Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody.

BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.

Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. METHODS/DESIGN: SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. DISCUSSION: This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. TRIAL REGISTRATION: ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).

Rehabilitation goals of people with spinal cord injuries can be classified against the International Classification of Functioning, Disability and Health Core Set for spinal cord injuries.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To establish whether inter-professional rehabilitation goals from people with non-traumatic spinal cord injury (SCI) can be classified against the International Classification of Functioning, Disability and Health (ICF) SCI Comprehensive and Brief Core Sets early postacute situation. SETTING: Neurological rehabilitation unit. METHODS: Rehabilitation goals of 119 patients with mainly incomplete and non-traumatic SCIs were classified against the ICF SCI Core Sets following established linking rules. RESULTS: A total of 119 patients generated 1509 goals with a mean (and s.d.) of 10.5 (9.1) goals per patient during the course of their inpatient rehabilitation stay. Classifying the 1509 rehabilitation goals against the Comprehensive ICF Core Set generated 2909 ICF codes. Only 69 goals (4.6%) were classified as 'not definable (ND)'. Classifying the 1509 goals against the Brief ICF Core Set generated 2076 ICF codes. However, 751(49.8%) of these goals were classified as 'ND'. In the majority of goals (95.7%), the ICF code description was not comprehensive enough to fully express the goals set in rehabilitation. In particular, the notion of quality of movement or specificity and measurability aspects of a goal (usually described with the criteria and acronyms SMART) could not be expressed through the ICF codes. CONCLUSION: Inter-professional rehabilitation goals can be broadly described by the ICF Comprehensive Core Set for SCI but not the Brief Core Set.

Identifying individuals at risk for surgical supravalvar aortic stenosis by polygenic risk score with graded phenotyping.

In a previous pathway-based, extreme phenotype study, we identified 1064 variants associated with supravalvar aortic stenosis (SVAS) severity in people with Williams syndrome (WS) and either no SVAS or surgical SVAS. Here, we use those variants to develop and test polygenic risk scores (PRS). We used the clumping and thresholding (CT) approach on the full 1064 variants and a 427-variant subset that was part of 13 biologically relevant pathways identified in the previous study. We also used a lasso approach on the full set. We were able to achieve an area under the curve (AUC) of >0.99 for the two CT PRS methods, using only 622 and 320 variants respectively when 2/3 of the initial 217 participants data were used for training and 1/3 for testing. The lasso performed less well. We then evaluated the performance of those PRS variant sets on an additional group of 138 patients with WS with intermediate severity SVAS and found a misclassification rate of <10% between the surgical and intermediate groups, suggesting potential for clinical utility of the score.

Qualitative evaluation of a community peer support service for people with spinal cord injury.

STUDY DESIGN: Qualitative study involving individual semistructured in-depth interviews. OBJECTIVES: To evaluate peer support provided in general hospitals for people with spinal cord injuries (SCIs). SETTING: The South West of the United Kingdom. METHODS: Fourteen in-depth qualitative interviews were conducted with people with SCI and their close relatives, and with health-care professionals involved in their care. Transcribed interviews were coded inductively and analysed thematically. Themes were patterned around positive and less positive aspects of the experience of the peer support service. RESULTS: The psychological and emotional support provided by the peer support officer was highly valued by the participants. The peer support officer's direct experience of living with a spinal injury gave credibility to the practical advice, information and signposting provided; as well as to the empathy demonstrated by them during their involvement with people with SCI and their families. Health-care professionals appreciated their unique perspective and considered them as a valuable member of the multidisciplinary team. CONCLUSION: Peer support is valued by the people affected by SCI. There is a need to further investigate the key aspects of the service, including the optimal timing for introducing this peer support as well as more formal training of mentors.

Balance Right in Multiple Sclerosis (BRiMS): a feasibility randomised controlled trial of a falls prevention programme.

BACKGROUND: Balance, mobility impairments and falls are problematic for people with multiple sclerosis (MS). The "Balance Right in MS (BRiMS)" intervention, a 13-week home and group-based exercise and education programme, aims to improve balance and minimise falls. This study aimed to evaluate the feasibility of undertaking a multi-centre randomised controlled trial and to collect the necessary data to design a definitive trial. METHODS: This randomised controlled feasibility study recruited from four United Kingdom NHS clinical neurology services. Patients ≥ 18 years with secondary progressive MS (Expanded Disability Status Scale 4 to 7) reporting more than two falls in the preceding 6 months were recruited. Participants were block-randomised to either a manualised 13-week education and exercise programme (BRiMS) plus usual care, or usual care alone. Feasibility assessment evaluated recruitment and retention rates, adherence to group assignment and data completeness. Proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls) and economic data were collected at baseline, 13 and 27 weeks, and participants completed daily paper falls diaries. RESULTS: Fifty-six participants (mean age 59.7 years, 66% female, median EDSS 6.0) were recruited in 5 months; 30 randomised to the intervention group. Ten (18%) participants withdrew, 7 from the intervention group. Two additional participants were lost to follow up at the final assessment point. Completion rates were > 98% for all outcomes apart from the falls diary (return rate 62%). After adjusting for baseline score, mean intervention-usual care between-group differences for the potential primary outcomes at week 27 were MS Walking Scale-12v2: - 7.7 (95% confidence interval [CI] - 17.2 to 1.8) and MS Impact Scale-29v2: physical 0.6 (CI - 7.8 to 9), psychological - 0.4 (CI - 9.9 to 9). In total, 715 falls were reported, rate ratio (intervention:usual care) for falls 0.81 (0.41 to 2.26) and injurious falls 0.44 (0.41 to 2.23). CONCLUSIONS: Procedures were practical, and retention, programme engagement and outcome completion rates satisfied a priori progression criteria. Challenges were experienced in completion and return of daily falls diaries. Refinement of methods for reporting falls is therefore required, but we consider a full trial to be feasible. TRIAL REGISTRATION: ISRCTN13587999 Date of registration: 29 September 2016.

The effect of core stability training on balance and mobility in ambulant individuals with multiple sclerosis: a multi-centre series of single case studies.

BACKGROUND: Core stability training is popular in the management of people with multiple sclerosis (MS); however, scientific evidence to support its effectiveness is scarce. OBJECTIVE: To explore the effectiveness of core stability training on balance and mobility. METHOD: A multi-centre series of eight single case studies was undertaken. Eight ambulant individuals with stable MS participated in 16 face-to-face core stability training sessions, delivered by a neurophysiotherapist, plus a daily home exercise programme. A range of outcomes were measured: 10-m timed walk, 12-item MS walking scale, timed get up and go, functional reach tests, timed single leg stance, visual analogue scales of two activities, and the Activities-specific Balance Confidence Scale. RESULTS: Visual analysis of trend, level and slope demonstrated improvement in five subjects (62%) in seven measures. This was confirmed by the two standard deviation band method of analysis for six measures. Analysis of group data (repeated measures within subjects analysis of variance) indicated significant improvement between baseline and intervention phases for timed walk (p = 0.019), MSWS-12 Scale (p = 0.041), forward (p = 0.015) and lateral reach (p = 0.012). In general, no further improvements were made following withdrawal of the intervention. CONCLUSIONS: This study provides preliminary evidence of the effectiveness of an 8-week core stability training programme in improving balance and mobility in ambulant people with MS. Variations in response to intervention are evident. Assessor-blinded randomized controlled studies are required to confirm these findings and determine patient characteristics which identify those who benefit most from this intervention.

Magnetic field of a nerve impulse: first measurements.

The magnetic field of the action potential from an isolated frog sciatic nerve was measured by a SQUID magnetometer with a novel room-temperature pickup coil. The 1.2 x 10(-10) tesla field was measured 1.3 millimeters from the nerve with a signal-to-noise ratio of 40 to 1.

Dendritic spikes and their inhibition in alligator Purkinje cells.

Alligator Purkinje cells generate action potentials in the peripheral dendritic tree, after synaptic depolarization via superficial parallel fibers. These action potentials are inhibited at the dendrite level by preceding parallel-fiber volleys at close intervals. We conclude that this inhibition is produced by the activation of the inhibitory interneurons of the molecular layer, the stellate cells, which establish synaptic contacts with the dendrites of the Purkinje cells.

Cloning of complementary DNA for GAP-43, a neuronal growth-related protein.

GAP-43 is one of a small subset of cellular proteins selectively transported by a neuron to its terminals. Its enrichment in growth cones and its increased levels in developing or regenerating neurons suggest that it has an important role in neurite growth. A complementary DNA (cDNA) that encodes rat GAP-43 has been isolated to study its structural characteristics and regulation. The predicted molecular size is 24 kilodaltons, although its migration in SDS-polyacrylamide gels is anomalously retarded. Expression of GAP-43 is limited to the nervous system, where its levels are highest during periods of neurite outgrowth. Nerve growth factor or adenosine 3',5'-monophosphate induction of neurites from PC12 cells is accompanied by increased GAP-43 expression. GAP-43 RNA is easily detectable, although at diminished levels, in the adult rat nervous system. This regulation of GAP-43 is concordant with a role in growth-related processes of the neuron, processes that may continue in the mature animal.

A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes.

Growth cones are specialized structures that form the distal tips of growing axons. During both normal development of the nervous system and regeneration of injured nerves, growth cones are essential for elongation and guidance of growing axons. Developmental and regenerative axon growth is frequently accompanied by elevated synthesis of a protein designated GAP-43. GAP-43 has now been found to be a major component of growth-cone membranes in developing rat brains. Relative to total protein, GAP-43 is approximately 12 times as abundant in growth-cone membranes as in synaptic membranes from adult brains. Immunohistochemical localization of GAP-43 in frozen sections of developing brain indicates that the protein is specifically associated with neuropil areas containing growth cones and immature synaptic terminals. The results support the proposal that GAP-43 plays a role in axon growth.

A role for the sodium pump in photoreception in Limulus.

The membranes of photoreceptor cells in Limulus have an electrogenic sodium pump which contributes directly to membrane potential and whose activity is changed by light. These light-induced changes in pump activity underlie the receptor potential.

Balance Right in Multiple Sclerosis (BRiMS): a guided self-management programme to reduce falls and improve quality of life, balance and mobility in people with secondary progressive multiple sclerosis: a protocol for a feasibility randomised controlled trial.

BACKGROUND: Impaired mobility is a cardinal feature of multiple sclerosis (MS) and is rated by people with MS as their highest priority. By the secondary progressive phase, balance, mobility and physical activity levels are significantly compromised; an estimated 70% of people with secondary progressive MS fall regularly. Our ongoing research has systematically developed 'Balance Right in MS' (BRiMS), an innovative, manualised 13-week guided self-management programme tailored to the needs of people with MS, designed to improve safe mobility and minimise falls. Our eventual aim is to assess the clinical and cost effectiveness of BRiMS in people with secondary progressive MS by undertaking an appropriately statistically powered, multi-centre, assessor-blinded definitive, randomised controlled trial. This feasibility study will assess the acceptability of the intervention and test the achievability of running such a definitive trial. METHODS/DESIGN: This is a pragmatic multi-centre feasibility randomised controlled trial with blinded outcome assessment. Sixty ambulant people with secondary progressive MS who self-report two or more falls in the previous 6 months will be randomly allocated (1:1) to either the BRiMS programme plus usual care or to usual care alone. All participants will be assessed at baseline and followed up at 15 weeks and 27 weeks post-randomisation. The outcomes of this feasibility trial include:Feasibility outcomes, including trial recruitment, retention and completionAssessment of the proposed outcome measures for the anticipated definitive trial (including measures of walking, quality of life, falls, balance and activity level)Measures of adherence to the BRiMS programmeData to inform the economic evaluation in a future trialProcess evaluation (assessment of treatment fidelity and qualitative evaluation of participant and treating therapist experience). DISCUSSION: The BRiMS intervention aims to address a key concern for MS service users and providers. However, there are several uncertainties which need to be addressed prior to progressing to a full-scale trial, including acceptability of the BRiMS intervention and practicality of the trial procedures. This feasibility trial will provide important insights to resolve these uncertainties and will enable a protocol to be finalised for use in the definitive trial. TRIAL REGISTRATION: ISRCTN13587999.

Bilateral ganglion cell branches in the normal rat: a demonstration with electrophysiological collision and cobalt tracing methods.

The application of microelectrode recording and anatomical tracing methods to the subcortical optic projections of the normal rat shows that the uncrossed pathway from the retina of this mammal is substantially composed of branches of crossed axons. In the recording experiments, paired stimuli to the optic tracts produces an attenuated antidromic response in the optic nerve which is best explained by the collision of impulses which travel in branches of the same parent axon. Cobalt injection of one optic tract results in retrograde filling of axons in the entire contralateral optic nerve and filling of axons in restricted regions of the ipsilateral optic nerve. This procedure also results in the filling of axons in the opposite optic tract. The locations of the filled axons in the opposite tract correspond to the positions of crossed and uncrossed projections from the temporal retinae: ventrolateral and dorsomedial, respectively. The position of the temporal retinal projections in both optic tracts was determined by applying silver degeneration methods after small lesions of the retina.

Does adding MS-specific items to a generic measure (the SF-36) improve measurement?

OBJECTIVE: The 36-item Short Form Health Survey Questionnaire (SF-36) is a widely used generic health status measure. Recently it has been adapted to produce a disease-specific measure for MS-the 54-item Multiple Sclerosis Quality of Life Scale (MSQOL-54)-composed of five unchanged SF-36 scales; three altered SF-36 scales (one item added to each scale); and five new scales incorporating 15 additional items. This study evaluates the impact of these additions by comparing the measurement properties of the MSQOL-54 with the SF-36. METHODS: A total of 150 patients with MS, representing a broad spectrum of disease severity, completed a range of questionnaires, which included the MSQOL-54 (from which the SF-36 score was computed). Of these, 44 people completed the measures before and after inpatient rehabilitation to evaluate responsiveness. Standard psychometric methods were used to evaluate the measurement properties. RESULTS: The measurement properties of the unchanged scales, inevitably, remain identical. Those of the three altered scales are virtually identical. Of the five new scales, the validity of the two sexual scales is questioned because of the high percentage of missing data, and the validity of the overall quality-of-life scale is limited as demonstrated by the low to moderate correlations with other related and unrelated measures. Responsiveness of the new scales also appears limited. CONCLUSION: Modifying existing measures by simply adding clinically chosen items may not be as useful as anticipated in improving the measurement properties of an instrument.

Inpatient rehabilitation in multiple sclerosis: do the benefits carry over into the community?

OBJECTIVE: To determine the duration and pattern of carry-over of benefits gained after a short period of multidisciplinary inpatient rehabilitation. BACKGROUND: Few studies have evaluated the outcome of rehabilitation after discharge. Long-term follow-up is required to establish whether gains made during the inpatient stay are sustained over time and in the patient's own environment. METHODS: Prospective single-group longitudinal study. Fifty consecutive patients with progressive MS undergoing inpatient rehabilitation were followed for 12 months after discharge. Assessments were undertaken on admission (A), at discharge, and subsequently at 3-month intervals for 1 year (1Y) with a battery of measures addressing neurologic status, disability, handicap, quality of life, and emotional well-being. The time taken to return to baseline level was calculated using summary measures, and trends in performance levels were plotted. RESULTS: Twelve-month data were collected for 92% of patients. Although neurologic status declined (median Expanded Disability Status Scale scores: A = 6.8, 1Y = 8.0), improvements were maintained in disability and handicap for 6 months, emotional well-being for 7 months, and health-related quality of life (physical component) for 10 months. CONCLUSIONS: The benefits gained from rehabilitation were partly maintained after discharge despite worsening neurologic status. Carry-over of benefits, however, declined over time, reinforcing the need for continuity of care between the inpatient setting and the community.

Interferon-beta1b in the treatment of secondary progressive MS: impact on quality of life.

BACKGROUND: The recent randomized, controlled trial of interferon-beta1b (IFN-beta1b) in 718 patients with secondary progressive MS (SP-MS) demonstrated a significant effect on the development of disability as evaluated by the physician. Its effect on patient-reported health-related quality of life (HrQoL) is reported herein. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, outpatients with SP-MS scoring between 3.0 and 6.5 on the Expanded Disability Status Scale received either 8 x 10(6) IU of IFN-beta1b or placebo for up to 3 years. A range of outcomes was measured, including HrQoL, which was assessed using the Sickness Impact Profile (SIP), a self-report questionnaire validated for use in MS. Measurements were undertaken at baseline and at 6-monthly intervals thereafter for 36 months. RESULTS: A slight positive effect on the HrQoL of the IFN group in comparison with the placebo group was found, which reached significance in the physical scale of the SIP at 6 and 12 months and at last visit. There was moderate correlation between physician-assessed evaluation of change and patient-reported change. CONCLUSIONS: IFN-beta1b may delay sustained deterioration in patient-reported HrQoL in SP-MS. Methods of interpreting change in HrQoL are currently insufficiently developed to determine how clinically important these changes are for this population.

Evidence-based measurement: which disability scale for neurologic rehabilitation?

OBJECTIVE: To compare the 10-item Barthel Index (BI), 18-item Functional Independence Measure (FIM), and 30-item Functional Independence Measure + Functional Assessment Measure (FIM+FAM) as measures of disability outcomes for neurologic rehabilitation. METHODS: A total of 149 inpatients from two rehabilitation units in South England specializing in neurologic disorders were studied. Traditional psychometric methods were used to evaluate and compare acceptability (score distributions), reliability (internal consistency, intrarater reproducibility), validity (concurrent, convergent and discriminant construct), and responsiveness (standardized response mean). RESULTS: All three rating scales satisfied recommended criteria for reliable and valid measurement of disability, and are acceptable and responsive in this study sample. The FIM and FIM+FAM total scales are psychometrically similar measures of global disability. The BI, FIM, and FIM+FAM motor scales are psychometrically similar measures of physical disability. The FIM and FIM+FAM cognitive scales are psychometrically similar measures of physical disability. CONCLUSIONS: In the sample studied, the BI, FIM, FIM+FAM have similar measurement properties, when examined using traditional psychometric analyses. Although instruments with more items and item response categories generate more qualitative information about an outcome, they may not improve its measurement. Results highlight the importance of using recognized techniques of scale construction to develop health outcome measures.

Modification of cysteine residues within G(o) and other neuronal proteins by exposure to nitric oxide.

Nitric oxide (NO), a free-radical gas produced endogenously by some neurons, functions as a diffusible intercellular messenger and appears to play a role in activity-dependent modification of synaptic efficacy in the mammalian CNS. The molecular targets and mechanisms of action of NO in neurons remain largely uncharacterized. Employing in vitro brain slices and isolated synaptosomes, we show here that exposure to exogenous or endogenously generated NO results in the modification of cysteine residues within neuronal proteins, as revealed by reduced binding of agents which react with cysteine sulfhydryls. In particular, exposure of synaptosomes to NO inhibits subsequent thiol-linked ADP-ribosylation of the heterotrimeric G-protein, G(o), by pertussis toxin. Our results demonstrate directly that NO may exert its neuronal effects through modification of protein cysteine thiols, and identify G(o) as a potential synaptic target of NO.