Galanin pathogenic mutations in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatmen

Descriptive epidemiology of somatising tendency: findings from the CUPID study.

Somatising tendency, defined as a predisposition to worry about common somatic symptoms, is importantly associated with various aspects of health and health-related behaviour, including musculoskeletal pain and associated disability. To explore its epidemiological characteristics, and how it can be specified most efficiently, we analysed data from an international longitudinal study. A baseline questionnaire, which included questions from the Brief Symptom Inventory about seven common symptoms, was completed by 12,072 participants aged 20-59 from 46 occupational groups in 18 countries (response rate 70%). The seven symptoms were all mutually associated (odds ratios for pairwise associations 3.4 to 9.3), and each contributed to a measure of somatising tendency that exhibited an exposure-response relationship both with multi-site pain (prevalence rate ratios up to six), and also with sickness absence for non-musculoskeletal reasons. In most participants, the level of somatising tendency was little changed when reassessed after a mean interval of 14 months (75% having a change of 0 or 1 in their symptom count), although the specific symptoms reported at follow-up often differed from those at baseline. Somatising tendency was more common in women than men, especially at older ages, and varied markedly across the 46 occupational groups studied, with higher rates in South and Central America. It was weakly associated with smoking, but not with level of education. Our study supports the use of questions from the Brief Symptom Inventory as a method for measuring somatising tendency, and suggests that in adults of working age, it is a fairly stable trait

Classification of neck/shoulder pain in epidemiological research : a comparison of personal and occupational characteristics, disability, and prognosis among 12,195 workers from 18 countries

To inform case definition for neck/shoulder pain in epidemiological research, we compared levels of disability, patterns of association, and prognosis for pain that was limited to the neck or shoulders (LNSP) and more generalised musculoskeletal pain that involved the neck or shoulder(s) (GPNS). Baseline data on musculoskeletal pain, disability, and potential correlates were collected by questionnaire from 12,195 workers in 47 occupational groups (mostly office workers, nurses, and manual workers) in 18 countries (response rate 70%). Continuing pain after a mean interval of 14 months was ascertained through a follow-up questionnaire in 9150 workers from 45 occupational groups. Associations with personal and occupational factors were assessed by Poisson regression and summarised by prevalence rate ratios (PRRs). The 1-month prevalence of GPNS at baseline was much greater than that of LNSP (35.1% vs 5.6%), and it tended to be more troublesome and disabling. Unlike LNSP, the prevalence of GPNS increased with age. Moreover, it showed significantly stronger associations with somatising tendency (PRR 1.6 vs 1.3) and poor mental health (PRR 1.3 vs 1.1); greater variation between the occupational groups studied (prevalence ranging from 0% to 67.6%) that correlated poorly with the variation in LNSP; and was more persistent at follow-up (72.1% vs 61.7%). Our findings highlight important epidemiological distinctions between subcategories of neck/shoulder pain. In future epidemiological research that bases case definitions on symptoms, it would be useful to distinguish pain that is localised to the neck or shoulder from more generalised pain that happens to involve the neck/shoulder region

International variation in absence from work attributed to musculoskeletal illness : findings from the CUPID study

To quantify the variation in rates of absence due to musculoskeletal pain across 47 occupational groups (mostly nurses and office workers) from 18 countries, and to explore personal and group-level risk factors that might explain observed differences. METHODS: A standardised questionnaire was used to obtain information about musculoskeletal pain, sickness absence and possible risk factors in a cross-sectional survey of 12 416 workers (92-1017 per occupational group). Additionally, group-level data on socioeconomic variables, such as sick pay and unemployment rates, were assembled by members of the study team in each country. Associations of sickness absence with risk factors were examined by Poisson regression. RESULTS: Overall, there were more than 30-fold differences between occupational groups in the 12-month prevalence of prolonged musculoskeletal sickness absence, and even among office workers carrying out similar occupational tasks, the variation was more than tenfold. Personal risk factors included older age, lower educational level, tendency to somatise, physical loading at work and prolonged absence for non-musculoskeletal illness. However, these explained little of the variation between occupational groups. After adjustment for individual characteristics, prolonged musculoskeletal sickness absence was more frequent in groups with greater time pressure at work, lower job control and more adverse beliefs about the work-relatedness of musculoskeletal disorders. CONCLUSIONS: Musculoskeletal sickness absence might be reduced by eliminating excessive time pressures in work, maximising employees' responsibility and control and providing flexibility of duties for those with disabling symptoms. Care should be taken not to overstate work as a cause of musculoskeletal injury

Epidemiological Differences between Localized and Nonlocalized Low Back Pain

Study Design. A cross-sectional survey with a longitudinal follow-up. Objectives. The aim of this study was to test the hypothesis that pain, which is localized to the low back, differs epidemiologically from that which occurs simultaneously or close in time to pain at other anatomical sites Summary of Background Data. Low back pain (LBP) often occurs in combination with other regional pain, with which it shares similar psychological and psychosocial risk factors. However, few previous epidemiological studies of LBP have distinguished pain that is confined to the low back from that which occurs as part of a wider distribution of pain. Methods. We analyzed data from CUPID, a cohort study that used baseline and follow-up questionnaires to collect information about musculoskeletal pain, associated disability, and potential risk factors, in 47 occupational groups (office workers, nurses, and others) from 18 countries. Results. Among 12,197 subjects at baseline, 609 (4.9%) reported localized LBP in the past month, and 3820 (31.3%) nonlocalized LBP. Nonlocalized LBP was more frequently associated with sciatica in the past month (48.1% vs. 30.0% of cases), occurred on more days in the past month and past year, was more often disabling for everyday activities (64.1% vs. 47.3% of cases), and had more frequently led to medical consultation and sickness absence from work. It was also more often persistent when participants were followed up after a mean of 14 months (65.6% vs. 54.1% of cases). In adjusted Poisson regression analyses, nonlocalized LBP was differentially associated with risk factors, particularly female sex, older age, and somatizing tendency. There were also marked differences in the relative prevalence of localized and nonlocalized LBP by occupational group. Conclusion. Future epidemiological studies should distinguish where possible between pain that is limited to the low back and LBP that occurs in association with pain at other anatomical locations

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson’s disease: a study protocol for a randomised controlled trial

Abstract: Background: Parkinson’s disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals’ needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. Methods/design: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. Primary outcome: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson’s Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. Discussion: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson’s disease: a study protocol for a randomised controlled trial

Abstract: Background: Parkinson’s disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals’ needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. Methods/design: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. Primary outcome: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson’s Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. Discussion: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016