Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) EMBASE (1980- present), PsycINFO (1987- present), and SCOPUS (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, Non 24- hour sleep wake syndrome in people who are blind, and REM-Behaviour Disorder. Meta-analyses were performed to determine the effect of magnitude in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 13 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p=0.002), delayed sleep phase syndrome (p<0.0001), and regulating the sleepwake patterns in blind patients compared with placebo. These findings highlight the potential importance of melatonin in treating certain first degree sleep disorders. The development of large-scale, randomised, controlled trials is recommended to provide further evidence for therapeutic use of melatonin in a variety of sleep difficulties

Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.

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Copper is an essential trace element that is involved in a number of important enzymatic processes throughout the body. Recent single case reports and small studies have shown that deficiency of copper can cause reversible haematological changes and irreversible neurological injury. We chose to undertake a national study, looking at all cases of copper deficiency in Scotland over a 5-yr period using information from a national reference laboratory. From 16 identified patients, we determined that 86% had both haematological and neurological features of copper deficiency, while 18% had haematological features only at presentation. Twelve of the sixteen patients had high serum zinc concentrations (>18 lm/L) nine patients were using zinc-containing dental fixatives at time of diagnosis. 94% of patients had haematological features as an initial manifestation of copper deficiency, which included anaemia, thrombocytopenia and neutropenia. Patients who underwent later bone marrow testing had appearances in keeping with refractory cytopenia with multilineage dysplasia, refractory anaemia with excess of blasts, unclassified marrow dysplasia or probable myelodysplasia (MDS). 75% of patients had neurological symptoms or signs, including progressive walking difficulties and paraesthesia, or gait difficulties without sensory signs. Clinical examination was in keeping with spastic paraparesis (either with or without sensory neuropathy). Magnetic resonance imaging (MRI) showed multifocal T2 hyper intense foci in the subcortical white matter, and atrophy of the cerebrum and cerebellum was also seen on computerised tomography (CT). MRI of the spinal cord showed signal change in the dorsal columns in either the cervical or thoracic cord. 93% of cytopenias responded to copper replacement and addressing the original cause of the copper deficiency, but only 25% of patients had improvement in their neurological function, while 33% deteriorated and 42% remained unchanged. Our study demonstrates that copper deficiency is an underrecognised cause of several types of cytopenia, which are reversible but can progress to significant neurological injury if left untreated. We illustrate the importance of identifying these patients early to prevent irreversible neurological injury.

ObjectivesScotland benefits from an integrated national healthcare team for motor neurone disease (MND) and a tradition of rich clinical data capture using the Scottish MND Register (launched in 1989; one of the first national registers). The Scottish register was relaunched in 2015 as Clinical Audit Research and Evaluation of MND (CARE-MND), an electronic platform for prospective, population-based research. We aimed to determine if incidence of MND is changing over time. Methods Capture-recapture methods determined incidence of MND in 2015-16. Incidence rates for 2015-16 and 1989-98 were direct age and sex standardised to allow time period comparison. Phenotypic characteristics and socioeconomic status of the cohort are Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation described. ResultsCoverage of the CARE-MND platform was 99%. Crude incidence in the 2015-17 period was 3.83/100,000 person-years (95% CI 3.53-4.14). Direct age standardised incidence in 2015 was 3.42/100,000 (95% CI 2.99-3.91); in 2016, 2.89/100,000 (95% CI 2.50-3.34). The 1989-98 direct standardised annual incidence estimate was 2.32/100,000 (95% CI 2.26-2.37). 2015-16 standardised incidence was 66.9% higher than Northern European estimates. Socioeconomic status was not associated with MND. ConclusionsOur data show a changing landscape of MND in Scotland, with a rise in incidence by 36.0% over a 25-year period. This is likely attributable to ascertainment in the context of improved neurological services in Scotland. Our data suggest that CARE-MND is a reliable national resource and findings can be extrapolated to other Northern European populations.

Ganglioside binding properties were calculated from half-maximal binding studies and graded as follows: 0,-; <10 2 , +; >10 2 <10 3 , ++; >10 3 , +++. LPS reactivity as assessed by ELISA and TLC overlay is scored as present (+) or absent (-). See Methods.

Abstract.We report on an investigation of four-dimensional terminal cyclic quotient singularities which are not Gorenstein.(For simplicity, we focus on quotients by cyclic groups of prime order.) An enumeration, using a computer, of all such singularities for primes < 1600 led us to conjecture a structure theorem for these singularities (which is rather more complicated than the known structure theorem in dimension three). We discuss this conjecture and our evidence for it; we also discuss properties of the anticanonical and antibicanonical linear systems of these singularities.Introduction.The recent successes in understanding the birational geometry of algebraic varieties of dimension greater than two have focused attention on a class of singularities (called terminal singularities) which appear on the birational models which the theory selects. In dimension three, the structure of these terminal singularities is known in some detail: The terminal quotient singularities were classified, in what is now called the "terminal lemma", by several groups of people working independently (cf. A consequence of this classification, apparently first observed by Reid [12], is that for any three-dimensional terminal singularity T, the general element of the anticanonical linear system | -KT\ has only canonical singularities. This in turn implies that if we form the double cover of T branched on the general antibicanonical

Zinc deficiency is frequently misdiagnosed on the basis of low plasma zinc concentrations. The potential risk of copper deficiency developing in patients prescribed high doses of zinc is apparently infrequently considered. It is probable that a significant minority of patients prescribed with high doses of zinc develop iatrogenic copper deficiency.