Optical coherence tomography in multiple sclerosis: A 3-year prospective multicenter study

Prospective multicenter study; Multiple sclerosis; TomographyEstudi prospectiu multicèntric; Esclerosi múltiple; TomografiaEstudio multicéntrico prospectivo; Esclerosis múltiple; TomografíaObjective To evaluate changes over 3 years in the thickness of inner retinal layers including the peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (mGCIPL), in individuals with relapsing-remitting multiple sclerosis (RRMS) versus healthy controls; to determine whether optical coherence tomography (OCT) is sufficiently sensitive and reproducible to detect small degrees of neuroaxonal loss over time that correlate with changes in brain volume and disability progression as measured by the Expanded Disability Status Scale (EDSS). Methods Individuals with RRMS from 28 centers (n = 333) were matched with 64 healthy participants. OCT scans were performed on Heidelberg Spectralis machines (at baseline; 1 month; 6 months; 6-monthly thereafter). Results OCT measurements were highly reproducible between baseline and 1 month (intraclass correlation coefficient >0.98). Significant inner retinal layer thinning was observed in individuals with multiple sclerosis (MS) compared with controls regardless of previous MS-associated optic neuritis––group differences (95% CI) over 3 years: pRNFL: −1.86 (−2.54, −1.17) µm; mGCIPL: −2.03 (−2.78, −1.28) µm (both p 5 years (pRNFL: p < 0.05; mGCIPL: p < 0.01). Brain volume decreased by 1.3% in individuals with MS over 3 years compared to 0.5% in control subjects (effect size 0.76). mGCIPL atrophy correlated with brain atrophy (p < 0.0001). There was no correlation of OCT data with disability progression. Interpretation OCT has potential to estimate rates of neurodegeneration in the retina and brain. The effect size for OCT, smaller than for magnetic resonance imaging based on Heidelberg Spectralis data acquired in this study, was increased in early disease.The authors wish to thank Carolyn M. Ervin for her substantial contribution in the data analyses, as well as Mark Kirby, Aisling Towell, and Marie-Catherine Mousseau (Novartis Ireland Ltd.) for their writing support, funded by Novartis Pharma AG, Basel, Switzerland. FB is supported by the NIHR biomedical research center at UCLH

Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus

Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes that is known to cause severe arthritis and myositis in affected patients. The ongoing epidemic began in eastern Africa in 2004 and then spread to islands of the Indian Ocean, India, and Southeast Asia, ultimately afflicting millions. During this outbreak, more severe disease manifestations, including fatalities, have been documented. The reasons for this change in pathogenesis are multifactorial but likely include mutations that have arisen in the viral genome which could alter disease pathogenesis. To test this hypothesis, we used a murine model of CHIKV to compare the disease pathogeneses of two recombinant strains of CHIKV, the first derived from the La Reunion outbreak in 2006 (LR2006 OPY1) and the second isolated from Senegal in 1983 (37997). While the two strains exhibited similar growth in mammalian cells in vitro, we observed more severe clinical disease and pathology in mice infected with the LR2006 OPY1 strain of CHIKV, which included prolonged viremia and elevated viral titers and persistence in the muscle, resulting in devastating myonecrosis. Both CHIKV strains infected connective tissue fibroblasts of the muscle, but only the LR2006 OPY1 strain replicated within myofibers in vivo, despite similar growth of the two strains in these cell types in vitro. However, when the 37997 strain was administered directly into muscle, myofiber infection was comparable to that in LR2006 OPY1-infected mice. These results indicate that differences in the ability of the strain of CHIKV to establish infection in myofibers may contribute to the increased disease severity. IMPORTANCE CHIKV is an emerging pathogen that causes significant morbidity. Little is known about the pathogenesis of the disease, and this study suggests that the ability of a recent epidemic strain to infect myofibers results in increased disease severity. Better understanding of how CHIKV causes disease contributes to the ultimate goal of creating therapeutics to alleviate the impact of this debilitating virus

Deficits in visual system functional connectivity after blast-related mild TBI are associated with injury severity and executive dysfunction

INTRODUCTION: Approximately, 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Visual processing problems and cognitive dysfunction are common complaints following blast‐related mTBI. METHODS: In 127 veterans, we examined resting fMRI functional connectivity (FC) of four key nodes within the visual system: lateral geniculate nucleus (LGN), primary visual cortex (V1), lateral occipital gyrus (LO), and fusiform gyrus (FG). Regression analyses were performed (i) to obtain correlations between time‐series from each seed and all voxels in the brain, and (ii) to identify brain regions in which FC variability was related to blast mTBI severity. Blast‐related mTBI severity was quantified as the sum of the severity scores assigned to each of the three most significant blast‐related injuries self‐reported by subjects. Correlations between FC and performance on executive functioning tasks were performed across participants with available behavioral data (n = 94). RESULTS: Greater blast mTBI severity scores were associated with lower FC between: (A) LGN seed and (i) medial frontal gyrus, (ii) lingual gyrus, and (iii) right ventral anterior nucleus of thalamus; (B) V1 seed and precuneus; (C) LO seed and middle and superior frontal gyri; (D) FG seed and (i) superior and medial frontal gyrus, and (ii) left middle frontal gyrus. Finally, lower FC between visual network regions and frontal cortical regions predicted worse performance on the WAIS digit‐symbol coding task. CONCLUSION: These are the first published results that directly illustrate the relationship between blast‐related mTBI severity, visual pathway neural networks, and executive dysfunction – results that highlight the detrimental relationship between blast‐related brain injury and the integration of visual sensory input and executive processes

Effect of Treatment with Salsalate, Menhaden Oil, Combination of Salsalate and Menhaden Oil, or Resolvin D1 of C57Bl/6J Type 1 Diabetic Mouse on Neuropathic Endpoints

Aims. In this study a streptozotocin induced type 1 diabetes mouse model was used to assess the effectiveness of salsalate, menhaden oil, the combination of salsalate and menhaden oil, or resolvin D1 on neuropathic endpoints. Materials and Methods. Changes in body weight, blood glucose, serum markers for triglycerides, free fatty acids, cholesterol, and resolvin D1, motor and sensory nerve conduction velocities and thermal sensitivity were assessed, as well as performing in vivo confocal microscopy of subepithelial corneal nerves and immunohistochemistry of nerves in the cornea and foot pad. Results. Diabetic animals failed to gain weight and had elevated blood glucose levels. Diabetic mice had slowed nerve conduction velocity, reduced innervation of the foot pad and cornea subepithelial and epithelial layers, and reduced thermal sensitivity. Monotherapy treatment with salsalate, menhaden oil, and resolvin D1 reduced the pathological signs of diabetic neuropathy. The combination of salsalate and menhaden oil also reduced signs of pathology and generated elevated plasma levels of resolvin D1 compared to other groups. Conclusions. Additional studies are needed to determine whether the combination of salsalate and menhaden oil may be more efficacious than monotherapy alone for the treatment of diabetic peripheral neuropathy

Buzzing Sympathetic Nerves: A New Test to Enhance Anisocoria in Horner's Syndrome

Introduction: Patients with suspected Horner's syndrome having equivocal pupil dilation lag and pharmacologic testing may undergo unnecessary MR imaging and work up in the case of false positive pupil test results. Our goal was to increase the diagnostic accuracy of pupillometry by accentuating the inter-ocular asymmetry of sympathetic innervation to the iris dilator with surface electrical stimulation of the median nerve using a standard electromyography machine. We hypothesized that an accentuated difference in sympathetic response between the two eyes would facilitate the diagnosis of Horner's syndrome.Methods: Eighteen patients with pharmacologically proven Horner's syndrome were compared to ten healthy volunteers tested before and after monocular instillation of 0.2% brimonidine tartrate ophthalmic solution to induce pharmacological Horner's syndrome. Pupillary responses were measured with binocular pupillometry in response to sympathetic activation by electrical stimulation of the median nerve in darkness and at various times after extinction of a light stimulus. Sudomotor sympathetic responses from the palm of the stimulated arm were recorded simultaneously.Results: In subjects with Horner's syndrome and pharmacologically induced unilateral sympathetic deficit, electrical stimulation in combination with the extinction of light greatly enhanced the anisocoria during the evoked pupil dilation, while there was no significant increase in anisocoria in healthy subjects. The asymmetry of the sympathetic response was greatest when the electrical stimulus was given 2 s after termination of the light or under constant low light conditions. When given 2 s after termination of light, the electrical stimulation increased the mean anisocoria from 1.0 to 1.2 mm in Horner's syndrome (p = 0.01) compared to 0.22–0.26 mm in healthy subjects (p = 0.1). In all subjects, the maximal anisocoria induced by the electrical stimulation appeared within a 2 s interval after the stimulus. Correspondingly, the largest change in anisocoria between light and dark without electrical stimulation was seen between 3 and 4 s after light-off. While stronger triple stimulation further enhanced the anisocoria, it was less well tolerated.Conclusions: Electrical stimulation 2 s after light-off greatly enhances the sensitivity of pupillometry for diagnosing Horner's syndrome. This new method may help to rule in or rule out a questionable Horner's syndrome, especially if the results of topical pharmacological testing are inconclusive

Circuit dissection of the role of somatostatin in itch and pain

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide

First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder?

We present the first two reported unrelated patients with an isolated sedoheptulokinase (SHPK) deficiency. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Both patients had elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense mutation in SHPK. SHPK is an enzyme that phosphorylates sedoheptulose to sedoheptulose-7-phosphate, which is an important intermediate of the pentose phosphate pathway. It is questionable whether SHPK deficiency is a causal factor for the clinical phenotypes of our patients. This study illustrates the necessity of extensive functional and clinical workup for interpreting a novel variant, including nonsense variants

Analysis of talpid3 and wild-type chicken embryos reveals roles for Hedgehog signalling in development of the limb bud vasculature

Chicken talpid mutant embryos have a wide range of Hedgehog-signalling related defects and it is now known that the talpid gene product encodes a novel protein essential for Hedgehog signalling which is required for both activator and repressor functions of Gli transcription factors (Davey, M.G., Paton, I.R., Yin, Y., Schmidt, M., Bangs, F.K., Morrice, D.R., Gordon-Smith, T., Buxton, P., Stamataki, D., Tanaka, M., Münsterberg, A.E., Briscoe, J., Tickle, C., Burt, D.W. (2006). The chicken talpid gene encodes a novel protein essential for Hedgehog signalling. Genes Dev 20 1365-77). Haemorrhaging, oedema and other severe vascular defects are a central aspect of the talpid phenotype (Ede, D.A. and Kelly, W.A (1964a). Developmental abnormalities in the head region of the talpid mutant fowl. J. Embryol. exp. Morp. 12:161-182) and, as Hedgehog (Hh) signalling has been implicated in every stage of development of the vascular system, the vascular defects seen in talpid are also likely to be attributable to abnormal Hedgehog signalling. Gene expression of members of the VEGF and Angiopoietin families of angiogenic growth factors has been linked to haemorrhaging and oedema and we find widespread expression of VEGF-D, rigf and Ang2a in the talpid limb. Furthermore, ectopic expression of these genes in talpid limbs points to regulation via Gli repression rather than activation. We monitored specification of vessel identity in talpid limb vasculature by examining expression of artery-specific genes, Np1 and EphrinB2, and the vein-specific genes, Np2a and Tie2. We show that there are supernumerary subclavian arteries in talpid limb buds and abnormal expression of an artery-specific gene in the venous submarginal sinus, despite the direction of blood flow being normal. Furthermore, we show that Shh can induce Np1 expression but has no effect on Np2a. Finally, we demonstrate that induction of VEGF and Ang2a expression by Shh in normal limb buds is accompanied by vascular remodelling. Thus Hedgehog signalling has a pivotal role in the cascade of angiogenic events in a growing embryonic organ which is similar to that proposed in tumours

Roles of Dynein and Dynactin in Early Endosome Dynamics Revealed Using Automated Tracking and Global Analysis

Microtubule-dependent movement is crucial for the spatial organization of endosomes in most eukaryotes, but as yet there has been no systematic analysis of how a particular microtubule motor contributes to early endosome dynamics. Here we tracked early endosomes labeled with GFP-Rab5 on the nanometer scale, and combined this with global, first passage probability (FPP) analysis to provide an unbiased description of how the minus-end microtubule motor, cytoplasmic dynein, supports endosome motility. Dynein contributes to short-range endosome movement, but in particular drives 85–98% of long, inward translocations. For these, it requires an intact dynactin complex to allow membrane-bound p150Glued to activate dynein, since p50 over-expression, which disrupts the dynactin complex, inhibits inward movement even though dynein and p150Glued remain membrane-bound. Long dynein-dependent movements occur via bursts at up to ∼8 µms−1 that are linked by changes in rate or pauses. These peak speeds during rapid inward endosome movement are still seen when cellular dynein levels are 50-fold reduced by RNAi knock-down of dynein heavy chain, while the number of movements is reduced 5-fold. Altogether, these findings identify how dynein helps define the dynamics of early endosomes