciculation syndrome and one with multifocal motor neuropathy) underwent 30-minute HDSEMG from biceps and gastrocnemius monthly. In MATLAB we developed a novel, innovative method to identify FPs amidst fluctuating noise levels. One hundred repeats of 5-fold cross validation estimated the model's predictive ability. RESULTS: By applying this method, we identified 5,318 FPs from 80 minutes of recordings with a sensitivity of 83.6% (+/- 0.2 SEM), specificity of 91.6% (+/- 0.1 SEM) and classification accuracy of 87.9% (+/- 0.1 SEM). An amplitude exclusion threshold (100 µV) removed excessively noisy data without compromising sensitivity. The resulting automated FP counts were not significantly different to the manual counts (p = 0.394). CONCLUSION: We have devised and internally validated an automated method to accurately identify FPs from HDSEMG, a technique we have named Surface Potential Quantification Engine (SPiQE). SIGNIFICANCE: Longitudinal quantification of fasciculations in ALS could provide unique insight into motor neuron health.

Correction to: Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials.

In the original publication of the article, under the heading Discussion, 1st paragraph, the sentence that reads as, "Nonetheless, our observed improvements of over 50% for OS and over 30% for DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies" should read as "Nonetheless, our observed improvements of over 50% for OS and DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies." Under the heading Discussion, 3rd paragraph, the sentence that reads as "We cannot discount the possibility …such as education, income and access to care [1, 7]" should read as "We cannot discount the possibility…such as education, income and access to care, which ultimately have on survival outcomes [1, 7]."

Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials.

PURPOSE: The Exercise for Health trials were randomised, controlled trials designed to evaluate an 8-month pragmatic exercise intervention, commencing 6 weeks post-surgery for women with newly diagnosed breast cancer residing in urban or rural/regional Australia. For these exploratory analyses, the primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. METHODS: Consenting urban- (n = 194) and rural/regional-residing women (n = 143) were randomised to exercise (intervention delivered face-to-face or by telephone) or usual care. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for survival outcomes (exercise group, n = 207, 65% urban women; usual care group, n = 130, 46% urban women). RESULTS: After a median follow-up of 8.3 years, there were 11 (5.3%) deaths in the exercise group compared with 15 (11.5%) deaths in the usual care group (OS HR for the exercise group: 0.45, 95% CI 0.20-0.96; p = 0.04). DFS events for the exercise versus usual care group were 25 (12.1%) and 23 (17.7%), respectively (HR: 0.66, 95% CI 0.38-1.17; p = 0.16). HRs for OS favoured exercise irrespective of age, body mass index, stage of disease, intervention compliance, and physical activity levels at 12 months post-diagnosis, although were stronger (p < 0.05) for younger women, women with stage II + disease, women with 1 + comorbidity at time of diagnosis, higher intervention compliance and for those who met national physical activity guidelines at 12 months post-diagnosis. CONCLUSION: An exercise intervention delivered during and beyond treatment for breast cancer, and that was designed to cater for all women irrespective of place of residence and access to health services, has clear potential to benefit survival. Trial numbers: ACT RN: 012606000233527; ACT RN: 12609000809235.

Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot, randomised controlled trial.

Adverse changes in nutrition-related outcomes including quality of life (QoL) occur after PBSC transplantation. This randomised controlled trial aims to evaluate the impact of nutrition and exercise counselling provided at hospital discharge on nutritional status, body composition and QoL post transplantation. Usual care (UC) (n=19) received no intervention after discharge; extended care (EC) (n=18) received fortnightly telephone counselling from a dietitian and exercise physiologist up to 100 days post transplantation. Nutritional status (patient-generated subjective global assessment, and diet history), QoL (EORTC QLQ-C30 version 3) and body composition (air displacement plethysmography) were assessed at pre-admission, discharge and 100 days post transplantation. Intervention groups were compared using two-sample t-tests of changes in the outcomes; results were adjusted using analysis of covariance. EC exhibited clinically important but not statistically significant increases in protein intake (14.7 g; confidence interval (CI) 95% -6.5, 35.9, P=0.165), cognitive functioning (7.2; CI 95% -7.9, 22.2, P=0.337) and social functioning (16.5; CI 95% -7.3, 40.3, P=0.165) compared with UC. Relative to pre-admission, EC experienced less weight loss than UC (-3.3 kg; CI 95% -6.7, 0.2, P=0.062). Physical activity was not significantly different between the groups. Ongoing nutrition and exercise counselling may prevent further weight loss and improve dietary intake and certain QoL components in autologous PBSC transplantation patients following hospitalisation.

When Spectral Smearing Can Increase Speech Intelligibility.

Sentences were reduced to an array of sixteen effectively rectangular bands (RBs) having center frequencies ranging from 0.25 to 8 kHz spaced at ⅓-octave intervals. Four arrays were employed, each having uniform subcritical bandwidths which ranged from 40 Hz to 5 Hz. The 40 Hz width array had intelligibility near ceiling, and the 5 Hz array about 1%. The finding of interest was that when the subcritical speech RBs were used to modulate RBs of noise having the same center frequency as the speech but having bandwidths increased to a critical (ERBn) bandwidth at each center frequency, these spectrally smeared arrays were considerably more intelligible in all but the 40 Hz (ceiling) condition. For example, when the 10 Hz bandwidth speech array having an intelligibility of 8% modulated the ERBn noise array, intelligibility increased to 48%. This six-fold increase occurred despite elimination of spectral fine structure and addition of stochastic fluctuation to speech envelope cues. (As anticipated, conventional vocoding with matching bandwidths of speech and noise reduced the 10-Hz-speech array intelligibility from 8% to 1%). These effects of smearing confirm findings by Bashford, Warren, and Lenz (2010) that optimal temporal processing requires stimulation of a critical bandwidth. [Supported by NIH].

How Broadband Speech May Avoid Neural Firing Rate Saturation at High Intensities and Maintain Intelligibility.

While broadband speech may remain perfectly intelligible at levels exceeding 90 dB, narrowband speech intelligibility (e.g., 2/3-octave passband centered at 1.5 kHz) may decline by 25% or more at moderate intensities (e.g., 75 dB). This "rollover" effect is substantially reduced, however, when a speech band is accompanied by flanking bands of white noise [J.A. Bashford, R.M. Warren, & P.W. Lenz, 2005, J. Acoust. Soc. Am. 117, 365-369 (2005)], suggesting that lateral suppression helps preserve broadband speech intelligibility at high levels. The present study found that when noise flankers were presented individually at a low spectrum level (-30 dB relative to the speech) only the higher-frequency flanker produced a significant intelligibility increase. However, the lower-frequency flanking noise did produce an equivalent increase when its spectrum level was raised 10 dB. This asymmetrical intensity requirement for noise flankers links the effective dynamic range of speech intelligibility to reported characteristics of both lateral (two-tone) suppression of auditory nerve (AN) fiber activity and lateral inhibition of secondary cells of the cochlear nucleus. These and other observations will be discussed in the broader context of how various auditory mechanisms help preserve speech intelligibility at high intensities by reducing firing rate saturation. [Supported by NIH.].

Reducing variation in antibacterial prescribing rates for 'cough/cold' and sore throat between 1993 and 2001: regional analyses using the general practice research database.

OBJECTIVE: To use the General Practice Research Database (GPRD) to explore the regional variation in prescribing for single diagnostic episodes of 'cough/cold' and sore throat and how this changed between 1993 and 2001. METHODS: Data from the GPRD was used to conduct a longitudinal survey of morbidity and antibiotic prescribing data. RESULTS: Nationally there has been a substantial reduction in diagnosed episodes per 1000 patient years at risk for both diagnoses: from 104.6 (104.0-105.2) to 86.5 (86.0-86.9) for cough/cold (-17.3%) and from 102.8 (102.2-103.4) to 69.2 (68.8-69.6) for sore throat (-32.6%). In addition to the changes in diagnostic rate there have been reductions in diagnosis-related prescribing: from 41.8% to 34.8% of cough/cold episodes (-7.0%) and from 77.3% to 60.8% of sore throat episodes (-16.4%). These aggregated data conceal wide regional variations. For cough/cold the change in prescribing rate during the study varied from -16.0% to +5.3% and for sore throat from -28.3% to -7.3%. CONCLUSIONS: In addition to a substantial reduction in diagnosis of cough/cold and sore throat, there has been a reduction in diagnosis-related prescribing episodes in almost all regions. Although there continues to be regional variation in diagnosis-related prescribing this has reduced substantially over the 9-year study period.

Salerno's model of DNA re-analysed: could breather solitons have biological significance?

We investigate the sequence-dependent behaviour of localised excitations in a toy, nonlinear model of DNA base-pair opening originally proposed by Salerno. Specifically we ask whether "breather" solitons could play a role in the facilitated location of promoters by RNA polymerase (RNAP). In an effective potential formalism, we find excellent correlation between potential minima and Escherichia coli promoter recognition sites in the T7 bacteriophage genome. Evidence for a similar relationship between phage promoters and downstream coding regions is found and alternative reasons for links between AT richness and transcriptionally-significant sites are discussed. Consideration of the soliton energy of translocation provides a novel dynamical picture of sliding: steep potential gradients correspond to deterministic motion, while "flat" regions, corresponding to homogeneous AT or GC content, are governed by random, thermal motion. Finally we demonstrate an interesting equivalence between planar, breather solitons and the helical motion of a sliding protein "particle" about a bent DNA axis.

Autografting followed by rituximab for chemosensitive mantle cell lymphoma: a pilot study and literature review.

Mantle cell lymphoma (MCL) is rarely cured with either conventional-dose chemotherapy or autografting. Recent evidence suggests that anti-CD20 monoclonal antibody therapy (rituximab) in combination with chemotherapy may improve the response rate. We report a pilot study of autografting using busulfan-melphalan conditioning followed by rituximab in 9 patients (median age 52 years) with chemosensitive MCL. Rituximab was given for 4 doses of 375 mg/m(2) between 4 and 10 weeks post-transplant. Three of 5 patients autografted after induction therapy remain alive in clinical and molecular complete remission at 33-50 months post-transplant. Only 1 of 4 patients autografted after relapse remains in complete remission. Two of the 3 patients with persistent marrow molecular positivity post-autograft became negative after rituximab therapy. Molecular negativity was first observed in 2 patients only after rituximab therapy. Overall, 2 patients have relapsed and the remaining 3 died of late-onset respiratory failure, probably reflecting infection and/or aggressive conditioning in an older patient population. These preliminary results, together with a review of the literature, suggest that the combination of autografting and rituximab may lead to durable molecular remissions in patients with chemosensitive MCL. Further studies are required to clarify whether the administration of rituximab: (1) is optimal pre- or post-autograft and (2) impacts on the incidence of infection and idiopathic pneumonitis in this context.

A base-pairing model of duplex formation. I. Watson-Crick pairing geometries.

We present a base-pairing model of oligonucleotide duplex formation and show in detail its equivalence to the nearest-neighbor dimer methods from fits to free energy of duplex formation data for short DNA-DNA and DNA-RNA hybrids containing only Watson-Crick pairs. For completeness, the corresponding RNA-RNA parameters are included. In this approach, the connection between rank-deficient polymer and rank-determinant oligonucleotide parameter sets for DNA duplexes is transparent. The method is generalized to include RNA-DNA hybrids where the rank-deficient model with 11 dimer parameters in fact provides slightly improved predictions relative to the standard method with 16 independent dimer parameters (DeltaG mean errors of 4.5 and 5.4%, respectively).

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Role of a mixed type, moderate intensity exercise programme after peripheral blood stem cell transplantation.

OBJECTIVES: To evaluate the effect of peripheral blood stem cell transplantation on functional capacity, and to determine the role of a mixed type, moderate intensity exercise programme in the recovery of patients after intensive cancer treatment. METHODS: Peak aerobic capacity and muscular strength (upper body, lower body, and handgrip strength) measures were assessed before (PI) and after (PII) transplant and after a 12 week intervention period (PIII). After PII, 12 patients aged 16-64 years were allotted in equal numbers to a control group or exercise intervention group. RESULTS: Mean peak aerobic capacity and muscular strength were reduced after the transplant, with significant (p<0.05) decreases for upper body strength. No change was found in aerobic capacity and muscular strength between PII and PIII for the control group. In contrast, participation in the exercise programme led to significant improvements in peak aerobic capacity (p<0.05) and upper and lower body strength (p<0.01). In addition, values recorded after the three month intervention period were significantly higher than before treatment for peak aerobic capacity (litres/min (p<0.05) and ml/kg/min (p<0.01)) and lower body strength (p<0.01). CONCLUSION: Intensive treatment for cancer can adversely affect aerobic capacity and muscular strength. A mixed type, moderate intensity exercise programme can help patients to regain fitness and strength within three months. No exercise can exacerbate physical losses resulting from treatment.