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Neuromyelitis optica (NMO) is an uncommon, demyelinating disease that causes long-term disability in adults. Though much has recently been learned about its pathogenesis, there are still only a few studies regarding the epidemiology of NMO. The aim of the study was to describe the epidemiology of NMO among adults in the Merseyside county of the United kingdom. Multiple overlapping sources of data were used including hospital records of The Walton Centre for Neurology and Neurosurgery in Liverpool, regional district general hospital data, central Aquaporin-4 antibody testing laboratory data and the British Neurological Surveillance Unit- to identify adults with a first-ever-in-a-lifetime diagnosis of NMO. As of December 31, 2010, there were eight cases (five NMO; three NMO spectrum disorder), indicating a prevalence of 7.2/million (95 % CI 3.1-14.2). Four incident cases of NMO and three incident cases of NMO spectrum disorder were identified in this period, indicating a minimum combined average annual incidence rate of 0.8/million (95 % CI 0.3-1.6). NMO still remains an uncommon condition, but the prevalence is rising with early diagnosis.

Cytoplasmic lipid droplets (LDs) are dynamic cellular organelles; their accumulation is associated with several cellular processes, such as cell proliferation, apoptosis and necrosis. 1H Nuclear Magnetic Resonance (NMR) spectroscopy detects resonances from lipids present in cytoplasmic (LDs); an understanding of the relationship between LD characteristics and NMR lipid signals is important. In this study, five nervous system cancer cell lines were investigated. Nile red staining was used to measure the diameter of LDs. High-resolution magic angle spinning NMR (HR-MAS) was performed on harvested cell pellets to quantify the patterns of lipid signals. LDs were present in all five cell lines with different morphology. An average LD diameter of approximately 0.2 μm was found in all cell types. Diameter of the largest LDs varied across the cell lines. The intensity of NMR lipid signals varied greatly between cell types, and a good correlation was found between total volume of LDs and the proton NMR lipid signal intensity at 0.9 and 1.3 ppm. The correlation implied that little NMR signal is detected from LDs of diameters less than approximately 0.34 μm, most likely due to restriction of rotational motion of the lipids.

Human medulloblastomas exhibit diverse molecular pathology. Aberrant hedgehog signalling is found in 20–30% of human medulloblastomas with largely unknown metabolic consequences. Transgenic mice over-expressing smoothened (SMO) receptor in granule cell precursors with high incidence of exophytic medulloblastomas were sequentially followed up by magnetic resonance imaging (MRI) and characterised for metabolite phenotypes by 1H MR spectroscopy (MRS) in vivo and ex vivo using high-resolution magic angle spinning (HR-MAS) 1H MRS. Medulloblastomas in the SMO mice presented as T2 hyperintense tumours in MRI. These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice. In contrast, 1H MRS metabolite concentrations in normal appearing cerebellum of the SMO mice were not different from those in the WT mice. Macromolecule and lipid 1H MRS signals in SMO medulloblastomas were not different from those detected in the cerebellum of WT mice. The HR-MAS analysis of SMO medulloblastomas confirmed the in vivo 1H MRS metabolite profiles, and additionally revealed that phosphocholine was strongly elevated in medulloblastomas accounting for the high in vivo CCM. These metabolite profiles closely mirror those reported from human medulloblastomas confirming that SMO mice provide a realistic model for investigating metabolic aspects of this disease. Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas. The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours.

T(1) relaxation time (T(1)) is a quantitative magnetic resonance measure that enables a global evaluation of white matter disease in multiple sclerosis (MS). We aimed to investigate whether mapping of T(1) values in critical white matter tracts, defined by diffusion tensor (DT) imaging, could provide a stronger surrogate marker of disability. 25 patients with relapsing-remitting MS and 14 healthy controls were imaged with a dual-echo T(2)-weighted sequence. Whole brain T(1) maps were acquired using a multi-slice inversion recovery sequence and DT images generated from a spin-echo, echo-planar diffusion weighted sequence. Trajectories were defined to follow the course of white matter fibre tracts in the pyramidal pathways and corpus callosum. T(1) values were sampled along these trajectories. Total white matter T(1) was sampled by defining white matter masks on axial slices of the T(1) maps. Median T(1) in the pyramidal tracts, corpus callosum and total white matter of MS patients was significantly longer than in controls (p0.0001). Median pyramidal tract T(1) correlated significantly with the pyramidal Kurtzke Functional Systems Score (r = 0.64, p = 0.0007) and the Expanded Disability Status Scale (r = 0.55, p = 0.005). By contrast, no correlation with disability was observed for corpus callosum T(1) or total white matter T(1). Our findings show that quantifying pathology within the pyramidal tracts, by utilizing T(1), provides a strong correlate of disability compared with the overall white matter burden of disease. Pyramidal tract T(1) may also provide an objective, sensitive measure for monitoring the progression of motor deficits and disability.

Quantitative diffusion-weighted MRI has been applied to the study of neurological diseases, including multiple sclerosis, where the molecular self-diffusion coefficient D has been measured in both lesions and normal-appearing white matter. Histograms of D have been used as a novel measure of the "lesion load", with potential applications that include the monitoring of efficacy in new treatment trials. However different ways of measuring D may affect its value, making comparison between different centres and research groups impossible. We aimed to assess the effect, if any, of using two different MRI sequences on the value of D. We studied 13 healthy volunteers, using two different quantitative diffusion sequences (including different b(max) values and gradient applications). Maps of D were analysed using both regions of interest (ROI) in white matter and "whole brain" histograms, and compared between the two sequences. In addition, we studied three standardised test liquids (with known values of D) using both sequences. Histograms from the two sequences had different distributions, with a greater spread and higher peak position from the sequence with lower b(max). This greater spread of D was also evident in the white matter and test liquid ROI. "Limits of agreement" analysis demonstrated that the differences could be clinically relevant, despite significant correlations between the sequences obtained using simple rank methods. We conclude that different quantitative diffusion sequences are unlikely to produce directly comparable values of D, particularly if different b(max) values are used. In addition, the use of inappropriate statistical tests may give false impressions of close agreement. Standardisation of methods for the measurement of D are required if these techniques are to become useful tools, for example in monitoring changes in the disease burden of multiple sclerosis.

When mapped with a small spot of light, the central receptive fields of bipolar cells in the salamander retina are much larger than the extent of bipolar cell dendrites. Furthermore responses of bipolar cells to distant spots of light are considerably delayed relative to proximal spots. Using quantitative modelling, electrical coupling between bipolar cells is examined and rejected as a sufficient explanation of the data. An active process appears to shape signal waveform as signals spread laterally in the bipolar cell layer. Chemical synaptic coupling between bipolar cells is considered and shown to be inconsistent with the data. It is suggested that local, transient negative feedback from amacrine cells is involved in shaping bipolar cell signals.

Background Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes. Methods Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging. Results MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group. Conclusions The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction.

Background Brain and nervous system tumours are the most common solid cancers in children. Molecular characterisation of these tumours is important for providing novel biomarkers of disease and identifying molecular pathways which may provide putative targets for new therapies. 1H magic angle spinning NMR spectroscopy (1H HR-MAS) is a powerful tool for determining metabolite profiles from small pieces of intact tissue and could potentially provide important molecular information. Methods Forty tissue samples from 29 children with glial and primitive neuro-ectodermal tumours were analysed using HR-MAS (600 MHz Varian gHX nanoprobe). Tumour spectra were fitted to a library of individual metabolite spectra to provide metabolite values. These values were then used in a two tailed t-test and multi-variate analysis employing a principal component analysis and a linear discriminant analysis. Classification accuracy was estimated using a leave-one-out analysis and B632+ bootstrapping. Results Glial tumours had significantly (two tailed t-test p < 0.05) higher creatine and glutamine and lower taurine, phosphoethanolamine, phosphorylcholine and choline compared with primitive neuro-ectodermal tumours. Classification accuracy was 90%. Medulloblastomas (n = 9) had significantly (two tailed t-test p < 0.05) higher creatine, glutamine, phosphorylcholine, glycine and scyllo-inositol than neuroblastomas (n = 7), classification accuracy was 94%. Supratentorial primitive neuro-ectodermal tumours had metabolite profiles in keeping with other primitive neuro-ectodermal tumours whilst ependymomas (n = 2) had metabolite profiles intermediate between pilocytic astrocytomas (n = 10) and primitive neuro-ectodermal tumours. Conclusion HR-MAS identified key differences in the metabolite profiles of childhood brain and nervous system improving the molecular characterisation of these tumours. Further investigation of the underlying molecular pathways is required to assess their potential as targets for new agents.

The light-dependent pigment migration system of dragonfly ocelli was studied by optical, non-invasive techniques. The median ocellus is comprised of two lateral halves, as can be demonstrated in the intact animal since illumination of the receptors in one half of the median ocellus only induces a movement of pigment located in that half. Measurable pigment migration can occur within a few seconds, but its speed and extent depends on light intensity. Dispersal of pigment, which occurs upon light adaptation, proceeds faster than retraction, which occurs upon dark adaptation. Action spectra for pigment movement have been determined in Sympetrum and Anax. The spectrum for Sympetrum has a prominent UV peak, moderate blue sensitivity, and very low green sensitivity. A similar profile is obtained in Anax, but only after intense orange adaptation which suppresses the green sensitivity. The results conform to the known spectral sensitivities of Libellulid and Aeschnid ocellar receptors. It is concluded that the photoreceptors drive pigment movement through an unknown mechanism. The effect of the migration of pigment is the selective reduction of radiant flux on the retina from luminous sources at high elevations relative to the animal's normal flying posture.

1. The electric properties of the large second order neurons (L neurons) of locust ocellus have been examined with two independently controlled intracellular microelectrodes placed in the same cell. 2. L neurons showed delayed rectification and could produce action potentials in response both to current and on termination of light stimulation. Action potentials are generated at a site in the brain and are conducted passively, with considerable attenuation along L neuron axons. 3. Severe hyperpolarisation of an L neuron induced by extrinsic current turned on a slowly developing conductance. The time taken for full development of this conductance was strongly voltage-dependent but on the order of 1 s. After termination of the extrinsic current the conductance increase typically persisted for several hundred ms. 4. Saturating light intensities were always associated with an increase in input conductance in L neurons. Lower intensities produced either a small increase or decrease in conductance. Conductance increase at the postsynaptic membrane is thought to be opposed by a voltage-sensitive conductance decrease elsewhere in the cell. 5. The mean reversal potential for the peak hyperpolarisation during light stimulation was 41 mV negative to dark resting potential. In the majority of cells the plateau phase of the light response reversed at the same potential. 6. Following termination of the light pulse the input conductance of the cell was shown to return briefly to its dark value probably as a consequence of the turning off of receptor transmitter release. The input conductance of the cell, probably to Na+ or Ca++ ions, was then seen to rise transiently to produce a small depolarising “off” potential. 7. Hyperpolarisation of cells by extrinsic current, within their normal voltage range, failed to decrease their sensitivity to light. Severe hyperpolarisation, outside a cell's normal voltage range could decrease it's sensitivity by up to 1.26 log units. This effect is thought to be due to the decrease in the cell's input resistance produced by severe hyperpolarisation. 8. Hyperpolarising signals produced in the subretinal neuropile show decrement along L neuron axons. Data from ocellar L neurons are consistent in principle with passive propagation of graded potentials.

1. The behaviour of the large second order neurons (L neurons) of the isolated locust ocellus and brain has been examined at low light intensities. Some experiments conducted on the ocellar receptors of dragonfly are also described. 2. At low light intensities L neurons show discrete hyperpolarising potentials (DHPs) whose frequency is a function of intensity. DHPs occur in darkness with a low frequency, typically one every 10 s. In addition to DHPs, L neurons show fluctuations in membrane potential that are reduced by Co–– ions and strong illumination but cannot be resolved into discrete potentials. 3. A high proportion of DHPs occur simultaneously in different L neurons, even though these cells are not strongly coupled electrically. 4. DHP amplitude distributions shift towards smaller amplitude in the presence of Co–– ions. Continued exposure to Co–– reduces DHP amplitudes below the noise level of the recording and brings a large increase in the light intensity required to evoke a given mean hyperpolarisation. Hyperpolarisations thus evoked show much less voltage variance than those evoked from the same cell in normal saline. 5. Increased concentrations of K– ions in the bathing medium depolarise dragonfly ocellar receptors andhyperpolarise locust L neurons. The hyperpolarisation of second order neurons with K– does not result from an increased frequency of DHPs although it is accompanied by a slight increase in voltage variance. 6. Cells examined shortly after the preparation of the ocellus for experiment show linearity of DHP frequency with intensity and a random distribution of DHPs with respect to time. 7. Cells that had been left to dark-adapt for several hours, especially in ringer solutions of different osmolarity to that finally used, showed behaviour, different from that of normal cells, that suggests depolarisation of an L neuron increases the likelihood of a DHP in that cell, whereas hyperpolarisation decreases its likelihood. 8. It is concluded that discrete hyperpolarising potentials in L neurons are not the postsynaptic responses to single quanta of transmitter released from receptor terminals but are instead the result of discrete depolarisations in receptors. These postulated discrete depolarisations probably correspond to the “quantum bumps” seen in a number of other invertebrate photoreceptors.

Angular sensitivity functions for light and dark-adapted locust retinula cells have been measured. The angular sensitivity for light-adapted cells follows a Gaussian function but in the dark-adapted condition the measured function is broader than Gaussian at its base. Acceptance angles for light-adapted cells are 1.5°±0.2° (horizontal), 1.4°±0.1° (vertical) and for dark-adapted cells, 2.4°±0.5° (horizontal) and 2.5°±0.4° (vertical). These values are significantly smaller than those previously reported and show the locust eye to be closer to its theoretical limit of resolution than was previously indicated.

The properties of synapses between retinal neurons make an essential contribution to early visual processing. Light produces a graded hyperpolarization in photoreceptors, up to 25 mV in amplitude1, and it is conventionally assumed that all of this response range is available for coding visual information. We report here, however, that the rod output synapse rectifies strongly, so that only potential changes within 5 m V of the rod dark potential are transmitted effectively to postsynaptic horizontal cells. This finding is consistent with the voltage-dependence of the calcium current presumed to control neurotransmitter release from rods2. It suggests functional roles for the strong electrical coupling of adjacent rods3 and the weak electrical coupling of adjacent rods and cones4. The existence of photoreceptor coupling resolves the apparent paradox that rods have a 25 mV response range, while signals greater than 5 mV in amplitude are clipped during synaptic transmission. We predict that the strengths of rod-rod and rod-cone coupling are quantitatively linked to the relationship between the rod response range and the synapse operating range.

A new method is described for obtaining isolated rods and cones by physical dissociation of the retina. The method gives a large yield of isolated photoreceptors, without any changes in membrane properties that enzymatic dissociation techniques might produce. Photovoltages and photocurrents recorded from rods isolated in this way are presented.

1. The ommatidium or functional unit of the locust compound eye comprises a compound corneal lens, 4 cone cells, 2 primary pigment cells, 16 secondary pigment cells and 8 retinula cells. 2. All retinula cells run the entire length from the cone to the basal lamina, although two, called the proximal cells, only contribute to the lowest third of the rhabdom, and one of either cell 6 or cell 7 on our arbitrary numbering system forms its axon one third the way up the ommatidium. 3. 84% of the 417 ommatidia examined had five cone cell processes. The position of three cone cell processes (cone threads) is almost invariable with respect to numbered retinula cells but the remaining threads can take any of three intercellular locations. 4. The position of these threads correlates with the number of the cell distally displaced from the rhabdom. We suggest that cone thread position in the developing ommatidium determines some features of retinula cells and we propose a simple model to account for this.

Retinal bipolar cells constitute the output stage of the outer layer of the retina. There are several constraints on the ability of the bipolar cell array to respond to the different spatial frequency components of the visual image, including (i) electrical coupling in the dendritic tree receiving receptor input; (iii) the "lateral inhibition" mediated by horizontal cells. Using simple mathematical models, we derive analytical expressions for the spatial frequency response of the bipolar cell array for the case in which horizontal cells are presynaptic to bipolar cells (feedforward model) and also for the case in which horizontal cells are presynaptic to receptors (feedback model). The results illustrate the importance of the three factors mentioned in determining the bipolar cells' properties. The optimal spptial frequency for stimulating the bipolar cell array, and the range of spatial frequencies transmitted onward to the inner plexiform layer, are thus related to the anatomical and electrical properties of the cells in the outer plexiform layer.