The Association of Health Locus of Control with Clinical and Psychosocial Aspects of Living with Multiple Sclerosis.

Health Locus of control (LOC) refers to one's beliefs regarding control over one's health. This study aimed to determine the relationship between LOC on clinical and psychosocial aspects associated with multiple sclerosis (MS). 5059 participants with MS completed a questionnaire pack including the Multidimensional Health Locus of Control Scale. Associations between LOC and sociodemographic (age, gender, educational level) and clinical variables (duration, disability, depression, anxiety, self-efficacy, QoL) were explored. LOC was found to be significantly associated with all of the clinical variables and age, but not gender or educational level. When controlling for level of disability, Chance (CLOC) was associated with higher self-efficacy, lower anxiety and higher QoL than Powerful Others (PLOC), while Internal (ILOC) had no association. The proportion with ILOC preference was lower in increased disability. In MS, believing that health is controlled mainly by chance confers the most benefit with regard to quality of life. There is prima-facie evidence that LOC preference changes with MS progression, in a pattern that is protective against psychological distress.

Prevalence of depression in amyotrophic lateral sclerosis/motor neuron disease: multi-attribute ascertainment and trajectories over 30 months.

Objective: Evidence is equivocal about the prevalence of depression in amyotrophic lateral sclerosis (ALS). This study uses a multi-attribute ascertainment of the prevalence of depression and examines this prevalence over time. Methods: Patients with ALS were recruited into the Trajectories of Outcome in Neurological Conditions (TONiC-ALS) study. Caseness was identified by the Modified-Hospital Anxiety and Depression Scale (M-HADS). In addition, participants provided data on co-morbidities and medication use. A combination of the three was used to derive the estimate for the prevalence of depression, treated or untreated. Longitudinal data were analyzed by trajectory analysis of interval level M-HADS-Depression data. Results: Among 1120 participants, the mean age was 65.0 years (SD 10.7), 60.4% male, and the median duration since diagnosis was 9 months (IQR 4-24). Caseness of probable depression at baseline, defined by M-HADS-Depression, was 6.45% (95%CI: 5.1-8.0). Taken together with antidepressant medication and co-morbidity data, the prevalence of depression was 23.1% (95%CI: 20.7-25.6). Of those with depression, 17.8% were untreated. Trajectory analysis identified three groups, one of which contained the most cases; the level of depression for each group remained almost constant over time. Conclusion: Depression affects almost a quarter of those with ALS, largely confined to a single trajectory group. Prevalence estimates based on screening for current depressive symptoms substantially under-estimate the population experiencing depression. Future prevalence studies should differentiate data based on current symptoms from those including treated patients. Both have their place in assessing depression and the response by the health care system, including medication, depending upon the hypothesis under test.

In vitro assessment of the DNA damage and senility of CD117+ stem cells collected from diabetic mice.

OBJECTIVE: Angiogenesis impairment is a common feature of diabetes mellitus (DM), whereas CD117+ bone marrow cells (BMCs) injury might be responsible for such complication. In this study, we studied the effect of hyperglycemia on the DNA damage and senility of CD117+ bone marrow cells. MATERIALS AND METHODS: We isolated CD117+ BMCs from the Streptozotocin (STZ) induced diabetes and healthy control mice. Oxidative stress was detected by flow cytometric analysis. γ-H2AX, which is the DNA damage mark, was detected by using Western blotting and immunofluorescence histochemistry. We also detected the expression of γ-H2AX and p16 by using Western blotting. RESULTS: Compared with the control mice, the level of reactive oxygen species (ROS) was increased significantly in the CD117+ BMCs collected from the diabetic mice (p<0.05), and the percentage of γ-H2AX positive cells was higher significantly (p<0.01). The expression of γ-H2AX and p16 was increased significantly in the CD117+ BMCs from the diabetic mice. CONCLUSIONS: Our experiments demonstrated the oxidative stress in CD117+ BMCs under DM conditions, while accelerating the DNA damage and senility in CD117+ BMCs as well.

Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: A patient derived, Rasch compliant scale.

OBJECTIVE: The progressively disabling and terminal nature of ALS/MND imposes major coping demands on patients. We wished to improve the psychometric properties of our previously published MND-Coping Scale, so that parametric analyses were valid, and to make it simpler for patients to complete and clinicians to score. METHODS: After a new qualitative analysis of 26 patients with ALS/MND, the draft Coping Index-ALS (CI-ALS) was administered to 465 additional patients, alongside COPE-60, General Perceived Self Efficacy scale, and WHOQOL-BREF. Validity of the CI-ALS was assessed using the Rasch model. External validity was checked against comparator measures. RESULTS: Thirteen centres contributed 465 patients, mean age 64.9 years (SD 10.8), mean disease duration 28.4 months (SD 37.5). The CI-ALS-Self and CI-ALS-Others both satisfied Rasch model expectations and showed invariance across age, gender, marital status and type of onset. Expected correlations were observed with comparator scales. A nomogram is available to convert the raw scores to interval level measures suitable for parametric analysis. CONCLUSIONS: Coping abilities in ALS/MND can now be measured using a simple 21 item self-report measure, offering two subscales with a focus of 'coping by self ' and 'coping with others'. This allows clinicians to identify individuals with poor coping and facilitates research on interventions that may improve coping skills.

The WHOQOL-BREF: a modern psychometric evaluation of its internal construct validity in people with multiple sclerosis.

PURPOSE: Symptoms of Multiple Sclerosis (MS) differentially impact upon quality of life (QoL) and a comprehensive measure is required for use in observational and interventional studies. This study examines the abbreviated World Health Organisation Quality of Life tool (WHOQOL-BREF) which was designed to be used as a broad measure of QoL across different cultures and diseases. METHODS: Data were collected from 3186 subjects as part of the TONiC study in MS and was examined with a systematic, iterative approach using Rasch analysis to investigate the internal construct validity of the WHOQOL-BREF. RESULTS: Mean age was 49.8 years (SD 11.8), disease duration was 11.2 years (SD 9.6) and 73.2% were female. Subjects represented all stages of MS with EDSS scores of 0-4, 4.5-6.5, 7-7.5 and ≥ 8 seen in 49.8%, 38.5%, 6.8% and 4.9% of patients, respectively. Using a super-item approach, it was possible to demonstrate fit to the assumptions of the Rasch model for 3 of the 4 domains of the WHOQOL-BREF (physical, psychological and environment) as well as a broad 24-item total score. In addition, item subsets derived from the stem of each question were shown to function as novel scales measuring impact and life satisfaction. We have provided transformation tables from ordinal raw scores to interval scales where data are complete. CONCLUSIONS: The validation of multiple conceptual frameworks validates the WHOQOL-BREF as a powerful and flexible end-point for use in clinical trials and in testing conceptual models of factors influencing QoL in MS.

Use of coping strategies in multiple sclerosis: Association with demographic and disease-related characteristics✰.

BACKGROUND: Coping positively and negatively influences psychosocial and other outcomes in multiple sclerosis (MS), but there is conflicting evidence about the use of different coping strategies and their associations with demographic and disease characteristics. Our aims were to examine which coping strategies are used by a large sample of people with MS, then to identify any associations between demographic and disease related factors with use of individual coping strategies. METHODS: Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the Coping Orientations to Problems Experienced (COPE60) questionnaire. Relationships between demographic and clinical characteristics and coping strategies were examined by multiple ordinal logistic regression to assess the effect of each potential predictor after adjustment for other possible covariates. RESULTS: From 722 patients, the most commonly used strategy was Acceptance, followed by Active Coping, Planning and Positive Reinterpretation and Growth. All but two strategies showed significant associations with demographic and clinical characteristics. The most marked effects were found for Restraint, with people in employment 2.1 times as likely to utilise this strategy compared to those unemployed, and Seeking of Emotional Social Support and Focus on and Venting of Emotions, which were utilised twice as much by women compared to men. Behavioural and Mental Disengagement were highly associated with greater disability and not being in employment. CONCLUSION: Clinicians should be aware of several disease and demographic characteristics that are associated with use of potentially maladaptive coping strategies.

Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.

OBJECTIVES: Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS-specific measures of spasticity. The aim of this study was to develop and use a self-report outcome measure for spasticity in ALS. METHODS: Following semi-structured interviews with 11 ALS patients, a draft scale was administered across ALS clinics in the UK. Internal validity of the scale was examined using the Rasch model. The numerical rating scale (NRS) for spasticity and Leeds Spasticity scale (LSS) were co-administered. The final scale was used in a path model of spasticity and quality of life. RESULTS: A total of 465 patients (mean age 64.7 years (SD 10), 59% male) with ALS participated. Spasticity was reported by 80% of subjects. A pool of 71 items representing main themes of physical symptoms, negative impact and modifying factors was subject to an iterative process of item reduction by Rasch analysis resulting in a 20-item scale-the Spasticity Index for ALS (SI-ALS)-which was unidimensional and free from differential item functioning. Moderate correlations were found with LSS and NRS-spasticity. Incorporating the latent estimate of spasticity into a path model, greater spasticity reduced quality of life and motor function; higher motor function was associated with better quality of life. CONCLUSIONS: The SI-ALS is a disease-specific self-report scale, which provides a robust interval-level measure of spasticity in ALS. Spasticity has a substantial impact on quality of life in ALS.

Spasticity in multiple sclerosis: Associations with impairments and overall quality of life.

DESIGN: Cross-sectional survey. SETTING: A convenience sample of people with MS routinely attending an appointment with their local MS service. PARTICIPANTS: 701 patients with clinically definite MS. MAIN OUTCOME MEASURES: Demographic details were obtained and patients completed a battery of measures including spasticity (Multiple Sclerosis Spasticity Scale - 88), fatigue (Neurological Fatigue Index - MS), urinary dysfunction (Qualiveen-SF), pain (Neuropathic Pain Scale), mood disorder (Hospital Anxiety and Depression Scale), disability (World Health Organisation Disability Assessment Schedule) and QOL (Leeds Multiple Sclerosis QOL Scale). RESULTS: 85.7% of patients reported spasticity. Patients with higher levels of spasticity were more likely to be disabled, suffer from depression and anxiety, have higher levels of fatigue and report more pain and bladder problems (p<0.01). Spasticity remained as a significant direct effect upon QOL in a multivariate model adjusted for other impairments, activity limitation and depression. CONCLUSIONS: There is a strong association between spasticity and fatigue, depression, anxiety, pain and bladder problems. The retention of a significant direct relationship with QOL in a multivariate model emphasises its influence upon the everyday lives of people with MS.

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group.

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Systematic review of the influence of spasticity on quality of life in adults with chronic neurological conditions.

OBJECTIVE: To conduct a systematic review of the published evidence on the relationship between spasticity and quality of life (QOL) in chronic neurological conditions in adults. DATA SOURCES: MEDLINE, Embase, CINAHL and PsycINFO databases. METHODS: The databases were searched from inception to October 2014 using keywords 'spasticity' and 'quality of life' for publications in English language. Cross-sectional and longitudinal studies reporting quantitative analyses on the association between spasticity and QOL were included. Appraisal of the studies and data extraction were conducted in accordance with Strengthening the Reporting of Observational Studies in Epidemiology guidance. RESULTS: 17/652 studies (total of 27 827 patients) met inclusion criteria for review. These examined the relationship between spasticity and QOL in multiple sclerosis (MS), spinal cord injury (SCI) and stroke. Spasticity was found to be associated with significantly lower scores on health status measures, namely SF-12, SF-36 and EQ-5D, in MS and SCI, but less so in stroke. Spasticity was associated with considerably lower scores on physical components of the health status questionnaires, but with only marginally lower scores on mental components. The studies that employed global QOL measures, such as the World Health Organisation Quality of Life - BREF, found no significant relationship between spasticity and QOL. Spasticity was often associated with pain, sleep problems, fatigue and urinary dysfunction. CONCLUSIONS: Spasticity is associated with worse health status, however its relationship with overall QOL is not established. The relationship between spasticity and QOL is confounded by other impairments and requires multivariate analysis. Implications for Rehabilitation Effective management of spasticity may result in significant improvements in HRQOL. It is important to address multiple factors in the management of spasticity including pain, bladder problems, fatigue and sleep, as the interplay of these may have significant negative effects on HRQOL. Clinician-administered methods for measuring spasticity, such as the Ashworth scale, may not provide comprehensive assessment of spasticity. Incorporation of patient-reported measures for spasticity is pivotal in the assessment of therapeutic interventions.

The Neurological Sleep Index: A suite of new sleep scales for multiple sclerosis.

OBJECTIVE: The objective of this study was to develop patient-reported outcome measures for sleep dysfunction and sleepiness in multiple sclerosis (MS), since there are currently no MS-specific measurement tools for these clinically important entities. METHODS: Items were generated from semi-structured interviews followed by cognitive debrief. A 42-item pool was administered to patients with MS at three neuroscience centres in the UK. Comparator scales were co-administered. Constructs were validated by Rasch analysis, guided by initial exploratory factor analysis. RESULTS: There were two supraordinate qualitative themes of diurnal sleepiness and non-restorative nocturnal sleep. Rasch analysis on 722 records produced three scales, which corresponded to diurnal sleepiness, non-restorative nocturnal sleep and fragmented nocturnal sleep. All had excellent fit parameters, were unidimensional and were free from differential item functioning. A summed raw score cut-point of 31/48 in the Diurnal Sleepiness Scale equated to the standard cut-point of 10 on the Epworth Sleepiness Scale (ESS). CONCLUSION: Three high-quality measurement scales were developed, and together they compose the Neurological Sleep Index for MS (NSI-MS). The Diurnal Sleepiness Scale might provide an alternative to the ESS. The Non-Restorative Nocturnal Sleep Scale and the Fragmented Nocturnal Sleep Scale appear to be the only such measures for use in MS.

Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function.

Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.

De Novo Assembly and Characterization of Tall Fescue Transcriptome under Water Stress.

Water stress is a fundamental problem for tall fescue [Lolium arundinaceum (Schreb.) Darbysh.] cultivation in the south-central United States. Genetic improvement of tall fescue for water-stress tolerance is the key strategy for improving its persistence in the region. Genotypes with contrasting characteristics for relative water content and osmotic potential were identified from a tall fescue population. Transcriptome profiling between water-stress-tolerant (B400) and water-stress-susceptible (W279) genotypes was performed to unravel the genetic regulatory mechanism of water-stress responses in tall fescue. RNA samples from leaf, shoot, root, and inflorescence were pooled and sequenced through Illumina paired-end sequencing. A total of 199,399 contigs were assembled with an average length of 585 bp. Between the two genotypes, 2986 reference transcripts (RTs) were significantly differentially expressed and 1048 of them could be annotated and found to associate with metabolic pathways and enzyme coding genes. In total, 175 differentially expressed RTs were reported for various stress-related functions. Among those, 65 encoded kinase proteins, 40 each encoded transposons, and transporter proteins were previously reported to be involved with abiotic stress responses. A total of 6348 simple sequence repeats and 6658 single-nucleotide polymorphisms were identified in the contig sequences. Primers were developed from the corresponding sequences, which might be used as candidate gene markers in tall fescue. This study will lead to identification of genes or transcription factors related to water-stress tolerance and development of a comprehensive molecular marker system to facilitate marker-assisted breeding in tall fescue.

Highly Sensitive End-Point PCR and SYBR Green qPCR Detection of Phymatotrichopsis omnivora, Causal Fungus of Cotton Root Rot.

Phymatotrichopsis omnivora, the causal pathogen of cotton root rot, is a devastating ascomycete that affects numerous important dicotyledonous plants grown in the southwestern United States and northern Mexico. P. omnivora is notoriously difficult to isolate from infected plants; therefore methods for accurate and sensitive detection directly from symptomatic and asymptomatic plant samples are needed for disease diagnostics and pathogen identification. Primers were designed for P. omnivora based on consensus sequences of the nuclear ribosomal internal transcribed spacer (ITS) region of geographically representative isolates. Primers were compared against published P. omnivora sequences and validated against DNA from P. omnivora isolates and infected plant samples. The primer combinations amplified products from a range of P. omnivora isolates representative of known ITS haplotypes using standard end-point polymerase chain reaction (PCR) methodology. The assays detected P. omnivora from infected root samples of cotton (Gossypium hirsutum) and alfalfa (Medicago sativa). Healthy plants and other relevant root pathogens did not produce PCR products with the P. omnivora-specific primers. Primer pair PO2F/PO2R was the most sensitive in end-point PCR assays and is recommended for use for pathogen identification from mycelial tissue and infected plant materials when quantitative PCR (qPCR) is not available. Primer pair PO3F/PO2R was highly sensitive (1 fg) when used in SYBR Green qPCR assays and is recommended for screening of plant materials potentially infected by P. omnivora or samples with suboptimal DNA quality. The described PCR-based detection methods will be useful for rapid and sensitive screening of infected plants in diagnostic laboratories, plant health inspections, and plant breeding programs.

Poststroke fatigue: the patient perspective.

PURPOSE: Fatigue is reported as a prevalent symptom post stroke. The purpose of this study is to explore the patent perspective of this symptom, how it is experienced, and its subjective impact on the patient. METHOD: The qualitative procedure of interpretative phenomenological analysis (IPA) was used to analyze the narratives of 10 subjects with previous stroke, who each undertook a single, semi-structured interview. RESULTS: Fatigue was a salient symptom for all the patients. Six main themes were identified. Tiredness/sleep was recognized in all the narratives, and themes of restriction, frustration, and determination/coping reflected varying degrees of physical, cognitive, and psychological dimensions to fatigue. Depression/motivation was also identified, reflecting low mood and helplessness. The remaining theme support indicated a social dimension, with patients recognizing the need for professional and familial support. Further subthemes were identified, and the thematic descriptions of the physical and psychosocial aspects indicated the complexity of fatigue and unique patient profiles. A holistic overview of each narrative furthered an understanding of the dynamic interrelationships between these aspects and their impact on the patient. There were prevalent patterns, but these were different for each patient. CONCLUSION: A better understanding of the varied dimensions or themes elaborated for poststroke fatigue, and their interrelationships, should help in mitigating its impact. The analysis cautions against giving any simplistic and unitary advice to patients about dealing with fatigue.

Is the Epworth sleepiness scale suitable for use in stroke?

BACKGROUND: The Epworth Sleepiness Scale (ESS-8) is frequently used in stroke but has never been validated for this condition. There is concern regarding the suitability of the driving item (item 8). A summed raw score of 10 or more (from a maximum of 24) signifies pathological sleepiness. OBJECTIVE: To determine the construct validity of the ESS-8 by Rasch analysis and in particular to determine whether omission of item 8 confounds the scale. METHOD: A pack containing the ESS-8 and questions regarding sleep and demographics was sent to 999 patients who had experienced a stroke within the past 4 years. Data were assessed for fit to the Rasch model. RESULTS: Analysis of 269 records revealed a unidimensional scale that was free from differential item functioning by age and sex with good overall fit to the Rasch model. Item 4 had disordered thresholds. Analysis of the ESS without item 8 (ESS-7) also revealed a valid scale. Equating person locations between the ESS-8 and ESS-7 showed no differences below a summed raw score of 18. CONCLUSION: The ESS-8 has good construct validity for use in stroke and is reliable at the cutpoint of 10. Summed raw scores below 18 will be unaffected if nondrivers either score as zero or simply omit item 8. The scale is therefore robust for detecting cases of pathological sleepiness in stroke but may not be suitable for measuring high levels of sleepiness in a sample containing both drivers and nondrivers. Instead, the ESS-7 could be used for this purpose.

The efficacy of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil combined with cisplatin concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: a matched pair analysis.

AIMS: The role of induction chemotherapy (ICT) for head and neck squamous cell carcinoma (HNSCC) is controversial. The aim of the study was to assess the benefit of ICT with docetaxel, cisplatin and 5-fluorouracil (5-FU) (TPF) when combined with concurrent cisplatin chemoradiotherapy (CRT) for HNSCC. MATERIALS AND METHODS: Patients with HNSCC treated between January 2005 and December 2010 with radical intent with either TPF or cisplatin and 5-FU (PF) ICT and documented intention to proceed with concurrent cisplatin CRT were identified retrospectively. The use and choice of ICT regimen was at the clinician's discretion. In total, 68 patients treated with TPF were identified and were matched for T and N stage and tumour site to 68 patients treated with PF. A survival analysis was carried out using Kaplan-Meier and the Cox proportional hazards model. RESULTS: The median follow-up was 29.9 versus 36.3 months for the TPF and PF groups, respectively. Three year locoregional relapse-free survival (RFS), distant RFS, RFS, cancer-specific survival and overall survival rates for the TPF and PF groups were 84.2, 91.6, 82.6, 81.3 and 74.9% versus 73.7, 84.9, 71.9, 72.1 and 62.9%, respectively. On multivariate analysis, treatment with TPF predicted for improved locoregional RFS (P = 0.03) and overall survival (P = 0.05). CONCLUSION: The addition of docetaxel to a cisplatin doublet ICT regimen before concurrent CRT may improve disease control for locally advanced HNSCC.

Tumefactive demyelination: an unusual cause of a spontaneously resolving homonymous hemianopia.

A 21-year-old man presented to eye casualty complaining of altered vision associated with headache and vomiting upon waking. Clinical examination was unremarkable except for a right-sided homonymous hemianopia. The MRI scan of the brain revealed a space occupying lesion within the occipital lobe and MR spectroscopy highlighted this to be inflammatory in nature, most likely a tumefactive demyelinating lesion (TDL). Lumbar puncture displayed positive oligoclonal bands. The patient was managed conservatively and made a full recovery, with normal visual fields recorded after a 3 month follow-up. This is a case of a TDL manifesting itself as an unusual cause of homonymous hemianopia; misdiagnosis of TDL is common and potentially damaging to the patient.

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Forages and pastures symposium: fungal endophytes of tall fescue and perennial ryegrass: pasture friend or foe?

Tall fescue [Lolium arundinaceum (Schreb.) Darbysh. syn. Festuca arundinacea Schreb.] and perennial ryegrass (Lolium perenne L.) are important perennial forage grasses utilized throughout the moderate- to high-rainfall temperate zones of the world. These grasses have coevolved with symbiotic fungal endophytes (Epichloë/Neotyphodium spp.) that can impart bioactive properties and environmental stress tolerance to the grass compared with endophyte-free individuals. These endophytes have proven to be very important in pastoral agriculture in the United States, New Zealand, and Australia, where forage grasses are the principal feed for grazing ruminants. In this review, we describe the biology of these grass-endophyte associations and implications for the livestock industries that are dependent on these forages. Endophyte alkaloid production is put in context with endophyte diversity, and we illustrate how this has facilitated utilization of grasses infected with different endophyte strains that reduce livestock toxicity issues. Utilization of tall fescue and use of perennial ryegrass in the United States, New Zealand, and Australia are compared, and management strategies focused predominantly on the success of endophyte-infected perennial ryegrass in New Zealand and Australia are discussed. In addition, we consider the impact of grass-endophyte associations on the sustainability of pasture ecosystems and their likely response to future changes in climate.